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: "We performed permuted block randomisation with a block size of 2 or 4 using an Interactive Response Technology system (ClinPhone RTSM; version 4.0), and stratification according to site... The active treatment and placebo were identical in colour and appearance."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: "double-blind" trial.
Comment: Blinded study (participants and personnel/carers). MORTALITY, CLINICAL IMPROVEMENT, ADVERSE AND SERIOUS ADVERSE EVENTS Our analysis for the 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 for the outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). Adverse events. Serious adverse events. TIME TO DEATH Participants were analyzed according to their randomized groups for the outcome. Of note, 1 vs 0 participants were excluded from the analysis post-randomization because they were randomly assigned in error. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably negligible impact of failure to analyze participants according to their randomized groups since this accounted for only 1/369 participants and a total of 149 participants died. Risk assessed to be low for the outcomes: Time to death. |
| Missing outcome data |
Some concerns |
Comment: 369 participants randomized; 368 participants analyzed.
Data not available for nearly all participants randomized. No evidence that the result is not biased. Reasons: 4 vs 1 lost to followup, 6 vs 5 withdrawn, 2 vs 4 transfered to another hospital, 1 emergency unmasking because of wish to breastfeed, and 1 randomly assigned in error (the latter participant was accounted for in domain 2 for time-to-death outcome). 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: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (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: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan, and prospective registry were available (dated April 3, 2020).
MORTALITY. CLINICAL IMPROVEMENT. ADVERSE AND SERIOUS ADVERSE EVENTS 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 outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). Adverse events. Serious adverse events. TIME TO DEATH Outcome not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Time to death. |
| Overall risk of bias |
Some concerns |