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 |
Supplementary Appendix: "The trial statisticians generated a permuted block randomization sequence using variably sized blocks of two, four, and eight. A research pharmacist sequentially assigned participants. Treatment assignments were concealed from investigators and participants; the pharmacies were the only entities with access to the randomization sequence. Blinded hydroxychloroquine sulfate or placebo was dispensed and shipped over two days to participants by commercial courier. Placebo tablets (folic acid 400mcg in USA, 1000mcg in Canada) were similar but not identical in appearance."
Comment: Allocation sequence random. Allocation sequence concealed. Any baseline imbalances appear compatible with chance. |
| Deviations from intervention |
Low |
Quote: "double-blind, placebo-controlled"
Comment: Blinded study (participants and personnel/carers) EFFICACY and SAFETY Of note, 13 participants were excluded from the efficacy analysis due to having reached the primary endpoint by the start of the drug. This a post-randomization exclusion of ineligible participants, hence acceptable. Of note, apart from the previous 13 participants, 78 more participants were excluded from the safety analysis for unknown reasons but likely due to missing data. The bias will be taken into account in ROB domain 3. 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. Symptomatic confirmed COVID-19. Hospital admission or death. ICU admission or death. Mortality. Adverse events. |
| Missing outcome data |
Some concerns |
Comment: 1496 participants randomized; 1483 participants analyzed for all outcomes except adverse and serious adverse events.
Data available for all participants randomized. Risk assessed to be low for the outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Confirmed COVID-19. Symptomatic confirmed COVID-19. Hospital admission or death. ICU admission or death. Mortality. 1496 participants randomized; 1405 participants analyzed for safety outcomes. Data not available for all or nearly participants randomized. No evidence the result was not biased. Reasons for missing data: unknown, except for the 13 who reached the primary endpoint by start of study drug. No information on whether missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (equal proportion among arms). Risk assessed to be some concerns for the outcomes: Adverse events. |
| Measurement of the outcome |
Low |
Quote: "Three blinded infectious diseases physicians independently adjudicated cases of symptomatic participants"
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 outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Confirmed COVID-19. Symptomatic confirmed COVID-19. Hospital admission or death. ICU admission or death. Mortality. Adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan and 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 or probable symptomatic COVID-19. Confirmed COVID-19. Hospital admission or death. ICU admission or death. Mortality. Adverse events. Confirmed symptomatic or asymptomatic COVID-19 and symptomatic confirmed COVID-19 were 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: Confirmed symptomatic or asymptomatic COVID-19. Symptomatic confirmed COVID-19. |
| Overall risk of bias |
Some concerns |