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: "The study analyst generated the randomization allocation stratified by site and contact type (household versus health careassociated exposure). The study staff did not have access to the randomization codes. Once eligibility was confirmed and the enrollment visit completed, a prescription was sent to the unblinded pharmacist who accessed the randomization allocation via REDCap and dispensed the study medication. Eligible participants in the same household were randomly assigned to the same group to prevent unblinding between study participants." "Study data were managed at the University of Washington International Clinical Research Center; site monitoring, including monitoring of randomization, was conducted by an external, independent clinical trials monitoring group." Comment: Allocation sequence random. Allocation sequence concealed. Minor imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: “Both hydroxychloroquine and ascorbic acid tablets were round, pale, and had a bitter or sour taste. The labeling and packaging of the drug was identical in both groups. The pharmacist was unblinded, but the participants, investigators, laboratory technicians, and study team members were blinded to participant allocation.”
Comment: Blinded study (participants and personnel/carers). EFFICACY Of note, 29 vs 54 participants were excluded from the analysis due to SARS-CoV-2 positive at baseline. A further 25 vs 32 participants were excluded from the analysis due to unavailable baseline result. These are post-randomization exclusion of ineligible participants, hence acceptable. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed appropriately. Risk assessed to be low for the outcomes. Confirmed COVID-19. Confirmed symptomatic COVID-19. SAFETY Data were analyzed using full randomization set. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed appropriately. Risk assessed to be low for outcomes: Adverse events. |
| Missing outcome data |
Low |
Comment: 829 participants randomized; 829 participants analyzed for adverse events; 689 participants analyzed for COVID-19 efficacy outcomes.
Data available for all participants for adverse events outcome. Data not available for all or nearly all participants for the COVID-19 efficacy outcomes. No evidence that the result is not biased. Reasons: "Participants who tested SARS-CoV-2 positive at baseline (83 of 829 [10%]) or for whom a baseline result was not available (57 of 829 [7%]) were excluded from the mITT primary analysis". This a post-randomization exclusion of ineligible participants, hence acceptable. Missingness could not depend on the true value of the outcome. Retention rates for survey completion and swab collection were high (91-92%), balanced between groups, but reasons for missing data were not reported. Risk assessed to be low for the outcomes: Confirmed COVID-19. Symptomatic confirmed COVID-19. 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: Confirmed COVID-19. Symptomatic confirmed COVID-19. Adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan, and online 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: Confirmed COVID-19. Adverse events. Symptomatic confirmed COVID-19 was not pre-specified. No information on whether the results were selected from multiple outcome measurements or analyses of the data. No information on whether the trial was analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Symptomatic confirmed COVID-19. |
| Overall risk of bias |
Some concerns |