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: "Study medications were dispensed according to a computer-generated randomization sequence."
Protocol: "The randomization plan will be overseen by the Study Statistician. The randomization code and resulting allocation list will be generated and overseen by the Study Statistician." Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Quote: “Participants will be blinded. Treating clinicians will be blinded, as the study medication will be dispensed directly to participants. Laboratory testing for viral shedding will be blinded.”
Comment: Blinded study (participants and personnel/carers). MORTALITY, HOSPITALIZATION OR DEATH, CLINICAL IMPROVEMENT Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcome: Mortality (D28). Hospitalization or death. Clinical improvement (D28). (TIME TO) VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the viral negative conversion outcome. Of note, 22 vs 26 vs 31 participants were excluded from the analysis post-randomization, of which 16 vs 23 vs 28 were due to reasons other than missing data (they did not have SARSCoV-2 detected). This is a post-randomization exclusion of ineligible participants and 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). Time to viral negative conversion. TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the viral negative conversion outcome. Of note, 11 vs 12 vs 11 participants were excluded from the analysis post-randomization because they did not meet the COVID-19 definition at screening. This is a post-randomization exclusion of ineligible participants and was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcome: Time to clinical improvement. |
| Missing outcome data |
Some concerns |
Comment: 231 participants randomized; 219 patients analyzed for mortality and hospitalization or death outcomes; 152 participants analyzed for negative viral conversion outcome; 197 participants analyzed for clinical improvement outcome.
MORTALITY, HOSPITALIZATION OR DEATH Data available for all or nearly all participants randomized. Reasons for missing data: 9 refused study participation, 2 were unable to complete study procedures, 1 lost to follow-up. Risk assessed to be low for the outcomes: Mortality (D28). Hospitalization or death. (TIME TO) VIRAL NEGATIVE CONVERSION Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for exclusions: 67 participants were excluded from viral shedding analyses if the first two collected swabs were negative for SARS-CoV-2 (accounted for in domain 2); 3 vs 3 vs 3 refused study participation , 2 vs 0 vs 0 were unable to complete study procedures, 1 vs 0 vs 0 lost to follow-up. Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (even though reasons and proportion of missingness were not balanced, they only represented 5% of the participants). Risk assessed to be some concerns for the outcomes: Incidence of negative viral conversion (D7). Time to negative viral conversion. (TIME TO) CLINICAL IMPROVEMENT Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for exclusions: 34 participants were excluded from analysis because they did not meet COVID-19 definition at screening (accounted for in domain 2) Missingness could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Clinical improvement (D28). Time to clinical improvement. |
| 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). Hospitalization or death. Incidence of negative viral conversion (D7). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. |
| Selection of the reported results |
Some concerns |
Comment: The protocol (dated April 11th, 2020), and trial registry (version dated April 16th, 2020) were available and consulted.
HOSPITALIZATION OR DEATH, TIME TO VIRAL NEGATIVE CONVERSION 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: Hospitalization or death. Time to viral negative conversion. MORTALITY Mortality outcome was not pre-specified in the protocol/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, (TIME TO) CLINICAL IMPROVEMENT Outcome not pre-specified No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7). Clinical improvement (D28). Time to clinical improvement. |
| Overall risk of bias |
Some concerns |