| 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 |
Some concerns |
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 carers). Probably inappropriate method of analysis used to analyze effect of assignment to intervention (intent-to-treat); post-randomization exclusions of those with unknown test results. Imbalanced between groups. Not substantial impact of failure to analyze participants in randomized groups. |
| Missing outcome data |
Low |
Comment: 829 participants randomized; 829 participants analyzed for adverse events; 689 participants analyzed for Covid-19 outcomes. Data avilable for < 95% of population. Quote: "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". Comment: Exclusions were not due to missing outcome data. 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. Symptomatic confirmed COVID. Adverse events. |
| Measurement of the outcome |
Low |
Comment: Blinded study, participants reporting symptoms and adverse events on an online questionnaire and laboratory technicians processing the test swabs for Covid infection were blinded to participant allocation. Risk assessed to be low for the outcomes: Confirmed COVID. Symptomatic confirmed COVID. Adverse events. |
| Selection of the reported results |
Low |
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. Symptomatic confirmed COVID. Adverse events. |
| Overall risk of bias |
Some concerns |