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: “Using a centralized electronic system, we randomly assigned enrolled patients to hydroxychloroquine or placebo in a 1:1 ratio stratified by enrolling hospital using randomization block sizes of 2 and 4. Allocation was concealed.”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: “Patients, treating clinicians, trial personnel, and outcome assessors were blinded to group assignment.”
Comment: Blinded study (participants and personnel/carers). MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE 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 low for the outcomes: Mortality (D28). Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO DEATH Participants were analyzed according to their randomized groups for the outcome. Of note, 1 vs 1 participants were excluded from the analysis post-randomization due to missing data which is accounted for in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcome: Time to death. |
| Missing outcome data |
Low |
Comment: 479 participants randomized; 479 participants analyzed by imputation..
Quote: "Primary outcome assessment of the COVID Outcomes Scale 14 days after randomization was completed for 433 (90.4%) of 479 randomized patients; 46 patients who were discharged from the hospital before primary outcome assessment, including 25 in the hydroxychloroquine group and 21 in the placebo group, were not successfully contacted for primary outcome evaluation and had values imputed based on a follow-up call on day 7 or were assigned a score of 6 if no call was completed on day 7. Follow-up information on survival through day 28 was completed for 477 (99.6%) of 479 randomized patients; 1 patient in the hydroxychloroquine group and 1 patient in the placebo group were lost to follow-up for vital status." (TIME TO) CLINICAL IMPROVEMENT For clinical improvement (discharge) there is no missing data since those 'missing' were discharged. Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Clinical improvement (D28). Time to clinical improvement. MORTALITY, TIME TO DEATH Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to death. WHO SCORE 7 AND ABOVE Unclear if data available for all or nearly all participants randomized. No evidence that the result is not biased. Missingness probably could not depend on the true value of the outcome, since those 'missing' were discharged (a low score, not probable to be score 7 or above). Risk assessed to be low for the outcome: WHO score 7 and above (D28). ADVERSE and SERIOUS ADVERSE EVENTS Data probably available for all or nearly all participants randomized. Safety data were collected during the first 7 days or until hospital discharge (according to the protocol), hence it is probable that all or nearly all data from participants were available. Furthermore, serious adverse events (defined as death or prolongation of hospitalization) and those 'missing' were discharged (not still hospitalized). Also, nearly all data available for death (vital status). Risk assessed to be low for the outcome: 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: Mortality (D28). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The trial registry, protocol and statistical analysis plan were available. The protocol was dated June 4th, 2020 (retrospective) but revealed the changes made to the previous prospective version and outcomes measures were not changed. Prospective versions of the registry were also accessed. Both documents were consulted for this domain.
MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Outcomes pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Risk assessed to be low for the outcomes: Mortality (D28). Clinical improvement (D28).WHO score 7 and above (D28). Serious adverse events. TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT Outcome not pre-specified. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Time to death. Time to clinical improvement. |
| Overall risk of bias |
Some concerns |