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 |
Some concerns |
This study's allocation sequence is adequately randomised and concealed however, 100 participants assigned to the intervention and control were randomized in a separate study (https://www.nejm.org/doi/full/10.1056/NEJMoa2016638?query=TOC) but included in this study. Quote: "Sequential randomization occurred at research pharmacies in Minneapolis, Minnesota, and Montreal, Canada. The trial statistician generated a permuted block randomization sequence using differently sized blocks in a 1:1 allocation, stratified by country. A separate randomization stratum also existed for persons who were initially asymptomatic at the time of informed consent but became symptomatic before receiving the study medication on day 1. The research pharmacies held this list, and statisticians verified that the randomization sequence was followed." |
| Deviations from intervention |
Low |
Quote: "double-blind, placebo-controlled"
Comment: Blinded study (participants and personnel/carers). 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 outcomes: Hospitalization or Death. Mortality (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 491 participants randomized; 465 participants analyzed for mortality, hospitalization or death, WHO 7 and above outcomes, 423 analyzed for adverse and serious adverse events outcomes.
MORTALITY, HOSPITALIZATION OR DEATH, WHO SCORE 7 AND ABOVE Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data: 13 vs 13 had no follow-up data Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (same reasons and equal proportion of missing data between arms). Risk assessed to be some concerns for the outcomes: Hospitalization or Death. Mortality (D28). WHO score 7 and above (D28). ADVERSE and SERIOUS ADVERSE EVENTS Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for missing data: 13 vs 13 had no follow-up data; 19 vs 23 had vital status data Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (same reasons and equal proportion of missing data between arms). Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events. |
| 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: Hospitalization or Death. Mortality (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol and statistical analysis plan were available but was retrospective. Prospective versions of the registry were available and consulted.
ADVERSE EVENTS 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 outcome: Adverse events. MORTALITY, WHO SCORE 7 AND ABOVE, SAE Outcome data acquired from contact with authors. 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). WHO score 7 and above (D28). Serious adverse events. HOSPITALIZATION OR DEATH Outcome pre-specified in prospective registry. 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 outcome: Hospitalization or Death. |
| Overall risk of bias |
Some concerns |