Note: The risk of bias by domain corresponds to the highest risk of bias among outcomes by domain.
The overall risk of bias corresponds to the overall highest risk of bias assessed among outcomes.
| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: "Allocation of participants to treatment groups will proceed through the use of an IRT system (IWR). The site personnel (study coordinator or specified designee) will be required to enter or select information including but not limited to the user’s ID and password, the protocol number, and the participant number. The site personnel will then be provided with a treatment assignment, randomization number, and DU or container number when study intervention is being supplied via the IRT system. The IRT system will provide a confirmation report containing the participant number, randomization number, and DU or container number assigned. The confirmation report must be stored in the site’s files"
Comment: Allocation sequence random Allocation sequence concealed |
| Deviations from intervention |
Low |
Quote: "phase 2–3 double-blind, randomized, controlled trial"
Comment: Blinded study (participants and personnel/carers) Our analysis for the binary outcome is an intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low or the outcomes: Mortality (D28). Hospitalization or death. Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 2246 participants randomized; 2246 analyzed for safety, 2224 analyzed for efficacy, and 2246 analyzed for mortality.
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 67 vs 77 discontinued trial (43 vs 43 withdrew, 11 vs 9 were lost to follow up, 13 vs 12 had other reasons and 13 participants died (placebo group). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome. Risk assessed to be some concerns for the outcomes: Hospitalization or death. Mortality (D28). Adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Hospitalization or death. Mortality (D28). Adverse events. Serious adverse events |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, registry (submitted 10th July 2021) were available (16th February 2022).
Outcome pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcome: Hospitalization or death. Mortality (D28).Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |