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[BB1]

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

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 randomisation.

High 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 not appropriate (as‐treated).

Low risk of bias

2.8% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

High risk of bias

Measurement of SAEs could have differed between intervention groups due to longer follow‐up of the intervention arm.

Low risk of bias

A study protocol with SAP available. Safety analysis was pre‐specified in the protocol and SAP.

High risk of bias

Overall judged high risk of bias due to inappropriate method of analysis; probable differences in outcome measurement between intervention arms.

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.

High 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 not appropriate (as‐treated).

Low risk of bias

2.7% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Low risk of bias

Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Low risk of bias

A study protocol with SAP available. Safety analysis was pre‐specified in the protocol and SAP.

High risk of bias

Overall judged high risk of bias due to inappropriate method of analysis.

NCT00065468 Comparison 1 (TEM+IFN) Total trial population (only intermediate and poor risk groups included in the trial)

Some concerns

Participants were randomised, 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. Only 1 participant randomised to the single‐drug arm and 7 participants randomised to the control arm did not receive any treatment. No precise information provided about the method of analysis (as‐treated is indicated).

Low risk of bias

1.9% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about allocation concealment, method of analysis and method of outcome measurement; missing study protocol and SAP.

NCT00065468 comparison 2 Comparison 2 (IFN+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 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. Only 2 participants randomised to the combination arm and 7 participants randomised to the control arm did not receive any treatment. No precise information provided about the method of analysis (as‐treated is indicated).

Low risk of bias

2.2% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about allocation concealment, method of analysis and method of outcome measurement; missing study protocol and SAP.

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.

High 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. No precise information provided about the method of analysis.

Low risk of bias

3% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about method of analysis and method of outcome measurement; missing study protocol and SAP.

NCT01835158 Total trial population (only intermediate and poor risk groups included in the trial)

Low risk of bias

Randomisation was performed centrally. 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. Only 1 participant randomised to the experimental arm and 6 participants randomised to the control arm did not receive any treatment. No precise information provided about the method of analysis.

Low risk of bias

4.5% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Low risk of bias

Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

Study protocol available with some statistical considerations briefly 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 lack of information about the method of analysis; missing SAP.

NCT01984242 Comparison 1 (ATE vs. SUN) Total 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. No precise information provided about the method of analysis, but data for crossed‐over participants were reported separately. We assume participants were analysed as randomised in period 1.

Low risk of bias

0.3% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are very low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

Some concerns

Overall judged some concerns due to lack of information about method of outcome measurement; missing study protocol and SAP.

NCT01984242 Comparison 2 (ATE+BEV 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. No precise information provided about the method of analysis, but data for crossed‐over participants were reported separately. We assume participants were analysed as randomised in period 1.

Low risk of bias

0.3% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are very low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

Some concerns

Overall judged some concerns due to lack of information about method of outcome measurement; missing study protocol and SAP.

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.

High 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; 1 participant randomised to the experimental arm had no post baseline safety assessment. No precise information provided about the method of analysis.

Low risk of bias

1.1% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

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, allocation concealment, method of analysis and method of outcome measurement; missing study protocol and SAP.

NCT00720941 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.

Some concerns

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 not appropriate (as‐treated), but this probably did not have an effect on the outcome as there is evidence that participants actually received the assigned intervention.

Low risk of bias

Less than 1% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are small and probably did not have an effect on the outcome.

Low risk of bias

Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Low risk of bias

CSR and study protocol with SAP available. Safety analysis was pre‐specified in the protocol and SAP.

Some concerns

Overall judged some concerns due to inappropriate method of analysis.

NCT00732914 Total trial population (combined risk groups)

Low risk of bias

Randomisation 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. No precise information provided about the method of analysis, but data for first period reported separately. We assume participants in first period received their allocated intervention.

Low risk of bias

3.3% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

High risk of bias

No information provided about outcome assessors and method of measuring SAEs.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about outcome assessors and method of outcome measurement; missing study protocol and SAP.

NCT01613846 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 6 participants randomised to the one experimental arm and 5 participants randomised to the control arm did not receive any treatment. The method of analysis was appropriate.

Low risk of bias

2.9% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

High risk of bias

No information provided about outcome assessors and method of measuring SAEs.

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, allocation concealment, outcome assessors and method of outcome measurement; missing study protocol and SAP.

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.

High risk of bias

The study was double‐blind: both participants and those delivering the intervention were not aware of assigned interventions. Only 2 participants from the control arm and 6 participants from the intervention arm did not receive any treatment. The method of analysis was not appropriate (as‐treated).

Low risk of bias

1.2% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs and outcome assessors. However, we assume SAEs were assessed by the investigators and this was a double‐blind study. Furthermore, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to inappropriate method of analysis; lack of information about method of outcome measurement; missing study protocol and SAP.

NCT00117637 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. No precise information provided about the method of analysis, but data for crossed‐over participants were reported separately. We assume participants were analysed as randomised in period 1.

Low risk of bias

No indication of loss to follow‐up.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

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 outcome measurement; baseline imbalances; missing study protocol and SAP.

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.

High risk of bias

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. No precise information provided about the method of analysis.

Low risk of bias

2% did not receive the intended interventions and therefore did not have outcome data.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

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, allocation concealment, method of analysis and method of outcome measurement; missing study protocol and SAP.

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.

High 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. No precise information provided about the method of analysis.

Low risk of bias

All 108 participants were evaluable.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about method of analysis and method of outcome measurement; missing study protocol and SAP.

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. No precise information provided about the method of analysis, but data for crossed‐over participants were reported separately. We assume participants were analysed as randomised in period 1.

Low risk of bias

Less than 1% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Low risk of bias

Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

Study protocol available with some statistical methods described, but no separate SAP available to fully check the pre‐planned analyses.

Some concerns

Overall judged some concerns due to missing SAP.

NCT00619268 Comparison 1 (BEV+TEM vs. SUN) Total trial population (combined risk groups)

Low risk of bias

A computerised centrally located randomisation system was Used. 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 intervention. Only 1 participant randomised to the control arm did not receive any treatment. No precise information provided about the method of analysis.

Low risk of bias

Only 1 participant did not receive the intended intervention and therefore did not have outcome data.

High risk of bias

No information provided about outcome assessors and method of measuring SAEs.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about method of analysis, outcome assessors and method of outcome measurement; missing study protocol and SAP.

NCT00619268 Comparison 2 (BEV+IFN vs. SUN) Total trial population (combined risk groups)

Low risk of bias

A computerised centrally located randomisation system was Used. 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 intervention. Only 1 participant randomised to the control arm did not receive any treatment. No precise information provided about the method of analysis.

Low risk of bias

Only 1 participant did not receive the intended intervention and therefore did not have outcome data.

High risk of bias

No information provided about outcome assessors and method of measuring SAEs.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about method of analysis, outcome assessors and method of outcome measurement; missing study protocol and SAP.

NCT00631371 Total trial population (combined risk groups)

Low risk of bias

A computerised centrally located randomisation system was used. 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. Only 7 participants randomised to the experimental arm did not receive any treatment. No precise information provided about the method of analysis.

Low risk of bias

Less than 1% did not receive the intended interventions and therefore, did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

High risk of bias

Overall judged high risk of bias due to lack of information about method of analysis; missing study protocol and SAP.

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.

High 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. No precise information provided about the method of analysis.

Low risk of bias

1.3% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are very low and probably did not have an effect on the outcome.

Low risk of bias

Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Low risk of bias

A study protocol with SAP available. Safety analysis was pre‐specified in the protocol and SAP.

High risk of bias

Overall judged high risk of bias due to lack of information about method of analysis.

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.

High 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. Conflicting information about method of analysis in the protocol.

Low risk of bias

2% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Low risk of bias

Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Low risk of bias

A study protocol with SAP available. Safety analysis was pre‐specified in the protocol and SAP.

High risk of bias

Overall judged high risk of bias due to conflicting information about method of analysis.

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.

Low risk of bias

Less than 1% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Low risk of bias

Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Low risk of bias

A study protocol with SAP available. Safety analysis was pre‐specified in the protocol and SAP.

Low risk of bias

Overall judged low risk of bias.

NCT00920816 Total trial population (combined risk groups)

Low risk of bias

A centralised 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. No precise information provided about the method of analysis, but data for first period reported separately. We assume participants in first period received their allocated intervention.

Low risk of bias

1% did not receive the intended interventions and therefore did not have outcome data. However, these numbers are low and probably did not have an effect on the outcome.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

Some concerns

Overall judged some concerns due to lack of information about method of outcome measurement; missing study protocol and SAP.

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.

Low risk of bias

No indication of loss to follow‐up.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

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, allocation concealment, deviations from intended interventions, method of analysis and method of outcome measurement; baseline imbalances; missing study protocol and SAP.

NCT00126594 Total trial population (combined risk groups)

Some concerns

No information provided about randomisation process and 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. The method of analysis was appropriate.

Low risk of bias

No indication of loss to follow‐up.

Some concerns

No information provided about method of measuring SAEs. Outcome assessors were not blinded. However, a standardised definition of SAEs was used and included objective outcome events.

Some concerns

No study protocol or SAP available.

Some concerns

Overall judged some concerns due to lack of information about randomisation process, allocation concealment, method of outcome measurement; missing study protocol and SAP.