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[null,"https://drive.google.com/file/d/1G5kARx5dq96qras_wzpOsWMWPpQvvY_M/view",null,null,null,null,null,"V9 update:"]
[null,null,null,null,null,null,null,"*Add a new button in Summary tab to synchronize results between Results and Summary tabs"]
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[null,null,null,null,null,null,null,"V8 update:"]
[null,null,null,null,null,null,null,"*Added judgement-level comment in the summary table"]
[null,null,null,null,null,null,null,"*Removed \"Double click on this column…\" label in the comments after enter"]
[null,null,null,null,null,null,null,"*Corrected spelling mistakes"]

{"sheet":"Results","index":1,"n_rows":24,"n_cols":85,"rows_kept":24,"cut":false,"hidden":false,"merged":[[0,0,0,12],[0,13,0,22],[0,80,0,83],[0,23,0,40],[0,41,0,53],[0,54,0,68],[0,69,0,79]]}
["Basic information",null,null,null,null,null,null,null,null,null,null,null,null,"Domain 1. Randomization process",null,null,null,null,null,null,null,null,null,"Domain 2. Deviations from intended interventions",null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Domain 3. Mising outcome data",null,null,null,null,null,null,null,null,null,null,null,null,"Domain 4. Measurement of the outcome",null,null,null,null,null,null,null,null,null,null,null,null,null,null,"Domain 5. Selection of the reported result",null,null,null,null,null,null,null,null,null,null,"Domain 6. Overall Bias"]
["Time","Unique ID","Assessor","Study ID","Reference","Experimental","Comparator","Outcome","Results","Aim","Effect of adhering to intervention?","Weight","Sources","1.1","1.2","Note for 1.1&1.2","1.3","Note for 1.3","1.0 Algorithm result","1.0 Assessor's Judgement","1.0 General note","1.0 Optional Question","1.0 Note for optional question","2.1","2.2","Note for 2.1&2.2","2.3","Note for 2.3","2.4","Note for 2.4","2.5","Note for 2.5","2.6","Note for 2.6","2.7","Note for 2.7","2.0 Algorithm result","2.0 Assessor's Judgement","2.0 General Notes","2.0 Optional Question","2.0 Note for optional question","3.1","Note for 3.1","3.2","Note for 3.2","3.3","Note for 3.3&3.4","3.4","Note for 3.4 (not use)","3.0 Algorithm result","3.0 Assessor's judgement","3.0 Gerenal notes","3.0 Optional Question","3.0 Note for optional question","4.1","Note for 4.1","4.2","Note for 4.2","4.3","Note for 4.3","4.4","Note for 4.4&4.5","4.5","Note for 4.5 (not use)","4.0 Algorithm result","4.0 Assessor's Judgement","4.0 General note","4.0 Optional Question","4.0 Note for optional question","5.1","Note for 5.1","5.2","Note for 5.2","5.3","Note for 5.3","5.0 Algorithm result","5.0 Assessor's Judgement","5.0 General note","5.0 Optional Question","5.0 Note for optional question","Algorithm's overall Judgement","Assessor's overall Judgement","6.0 General Note","6.0 Optional Question","6.0 Note for optional question"]
["2021.10.28 10.27","A1","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses) ","Disease-free survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.","N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.",null,null,"Y","Y","The clinical trial registration states that the trial was open-label and no blinding was described.","PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","Intention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. ","NA",null,"Low","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \n",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm.","NA",null,"NA",null,"NA",null,"Low","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.",null,null,"N","Events were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate.","N","Due to the nature of outcome the measurement or ascertainment could not have differed between the groups.","Y","No blinding was described.","N","Due to the nature of events the measurement or ascertainment could not have differed between the groups.","NA",null,"Low","Low","Events were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\rEvents were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.06","A2","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Relapse",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.","N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.",null,null,"Y","Y","The clinical trial registration states that the trial was open-label and no blinding was described.","PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","Intention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. ","NA",null,"Low","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm.","NA",null,"NA",null,"NA",null,"Low","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r",null,null,"N","Mandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate.","N","Due to the nature of outcome the measurement or ascertainment could not have differed between the groups.","Y","No blinding was described.","N","Due to the nature of events the measurement or ascertainment could not have differed between the groups.","NA",null,"Low","Low","Mandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate.\nDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\nNo blinding was described.\nDue to the nature of events the measurement or ascertainment could not have differed between the groups.\n",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rMandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.06","A3","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Hypersensitivity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.","N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.",null,null,"Y","Y","The clinical trial registration states that the trial was open-label and no blinding was described.","PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","Intention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. ","NA",null,"Low","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm.","NA",null,"NA",null,"NA",null,"Low","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r",null,null,"N","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was probably not influenced by knowledge of intervention received","NA",null,"Low","Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.05","A4","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Pancreatitis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.","N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.",null,null,"Y","Y","The clinical trial registration states that the trial was open-label and no blinding was described.","PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","Intention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. ","NA",null,"Low","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm.","NA",null,"NA",null,"NA",null,"Low","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r",null,null,"N","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was probably not influenced by knowledge of intervention received","NA",null,"Low","Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.05","A5","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Thromboembolism",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.","N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.",null,null,"Y","Y","The clinical trial registration states that the trial was open-label and no blinding was described.","PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","Intention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. ","NA",null,"Low","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \n",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm.","NA",null,"NA",null,"NA",null,"Low","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n",null,null,"N","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was probably not influenced by knowledge of intervention received","NA",null,"Low","Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n",null,null,"Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.05","A6","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Osteonecrosis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.","N","Baseline characteristics of randomly assigned patients were included in Table 1.","Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.",null,null,"Y","Y","The clinical trial registration states that the trial was open-label and no blinding was described.","PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","Intention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. ","NA",null,"Low","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm.","NA",null,"NA",null,"NA",null,"Low","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r",null,null,"N","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was probably not influenced by knowledge of intervention received","NA",null,"Low","Low","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.05","A7","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Asparaginase-associated toxicity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.","N","Baseline characteristics of randomly assigned patients were included in Table 1.","Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.",null,null,"Y","Y","The clinical trial registration states that the trial was open-label and no blinding was described.","PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","Intention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. ","NA",null,"Low","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm.","NA",null,"NA",null,"NA",null,"Low","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r",null,null,"N","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was probably not influenced by knowledge of intervention received","NA",null,"Low","Low","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.",null,null,"Low","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage."]
["2021.10.28 10.24","M1","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Overall survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","PY","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r","N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found.","Low","Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.",null,null,"Y","Y","According to NCT trial registration, the study was open-label and no blinding was described.","PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","In the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. ","PN","Data from all participants were included in the analysis of the intervention they were assigned to.","Some concerns","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.",null,null,"Y","All patients randomly assigned were included in the analyses.","NA",null,"NA",null,"NA",null,"Low","Low","All patients randomly assigned were included in the analyses.\r\r\r",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. ","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.","Y","No blinding was described.","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.","NA",null,"Low","Low","Due to the nature of the outcome the measure was assumed appropriate. \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r",null,null,"Some concerns","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.\rAll patients randomly assigned were included in the analyses.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.23","M2","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Event-free survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","PY","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r","N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found.","Low","Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.",null,null,"Y","Y","According to NCT trial registration, the study was open-label and no blinding was described.","PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","In the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. ","PN","Data from all participants were included in the analysis of the intervention they were assigned to.","Some concerns","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.",null,null,"Y","All patients randomly assigned were included in the analyses.","NA",null,"NA",null,"NA",null,"Low","Low","All patients randomly assigned were included in the analyses.\r\r\r",null,null,"N","Events were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate ","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.","Y","No blinding was described.","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.","NA",null,"Low","Low","Events were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r",null,null,"Some concerns","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.\rAll patients randomly assigned were included in the analyses.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.23","M3","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Relapse",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","PY","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r","N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found.","Low","Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.",null,null,"Y","Y","According to NCT trial registration, the study was open-label and no blinding was described.","PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","In the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. ","PN","Data from all participants were included in the analysis of the intervention they were assigned to.","Some concerns","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.",null,null,"Y","All patients randomly assigned were included in the analyses.","NA",null,"NA",null,"NA",null,"Low","Low","All patients randomly assigned were included in the analyses.\r\r\r",null,null,"N","Relapse should be histopathologically confirmed. The measure was assumed appropriate.","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.","Y","No blinding was described.","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.","NA",null,"Low","Low","Relapse should be histopathologically confirmed. The measure was assumed appropriate.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r",null,null,"Some concerns","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.\rAll patients randomly assigned were included in the analyses.\r\r\r\rRelapse should be histopathologically confirmed. The measure was assumed appropriate.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.23","M4","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Pancreatitis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","PY","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r","N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found.","Low","Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.",null,null,"Y","Y","According to NCT trial registration, the study was open-label and no blinding was described.","PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","No description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. ","PN","Data from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Some concerns","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r",null,null,"Y","All patients randomly assigned were included in the analyses.","NA",null,"NA",null,"NA",null,"Low","Low","All patients randomly assigned were included in the analyses.\r\r\r",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","According to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively.","NA",null,"Low","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rAccording to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r",null,null,"Some concerns","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rAccording to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.24","M5","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Osteonecrosis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","PY","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r","N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found.","Low","Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.",null,null,"Y","Y","According to NCT trial registration, the study was open-label and no blinding was described.","PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","No description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. ","PN","Data from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Some concerns","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r",null,null,"Y","All patients randomly assigned were included in the analyses.","NA",null,"NA",null,"NA",null,"Low","Low","All patients randomly assigned were included in the analyses.\r\r\r",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The diagnosis was confirmed by imaging, and the outcome was measured objectively.","NA",null,"Low","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe diagnosis was confirmed by imaging, and the outcome was measured objectively.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r",null,null,"Some concerns","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe diagnosis was confirmed by imaging, and the outcome was measured objectively.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.24","M6","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Hypersensitivity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","PY","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r","N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found.","Low","Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.",null,null,"Y","Y","According to NCT trial registration, the study was open-label and no blinding was described.","PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","No description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. ","PN","Data from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Some concerns","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r",null,null,"Y","All patients randomly assigned were included in the analyses.","NA",null,"NA",null,"NA",null,"Low","Low","All patients randomly assigned were included in the analyses.\r\r\r",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received","NA",null,"Low","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r",null,null,"Some concerns","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.24","M7","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Asparaginase-associated toxicity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial","Y","PY","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r","N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found.","Low","Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.",null,null,"Y","Y","According to NCT trial registration, the study was open-label and no blinding was described.","PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.","PN","Given the nature of the outcome it was not likely that these deviations affect the outcome.","NA",null,"PY","No description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. ","PN","Data from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Some concerns","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r",null,null,"Y","All patients randomly assigned were included in the analyses.","NA",null,"NA",null,"NA",null,"Low","Low","All patients randomly assigned were included in the analyses.\r\r\r",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received","NA",null,"Low","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","N","The outcome was pre-defined and was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.",null,null,"Some concerns","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.27","Vr1","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Overall survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,null,"Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.",null,null,"Low","Low","Due to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.28","Vr2","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Event-free survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,null,"Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Events were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","N","Due to the nature of events the measurement or ascertainment could not have differed between the groups.",null,null,"Low","Low","Events were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.27","Vr3","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Relapse",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. Randomisation procedure was not described further.\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,null,"Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups.",null,null,"Low","Low","Due to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. Randomisation procedure was not described further.\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.28","Vr4","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Pancreatitis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,null,"Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation).","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.","NA",null,"Low","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation).\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation).\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.28","Vr5","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Thromboembolism",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,null,"Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.","NA",null,"Low","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.29","Vr6","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Osteonecrosis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,null,"Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. ","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.","NA",null,"Low","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r",null,null,"PY","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan.","N","Only 5-year cumulative incidence were reported.","N","Only 5-year cumulative incidence were reported.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan.\rOnly 5-year cumulative incidence were reported.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan.\rOnly 5-year cumulative incidence were reported.\r"]
["2021.10.28 10.30","Vr7","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Hypersensitivity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,null,"Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.","NA",null,"Low","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["2021.10.28 10.30","Vr8","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Asparaginase-associated toxicity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Y","Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention","N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.",null,null,"Y","Y","According to clinical trial registration was the study open-label. No blinding was described.","PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.","PN",null,null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.",null,null,"Low","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r",null,null,"Y","Data from all patients were reported for the outcome.",null,null,null,null,null,"Low","Low","Low","Data from all patients were reported for the outcome.\r\r\r",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.","PN","No difference in measurement between groups was indicated.","Y","No blinding was described.","PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.","NA",null,"Low","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","N","Pre-planned outcome was measured and reported as planned at protocol stage.","Low","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,"Low","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]

{"sheet":"Summary","index":2,"n_rows":27,"n_cols":33,"rows_kept":27,"cut":false,"hidden":false,"merged":[]}
["Unique ID","Reviewer","Study ID","Reference","Experimental","Comparator","Outcome","Result","Aim","Effect of adhering to intervention?","Weight","Randomization process","Comment for randomization process","Deviations from intended interventions","Comment for deviations from intended interventions","Missing outcome data","Comment for missing outcome data","Measurement of the outcome","Comment for measurement of the outcome","Selection of the reported result","Comment for selection of the reported result","Overall Bias","Comment for overall bias",null,null,null,null,"Randomization process","Deviations from intended interventions","Mising outcome data","Measurement of the outcome","Selection of the reported result","Overall Bias"]
["A1","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses) ","Disease-free survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.","Low","Events were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\rEvents were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,null,"Assignment to intervention (the 'intention-to-treat' effect)"]
["A2","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Relapse",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r","Low","Mandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rMandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,null,"Total number of study = 26"]
["A3","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Hypersensitivity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r","Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,null,"Low risk"]
["A4","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Pancreatitis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r","Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,null,"Some concerns"]
["A5","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Thromboembolism",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r","Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,null,"High risk"]
["A6","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Osteonecrosis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r","Low","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r",null,null,null,"Adhering to intervention (the 'per-protocol' effect)"]
["A7","LSL/CUR","Albertsen 2019",null,"Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Asparaginase-associated toxicity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.","Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r","Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r","Low","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.","Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol, and all participant data was analysed according the intervention they were assigned to. A sensitivity analyses adding the six randomly assigned but noneligible patients was included in the manuscript, and did not make a notewothly change in the outcome data. The analysis was assessed as appropriate. \r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.",null,null,null,"Total number of study = 0"]
["J1","LSL/CUR","Jeha 2019",null,"Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Continous complete remission ",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.","Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r","Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r","Low","Continuous complete remission assessed from the date of randomisation to the first adverse event, including relapse at any site, death during remission, or second malignant neoplasm. Given the nature of the events, the measure of the events was assumed appropriate.\rDue to the nature of the events included in the outcome it was unlikely that the measurement or ascertainment differed between the groups\rNo blinding was described. \rDue to the nature of the events included in the outcome the measurement or ascertainment could not have differed between the groups.\r","Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan and in the clinical trial registration.\rThe outcome was measured and reported as planned at protocol stage.\r","Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rContinuous complete remission assessed from the date of randomisation to the first adverse event, including relapse at any site, death during remission, or second malignant neoplasm. Given the nature of the events, the measure of the events was assumed appropriate.\rDue to the nature of the events included in the outcome it was unlikely that the measurement or ascertainment differed between the groups\rNo blinding was described. \rDue to the nature of the events included in the outcome the measurement or ascertainment could not have differed between the groups.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan and in the clinical trial registration.\rThe outcome was measured and reported as planned at protocol stage.\r",null,null,null,"Low risk"]
["J2","LSL/CUR","Jeha 2019",null,"Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Pancreatitis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.","Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r","Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r","Low","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Pancreatitis ≥ grade 2 was reported, which means that the diagnosis was confirmed by enzyme elevation or radiologic findings.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r","Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r","Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rToxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Pancreatitis ≥ grade 2 was reported, which means that the diagnosis was confirmed by enzyme elevation or radiologic findings.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r",null,null,null,"Some concerns"]
["J3","LSL/CUR","Jeha 2019",null,"Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Thromboembolism",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.","Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r","Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r","Low","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Thrombosis ≥ grade 2 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r","Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r","Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rToxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Thrombosis ≥ grade 2 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r",null,null,null,"High risk"]
["J4","LSL/CUR","Jeha 2019",null,"Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Osteonecrosis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.","Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r","Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r","Low","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Osteonecrosis grade ≥ 3 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r","Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the trial protocol, but not included in the analysis plan.\rOnly number of events and cumulative incidence were reported.\r","Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population, and it apperas that all participant data was analysed according the intervention they were assigned to. The analysis was assessed as appropriate. \r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rToxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Osteonecrosis grade ≥ 3 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the trial protocol, but not included in the analysis plan.\rOnly number of events and cumulative incidence were reported.\r"]
["M1","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Overall survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.","Low","All patients randomly assigned were included in the analyses.\r\r\r","Low","Due to the nature of the outcome the measure was assumed appropriate. \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.\rAll patients randomly assigned were included in the analyses.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["M2","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Event-free survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.","Low","All patients randomly assigned were included in the analyses.\r\r\r","Low","Events were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.\rAll patients randomly assigned were included in the analyses.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["M3","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Relapse",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.","Low","All patients randomly assigned were included in the analyses.\r\r\r","Low","Relapse should be histopathologically confirmed. The measure was assumed appropriate.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIn the manuscript “per protocol design” is stated , but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was propbably appropriacte. \rData from all participants were included in the analysis of the intervention they were assigned to.\rAll patients randomly assigned were included in the analyses.\r\r\r\rRelapse should be histopathologically confirmed. The measure was assumed appropriate.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["M4","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Pancreatitis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Low","All patients randomly assigned were included in the analyses.\r\r\r","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rAccording to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rAccording to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["M5","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Osteonecrosis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Low","All patients randomly assigned were included in the analyses.\r\r\r","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe diagnosis was confirmed by imaging, and the outcome was measured objectively.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe diagnosis was confirmed by imaging, and the outcome was measured objectively.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["M6","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Hypersensitivity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Low","All patients randomly assigned were included in the analyses.\r\r\r","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["M7","LSL/CUR","Mattano 2020",null,"Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Asparaginase-associated toxicity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.","Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r","Low","All patients randomly assigned were included in the analyses.\r\r\r","Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.","Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rNo description of the analysis was included in the manuscript, but it appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was probably appropriate. \rData from all participants (excluding deaths) were included in the analysis of the intervention they were assigned to.\r\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
["Vr1","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Overall survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Due to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Vr2","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Event-free survival",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Events were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Vr3","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Relapse",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. Randomisation procedure was not described further.\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Due to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. Randomisation procedure was not described further.\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Vr4","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Pancreatitis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation).\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation).\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Vr5","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Thromboembolism",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Vr6","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Osteonecrosis",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan.\rOnly 5-year cumulative incidence were reported.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan.\rOnly 5-year cumulative incidence were reported.\r"]
["Vr7","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Hypersensitivity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Vr8","LSL/CUR","Vrooman 2021",null,"Calaspargase (11 doses)","Pegaspargase (16 doses)","Asparaginase-associated toxicity",null,"assignment to intervention (the 'intention-to-treat' effect)","NA",null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.","Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r","Low","Data from all patients were reported for the outcome.\r\r\r","Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r","Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r","Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.It appears that all participants (excluding induction death and induction failure) were included in the analysis of the intervention they were assigned to. The analysis was assessed as appropriate.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]

{"sheet":"Figure (ITT)","index":3,"n_rows":27,"n_cols":16,"rows_kept":27,"cut":false,"hidden":false,"merged":[]}
["Intention-to-treat","Unique ID","Study ID","Experimental","Comparator","Outcome","Weight","D1","D2","D3","D4","D5","Overall"]
[null,"A1","Albertsen 2019","Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses) ","Disease-free survival","NA",null,null,null,null,null,null,null,null,"Low risk"]
[null,"A2","Albertsen 2019","Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Relapse","NA",null,null,null,null,null,null,null,null,"Some concerns"]
[null,"A3","Albertsen 2019","Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Hypersensitivity","NA",null,null,null,null,null,null,null,null,"High risk"]
[null,"A4","Albertsen 2019","Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Pancreatitis","NA"]
[null,"A5","Albertsen 2019","Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Thromboembolism","NA",null,null,null,null,null,null,null,"D1","Randomisation process"]
[null,"A6","Albertsen 2019","Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Osteonecrosis","NA",null,null,null,null,null,null,null,"D2","Deviations from the intended interventions"]
[null,"A7","Albertsen 2019","Intermittent asparaginase treatment (8 doses)","Continuous asparaginase treatment (15 doses)","Asparaginase-associated toxicity","NA",null,null,null,null,null,null,null,"D3","Missing outcome data"]
[null,"J1","Jeha 2019","Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Continous complete remission ","NA",null,null,null,null,null,null,null,"D4","Measurement of the outcome"]
[null,"J2","Jeha 2019","Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Pancreatitis","NA",null,null,null,null,null,null,null,"D5","Selection of the reported result"]
[null,"J3","Jeha 2019","Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Thromboembolism","NA"]
[null,"J4","Jeha 2019","Pegaspargase 3500 IU/m2","Pegaspargase 2500 IU/m2","Osteonecrosis","NA"]
[null,"M1","Mattano 2020","Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Overall survival","NA"]
[null,"M2","Mattano 2020","Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Event-free survival","NA"]
[null,"M3","Mattano 2020","Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Relapse","NA"]
[null,"M4","Mattano 2020","Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Pancreatitis","NA"]
[null,"M5","Mattano 2020","Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Osteonecrosis","NA"]
[null,"M6","Mattano 2020","Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Hypersensitivity","NA"]
[null,"M7","Mattano 2020","Low-risk with additional doses of PEG-asparaginase (6 doses)","Low-risk standard (2 doses)","Asparaginase-associated toxicity","NA"]
[null,"Vr1","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Overall survival","NA"]
[null,"Vr2","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Event-free survival","NA"]
[null,"Vr3","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Relapse","NA"]
[null,"Vr4","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Pancreatitis","NA"]
[null,"Vr5","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Thromboembolism","NA"]
[null,"Vr6","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Osteonecrosis","NA"]
[null,"Vr7","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Hypersensitivity","NA"]
[null,"Vr8","Vrooman 2021","Calaspargase (11 doses)","Pegaspargase (16 doses)","Asparaginase-associated toxicity","NA"]

{"sheet":"Figure (PP)","index":4,"n_rows":1,"n_cols":13,"rows_kept":1,"cut":false,"hidden":false,"merged":[]}
["Per-protocol","Unique ID","Study ID","Experimental","Comparator","Outcome","Weight","D1","D2","D3","D4","D5","Overall"]

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["Unique ID","A1","Study ID","Albertsen 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Intermittent asparaginase treatment (8 doses)","Comparator","Continuous asparaginase treatment (15 doses) ","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Disease-free survival","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
[null,"Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","The clinical trial registration states that the trial was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Intention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Events were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of events the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Events were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Mandatory bone marrow investigations confirm diagnosis of relapse. Death was reported to the Leukemia register. Secondary malignancy was explored as thoroughly as any primary cancer. The measure of the events was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","A2","Study ID","Albertsen 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Intermittent asparaginase treatment (8 doses)","Comparator","Continuous asparaginase treatment (15 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Relapse","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
[null,"Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\nBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","The clinical trial registration states that the trial was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Intention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Mandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of events the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Mandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate.\nDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\nNo blinding was described.\nDue to the nature of events the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\nBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\nThe clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n\nMore than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n\nMandatory bone marrow investigations confirm diagnosis of relapse. The measure of the events was assumed appropriate.\nDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\nNo blinding was described.\nDue to the nature of events the measurement or ascertainment could not have differed between the groups.\n\nA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
[]
[]
["Unique ID","A3","Study ID","Albertsen 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Intermittent asparaginase treatment (8 doses)","Comparator","Continuous asparaginase treatment (15 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Hypersensitivity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
[null,"Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\nBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","The clinical trial registration states that the trial was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Intention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\nBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\nThe clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n\nMore than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n\nThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asparaginase treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n\nA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
[]
[]
["Unique ID","A4","Study ID","Albertsen 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Intermittent asparaginase treatment (8 doses)","Comparator","Continuous asparaginase treatment (15 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Pancreatitis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
[null,"Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","The clinical trial registration states that the trial was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Intention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\nBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\nThe clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n\nMore than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n\nThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by enzyme elevation or imaging. The toxicities were captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n\nA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
[]
[]
["Unique ID","A5","Study ID","Albertsen 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Intermittent asparaginase treatment (8 doses)","Comparator","Continuous asparaginase treatment (15 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Thromboembolism","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
[null,"Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","The clinical trial registration states that the trial was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Intention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were given and no baseline imbalance were found.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\r\r\rThe outcome was diagnosed and evaluated according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was confirmed by imaging. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","A6","Study ID","Albertsen 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Intermittent asparaginase treatment (8 doses)","Comparator","Continuous asparaginase treatment (15 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Osteonecrosis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of randomly assigned patients were included in Table 1."]
[null,"Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","The clinical trial registration states that the trial was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Intention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\nBaseline characteristics of randomly assigned patients were included in Table 1.\nThe clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n\nMore than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n\nThe outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n\nA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
[]
[]
["Unique ID","A7","Study ID","Albertsen 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Intermittent asparaginase treatment (8 doses)","Comparator","Continuous asparaginase treatment (15 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Asparaginase-associated toxicity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics of randomly assigned patients were included in Table 1."]
[null,"Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","The clinical trial registration states that the trial was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Six patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Intention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The clinical trial registration states that the trial was open-label and no blinding was described.\nSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","More than 98% of randomised patients were included in the analysis for each randomisation arm."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","More than 98% of randomised patients were included in the analysis for each randomisation arm.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","The outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage."]
["Overall bias","Risk of bias judgement",null,null,"Low","Block randomisation was computer assigned (three patient to each arm for every six patients randomly assigned), stratified by country, risk group, and 6-mercaptapurine randomisation arm.\rBaseline characteristics of randomly assigned patients were included in Table 1.\rThe clinical trial registration states that the trial was open-label and no blinding was described.\rSix patients were excluded due to withdrawal of consent or misinterpretation of randomisation arm, it was not indicated that this deviation arose from trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rIntention-to-treat analysis was described in the trial protocol. In the manuscript it was described that adding the six randomly assigned but noneligible patients did not make a notewothly change in the outcome data.\r\rMore than 98% of randomised patients were included in the analysis for each randomisation arm.\r\rThe outcome was diagnosed and evaluated toxicities according to the international Ponte di Legno consensus criteria. Only symptomatic events were included. The outcome was captured or recaptured by several strategies, including quarterly prospective toxicity registration of PEG-asparaginase associated hypersensitivity, osteonecrosis, pancreatitis, and thromboembolism; individual case report forms after discontinuation of PEG-asp treatment; and deep phenotyping studies of individual PEG-asp–associated toxicities. If toxicity information was inconsistent, the toxicities (including dates of onset) were clarified by contacting the treating centers. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","J1","Study ID","Jeha 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Pegaspargase 3500 IU/m2","Comparator","Pegaspargase 2500 IU/m2","Source"," Journal article(s); Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Continous complete remission ","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration the study was open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All statistical analyses were based on intention-to-treat population."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Number of patients randomly assigned were identical with number of patients in reported results."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Continuous complete remission assessed from the date of randomisation to the first adverse event, including relapse at any site, death during remission, or second malignant neoplasm. Given the nature of the events, the measure of the events was assumed appropriate."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of the events included in the outcome it was unlikely that the measurement or ascertainment differed between the groups"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the events included in the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Continuous complete remission assessed from the date of randomisation to the first adverse event, including relapse at any site, death during remission, or second malignant neoplasm. Given the nature of the events, the measure of the events was assumed appropriate.\rDue to the nature of the events included in the outcome it was unlikely that the measurement or ascertainment differed between the groups\rNo blinding was described. \rDue to the nature of the events included in the outcome the measurement or ascertainment could not have differed between the groups.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan and in the clinical trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan and in the clinical trial registration.\rThe outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rContinuous complete remission assessed from the date of randomisation to the first adverse event, including relapse at any site, death during remission, or second malignant neoplasm. Given the nature of the events, the measure of the events was assumed appropriate.\rDue to the nature of the events included in the outcome it was unlikely that the measurement or ascertainment differed between the groups\rNo blinding was described. \rDue to the nature of the events included in the outcome the measurement or ascertainment could not have differed between the groups.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan and in the clinical trial registration.\rThe outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","J2","Study ID","Jeha 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Pegaspargase 3500 IU/m2","Comparator","Pegaspargase 2500 IU/m2","Source"," Journal article(s); Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Pancreatitis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration the study was open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All statistical analyses were based on intention-to-treat population."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Number of patients randomly assigned were identical with number of patients in reported results."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Pancreatitis ≥ grade 2 was reported, which means that the diagnosis was confirmed by enzyme elevation or radiologic findings."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Pancreatitis ≥ grade 2 was reported, which means that the diagnosis was confirmed by enzyme elevation or radiologic findings.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rToxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Pancreatitis ≥ grade 2 was reported, which means that the diagnosis was confirmed by enzyme elevation or radiologic findings.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","J3","Study ID","Jeha 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Pegaspargase 3500 IU/m2","Comparator","Pegaspargase 2500 IU/m2","Source"," Journal article(s); Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Thromboembolism","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration the study was open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All statistical analyses were based on intention-to-treat population."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Number of patients randomly assigned were identical with number of patients in reported results."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"PN","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Thrombosis ≥ grade 2 was reported."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Thrombosis ≥ grade 2 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rToxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Thrombosis ≥ grade 2 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the analysis plan.\rThe outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","J4","Study ID","Jeha 2019","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Pegaspargase 3500 IU/m2","Comparator","Pegaspargase 2500 IU/m2","Source"," Journal article(s); Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Osteonecrosis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration the study was open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"NA"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","All statistical analyses were based on intention-to-treat population."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Number of patients randomly assigned were identical with number of patients in reported results."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Number of patients randomly assigned were identical with number of patients in reported results.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"PN","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Osteonecrosis grade ≥ 3 was reported."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described. "]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Osteonecrosis grade ≥ 3 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"PY","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the trial protocol, but not included in the analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Only number of events and cumulative incidence were reported."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Only number of events and cumulative incidence were reported."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the trial protocol, but not included in the analysis plan.\rOnly number of events and cumulative incidence were reported.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1). According to correspondance with the study authors was the randomisation computer based and the randomization sequence was concealed until a patient was randomized\rBaseline characteristics for each randomisation arm were given in appendix and no baseline imbalance was found.\rAccording to clinical trial registration the study was open-label. No blinding was described.\rOne and two patients in each randomisation arm, respectively, were included as intent-to-treat, but no information regarding trial context was given.\r\r\rAll statistical analyses were based on intention-to-treat population.\r\rNumber of patients randomly assigned were identical with number of patients in reported results.\r\r\r\rToxicities were recorded and graded prospectively. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used. Osteonecrosis grade ≥ 3 was reported.\rNo difference in measurement between groups was indicated.\rNo blinding was described. \rThe assessment of the outcome was probably not influenced by knowledge of intervention received since it was measured objectively.\r\rA pre-specified analysis plan was found in the trial protocol provided by the study authors.The outcome was pre-specified in the trial protocol, but not included in the analysis plan.\rOnly number of events and cumulative incidence were reported.\r"]
[]
[]
["Unique ID","M1","Study ID","Mattano 2020","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Low-risk with additional doses of PEG-asparaginase (6 doses)","Comparator","Low-risk standard (2 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Overall survival","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\n\nBaseline characteristics for each randomisation group were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to NCT trial registration, the study was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Per protocol design was stated in manuscript."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"N","According to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
[null,"Risk of bias judgement",null,null,"Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\nFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nPer protocol design was stated in manuscript.\nAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","All patients randomly assigned were included in the analyses."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All patients randomly assigned were included in the analyses.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Due to the nature of the outcome the measure was assumed appropriate. \nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\nNo blinding was described.\nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group.\rAll patients randomly assigned were included in the analyses.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","M2","Study ID","Mattano 2020","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Low-risk with additional doses of PEG-asparaginase (6 doses)","Comparator","Low-risk standard (2 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Event-free survival","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to NCT trial registration, the study was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Per protocol design was stated in manuscript."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"N","According to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
[null,"Risk of bias judgement",null,null,"Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","All patients randomly assigned were included in the analyses."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All patients randomly assigned were included in the analyses.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Events were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Events were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate \nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\nNo blinding was described.\nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group.\rAll patients randomly assigned were included in the analyses.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Relapse and secondary malignancy should be histopathologically confirmed. The measure was assumed appropriate \rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","M3","Study ID","Mattano 2020","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Low-risk with additional doses of PEG-asparaginase (6 doses)","Comparator","Low-risk standard (2 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Relapse","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to NCT trial registration, the study was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Per protocol design was stated in manuscript."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"PN","According to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
[null,"Risk of bias judgement",null,null,"Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\nFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nPer protocol design was stated in manuscript.\nAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","All patients randomly assigned were included in the analyses."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All patients randomly assigned were included in the analyses.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Relapse should be histopathologically confirmed. The measure was assumed appropriate."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Relapse should be histopathologically confirmed. The measure was assumed appropriate.\nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\nNo blinding was described.\nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group.\rAll patients randomly assigned were included in the analyses.\r\r\r\rRelapse should be histopathologically confirmed. The measure was assumed appropriate.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","M4","Study ID","Mattano 2020","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Low-risk with additional doses of PEG-asparaginase (6 doses)","Comparator","Low-risk standard (2 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Pancreatitis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to NCT trial registration, the study was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Per protocol design was stated in manuscript."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"PN","According to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
[null,"Risk of bias judgement",null,null,"Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\nFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nPer protocol design was stated in manuscript.\nAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","All patients randomly assigned were included in the analyses."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All patients randomly assigned were included in the analyses.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","According to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\nNo difference in measurement between groups was indicated.\nNo blinding was described.\nAccording to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group.\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Only pancreatitis ≥2 was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rAccording to the CTCAE grade, the diagnosis was confirmed by elevated enzymes or imaging. The outcome was measured objectively.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","M5","Study ID","Mattano 2020","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Low-risk with additional doses of PEG-asparaginase (6 doses)","Comparator","Low-risk standard (2 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Osteonecrosis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\n\nBaseline characteristics for each randomisation group were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to NCT trial registration, the study was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Per protocol design was stated in manuscript."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"PN","According to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
[null,"Risk of bias judgement",null,null,"Some concerns","According to NCT trial registration, the study was open-label and no blinding was described.\nFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nPer protocol design was stated in manuscript.\nAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","All patients randomly assigned were included in the analyses."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All patients randomly assigned were included in the analyses.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The diagnosis was confirmed by imaging, and the outcome was measured objectively."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe diagnosis was confirmed by imaging, and the outcome was measured objectively.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration, the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group.\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. Osteonecrosis grade ≥1 confirmed by imaging was reported. The outcome measurement was judged as an appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe diagnosis was confirmed by imaging, and the outcome was measured objectively.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","M6","Study ID","Mattano 2020","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Low-risk with additional doses of PEG-asparaginase (6 doses)","Comparator","Low-risk standard (2 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Hypersensitivity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\n"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to NCT trial registration, the study was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Per protocol design was stated in manuscript."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"PN","According to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
[null,"Risk of bias judgement",null,null,"Some concerns","According to NCT trial registration the study was open-label and no blinding was described.\nFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nPer protocol design was stated in manuscript.\nAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","All patients randomly assigned were included in the analyses."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All patients randomly assigned were included in the analyses.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage."]
["Overall bias","Risk of bias judgement",null,null,"Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group.\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage."]
[]
[]
["Unique ID","M7","Study ID","Mattano 2020","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Low-risk with additional doses of PEG-asparaginase (6 doses)","Comparator","Low-risk standard (2 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record); Conference abstract(s) about the trial"]
["Outcome","Asparaginase-associated toxicity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol, the randomisation was done by computer, but the randomisation procedure was not further described.\n"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"PY"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation group were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to NCT trial registration, the study was open-label and no blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PY","Following information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome it was not likely that these deviations affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,"NA"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"PY","Per protocol design was stated in manuscript."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"PN","According to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
[null,"Risk of bias judgement",null,null,"Some concerns","According to NCT trial registration the study was open-label and no blinding was described.\nFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\nGiven the nature of the outcome it was not likely that these deviations affect the outcome.\n\nPer protocol design was stated in manuscript.\nAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group."]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","All patients randomly assigned were included in the analyses."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All patients randomly assigned were included in the analyses.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","All adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","The outcome was pre-defined and was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage.\nThe outcome was pre-defined and was measured and reported as planned at protocol stage."]
["Overall bias","Risk of bias judgement",null,null,"Some concerns","Patients were randomly assigned (1:1 using method of permuted blocks). According to trial protocol the randomisation was done by computer, but the randomisation procedure was not further described.\r\rBaseline characteristics for each randomisation group were given and no baseline imbalance was found.\rAccording to NCT trial registration the study was open-label and no blinding was described.\rFollowing information regarding reasons for not completing the study was given: Consent issue (1/0), lost to follow-up/withdrawal (10/17), non-compliance (3/1), refusal/physician choice (16/60), relapse (18/9), no longer COG site (11/9), toxicity (7/13) and protocol deviation (3/3). Some of these deviations probably arose from the trial context.\rGiven the nature of the outcome it was not likely that these deviations affect the outcome.\r\rPer protocol design was stated in manuscript.\rAccording to number of patients randomised to intervention or comparison and the number of patients analysed in each group.\rAll patients randomly assigned were included in the analyses.\r\r\r\rAll adverse event data were collected using the NCI Common Terminology Criteria for Adverse Events (reported using version 4.0), supplemented with the NCI Adverse Event Expedited Reporting System. The outcome measurement was probably appropriate measure and was reported as described in protocol.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was prospectively given in the trial protocol and in the trial registration.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage.\rThe outcome was pre-defined and was measured and reported as planned at protocol stage."]
[]
[]
["Unique ID","Vo1","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Overall survival","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\nBaseline characteristics for each radomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided).\nGiven the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome.\n\nAnalyses were by intention to treat.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients randomly assigned were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Due to the nature of the outcome the measure was assumed appropriate. \nDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\nThe study was unblinded.\nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage\nPre-planned outcome was measured and reported as planned at protocol stage"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each radomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided).\rGiven the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome.\r\rAnalyses were by intention to treat.\r\rData from all patients randomly assigned were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rThe study was unblinded.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage\rPre-planned outcome was measured and reported as planned at protocol stage"]
[]
[]
["Unique ID","Vo2","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Event-free survival","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. \nGiven the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome.\n\nAnalyses were by intention to treat.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients randomly assigned were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Events were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of events the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Events were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\nDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\nThe study was unblinded.\nDue to the nature of events the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. \rGiven the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome.\r\rAnalyses were by intention to treat.\r\rData from all patients randomly assigned were reported for the outcome.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rThe study was unblinded.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vo3","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Relapse","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","Given the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome."]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. \nGiven the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome.\n\nAnalyses were by intention to treat.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients randomly assigned were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"N","Due to the nature of outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Due to the nature of the outcome the measure was assumed appropriate. \nDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\nThe study was unblinded.\nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but was not specified as outcome. Registration of the specific outcome was described in the protocol."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but was not specified as outcome. Registration of the specific outcome was described in the protocol.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. \rGiven the nature of the outcome and using intention-to-treat analyses it was not likely to affect the outcome.\r\rAnalyses were by intention to treat.\r\rData from all patients randomly assigned were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rDue to the nature of outcome the measurement or ascertainment could not have differed between the groups.\rThe study was unblinded.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but was not specified as outcome. Registration of the specific outcome was described in the protocol.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vo4","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Pancreatitis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","The outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided).\nThe outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome\n\nAnalyses were by intention to treat.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients randomly assigned were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events confirmed by enzyme elevation were reported and evaluated by a trial coordinator."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events confirmed by enzyme elevation were reported and evaluated by a trial coordinator.\nNo difference in measurement between groups was indicated.\nThe study was unblinded.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"PY","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but thromboembolism was not specified as outcome. Registration of thromboembolism was described in the protocol."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"PN","Only number of patients in each group were reported."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"PN","Only number of patients in each group were reported."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but thromboembolism was not specified as outcome. Registration of thromboembolism was described in the protocol.\nOnly number of patients in each group were reported.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided).\rThe outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome\r\rAnalyses were by intention to treat.\r\rData from all patients randomly assigned were reported for the outcome.\r\r\r\rOutcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events confirmed by enzyme elevation were reported and evaluated by a trial coordinator.\rNo difference in measurement between groups was indicated.\rThe study was unblinded.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but thromboembolism was not specified as outcome. Registration of thromboembolism was described in the protocol.\rOnly number of patients in each group were reported.\r"]
[]
[]
["Unique ID","Vo5","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Thromboembolism","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each radomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","The outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided).\nThe outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome\n\nAnalyses were by intention to treat.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients randomly assigned were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator.\nNo difference in measurement between groups was indicated.\nThe study was unblinded.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"PY","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but pancreatitis was not specified as outcome. Registration of pancreatitis was described in the protocol."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"PN","Only number of patients in each group were reported."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"PN","Only number of patients in each group were reported."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but pancreatitis was not specified as outcome. Registration of pancreatitis was described in the protocol.\nOnly number of patients in each group were reported.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each radomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided).\rThe outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome\r\rAnalyses were by intention to treat.\r\rData from all patients randomly assigned were reported for the outcome.\r\r\r\rOutcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator.\rNo difference in measurement between groups was indicated.\rThe study was unblinded.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but pancreatitis was not specified as outcome. Registration of pancreatitis was described in the protocol.\rOnly number of patients in each group were reported.\r"]
[]
[]
["Unique ID","Vo6","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Osteonecrosis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","The outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. \nThe outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome\n\nAnalyses were by intention to treat.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients randomly assigned were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"PN","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator, diagnosis of avascular necrosis was not described."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator, diagnosis of avascular necrosis was not described.\nNo difference in measurement between groups was indicated.\nThe study was unblinded.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"PY","A pre-specified analysis plan was included in the trial protocol. Acute and late toxicity was given as outcome in the trial protocol, but avascular necrosis was not specified as outcome. Avascular Necrosis was described as toxicity in the protocol."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"PN","Only number of patients in each group were reported."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"PN","Only number of patients in each group were reported."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was included in the trial protocol. Acute and late toxicity was given as outcome in the trial protocol, but avascular necrosis was not specified as outcome. Avascular Necrosis was described as toxicity in the protocol.\nOnly number of patients in each group were reported.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done.\rBaseline characteristics for each randomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. \rThe outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome\r\rAnalyses were by intention to treat.\r\rData from all patients randomly assigned were reported for the outcome.\r\r\r\rOutcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator, diagnosis of avascular necrosis was not described.\rNo difference in measurement between groups was indicated.\rThe study was unblinded.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA pre-specified analysis plan was included in the trial protocol. Acute and late toxicity was given as outcome in the trial protocol, but avascular necrosis was not specified as outcome. Avascular Necrosis was described as toxicity in the protocol.\rOnly number of patients in each group were reported.\r"]
[]
[]
["Unique ID","Vo7","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Hypresensitivity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trials unit, where computer randomisation was done.\rBaseline characteristics for each radomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","The outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from Augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided)\nGiven the nature of the outcome it was not likely to affect the outcome.\n\nAnalyses were by intention to treat\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator.\nNo difference in measurement between groups was indicated.\nThe study was unblinded.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"PY","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but hypersensitivity was not specified as outcome. Registration of hypersensitivity and management was described in the protocol."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"PN","Only number of patients in each group were reported."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"PN","Only number of patients in each group were reported."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but hypersensitivity was not specified as outcome. Registration of hypersensitivity and management was described in the protocol.\nOnly number of patients in each group were reported.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trials unit, where computer randomisation was done.\rBaseline characteristics for each radomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from Augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided)\rGiven the nature of the outcome it was not likely to affect the outcome.\r\rAnalyses were by intention to treat\r\rData from all patients were reported for the outcome.\r\r\r\rOutcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator.\rNo difference in measurement between groups was indicated.\rThe study was unblinded.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but hypersensitivity was not specified as outcome. Registration of hypersensitivity and management was described in the protocol.\rOnly number of patients in each group were reported.\r"]
[]
[]
["Unique ID","Vo8","Study ID","Vora 2014","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Augmented therapy (12 doses)","Comparator","Standard therapy (4 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Asparaginase-associated toxicity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trial unit, where computer randomisation was done."]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics for each randomisation arm were given and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trials unit, where computer randomisation was done.\rBaseline characteristics for each radomisation arm were given and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","Patients, clinicians, and data analysts were not masked to treatment allocation."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","Five patients crossed-over from augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided). We assumed that the changes from the assigned intervention were consistent with dose-reduction described in the trial protocol and that non-adherence to intervention, were consistent with what could occur outside the trial context. "]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN","The outcome was objectively measured objectively and intention-to-treat analysis it not likely that deviations will affect the outcome"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Analyses were by intention to treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Patients, clinicians, and data analysts were not masked to treatment allocation.\nFive patients crossed-over from Augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided)\nGiven the nature of the outcome it was not likely to affect the outcome.\n\nAnalyses were by intention to treat\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients randomly assigned were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?",null,null,"NA"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,null,"NA"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","The study was unblinded."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Outcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator.\nNo difference in measurement between groups was indicated.\nThe study was unblinded.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"PY","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but hypersensitivity was not specified as outcome. Registration of hypersensitivity and management was described in the protocol."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"PN","Only number of patients in each group were reported."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"PN","Only number of patients in each group were reported."]
[null,"Risk of bias judgement",null,null,"Low","A pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but hypersensitivity was not specified as outcome. Registration of hypersensitivity and management was described in the protocol.\rOnly number of patients in each group were reported.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","Patients were randomly assigned in a 1:1 ratio. Treatment allocation was obtained by telephone call to the central trials unit, where computer randomisation was done.\rBaseline characteristics for each radomisation arm were given and no baseline imbalance was found.\rPatients, clinicians, and data analysts were not masked to treatment allocation.\rFive patients crossed-over from Augmented therapy to standard regimen due to toxicity (1 = prolonged neutropenia, 1 = neurotoxicity, 2 = Capizzi MTX related mucositis, 1 = other toxicity (no further info provided)\rGiven the nature of the outcome it was not likely to affect the outcome.\r\rAnalyses were by intention to treat\r\rData from all patients were reported for the outcome.\r\r\r\rOutcome was diagnosed and graded according to an adapted version of CTCAE. Only serious adverse events were reported and evaluated by a trial coordinator.\rNo difference in measurement between groups was indicated.\rThe study was unblinded.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received\r\rA pre-specified analysis plan was included in the trial protocol. Acute toxicity was given as outcome in the trial protocol, but hypersensitivity was not specified as outcome. Registration of hypersensitivity and management was described in the protocol.\rOnly number of patients in each group were reported.\r"]
[]
[]
["Unique ID","Vr1","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Overall survival","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?"]
[null,"Risk of bias judgement",null,null,"Low","Due to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vr2","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Event-free survival","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\nOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\n\n\nToxicity and time-to-event analyses were performed by intention-to-treat.\n"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\n\n\n"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Events were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of events the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?"]
[null,"Risk of bias judgement",null,null,"Low","Events were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\nNo difference in measurement between groups was indicated.\nNo blinding was described.\nDue to the nature of events the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\nPre-planned outcome was measured and reported as planned at protocol stage.\n"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rEvents were defined as relapse, death or secondary malignancy. Due to the nature of the events the measure was assumed appropriate.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of events the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vr3","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Relapse","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. Randomisation procedure was not described further.\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Due to the nature of the outcome the measure was assumed appropriate. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"N","Due to the nature of the outcome the measurement or ascertainment could not have differed between the groups."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?"]
[null,"Risk of bias judgement",null,null,"Low","Due to the nature of the outcome the measure was assumed appropriate. \nNo difference in measurement between groups was indicated.\nNo blinding was described.\nDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. Randomisation procedure was not described further.\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rDue to the nature of the outcome the measure was assumed appropriate. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rDue to the nature of the outcome the measurement or ascertainment could not have differed between the groups.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vr4","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Pancreatitis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation)."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation).\nNo difference in measurement between groups was indicated.\nNo blinding was described.\nThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\n"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Pancreatitis was further defined as severe (symptoms with enzyme elevation for ≥72 hours and/or development of pancreatic pseudocyst or life-threatening complication), or mild or moderate (symptoms, <72 hours with enzyme elevation).\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vr5","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Thromboembolism","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. Thrombosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vr6","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Osteonecrosis","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. "]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"PY","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Only 5-year cumulative incidence were reported."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Only 5-year cumulative incidence were reported."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan.\rOnly 5-year cumulative incidence were reported.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15.  Symptomatic osteonecrosis (≥ grade 2) confirmed with imaging was included as events. \rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome described in the trial protocol, but was not included in the statistical analysis plan.\rOnly 5-year cumulative incidence were reported.\r"]
[]
[]
["Unique ID","Vr7","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Hypersensitivity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
[]
[]
["Unique ID","Vr8","Study ID","Vrooman 2021","Assessor","LSL/CUR"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental","Calaspargase (11 doses)","Comparator","Pegaspargase (16 doses)","Source"," Journal article(s); Trial protocol; Non-commercial trial registry record (e.g. ClinicalTrials.gov record)"]
["Outcome","Asparaginase-associated toxicity","Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?",null,null,"Y","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?",null,null,"Y"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?",null,null,"N","Baseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
[null,"Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found."]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?",null,null,"Y","According to clinical trial registration was the study open-label. No blinding was described."]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,null,"Y"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?",null,null,"PN","One patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction."]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,null,"PN"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?",null,null,"Y","Toxicity and time-to-event analyses were performed by intention-to-treat."]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement",null,null,"Low","According to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?",null,null,"Y","Data from all patients were reported for the outcome."]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement",null,null,"Low","Data from all patients were reported for the outcome.\r\r\r"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?",null,null,"N","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included."]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?",null,null,"PN","No difference in measurement between groups was indicated."]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?",null,null,"Y","No blinding was described."]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?",null,null,"PN","The assessment of the outcome was objective and was probably not influenced by knowledge of intervention received."]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?",null,null,"NA"]
[null,"Risk of bias judgement",null,null,"Low","Toxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,"Y","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration."]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"5.3 ... multiple eligible analyses of the data?",null,null,"N","Pre-planned outcome was measured and reported as planned at protocol stage."]
[null,"Risk of bias judgement",null,null,"Low","A sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]
["Overall bias","Risk of bias judgement",null,null,"Low","At study entry, patients were randomly assigned, in a 1:1 ratio. According to author correspondance was the randomization centralized and computer based, and allocation was concealed until participants were enrolled and assigned to intervention\rBaseline characteristics on the basic of randomy assigned asparaginase arm were described and no baseline imbalance was found.\rAccording to clinical trial registration was the study open-label. No blinding was described.\rOne patient, randomly assigned to PEG-asparaginase, was ineligible and removed. One patient in each randomisation arm withdrew consent during induction.\r\r\rToxicity and time-to-event analyses were performed by intention-to-treat.\r\rData from all patients were reported for the outcome.\r\r\r\rToxicity was prospectively graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.15. All grades of allergy were included.\rNo difference in measurement between groups was indicated.\rNo blinding was described.\rThe assessment of the outcome was objective and was probably not influenced by knowledge of intervention received.\r\rA sufficient pre-specified analysis plan was included in the trial protocol. The outcome was given in the trial protocol and in the trial registration.\rPre-planned outcome was measured and reported as planned at protocol stage.\r"]

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["Unique ID",null,"Study ID",null,"Assessor"]
["Ref or Label",null,"Aim","adhering to intervention (the 'per-protocol' effect)","The effect of adhering to intervention…"]
["Experimental",null,"Comparator",null,"Source"]
["Outcome",null,"Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?"]
[null,"Risk of bias judgement"]
["Bias due to deviations from intended interventions","2.1 Were participants aware of their assigned intervention during the trial?"]
[null,"2.2 Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?"]
[null,"2.3. [If applicable:] If Y/PY/NI to 2.1 or 2.2: Were important non-protocol interventions balanced across intervention groups?"]
[null,"2.4. [If applicable:] Were there failures in implementing the intervention that could have affected the outcome?"]
[null,"2.5. [If applicable:] Was there non-adherence to the assigned intervention regimen that could have affected participants’ outcomes?"]
[null,"2.6. If N/PN/NI to 2.3, or Y/PY/NI to 2.4 or 2.5: Was an appropriate analysis used to estimate the effect of adhering to the intervention?"]
[null,"Risk of bias judgement"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?"]
[null,"Risk of bias judgement"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?"]
[null,"5.3 ... multiple eligible analyses of the data?"]
[null,"Risk of bias judgement"]
["Overall bias","Risk of bias judgement"]

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["Unique ID",null,"Study ID",null,"Assessor"]
["Ref or Label",null,"Aim","assignment to intervention (the 'intention-to-treat' effect)\n\n"]
["Experimental",null,"Comparator",null,"Source"]
["Outcome",null,"Results",null,"Weight"]
["Domain","Signalling question",null,null,"Response","Comments"]
["Bias arising from the randomization process","1.1 Was the allocation sequence random?"]
[null,"1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?"]
[null,"1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?"]
[null,"Risk of bias judgement"]
["Bias due to deviations from intended interventions","2.1.Were participants aware of their assigned intervention during the trial?"]
[null,"2.2.Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?"]
[null,"2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the experimental context?"]
[null,"2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?"]
[null,"2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?"]
[null,"2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?"]
[null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Risk of bias judgement"]
["Bias due to missing outcome data","3.1 Were data for this outcome available for all, or nearly all, participants randomized?"]
[null,"3.2 If N/PN/NI to 3.1: Is there evidence that result was not biased by missing outcome data?"]
[null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?"]
[null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?"]
[null,"Risk of bias judgement"]
["Bias in measurement of the outcome","4.1 Was the method of measuring the outcome inappropriate?"]
[null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?"]
[null,"4.3 Were outcome assessors aware of the intervention received by study participants?"]
[null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?"]
[null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?"]
[null,"Risk of bias judgement"]
["Bias in selection of the reported result","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?"]
[null,"5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?"]
[null,"5.3 ... multiple eligible analyses of the data?"]
[null,"Risk of bias judgement"]
["Overall bias","Risk of bias judgement"]

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[null,"Journal article(s)","NA","Yes",null,"1.1 Was the allocation sequence random?",null,"2.1 Were participants aware of their assigned intervention during the trial?","2.1 Were participants aware of their assigned intervention during the trial?",null,"3.1 Were data for this outcome available for all, or nearly all, participants randomized?","Individually Randomized, Parallel Group Trials","4.1 Was the method of measuring the outcome inappropriate?","assignment to intervention (the 'intention-to-treat' effect)","5.1 Were the data that produced this result analysed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?",null,null,null,"occurance of non-protocol interventions"]
["NA","Trial protocol","Favours experimental ","No (Please include reasons in the note)","Y","1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?","Low","2.2 Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?","2.2 Were carers and people delivering the interventions aware of participants' assigned intervention during the trial?",null,"3.2 If N/PN/NI to 3.1: Is there evidence that the result was not biased by missing outcome data?",null,"4.2 Could measurement or ascertainment of the outcome have differed between intervention groups?","adhering to intervention (the 'per-protocol' effect)","5.2 ... multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain?",null,null,null,"failures in implementing the intervention that could have affected the outcome"]
["Y","Statistical analysis plan (SAP)","Favours comparator ",null,"PY","1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?","High","2.3 [If applicable:] If Y/PY/NI to 2.1 or 2.2: Were important nonprotocol interventions balanced across intervention groups?","2.3 If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the trial context?",null,"3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?",null,"4.3 If N/PN/NI to 4.1 and 4.2: Were outcome assessors aware of the intervention received by study participants?",null,"5.3 ... multiple eligible analyses of the data?",null,null,null,"non-adherence to their assigned intervention by trial participants"]
["PY","Non-commercial trial registry record (e.g. ClinicalTrials.gov record)","Towards null ",null,"PN",null,"Some concerns","2.4 [If applicable:] Were there failures in implementing the intervention that could have affected the outcome?","2.4 If Y/PY to 2.3: Were these deviations likely to have affected the outcome?",null,"3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?",null,"4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received?"]
["PN","Company-owned trial registry record (e.g. GSK Clinical Study Register record)","Away from null ",null,"N",null,null,"2.5 [If applicable:] Was there non-adherence to the assigned intervention regimen that could have affected participants’ outcomes?","2.5. If Y/PY/NI to 2.4: Were these deviations from intended intervention balanced between groups?",null,null,null,"4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received?"]
["N","“Grey literature” (e.g. unpublished thesis)","Unpredictable",null,"NI",null,null,"2.6 If N/PN/NI to 2.3, or Y/PY/NI to 2.4 or 2.5: Was an appropriate analysis used to estimate the effect of adhering to the intervention?","2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?"]
["NI","Conference abstract(s) about the trial",null,null,null,null,null,null,"2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized?"]
[null,"Regulatory document (e.g. Clinical Study Report, Drug Approval Package)"]
[null,"Research ethics application"]
[null,"Grant database summary (e.g. NIH RePORTER, Research Councils UK Gateway to Research)"]
[null,"Personal communication with trialist"]
[null,"Personal communication with the sponsor"]