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: “Randomization is performed using a web-based system (Ennov Clinical software using a minimization algorithm. This study is double-blind with the use of a placebo that is impossible to distinguish from hydroxychloroquine tablets by appearance, odor, or taste. The presentation of treatments does not allow a distinction between HCQ and the placebo. Each item of treatment has a unique processing number. Only this number can identify the substance. The link between each processing number and the content is only known by the coordinating pharmacy. The coordinating pharmacy supervises the production, packaging, and distribution of treatment batches (HCQ/placebo). These tasks are carried out by an external service provider. The doctors and nurses taking care of the patients, as well as the patients themselves, do not know which treatment they have been assigned.”
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: "The doctors and nurses taking care of the patients, as well as the patients themselves, do not know which treatment they have been assigned."
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). WHO score 7 and above (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 22 vs 25 participants were excluded from the analysis post-randomization due to missing data at baseline 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 outcomes: Incidence of viral negative conversion (D7). |
| Missing outcome data |
Some concerns |
Comment: 250 participants randomized; 247 participants analyzed for all outcomes except viral negative conversion (203 participants analyzed).
MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Data available for all or nearly all participants randomized. Of note, 1 vs 2 participants withdrew consent. Risk assessed to be low for the outcomes: Mortality (D28). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. VIRAL NEGATIVE CONVERSION Data not available for all or nearly all participants No evidence that the result is not biased. Reasons: unknown Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome as, at baseline, RT-PCR could not be performed at certain centers due to a shortage of swabs or RT-PCR material and this is probably the reason for the missing data. Furthermore, there is an equal proportion of missingness between arms (22 vs 25). Risk assessed to be some concerns for the outcome: Incidence of viral negative conversion (D7). |
| 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). Incidence of viral negative conversion (D7). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol and statistical analysis plan were available but retrospective (dated May 29th, 2020) with no outline on changes made. Prospective versions of the trial registry were available and consulted.
MORTALITY, VIRAL NEGATIVE CONVERSION, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE 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). Incidence of viral negative conversion (D7). Clinical improvement (D28). WHO score 7 and above (D28). ADVERSE and SERIOUS ADVERSE EVENTS 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: Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |