Table 2 RoB 2 guidelines on risk of bias assessment

Low risk of bias

 (i.) The allocation sequence was adequately concealed

AND

 (ii.1) any baseline differences observed between intervention groups appear to be compatible with chance

 OR

 (ii.2) there is no information about baseline imbalances

 AND

 (iii.1) the allocation sequence was random

 OR

 (iii.2) there is no information about whether the allocation sequence was random

Some concerns

 (i.1) The allocation sequence was adequately concealed

 AND

 (i.2.1) the allocation sequence was not random

 OR

 (i.2.2) baseline differences between intervention groups suggest a problem with the randomisation process

 OR

 (ii.1) there is no information about concealment of the allocation

 AND

 (ii.2) any baseline differences observed between intervention groups appear to be compatible with chance

 OR

 (iii) there is no information to answer any of the signalling questions

High risk of bias

 (i.) The allocation sequence was not adequately concealed

 OR

 (ii.1) there is no information about concealment of the allocation sequence

 AND

 (ii.2) baseline differences between intervention groups suggest a problem with the randomisation process

Low risk of bias

 (i.1) Participants, carers and people delivering the interventions were unaware of intervention groups during the trial

 OR

 (i.2.1) participants, carers or people delivering the interventions were aware of intervention groups

 AND

 (i.2.2) [if applicable] the important non-protocol interventions were balanced across intervention groups

 AND (ii) [if applicable] failures in implementing the intervention could not have affected the outcome

 AND

 (iii) [if applicable] study participants adhered to the assigned intervention regimen.

Some concerns

 (i.1.1) Participants, carers and people delivering the interventions were unaware of intervention groups during the trial

 AND

 (i.1.2.1) [if applicable] failures in implementing the intervention could have affected the outcome

 OR

 (i.1.2.2) [if applicable] study participants did not adhere to the assigned intervention regimen

 OR

 (i.2.1) participants, carers or people delivering the interventions were aware of intervention groups and (i.2.2) [if applicable] the important non-protocol interventions were balanced across intervention groups

 AND

 (i.2.3.1) [if applicable] failures in implementing the intervention could have affected the outcome

 OR

 (i.2.3.2) [if applicable] study participants did not adhere to the assigned intervention regimen

 OR

 (i.3.1) participants, carers or people delivering the interventions were aware of intervention groups

 AND

 (i.3.2) [if applicable] the important non-protocol interventions were not balanced across intervention groups

 AND

 (ii) an appropriate analysis was used to estimate the effect of adhering to intervention.

High risk of bias

 (i.1.1) Participants, carers and people delivering the interventions were unaware of intervention groups during the trial

 AND

 (i.1.2.1) [if applicable] failures in implementing the intervention could have affected the outcome

 OR

 (i.1.2.2) [if applicable] study participants did not adhere to the assigned intervention regimen

 OR

 (i.2.1) participants, carers or people delivering the interventions were aware of intervention groups

 AND

 (i.2.2) [if applicable] the important non-protocol interventions were balanced across intervention groups

 AND

 (i.2.3.1) [if applicable] failures in implementing the intervention could have affected the outcome

 OR

 (i.2.3.2) [if applicable] study participants did not adhere to the assigned intervention regimen

 OR

 (i.3.1) participants, carers or people delivering the interventions were aware of intervention groups

 AND

 (i.3.2) [if applicable] the important non-protocol interventions were not balanced across intervention groups

 AND

 (ii) an appropriate analysis was not used to estimate the effect of adhering to intervention

Low risk of bias

 (i.) Outcome data were available for all, or nearly all, randomised participants

 OR

 (ii.) there is evidence that the result was not biased by missing outcome data

 OR

 (iii) missingness in the outcome could not depend on its true value.

Some concerns

 (i.) Outcome data were not available for all, or nearly all, randomized participants

 AND

 (ii.) there is not evidence that the result was not biased by missing outcome data

 AND

 (iii.) missingness in the outcome could depend on its true value

 AND

 (iv) it is not likely that missingness in the outcome depended on its true value.

High risk of bias

 (i.) Outcome data were not available for all, or nearly all, randomized participants

 AND

 (ii.) there is not evidence that the result was not biased by missing outcome data

 AND

missingness in the outcome could depend on its true value

 AND

 (iv) it is likely that missingness in the outcome depended on its true value

Low risk of bias

 (i.) The method of measuring the outcome was not inappropriate

 AND

 (ii.) the measurement or ascertainment of the outcome did not differ between intervention groups

 AND

 (iii.1) the outcome assessors were unaware of the intervention received by study participants

 OR

 (iii.2) the assessment of the outcome could not have been influenced by knowledge of the intervention received.

Some concerns

 (i.1) The method of measuring the outcome was not inappropriate

 AND

 (i.2) the measurement or ascertainment of the outcome did not differ between intervention groups

 AND

 (i.3) the assessment of the outcome could have been influenced by knowledge of the intervention received

 AND

 (i.4) it is unlikely that assessment of the outcome was influenced by knowledge of intervention received

 OR

 (ii.1) the method of measuring the outcome was not inappropriate

 AND

 (ii.2) there is no information on whether the measurement or ascertainment of the outcome could have differed between intervention groups

 AND

 (ii.3.1) the outcome assessors were unaware of the intervention received by study participants

 OR

 (ii.3.2) the assessment of the outcome could not have been influenced by knowledge of the intervention received.

High risk of bias

 (i.) The method of measuring the outcome was inappropriate

 OR

 (ii.) the measurement or ascertainment of the outcome could have differed between intervention groups

 OR

 (iii) it is likely that assessment of the outcome was influenced by knowledge of the intervention received

Low risk of bias

(i.) The data were analysed in accordance with a pre-specified plan that was finalised before unblinded outcome data were available for analysis

 AND

 (ii) the result being assessed is unlikely to have been selected, on the basis of the results, from multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain

 AND

 (iii) reported outcome data are unlikely to have been selected, on the basis of the results, from multiple eligible analyses of the data

Some concerns

 (i.1) The data were not analysed in accordance with a pre-specified plan that was finalised before unblinded outcome data were available for analysis

 AND

 (i.2) the result being assessed is unlikely to have been selected, on the basis of t he results, from multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain

 AND

(i.3) the result being assessed is unlikely to have been selected, on the basis of the results, from multiple eligible analyses of the data

 OR

  (ii) there is no information on whether the result being assessed is likely to have been selected, on the basis of the results, from multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain and from multiple eligible analyses of the data.

High risk of bias

 (i.) The result being assessed is likely to have been selected, on the basis of the results, from multiple eligible outcome measurements (e.g. scales, definitions, time points) within the outcome domain

 OR

 (ii) the result being assessed is likely to have been selected, on the basis of the results, from multiple eligible analyses of the data