Domain

Description

Random sequence generation

• Low risk: if sequence generation was achieved using computer random number generator or a random numbers table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were also considered adequate if performed by an independent adjudicator.

• Unclear risk: if the method of randomisation was not specified, but the trial was still presented as being randomised.

• High risk: if the allocation sequence was not randomised or only quasi‐randomised. We will exclude these trials.

Allocation concealment

• Low risk: if the allocation of participants was performed by a central independent unit, on‐site locked computer, identical‐looking numbered sealed envelopes, drug bottles, or containers prepared by an independent pharmacist or investigator.

• Uncertain risk: if the trial was classified as randomised but the allocation concealment process was not described.

• High risk: if the allocation sequence was familiar to the investigators who assigned participants.

Blinding of participants and personnel

• Low risk: if the participants and the personnel were blinded to intervention allocation and this was described.

• Uncertain risk: if the procedure of blinding was insufficiently described.

• High risk: if blinding of participants and the personnel was not performed.

Blinding of outcome assessment

• Low risk of bias: if it was mentioned that outcome assessors were blinded and this was described.

• Uncertain risk of bias: if it was not mentioned if the outcome assessors in the trial were blinded, or the extent of blinding was insufficiently described.

• High risk of bias: if no blinding or incomplete blinding of outcome assessors was performed.

Incomplete outcome data

• Low risk of bias: if missing data were unlikely to make treatment effects depart from plausible values. This could either be: 1) there were no drop‐outs or withdrawals for all outcomes, or 2) the numbers and reasons for the withdrawals and drop‐outs for all outcomes were clearly stated and could be described as being similar in both groups. Generally, the trial is judged as at a low risk of bias due to incomplete outcome data if drop‐outs are less than 5%. However, the 5% cut‐off is not definitive.

• Uncertain risk of bias: if there was insufficient information to assess whether missing data were likely to induce bias on the results.

• High risk of bias: if the results were likely to be biased due to missing data either because the pattern of drop‐outs could be described as being different in the two intervention groups or the trial used improper methods in dealing with the missing data (e.g. last observation carried forward).

Selective outcome reporting

• Low risk of bias: if a protocol was published before or at the time the trial was begun and the outcomes specified in the protocol were reported on. If there is no protocol or the protocol was published after the trial has begun, reporting of all‐cause mortality and serious adverse events will grant the trial a grade of low risk of bias.

• Uncertain risk of bias: if no protocol was published and the outcomes all‐cause mortality and serious adverse events were not reported on.

• High risk of bias: if the outcomes in the protocol were not reported on.

Other risks of bias

• Low risk of bias: if the trial appears to be free of other components (for example, academic bias or for‐profit bias) that could put it at risk of bias.

• Unclear risk of bias: if the trial may or may not be free of other components that could put it at risk of bias.

• High risk of bias: if there are other factors in the trial that could put it at risk of bias (for example, authors have conducted trials on the same topic, for‐profit bias etc).

Overall risk of bias

• Low risk of bias: the trial will be classified as overall 'low risk of bias' only if all of the bias domains described in the above paragraphs are classified as 'low risk of bias'.

• High risk of bias: the outcome result will be classified 'high risk of bias' if any of the bias risk domains described in the above are classified as 'unclear' or 'high risk of bias'.