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: "Randomization occurred at research pharmacies in Minneapolis and Montreal. The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country. A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants; only pharmacies had access to the randomization sequence." Comment: Allocation sequence random. Allocation sequence concealed. Any baseline imbalances appear compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "double-blind, placebo-controlled trial"
Comment: Blinded study (participants and personnel/carers). EFFICACY Of note, 100 participants were excluded from analysis due to being initially asymptomatic but were symptomatic by day 1 (at time of receiving trial intervention). This a 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 symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Confirmed COVID-19. Hospital admission or death. Mortality. SAFETY Per-protocol analysis was performed on the safety outcomes. Reasons for exclusion: did not receive either hydroxychloroquine or placebo. As we are assessing the effect of assignment to intervention (intention-to-treat effect), we considered that the data were analyzed inappropriately. There was probably no substantial impact of failure to analyze participants according to their randomized assignment. Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 921 participants randomized; 821 participants analyzed for all outcomes except safety outcomes (700 analyzed).
Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons for 100 exclusions were not due to missing data and were accounted for in domain 2. For adverse events, most patients were excluded because the planned analysis was per-protocol and the bias had been taken into account in domain 2. Risk assessed to be low for the outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Confirmed COVID-19. Hospital admission or death. Mortality. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Quote: ""double blind, placebo-controlled"".
""Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition."" Comment: Some outcomes (symptoms and adverse events) were self reported by participants via online survey. Method of measuring the outcome probably appropriate. Measurement or ascertainment of outcomes probably do not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Confirmed COVID-19. Hospital admission or death. Mortality. Adverse events. Serious 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 outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Confirmed COVID-19. Hospital admission or death. Mortality. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |