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: “Participants were randomized in a 1:1 ratio to receive HCQ or placebo at the level of the individual participant via the study portal. Randomization was stratified by clinical site using a permuted block design with varying block sizes.”
Comment: Allocation sequence random. Allocation sequence concealed Imbalances in baseline characteristics appear to be compatible with chance |
| Deviations from intervention |
Low |
Quotes: "double-blind" "The placebo was similar in appearance to the study drug and packaged and labeled in a masked manner in compliance with regulatory requirements." "HERO-HCQ used direct-to-participant recruitment"
Comment: Blinded study (participants and personnel/carers) Participants were analyzed according to their randomized groups for the outcome. Risk assessed to be low for the outcomes: Symptomatic confirmed or probable COVID-19. Confirmed COVID-19. Symptomatic confirmed COVID-19. Hospital admission or death. Mortality. Adverse events.Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 1360 participants randomized; 1316 participants analyzed for symptomatic COVID and symptomatic confirmed COVID; 1263 participants analyzed for Confirmed COVID; 1217 participants analyzed for safety.
SYMPTOMATIC CONFIRMED OR PROBABLE COVID, SYMPTOMATIC CONFIRMED COVID Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Symptomatic confirmed or probable COVID-19. Symptomatic confirmed COVID-19. CONFIRMED COVID, HOSPITALIZATION OR DEATH, MORTALITY, AE, SAE Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: positive RT-PCR at baseline (HCQ = 0, placebo = 1), lost to follow up (HCQ = 63, placebo = 57), withdrawal of consent (HCQ = 10, placebo = 12), physician decision (HCQ = 0, placebo = 1). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (similar proportion of missingness between arms). Risk assessed to be some concerns for the outcomes: Confirmed COVID-19. Hospital admission or death. Mortality. Adverse events. Serious 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: Symptomatic confirmed or probable COVID-19. Confirmed COVID-19. Symptomatic confirmed COVID-19. Hospital admission or death. Mortality. Adverse events.Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol (version 3.0 dated 7 July 2020, 2.5 months after commencement of study enrolment) and registry (dated prospectively, 6 April 2020) were available.
SYMPTOMATIC CONFIRMED OR PROBABLE COVID, AE, SAE. 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: Symptomatic confirmed or probable COVID-19. Adverse events. Serious adverse events. MORTALITY Mortality outcome was not pre-specified in the registry, however, we do not consider the reporting of this outcome to be selective since mortality should be reported even if not planned. Results were probably not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcome: Mortality. CONFIRMED COVID, SYMPTOMATIC CONFIRMED COVID. Outcomes not pre-specified. No information on whether results were selected from multiple outcome measurements or analyses of the data. No information on whther trial was analyzed as pre-specified. Risk assessed to be some concerns for the outcomes: Confirmed COVID-19. Symptomatic Confirmed COVID-19. |
| Overall risk of bias |
Some concerns |