| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: "All participants were centrally randomized to each study intervention using an interactive web response system. Before the study was initiated, the log-in information and directions for the interactive web response system was provided to each of the 49 US study sites."
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Low |
Quote: "double-blind, placebo-controlled"; “Double-blind. Neither participants, nor investigators, nor the sponsor study team will be aware of treatment assignments prior to the final data base locks at the conclusion of the study.’
Comment: Blinded study (participants, personnel/carers). Data for the safety outcomes were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Participants were analyzed according to their randomized groups for the viral negative conversion outcome. Of note, 10 vs 9 vs 7 participants were excluded from the analysis post-randomization for reasons likely related to missing data. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for outcomes: Mortality (D28). Incidence of viral negative conversion (D7). Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 592 patients randomized; 577 patients analyzed for mortality, adverse events and serious adverse events; 544 for viral clearance.
Data available for all or nearly all participants in the safety population. Risk assessed to be low for outcomes: Mortality (D28). Adverse events. Serious adverse events. For viral negative conversion (D7), data were not available for all or nearly all participants. No evidence that the result is not biased. Reasons for missing data unknown, hence no information on whether missingness could depend on its true value, but it is not considered likely to be related to the true value of the outcome as only 15 people in this population of outpatients with mild COVID-19 reported hospitalization or an ER visit, in which symptoms improved for the majority. Missing data were balanced among arms. Risk assessed to be some concerns for the outcome: Incidence of viral negative conversion (D7). |
| Measurement of the outcome |
Low |
Quote: “Neither participants, nor investigators, nor the sponsor study team will be aware of treatment assignments prior to the final data base locks at the conclusion of the study.”; :double-blind, placebo-controlled"
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). Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan and trial registry were available.
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). Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |