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 |
Quotes: "Participants were randomized using the REDCap randomization application" "The randomization schedule was generated using PROC PLAN in SAS Version 9.4 (SAS Institute Inc., Cary NC) by an independent statistician""permuted block design"
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Quote: "The investigator, subjects, and sponsor were blinded to the treatments received"
Comment: Blinded study (participants and investigators). MORTALITY. 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). Adverse events. Serious adverse events. INCIDENCE OF VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 11 vs 25 vs 32 vs 28 participants were excluded from the analysis post-randomization because they were not SARS-CoV2 positive at baseline.1 vs 19 vs 3 vs 9 participants were excluded from the analysis post-randomization for unknown reasons but participants were excluded from the analysis post-randomization likely due to missing data which will be assessed in ROB3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcomes: Incidence of viral negative conversion (D7). |
| Missing outcome data |
High |
Comment: 204 participants randomized; 202 participants analyzed for mortality and safety; 73 participants analyzed for viral negative conversion.
MORTALITY. ADVERSE AND SERIOUS ADVERSE EVENTS. Data on mortality and safety available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Adverse events. Serious adverse events. INCIDENCE OF VIRAL NEGATIVE CONVERSION Data on viral negative conversion were not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: 96 were not SARS-CoV2 positive at baseline (accounted for in domain 2), 2 were withdrawn before treatment (not reported which group/s), 31 did not have data on nasopharyngeal swab for unknown reasons. Missingness could depend on the true value of the outcome. Likely that missingness depended on the true value of the outcome (missing data was imbalanced between groups (1 vs 19 vs 3 vs 9)). Risk assessed to be high 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). Incidence of viral negative conversion (D7). Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The trial registry was available (prospectively registered on 28 May 2020).
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Adverse events 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: Adverse events. Serious adverse events. MORTALITY Mortality outcome was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. Results were probably 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). VIRAL NEGATIVE CONVERSION Timepoints for viral negative conversion were not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Incidence of viral negative conversion (D7). |
| Overall risk of bias |
High |