Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.

Criteria for a judgement of 'Low risk' of bias.

The investigators described a random component in the sequence generation process such as:

• referring to a random number table;

• using a computer random number generator;

• coin tossing;

• shuffling cards or envelopes;

• throwing dice;

• drawing of lots;

• minimisation.*

*Minimisation may be implemented without a random element, and this is considered to be equivalent to being random.

Criteria for the judgement of 'High risk' of bias.

The investigators described a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, e.g.:

• sequence generated by odd or even date of birth;

• sequence generated by some rule based on date (or day) of admission;

• sequence generated by some rule based on hospital or clinic record number.

Other non‐random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of non‐random categorisation of participants, e.g.:

• allocation by judgement of the clinician;

• allocation by preference of the participant;

• allocation based on the results of a laboratory test or a series of tests;

• allocation by availability of the intervention.

Criteria for the judgement of 'Unclear risk' of bias.

Insufficient information about the sequence generation process to permit judgement of 'Low risk' or 'High risk.'

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.

Criteria for a judgement of 'Low risk' of bias.

Participants and investigators enrolling participants could not have foreseen assignment because 1 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.

Criteria for the judgement of 'High risk' of bias.

Participants or investigators enrolling participants could possibly have foreseen assignments and thus introduced selection bias, such as allocation based on:

• using an open random allocation schedule (e.g. a list of random numbers);

• assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or not sequentially numbered);

• alternation or rotation;

• date of birth;

• case record number;

• any other explicitly unconcealed procedure.

Criteria for the judgement of 'Unclear risk' of bias.

Insufficient information to permit judgement of 'Low risk' or 'High risk.' This is usually the case if the method of concealment was not described or not described in sufficient detail to allow a definite judgement; e.g. if the use of assignment envelopes was described, but it remained unclear whether envelopes were sequentially numbered, opaque and sealed.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.

Criteria for a judgement of 'Low risk' of bias.

Any 1 of the following:

• no blinding or incomplete blinding, but the review authors judged that the outcome was 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.

Criteria for the judgement of 'High risk' of bias.

Any 1 of the following:

• no blinding or incomplete blinding, and the outcome was 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 was likely to be influenced by lack of blinding.

Criteria for the judgement of 'Unclear risk' of bias.

Any 1 of the following:

• insufficient information to permit judgement of 'Low risk' or 'High risk;'

• study did not address this outcome.

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Criteria for a judgement of 'Low risk' of bias.

Any 1 of the following:

• no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding;

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

Criteria for the judgement of 'High risk' of bias.

Any 1 of the following:

• no blinding of outcome assessment, and the outcome measurement was 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 was likely to be influenced by lack of blinding.

Criteria for the judgement of 'Unclear risk' of bias.

Any 1 of the following:

• insufficient information to permit judgement of 'Low risk' or 'High risk;'

• study did not address this outcome.

Incomplete outcome data

Attrition bias due to amount, nature, or handling of incomplete outcome data.

Criteria for a judgement of 'Low risk' of bias.

Any 1 of the following:

• 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 were imputed using appropriate methods.

Criteria for the judgement of 'High risk' of bias.

Any 1 of the following:

• reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention 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;

• potentially inappropriate application of simple imputation.

Criteria for the judgement of 'Unclear risk' of bias.

Any 1 of the following:

• 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);

• study did not address this outcome.

Selective reporting

Reporting bias due to selective outcome reporting.

Criteria for a judgement of 'Low risk' of bias.

Any of the following:

• study protocol was available and all of the study's prespecified (primary and secondary) outcomes that were of interest in the review were reported in the prespecified way;

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

Criteria for the judgement of 'High risk' of bias.

Any 1 of the following:

• not all of the study's prespecified primary outcomes were reported;

• ≥ 1 primary outcomes weres reported using measurements, analysis methods, or subsets of data (e.g. subscales) that were not prespecified;

• ≥ 1 reported primary outcomes were not prespecified (unless clear justification for their reporting was provided, such as an unexpected adverse effect);

• ≥ 1 outcomes of interest in the review were reported incompletely so that they could not be entered in a meta‐analysis;

• study report did not include results for a key outcome that would be expected to have been reported for such a study.

Criteria for the judgement of 'Unclear risk' of bias.

Insufficient information to permit judgement of 'Low risk' or 'High risk.' It is likely that the majority of studies will fall into this category.

Other bias

Bias due to problems not covered elsewhere in the table.

Criteria for a judgement of 'Low risk' of bias.

Study appeared to be free of other sources of bias.

Criteria for the judgement of 'High risk' of bias.

There was ≥ 1 important risk of bias; e.g. the study:

• had a potential source of bias related to the specific study design used; or

• was claimed to have been fraudulent; or

• had some other problem.

Criteria for the judgement of 'Unclear risk' of bias.

There may be a risk of bias, but there was either:

• insufficient information to assess whether an important risk of bias existed; or

• insufficient rationale or evidence that an identified problem would introduce bias.