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 performed via an Interactive Web Randomization System and maintained by a third party."
Comment: Allocation sequence random. Allocation sequence probably concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "double-blind" study.
Comment: Blinded study (participants and personnel/carers). MORTALITY. CLINICAL IMPROVEMENT. ADVERSE AND SERIOUS ADVERSE EVENTS 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 for the outcomes: Mortality (D28). Clinical improvement (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 959 total participants were excluded from the analysis post-randomization because they either: did not receive the drug (n=20), had smell or taste impairment as their only symptom criterion for inclusion (n=24), were not included in the viral shedding sub-study (n=705), or had undetectable viral load at baseline (n=210). 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 |
Some concerns |
Comment: 1231 participants randomized; 1211 participants analyzed for safety outcomes; 1120 (91%) completed follow-up for clinical improvement; 272 analyzed for negative conversion.
MORTALITY. ADVERSE AND SERIOUS ADVERSE EVENTS Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Data not available for nearly all participants randomized. No evidence that the result is not biased. Reasons: 959 participants in this sub-study accounted for in domain 2. 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). CLINICAL IMPROVEMENT Data not available for nearly all participants randomized. No evidence that the result is not biased. Reasons: 20 total participants did not receive the drug, 24 had smell or taste impairment as their only symptom criterion for inclusion, and 27 vs 26 had partial follow-up only (including 13 vs 11 withdrawals, and 12 vs 11 lost-to-followup). 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 outcome: Clinical improvement (D28). |
| 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). Incidence of viral negative conversion (D7). Clinical improvement (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The prospective registry was available (dated October 23, 2020).
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). Incidence of viral negative conversion (D7). Clinical improvement (D28). Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |