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 |
High |
Quote: “A computerized random number generator was used and the allocation was done in 2:1 sequence. Cards with each group assignment number randomly generated by the computer were placed in sequentially numbered envelopes, which were opened as the patients were enrolled.’
Comment: Allocation sequence not totally random. Unclear allocation concealment. Comment: Trial not fully randomized - patients who did not give consent for treatment with HCQ or had a known allergy to HCQ or chloroquine or had any other known contraindication to treatment with the study drug served were allocated as controls. Controls were matched with participants on the basis of age, gender, and co-morbidities. Insufficient data reported to judge whether imbalances in baseline characteristics were compatible with chance. A larger proportion of patients in the intervention arm had comorbidities than in the control arm. |
| Deviations from intervention |
Some concerns |
Quote: "open-label"
Comment: Unblinded study (participants and personnel/carers). Deviations from intended intervention arising because of the study context: No participant cross-over. No information on administration of co-interventions of interest: antivirals, biologics, and corticosteroids. Hence, no information on whether deviations arose because of the trial context. MORTALITY, ADVERSE and SERIOUS ADVERSE EVENTS Data for the outcome were analyzed using intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be some concerns for the outcomes: Mortality (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 11 vs 29 participants were excluded from the analysis post-randomization, of which 7 vs 15 were due to missing data and is accounted for in domain 3. The remaining 4 vs 14 participants were excluded due to protocol violations - symptomatic before onset of HCQ/supportive therapy (1 vs 4) [which is a post-randomization exclusion of ineligible participants, hence acceptable] and non-compliance to therapy (3 vs 10). This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Incidence of viral negative conversion (D7). |
| Missing outcome data |
Some concerns |
Comment: 540 participants randomized; 500 participants analyzed.
Data not available for all or nearly all participants randomized; >5% missing data. No evidence that the result is not biased. Reasons: withdrew consent (4 [1.1%] vs. 11 [6.1%]); became symptomatic before onset of therapy (1 [0.3%] vs. 4 [2.2%]); lost to follow-up (3 [0.8%] vs. 4 [2.2%]); non-compliant (3 [0.8%] vs. 10 [5.6%]). Non-compliance and becoming symptomatic before onset of therapy were accounted for in risk of bias domain 2 Missingness for the remaining reasons could depend on the true value of the outcome. Likely that missingness depended on the true value of the outcome because reasons and proportions of remining missing data between arms were not balanced. However, they only represented 4% of the participants. Risk assessed to be some concerns for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). 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. Comment: Unblinded study (outcome assessor). Mortality and viral negative conversion are observer-reported outcomes not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). The authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected events, which can be influenced by knowledge of the intervention assignment, but is not likely in the context of the pandemic. Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The trial registry was retrospective.
No information on whether the result was 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: Mortality (D28). Incidence of viral negative conversion (D7). Adverse events. Serious adverse events. |
| Overall risk of bias |
High |