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: “Participants were randomized using a centralized core randomization process handled by an independent unblinded pharmacist who was not aware of any protocol-related procedures and contracted specifically for this process. Sites requested randomization by text message to the pharmacist at the coordinating center. This maintained concealment of allocation. Patients were randomly assigned using a block randomization procedure for each participating site, stratified by age (< 50 years /≥ 50 years). ”
Comment: Allocation sequence random Allocation sequence concealed Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “The trial team, site staff and patients were blinded to treatment allocation.”
Comment: Blinded study (participants and personnel/carers) MORTALITY, TIME TO DEATH 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). Time to death. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 534 vs 535 participants were excluded from the analysis post-randomization due to reasons unrelated to missing data. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcome: Incidence of viral negative conversion (D7). |
| Missing outcome data |
Low |
Comment: 1472 participants randomized; 1472 participants analyzed for mortality; 435 participants analyzed for negative conversion.
MORTALITY Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. VIRAL NEGATIVE CONVERSION Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: RT-PCR tests were only conducted by the unselected first quarter of patients enrolled. Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcome: Incidence of viral negative conversion (D7). |
| 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). Time to death. Incidence of viral negative conversion (D7) |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, registry (dated January 27, 2021) were all available. The registry was retrospective but published before unblinded data was available for analysis.
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: Mortality (D28). Time to death. Incidence of viral negative conversion (D7). |
| Overall risk of bias |
Some concerns |