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: "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). MORTALITY, CLINICAL IMPROVEMENT, AE, SAE 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 outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). Adverse events. Serious adverse events. VIRAL NEGTAIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 10 vs 9 vs 7 participants were excluded from the analysis post-randomization for reasons likely related to missing data which is accounted for in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for outcomes: Incidence of viral negative conversion (D7). Time to viral negative conversion. TIME TO CLINCIAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 47 vs 13 vs 23 participants were excluded from the analysis post-randomization for reasons likely related to missing data which is accounted for in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for outcomes: Time to clinical improvement |
| Missing outcome data |
Some concerns |
Comment: 592 participants randomized; 577 participants analyzed for mortality, adverse events and serious adverse events; 544 participants analyzed for viral clearance; 487 participants analyzed for clinical improvement.
MORTALITY, AE, SAE Data available for all or nearly all participants randomized. Risk assessed to be low for outcomes: Mortality (D28). Mortality (D60 or more). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data unknown (10 vs 9 vs 7) Hence, no information on whether missingness could depend on its true value Not likely that missingness depended on 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). Time to viral negative conversion. CLINICAL IMPROVEMENT Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data unknown (47 vs 13 vs 23) Hence, no information on whether missingness could depend on its true value Not likely that missingness depended on the true value of the outcome (similar proportion of missing data among arms). Risk assessed to be some concerns for the outcome: Clinical improvement (D28). Time to clinical improvement. |
| 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). Mortality (D60 or more). Incidence of viral negative conversion (D7). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The original protocol (dated May 30th, 2020), statistical analysis plan (dated June 19th, 2020) and trial registry (dated June 11th, 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). Incidence of viral negative conversion (D7). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |