| Trial | Risk of bias | ||||||||||||||||||||||
| Randomisation process | Deviations from intended interventions | Missing outcome data | Measurement of the outcome | Selection of the reported results | Overall | ||||||||||||||||||
| Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | Authors' judgement | Support for judgement | ||||||||||||
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NCT03141177 IMDC favourable risk group |
Low risk of bias | Interactive Response Technology was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 8 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 1.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 3% of those who received treatment discontinued due to “other” reasons (not explained further). | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent central review committee. | High risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. However, the time point that produced this result was not pre‐specified in the protocol. The results of the final PFS analysis were already reported in a previous publication. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data and inconsistency with the protocol regarding the time point of analyses and reporting. | |||||||||||
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NCT03141177 IMDC intermediate risk group |
Low risk of bias | Interactive Response Technology was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 8 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 1.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 3% of those who received treatment discontinued due to “other” reasons (not explained further). | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent central review committee. | High risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. However, the time point that produced this result was not pre‐specified in the protocol. The results of the final PFS analysis were already reported in a previous publication. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data and inconsistency with the protocol regarding the time point of analyses and reporting. | |||||||||||
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NCT03141177 IMDC poor risk group |
Low risk of bias | Interactive Response Technology was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 8 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 1.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 3% of those who received treatment discontinued due to “other” reasons (not explained further). | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent central review committee. | High risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. However, the time point that produced this result was not pre‐specified in the protocol. The results of the final PFS analysis were already reported in a previous publication. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data and inconsistency with the protocol regarding the time point of analyses and reporting. | |||||||||||
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NCT02811861 Comparison 1 (LEN+PEM vs.SUN) Total trial population (combined risk groups) |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisations. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.8% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. All reported analyses were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 1 (LEN+PEM vs.SUN) MSKCC favourable risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.8% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not further explained). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 1 (LEN+PEM vs.SUN) MSKCC intermediate risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.8% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 1 (LEN+PEM vs.SUN) MSKCC poor risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.8% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not further explained). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 1 (LEN+PEM vs.SUN) IMDC favourable risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 2 participants randomised to the experimental arm and 4 participants randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without IMDC risk group allocation were excluded from subgroup analyses. | High risk of bias | 2.8% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 1 (LEN+PEM vs.SUN) IMDC intermediate risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 2 participants randomised to the experimental arm and 4 participants randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without IMDC risk group allocation were excluded from subgroup analyses. | High risk of bias | 2.8% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 1 (LEN+PEM vs.SUN) IMDC poor risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 2 participants randomised to the experimental arm and 4 participants randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without IMDC risk group allocation were excluded from subgroup analyses. | High risk of bias | 2.8% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 2 (LEN+EVE vs. SUN) Total trial population (combined risk groups) |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. All reported analyses were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 2 (LEN+EVE vs. SUN) MSKCC favourable risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 2 (LEN+EVE vs. SUN) MSKCC intermediate risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 2 (LEN+EVE vs. SUN) MSKCC poor risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 2 (LEN+EVE vs. SUN) IMDC favourable risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 6 participants randomised to the experimental arm and 4 participants randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without IMDC risk group allocation were excluded from subgroup analyses. | High risk of bias | 2.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 2 (LEN+EVE vs. SUN) IMDC intermediate risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 6 participants randomised to the experimental arm and 4 participants randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without IMDC risk group allocation were excluded from subgroup analyses. | High risk of bias | 2.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT02811861 Comparison 2 (LEN+EVE vs. SUN) IMDC poor risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 6 participants randomised to the experimental arm and 4 participants randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 17 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without IMDC risk group allocation were excluded from subgroup analyses. | High risk of bias | 2.7% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. 2% discontinued treatment due to “other” reasons (not explained further). | High risk of bias | Independent review was conducted but no statement whether it was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | A study protocol with SAP available. The subgroup analyses according to IMDC risk group were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; the outcome assessors’ probable awareness of the assigned interventions. | |||||||||||
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NCT01108445 Total trial population (combined risk groups) |
Low risk of bias | Participants were randomised in a 1:1 ratio. Randomisation was done under allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned intervention. Only 1 participant withdrew after consent, but before randomisation and before study drug was assigned. The method of analysis was appropriate (ITT). |
Low risk of bias | All 108 participants were evaluable. | High risk of bias | Scans were read by a trained radiologist, but no information whether the person was blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ probable awareness of the assigned interventions; missing study protocol and SAP. | |||||||||||
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NCT01108445 MSKCC favourable risk group |
Low risk of bias | Participants were randomised in a 1:1 ratio. Randomisation was done under allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned intervention. Only 1 participant withdrew after consent, but before randomisation and before study drug was assigned. The method of analysis was appropriate (ITT). |
Low risk of bias | All 108 participants were evaluable. | High risk of bias | Scans were read by a trained radiologist, but no information whether the person was blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ probable awareness of the assigned interventions; missing study protocol and SAP. | |||||||||||
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NCT01108445 MSKCC intermediate risk group |
Low risk of bias | Participants were randomised in a 1:1 ratio. Randomisation was done under allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned intervention. Only 1 participant withdrew after consent, but before randomisation and before study drug was assigned enrolment and randomisation). The method of analysis was appropriate (ITT). |
Low risk of bias | All 108 participants were evaluable | High risk of bias | Scans were read by a trained radiologist, but no information whether the person was blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ probable awareness of the assigned interventions; missing study protocol and SAP. | |||||||||||
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NCT01108445 MSKCC poor risk group |
Low risk of bias | Participants were randomised in a 1:1 ratio. Randomisation was done under allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned intervention. Only 1 participant withdrew after consent, but before randomisation and before study drug was assigned. The method of analysis was appropriate (ITT). |
Low risk of bias | All 108 participants were evaluable | High risk of bias | Scans were read by a trained radiologist, but no information whether the person was blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ probable awareness of the assigned interventions; missing study protocol and SAP. | |||||||||||
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NCT01392183 Total trial population (only intermediate and poor risk groups included in the trial) |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about the allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. | High risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. No statement about the method of analysis. | Low risk of bias | Detailed flow diagram provided, no indication of loss to follow‐up. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. The radiographic response was assessed by blinded radiologists. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about the allocation concealment and method of analysis; missing study protocol and SAP. | |||||||||||
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NCT00334282 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was blinded: both participants and those delivering the intervention were not aware of assigned interventions. The method of analysis was appropriate (ITT). | Low risk of bias | 1.3% of those who received treatment were lost to follow‐up. No analysis to correct for bias, but numbers are low and probably did not have an effect on the outcome. |
Low risk of bias | Outcome assessors were not aware of the assigned intervention. All imaging scans were evaluated by an independent imaging‐review committee (IRC) blinded to study treatment. | Low risk of bias | CSR and study protocol with SAP available. All reported analyses were pre‐specified in the protocol and SAP. | Low risk of bias | Overall judged low risk of bias. | |||||||||||
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NCT01030783 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | No information provided about loss to follow‐up. 2.3% discontinued due to “other” reasons (not explained further). | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent radiology review. | Some concerns | No SAP available. Study protocol available, but unclear whether it was finalized before unblinded outcome data were available. | High risk of bias | Overall judged high risk of bias due to lack of information about missing outcome data; missing study protocol and SAP. | |||||||||||
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NCT00065468 Comparison 1 (TEM vs. IFN) Total trial population (only intermediate and poor risk groups included in the trial) |
Some concerns | Participants were randomised, but no information provided about allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the single‐drug arm and 7 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 1.9% did not receive the intended interventions and therefore did not have outcome data. 2% of those who received treatment were lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent central review. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to lack of information about allocation concealment; missing study protocol and SAP. | |||||||||||
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NCT00065468 Comparison 2 (TEM+IFN vs. IFN) Total trial population (only intermediate and poor risk groups included in the trial) |
Some concerns | Participants were randomised, but no information provided about allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the combination arm and 7 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 2.2% did not receive the intended interventions and therefore did not have outcome data. 1.7% of those who received treatment were lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent central review. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to lack of information about allocation concealment; missing study protocol and SAP. | |||||||||||
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NCT00738530 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice recognition system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was double‐blind: both participants and those delivering the intervention were not aware of assigned interventions. Only 6 participants randomised to the experimental arm and 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 1.2% did not receive the intended interventions and therefore did not have outcome data. 3.9% of those who received treatment withdrew consent or were lost to follow‐up before interim data cut. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00738530 MSKCC favourable risk group |
Low risk of bias | Interactive voice recognition system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 28 participants randomised to the experimental arm and 24 participants randomised to the control arm. | Low risk of bias | The study was double‐blind: both participants and those delivering the intervention were not aware of assigned interventions. Only 6 participants randomised to the experimental arm and 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | 1.2% did not receive the intended interventions and therefore did not have outcome data. 3.9% of those who received treatment withdrew consent or were lost to follow‐up before interim data cut. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00738530 MSKCC intermediate risk group |
Low risk of bias | Interactive voice recognition system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 28 participants randomised to the experimental arm and 24 participants randomised to the control arm. | Low risk of bias | The study was double‐blind: both participants and those delivering the intervention were not aware of assigned interventions. Only 6 participants randomised to the experimental arm and 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | 1.2% did not receive the intended interventions and therefore did not have outcome data. 3.9% of those who received treatment withdrew consent or were lost to follow‐up before interim data cut. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00738530 MSKCC poor risk group |
Low risk of bias | Interactive voice recognition system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 28 participants randomised to the experimental arm and 24 participants randomised to the control arm. | Low risk of bias | The study was double‐blind: both participants and those delivering the intervention were not aware of assigned interventions. Only 6 participants randomised to the experimental arm and 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | 1.2% did not receive the intended interventions and therefore did not have outcome data. 3.9% of those who received treatment withdrew consent or were lost to follow‐up before interim data cut. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00072046 Total trial population (combined risk groups) |
Some concerns | Participants were randomised via a stratified random block design, but no information provided about the allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 13 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 2.2% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received the intervention were lost to follow‐up. These numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention and knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about the allocation concealment; the assessors’ awareness of assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00081614 (only favourable and intermediate risk groups included in the trial) |
Low risk of bias | Interactive voice response service was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | High risk of bias | The study was double‐blind: both participants and those delivering the intervention were not aware of assigned interventions. No information provided about the method of analysis. | Low risk of bias | 1 participant randomised to the experimental arm was lost to follow‐up, which probably did not have an effect on the outcome. | High risk of bias | No precise information provided about the outcome assessors. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about the method of analysis; the outcome assessors’ probable awareness of the assigned interventions; missing study protocol and SAP. | |||||||||||
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NCT00117637 Total trial population (combined risk groups) |
High risk of bias | Participants were randomised in a 1:1 ratio, but no information provided about the allocation concealment. There were some baseline imbalances that could suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. The method of analysis was appropriate (ITT). | Low risk of bias | 1.1% randomised to the control arm were lost to follow‐up. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS assessed by blinded independent radiological review. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about the allocation concealment; baseline imbalances; missing study protocol and SAP. | |||||||||||
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Jonasch 2010 Total trial population (combined risk groups) |
Low risk of bias | Randomisation method appropriate and allocation concealed. No imbalances. | Low risk of bias | No information provided about whether the participants or those delivering the intervention were blinded or not. Only 1 participant randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). |
Low risk of bias | 1 participant did not receive the intended intervention and therefore did not have outcome data. Of those who received treatment, 8.8% came off study before the first 8‐week response assessment. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | No information whether the investigator (outcome assessor) was blinded. We can only assume no (not blinded) because investigator assessment was compared to blinded review of 20 participants’ scans. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about blinding of outcome assessor; missing study protocol and SAP. | |||||||||||
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NCT00098657/NCT00083889 Total trial population (combined risk groups) |
Some concerns | Participants were randomised in a 1:1 ratio, but no information about allocation concealment. However, there were no baseline imbalances that would suggest a problem with randomisation. | Some concerns | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 15 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 2% did not receive the intended interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by blinded independent central review. | Some concerns | No study protocol or SAP available. | High risk of bias. | Overall judged high risk of bias due to lack of information about the randomisation process and allocation concealment; deviations from intended interventions only in the control group; lack of information about missing data; missing study protocol or SAP. | |||||||||||
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NCT00732914 Total trial population (combined risk groups) |
Low risk of bias | Randomszation was performed centrally. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 5 participants randomised to the experimental arm and 7 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 3.3% did not receive the intended interventions and therefore, did not have outcome data. 4.5% of those who received treatment discontinued due to “other” reasons, including (but not limited to) loss to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention and knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to the assessors’ awareness of assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00732914 MSKCC favourable risk group |
Low risk of bias | Randomisation was performed centrally. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 8 participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 5 participants randomised to the experimental arm and 7 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | 3.3% did not receive the intended interventions and therefore, did not have outcome data. 4.5% of those who received treatment discontinued due to “other” reasons, including (but not limited to) loss to follow‐up. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention and knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to the assessors’ awareness of assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00732914 MSKCC intermediate risk group |
Low risk of bias | Randomisation was performed centrally. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 8 participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 5 participants randomised to the experimental arm and 7 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | 3.3% did not receive the intended interventions and therefore, did not have outcome data. 4.5% of those who received treatment discontinued due to “other” reasons, including (but not limited to) loss to follow‐up. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention and knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due the assessors’ awareness of assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00920816 Total trial population (combined risk groups) |
Low risk of bias | A centralized registration system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 1% did not receive the intended interventions and therefore did not have outcome data. 2.1% of those who received treatment were lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a masked independent review committee. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00920816 MSKCC favourable risk group |
Low risk of bias | A centralized registration system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 7 participants randomised to the experimental arm and 1 participant randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). However, 8 participants for whom MSKCC risk group was not available were still included in the analysis and allocated to the intermediate/poor risk group. |
Low risk of bias | 1% did not receive the intended interventions and therefore did not have outcome data. 2.1% of those who received treatment were lost to follow‐up. Unclear how many of these were assigned to the favourable risk group. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a masked independent review committee. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00920816 MSKCC intermediate+poor risk groups combined |
Low risk of bias | A centralized registration system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 7 participants randomised to the experimental arm and 1 participant randomised to the control arm | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). However, 8 participants for whom MSKCC risk group was not available were still included in the analysis and allocated to the intermediate/poor risk group. |
Low risk of bias | 1% did not receive the intended interventions and therefore did not have outcome data. 2.1% of those who received treatment were lost to follow‐up. Unclear how many of these were assigned to the intermediate/poor risk group. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a masked independent review committee. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT01024920 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice randomisation system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate. | Low risk of bias | 3% did not receive the intended interventions and therefore did not have outcome data. 1 participant randomised to the control arm was lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to the assessors’ awareness of assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00631371 Total trial population (combined risk groups) |
Low risk of bias | A computerized centrally located randomisation system was used. There were no baseline imbalances that would suggest a problem with randomisation. |
Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 7 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 5.5% of those who received treatment were lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. An independent blinded assessment was conducted. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00631371 MSKCC favourable risk groups |
Low risk of bias | A computerized centrally located randomisation system was used. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. |
Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 7 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 5.5% of those who received treatment were lost to follow‐up. Unclear how many of these were assigned to the favourable risk group. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. An independent blinded assessment was conducted. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00631371 MSKCC intermediate risk groups |
Low risk of bias | A computerized centrally located randomisation system was used. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. |
Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 7 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 5.5% of those who received treatment were lost to follow‐up. Unclear how many of these were assigned to the intermediate risk group. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. An independent blinded assessment was conducted. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT00631371 MSKCC poor risk groups |
Low risk of bias | A computerized centrally located randomisation system was used. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. |
Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 7 participants randomised to the experimental arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 5.5% of those who received treatment were lost to follow‐up. Unclear how many of these were assigned to the poor risk group. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. An independent blinded assessment was conducted. | Some concerns | No study protocol or SAP available. | Some concerns | Overall judged some concerns due to missing study protocol and SAP. | |||||||||||
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NCT01835158 Total trial population (only intermediate and poor risk groups included in the trial) |
Low risk of bias | Randomszation was performed centrally. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the experimental arm and 6 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 4.5% did not receive the intended interventions and therefore did not have outcome data. 16% of those who received treatment had missing radiographic images or were unevaluable for tumour response assessments, but there is evidence that the result was not biased by missing outcome data. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent radiology review committee. | Some concerns | Study protocol available with some statistical considerations briefly described, but no separate SAP available to fully check the pre‐planned analyses. | Some concerns | Overall judged some concerns due to missing SAP. | |||||||||||
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NCT01835158 IMDC intermediate risk group |
Low risk of bias | Randomisation was performed centrally. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the experimental arm and 6 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 4.5% did not receive the intended interventions and therefore did not have outcome data. 16% of those who received treatment had missing radiographic images or were unevaluable for tumour response assessments, but there is evidence that the result was not biased by missing outcome data. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent radiology review committee. | Some concerns | Study protocol available with some statistical considerations briefly described, but no separate SAP available to fully check the pre‐planned analyses. | Some concerns | Overall judged some concerns due to missing SAP. | |||||||||||
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NCT01835158 IMDC poor risk group |
Low risk of bias | Randomisation was performed centrally. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the experimental arm and 6 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 4.5% did not receive the intended interventions and therefore did not have outcome data. 16% of those who received treatment had missing radiographic images or were unevaluable for tumour response assessments, but there is evidence that the result was not biased by missing outcome data. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent radiology review committee. | Some concerns | Study protocol available with some statistical considerations briefly described, but no separate SAP available to fully check the pre‐planned analyses. | Some concerns | Overall judged some concerns due to missing SAP. | |||||||||||
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NCT02231749 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 11 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 1.3% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | No information whether the independent radiological review committee was blinded. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | Study protocol and SAP available. Final revisions of both done before data cutoff (with extended follow‐up). Analyses were preplanned and reported. | High risk of bias | Overall judged high risk of bias due to lack of information about the outcome assessor and blinding to outcome assessment. | |||||||||||
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NCT02231749 IMDC favourable risk group |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 11 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 1.3% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome | High risk of bias | No information whether the independent radiological review committee. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | Study protocol and SAP available. Final revisions of both done before data cutoff (with extended follow‐up). Analyses were preplanned and reported. | High risk of bias | Overall judged high risk of bias due to lack of information about the outcome assessor and blinding to outcome assessment. | |||||||||||
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NCT02231749 IMDC intermediate and poor risk groups combined |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 11 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 1.3% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome | High risk of bias | No information whether the independent radiological review committee. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | Study protocol and SAP available. Final revisions of both done before data cutoff (with extended follow‐up). Analyses were preplanned and reported. | High risk of bias | Overall judged high risk of bias due to lack of information about the outcome assessor and blinding to outcome assessment. |
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NCT00720941 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice response system was used for randomszation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 5 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 2.9% of those who received treatment were lost to follow‐up. However, these numbers are small and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. PFS was assessed by a blinded independent review committee. | Low risk of bias | CSR and study protocol with SAP available. All reported analyses were pre‐specified in the protocol and SAP. | Low risk of bias | Overall judged low risk of bias. | |||||||||||
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NCT01984242 Comparison 1 (ATE vs. SUN) Total trial population (combined risk groups) |
Low risk of bias | Interactive voice/web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 0.3% did not receive the intended interventions and therefore did not have outcome data. 1.5% of those who received treatment were lost to follow‐up. These numbers are very low and probably did not have an effect on the outcome. | High risk of bias | No precise information provided about whether the outcome assessors were blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about blinding of outcome assessor; missing study protocol and SAP. | |||||||||||
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NCT01984242 Comparison 2 (ATE+BEV vs. SUN) Total trial population (combined all risk groups) |
Low risk of bias | Interactive voice/web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 0.3% did not receive the intended interventions and therefore did not have outcome data. 3.5% of those who received treatment were lost to follow‐up. These numbers are very low and probably did not have an effect on the outcome. | High risk of bias | No precise information provided about whether the outcome assessors were blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about blinding of outcome assessor; missing study protocol and SAP. | |||||||||||
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NCT02420821 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 15 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 2% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | The investigators were the outcome assessors and they were not blinded to treatment allocation. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | Study protocol and SAP available. All reported analyses were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of blinding of the outcome assessors. | |||||||||||
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NCT02420821 MSKCC favourable risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 15 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 2% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. Unclear to which risk groups they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | No precise information provided about the outcome assessors. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | Study protocol and SAP available. All reported subgroup analyses were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of blinding of the outcome assessors. | |||||||||||
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NCT02420821 MSKCC intermediate risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 15 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 2% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. Unclear to which risk groups they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | No precise information provided about the outcome assessors. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | Study protocol and SAP available. All reported subgroup analyses were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of blinding of the outcome assessors. | |||||||||||
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NCT02420821 MSKCC poor risk group |
Low risk of bias | Interactive voice and web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 15 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | 2% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. Unclear to which risk groups they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | No precise information provided about the outcome assessors. Knowledge of intervention received could have affected outcome measurement. | Low risk of bias | Study protocol and SAP available. All reported subgroup analyses were pre‐specified in the protocol and SAP. | High risk of bias | Overall judged high risk of bias due to lack of blinding of the outcome assessors. | |||||||||||
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NCT02684006 IMDC favourable risk group |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 5 participants randomised to the experimental arm and 1 participant randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants randomised to the experimental arm and 5 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate. Participants without IMDC risk group allocation were excluded from the analysis. |
Some concerns | 1.5% did not receive the intended interventions and therefore did not have outcome data. No information about study flow for the second interim analysis (which is the result considered in this review). | Low risk of bias | Outcome assessors were not aware of the assigned intervention. A blinded independent central review was conducted. | High risk of bias | Study protocol and SAP available but discrepancies were found between statements in the publications and the SAP about the pre‐specification of subgroup analyses. Also the time point that produced this result was not pre‐specified in the protocol (final PFS analysis was already reported). | High risk of bias | Overall judged high risk of bias due to lack of information about potential losses of follow‐up; lack of information about the subgroup analyses in the study protocol and SAP. | |||||||||||
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NCT02684006 IMDC intermediate risk group |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 5 participants randomised to the experimental arm and 1 participant randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants randomised to the experimental arm and 5 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate. Participants without IMDC risk group allocation were excluded from subgroup analyses. |
Some concerns | 1.5% did not receive the intended interventions and therefore did not have outcome data. No information about study flow for the second interim analysis (which is the result considered in this review). | Low risk of bias | Outcome assessors were not aware of the assigned intervention. A blinded independent central review was conducted. | High risk of bias | Study protocol and SAP available but discrepancies were found between statements in the publications and the SAP about the pre‐specification of subgroup analyses. Also the time point that produced this result was not pre‐specified in the protocol (final PFS analysis was already reported). | High risk of bias | Overall judged high risk of bias due to lack of information about potential losses of follow‐up; lack of information about the subgroup analyses in the study protocol and SAP. | |||||||||||
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NCT02684006 IMDC poor risk group |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. IMDC risk group was not available for 5 participants randomised to the experimental arm and 1 participant randomised to the control arm. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants randomised to the experimental arm and 5 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate. Participants without IMDC risk group allocation were excluded from subgroup analyses. |
Some concerns | 1.5% did not receive the intended interventions and therefore did not have outcome data. No information about study flow for the second interim analysis (which is the result considered in this review). | Low risk of bias | Outcome assessors were not aware of the assigned intervention. A blinded independent central review was conducted. | High risk of bias | Study protocol and SAP available but discrepancies were found between statements in the publications and the SAP about the pre‐specification of subgroup analyses. Also the time point that produced this result was not pre‐specified in the protocol (final PFS analysis was already reported). | High risk of bias | Overall judged high risk of bias due to lack of information about potential losses of follow‐up; lack of information about the subgroup analyses in the study protocol and SAP. | |||||||||||
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NCT02853331 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice response system or integrated web response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 4 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. No indication of loss to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | Low risk of bias | Outcome assessors were not aware of the assigned intervention. A blinded independent central review was conducted. | High risk of bias | Final PFS analysis was already reported in a previous publication. The timing of analysis (which is the time point for the final OS analysis) for this numerical result of PFS was not pre‐specified in the protocol. | High risk of bias | Overall judged high risk of bias due to the analysis time point not being pre‐specified. | |||||||||||
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NCT00719264 Total trial population (combined risk groups) |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about who conducted the randomisation and whether the allocation was concealed There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 1 participant randomised to the experimental arm and 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate. | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. Less than 1% of those who received treatment were lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | No information provided about whether the outcome assessors were blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about the randomisation and allocation concealment; the outcome assessors’ probable awareness of the assigned interventions; missing study protocol and SAP. | |||||||||||
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NCT00420888 Total trial population (only favourable and intermediate risk groups included in the trial) |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about who conducted randomisation and whether allocation was concealed. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants did not receive any treatment. The method of analysis was appropriate (ITT). |
High risk of bias | 1.5% did not receive the assigned interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. | High risk of bias | No precise information provided about the outcome assessors (including lack of information about blinding). Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about randomisation process and allocation concealment; missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00420888 MSKCC favourable risk group |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about who conducted randomisation and whether allocation was concealed. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants did not receive any treatment. The method of analysis was appropriate (ITT). |
High risk of bias | 1.5% did not receive the assigned interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. | High risk of bias | No precise information provided about the outcome assessors (including lack of information about blinding). Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about randomisation process and allocation concealment; missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00420888 MSKCC intermediate risk group |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about who conducted randomisation and whether allocation was concealed. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants did not receive any treatment. The method of analysis was appropriate (ITT). |
High risk of bias | 1.5% did not receive the assigned interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. | High risk of bias | No precise information provided about the outcome assessors (including lack of information about blinding). Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about randomisation process and allocation concealment; missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00420888 IMDC favourable risk group |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. HENG risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants did not receive any treatment. The method of analysis was appropriate (ITT). |
High risk of bias | 1.5% did not receive the assigned interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. | High risk of bias | No precise information provided about the outcome assessors (including lack of information about blinding). Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about randomisation process and allocation concealment; missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00420888 IMDC intermediate risk group |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. HENG risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants did not receive any treatment. The method of analysis was appropriate (ITT). |
High risk of bias | 1.5% did not receive the assigned interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. | High risk of bias | No precise information provided about the outcome assessors (including lack of information about blinding). Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about randomisation process and allocation concealment; missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00420888 IMDC poor risk group |
Some concerns | Participants were randomised in a 1:1 ratio, but no information provided about allocation concealment. There were no baseline imbalances that would suggest a problem with randomisation. HENG risk group was available for all randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 8 participants did not receive any treatment. The method of analysis was appropriate (ITT). |
High risk of bias | 1.5% did not receive the assigned interventions and therefore did not have outcome data. No information whether there was loss to follow‐up. | High risk of bias | No precise information provided about the outcome assessors (including lack of information about blinding). Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about randomisation process and allocation concealment; missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT00979966 Total trial population (combined risk groups) |
High risk of bias | Participants were randomised in a 1:1 ratio, but no information provided about who conducted randomisation and whether allocation was concealed. There were baseline imbalances that could suggest a problem with randomisation. Small study population. | High risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. No information whether there were deviations form intended interventions and no information provided about the method of analysis. | High risk of bias | No information about loss to follow‐up. | High risk of bias | No precise information provided about who assessed the outcome and whether they were blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to lack of information about the randomisation, the allocation concealment, the deviations from intended interventions, the method of analysis and missing outcome data; the outcome assessors’ probable awareness of the assigned interventions; missing study protocol and SAP. | |||||||||||
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NCT00903175 Total trial population (combined risk groups) |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 1 participant randomised to the control arm was lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention. Knowledge of intervention received could have affected outcome measurement. | Some concerns | Study protocol available with some statistical methods described, but no separate SAP available to fully check the pre‐planned analyses. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ awareness of the assigned intervention; missing SAP. | |||||||||||
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NCT00903175 MSKCC favourable risk group |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 2 randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 1 participant randomised to the control arm was lost to follow‐up. Unclear to which risk group they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention. Knowledge of intervention received could have affected outcome measurement. | Some concerns | Study protocol available with some statistical methods described, but no separate SAP available to fully check the pre‐planned analyses.. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ awareness of the assigned intervention; missing SAP. | |||||||||||
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NCT00903175 MSKCC intermediate risk group |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 2 randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 1 participant randomised to the control arm was lost to follow‐up. Unclear to which risk groups they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention. Knowledge of intervention received could have affected outcome measurement. | Some concerns | Study protocol available with some statistical methods described, but no separate SAP available to fully check the pre‐planned analyses. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ awareness of the assigned intervention; missing SAP. | |||||||||||
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NCT00903175 MSKCC poor risk group |
Low risk of bias | Interactive voice response system was used for randomisation. There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was not available for 2 randomised participants. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). Participants without MSKCC risk group allocation were excluded from subgroup analyses. | Low risk of bias | Less than 1% did not receive the intended interventions and therefore did not have outcome data. 1 participant randomised to the control arm was lost to follow‐up. Unclear to which risk groups they were assigned to. However, these numbers are low and probably did not have an effect on the outcome. | High risk of bias | Outcome assessors were aware of the assigned intervention. Knowledge of intervention received could have affected outcome measurement. | Some concerns | Study protocol available with some statistical methods described, but no separate SAP available to fully check the pre‐planned analyses.. | High risk of bias | Overall judged high risk of bias due to the outcome assessors’ awareness of the assigned intervention; missing SAP. | |||||||||||
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NCT01481870 Total trial population (only favourable and intermediate risk groups included) |
Low risk of bias | Participants were randomised in a 1:1 ratio. The assignment was obtained at enrolment by the investigator via the Internet. There were no baseline imbalances that would suggest a problem with randomisation. |
Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 1 participant randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 3.2% did not receive the intended interventions and therefore did not have outcome data. 22% of those who received treatment did not have outcome data. | High risk of bias | No information provided about who assessed the outcome and whether they were blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to high number of participants with missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT01481870 MSKCC favourable risk group |
Low risk of bias | Participants were randomised in a 1:1 ratio. The assignment was obtained at enrolment by the investigator via the Internet There were no baseline imbalances that would suggest a problem with randomisation. MSKCC risk group was available for all randomised participants. |
Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 3 participants randomised to the experimental arm and 1 participant randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). | High risk of bias | 3.2% did not receive the intended interventions and therefore did not have outcome data. 22% of those who received treatment did not have outcome data. | High risk of bias | No information provided about who assessed the outcome and whether they were blinded. Knowledge of intervention received could have affected outcome measurement. | Some concerns | No study protocol or SAP available. | High risk of bias | Overall judged high risk of bias due to high number of participants with missing outcome data; the outcome assessors’ probable awareness of the assigned intervention; missing study protocol and SAP. | |||||||||||
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NCT02761057 Comparison 1 (CAB vs. SUN) Total trial population (combined risk groups) |
Low risk of bias | The randomisation was done by the Study Center. There were no baseline imbalances that would suggest a problem with randomisation. | Low risk of bias | The study was open‐label: both participants and those delivering the intervention were aware of assigned interventions. Only 2 participants randomised to the experimental arm and 2 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate (ITT). |
Low risk of bias | 4.3% did not receive the intended interventions and therefore did not have outcome data. 2.2% had no protocol treatment. Only 1 participant was lost to follow‐up. However, these numbers are low and probably did not have an effect on the outcome. |
High risk of bias | No precise information provided about method of measuring PFS. Outcome assessors were aware of the assigned intervention. Knowledge of intervention received could have affected outcome measurement. |
Some concerns | Study protocol available, but no original SAP. | High risk of bias | Overall judged high risk of bias due to lack of information about method of outcome measurement; the outcome assessors’ awareness of the assigned intervention; missing SAP. | |||||||||||
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