1. Sequence generation (checking for possible selection bias)

Was the allocation sequence adequately generated?

For each included study, we will categorize the method used to generate the allocation sequence as either at:

• low risk (any truly random process, e.g. random number table; computer random number generator);

• high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);

• unclear risk.

2. Allocation concealment (checking for possible selection bias)

Was allocation adequately concealed?

For each included study, we will categorize the method used to conceal the allocation sequence as either at:

• low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

• unclear risk.

3. Blinding of participants and personnel (checking for possible performance bias)

Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we will categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes. We will categorize the methods as either at:

• low risk for participants or personnel;

• high risk for participants or personnel;

• unclear risk for participants or personnel.

4. Blinding of outcome assessment (checking for possible detection bias)

Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we will categorize the methods used to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes. We categorized the methods as at:

• low risk for outcome assessors;

• high risk for outcome assessors;

• unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether the study authors reported attrition and exclusions, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where the study authors report or supply sufficient information, we will include missing data in the analyses. We will categorize the methods as either at:

• low risk (< 20% missing data);

• high risk (≥ 20% missing data);

• unclear risk.

6. Selective reporting bias

Are reports of the study free of suggestion of selective outcome reporting?

For each included study, we will describe how we investigate the possibility of selective outcome reporting bias and what we find. We will assess the methods as either at:

• low risk (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

• high risk (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

• unclear risk.

7. Other sources of bias

Was the study apparently free of other problems that could put it at a high risk of bias?

For each included study, we will describe any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We will assess whether each study was free of other problems that could put it at risk of bias as at:

• low risk;

• high risk;

• unclear risk.

If needed, we will explore the impact of the level of bias through undertaking sensitivity analyses.