Item

Judgement

Description

1

Random sequence generation (selection bias)

Low risk

The investigators describe a random component in the sequence generation process such as: random‐number table; computer random‐number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation

High risk

The investigators describe a non‐random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; preference of the participant; results of a laboratory test or a series of tests; availability of the intervention

Unclear risk

Insufficient information about the sequence generation process to permit judgement of ‘Low risk’ or ‘High risk’

2

Allocation concealment (selection bias)

Low risk

Investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web‐based, and pharmacy‐controlled randomisation); sequentially‐numbered drug containers of identical appearance; sequentially‐numbered, opaque, sealed envelopes

High risk

Investigators enrolling participants could possibly foresee assignments and thus introduce selection bias because one of the following methods was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure

Unclear risk

Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement

3

Blinding of participants and providers (performance bias)

Objective outcomes

Low risk

No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

High risk

No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; the study did not address this outcome

4

Blinding of participants and providers (performance bias)

Subjective outcomes

Low risk

Blinding of participants and providers ensured, and unlikely that the blinding could have been broken

High risk

No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; the study did not address this outcome

5

Blinding of outcome assessor (detection bias)

Objective outcomes

Low risk

No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

High risk

No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; the study did not address this outcome

6

Blinding of outcome assessor (detection bias)

Subjective outcomes

Low risk

Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

High risk

No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

Unclear risk

Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; the study did not address this outcome

7

Incomplete outcome data (attrition bias)

For all outcomes except retention in treatment

Low risk

No missing outcome data;

Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias);

Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups;

For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate;

For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size;

Missing data have been imputed using appropriate methods;

All randomised participants are reported/analysed in the group they were allocated to by randomisation, irrespective of noncompliance and co‐interventions (intention‐to‐treat)

High risk

Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across interventions groups;

For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size;

‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation

Unclear risk

Insufficient reporting of attrition/exclusions to permit judgement of ‘Low risk’ or ‘High risk’ (e.g. number randomised not stated, no reasons for missing data provided; the study did not address this outcome)

8

Selective reporting (reporting bias)

Low risk

The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way;

The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon)

High risk

Not all of the study’s prespecified primary outcomes have been reported; One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not prespecified; one or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study

Unclear risk

Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’

9

Other sources of bias

Low risk

The study appears to be free of other sources of bias

High risk

There is at least one important risk of bias. For example, the study: had a potential source of bias related to the specific study design used; or has been claimed to have been fraudulent; or had some other problem

Unclear risk

There may be a risk of bias, but there is either: insufficient information to assess whether an important risk of bias exists; or insufficient rationale or evidence that an identified problem will introduce bias