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: “Randomization was stratified by study site and disease severity (i.e., ordinal score 5 or 6) at enrollment and was performed using a web-based Internet Data Entry System. The treatment allocation table was generated using SAS version 9.4.”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: “Only the unmasked group at the Emmes company (Rockville, MA, USA; the statistical and data coordinating centre) and the site unmasked pharmacist were aware of treatment assignment. All other trial staff and participants were masked. Tablets and intravenous injections had identical appearance.”
Comment: Blinded study (participants and personnel/carers) Our analysis for the binary outcomes is an intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Of note, 13 vs 12 participants were excluded from the analysis post-randomization for the safety outcomes because they did not receive at least one dose of the intervention but this will be accounted for in domain 3. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). WHO score 7 and above (D28). Adverse events and Serious adverse events. |
| Missing outcome data |
Low |
Comment: 1010 participants randomized; 1010 participants analyzed for efficacy; 985 participants analyzed for safety.
Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). WHO score 7 and above (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). WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and prospective registry 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). WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Overall risk of bias |
Low |