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 from contact with authors and published manuscript: "Randomization was performed remotely by a member of the study team not involved in participants’ enrollment by means of a random allocation sequence. Following ring randomization, investigators in each site verified the selection criteria of individual candidates and obtained informed consent for enrollment. The allocation was revealed to participants after providing written consent on day 1 (baseline)". Comment: Allocation sequence random. Allocation sequence probably concealed. Any baseline imbalances appear compatible with chance. |
| Deviations from intervention |
Some concerns |
Comment: Unblinded study (participants and personnel/carers)
Deviations from intended intervention arising because of the study context: 13/1300 in controls crossed over to the intervention group and received HCQ. Deviation too small to affect outcome. No co-interventions of interest (vaccines) were available at the time of the study. Hence, deviations did not arise because of the trial context. EFFICACY Of note, 40 participants excluded from analysis due to screening failure. 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 outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19 (confirmed or probable). Confirmed COVID-19. Confirmed symptomatic COVID-19. SAFETY Per-protocol analysis was performed on the safety outcomes. Reasons for exclusion: did not receive either hydroxychloroquine (n=28). 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: Hospital admission or death. Mortality. Adverse events. Serious adverse events. |
| Missing outcome data |
Low |
Comment: 2525 participants randomized, 2485 participants analyzed for all outcomes except Hospital admission or death, Mortality, Adverse events, Serious adverse events (2497 analyzed).
Data available for all or nearly all participants. Risk assessed to be low for outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Confirmed COVID-19. Confirmed symptomatic COVID-19. Hospital admission or death. Mortality. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study (outcome assessor) Mortality and PCR status do not involve judgement. Risk assessed to be low for outcome: Confirmed COVID-19. Confirmed symptomatic COVID-19. Mortality. Although mortality does not involve judgement, hospital admission could be influenced by knowledge of intervention assignment but was not considered likely to in the context of a pandemic. Incidence of symptomatic COVID-19 (which includes probable or suspected cases), serious adverse events and adverse events may contain clinically-detected and patient-reported outcomes which can be influenced by knowledge of intervention assignment but is not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcomes: Confirmed symptomatic or asymptomatic COVID-19. Confirmed or probable symptomatic COVID-19. Hospital admission or death. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol and 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. Mortality. Adverse events. Serious adverse events. Confirmed symptomatic or asymptomatic COVID-19, Confirmed symptomatic COVID-19 and Hospital admission or death 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. Confirmed symptomatic COVID-19. Hospital admission or death. |
| Overall risk of bias |
Some concerns |