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: “The randomization was stratified by country, with a block size of 4 within each stratum. It was implemented using an inter-active response technology system in which a new patient meeting the inclusion and exclusion criteria was randomly assigned to a treatment group based on a random allocation sequence. This sequence was created by a separate randomization office of the sponsor and kept blinded to the study team until the scheduled unblinding for data analysis.”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: “Randomized, double-blind, placebo-controlled phase 3 trial”
Comment: Blinded study (participants and personnel/carers) MORTALITY, (TIME TO) CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Data for the outcome were analyzed using 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). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO DEATH, TIME TO WHO SCORE 7 AND ABOVE Participants were analyzed according to their randomized groups for the outcome. Of note, 0 vs 3 participants were excluded from the analysis post-randomization because they were randomized in error (did not meet eligibility criteria). This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcomes: Time to death. Time to WHO score 7 and above. |
| Missing outcome data |
Low |
Comment: 454 participants randomized; 448 participants analyzed for safety; 451 to 454 participants analyzed for efficacy.
Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. 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). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and registry (NCT and EudraCT: April 15 & 27, 2020) were available.
Outcomes 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). Time to death. Clinical improvement (D28). Time to Clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Overall risk of bias |
Low |