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 |
Some concerns |
Quote: "Stratified random sampling was applied to stratify all eligible patients according to the disease severity (mild to moderate or severe) followed by random assignment (in a 1:1 ratio) in each stratum to ensure a balanced distribution of disease severity between treatment (HCQ plus SOC) and control (SOC only) groups. Randomization rules were designed by LL together with principal investigators and implemented by an independent statistician who was not involved in data analysis. Equal numbers of cards with each group assignment number randomly generated by computer were placed in sequentially numbered envelopes that were opened as the patients were enrolled."
Comment: Allocation sequence random. Allocation concealment unclear (authors do not report use of opaque envelopes). |
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: One participant who was allocated to the control group received HCQ. Deviation too small to affect the outcome. Administration of all co-interventions of interest: antivirals, biologics and corticosteroids were reported. >Biologics administration between arms (43/75 vs 32/75). The remaining co-interventions were balanced between arms. This deviation was not balanced and could affect the outcome. Nevertheless, this domain was rated as some concern as it is impossible to distinguish deviation because of trial context and deviation because of intervention effect. 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). Incidence or viral negative conversion (D7). Time to viral negative conversion. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
Missing outcome data |
Low |
Comment: 150 participants randomized, 150 participants analyzed.
Data available for all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Time to viral negative conversion. Incidence of viral negative conversion (D7). WHO score 7 and above (D28). 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 viral negative conversion are observer-reported outcomes not involving judgement. For WHO score 7 and above, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcome: Mortality (D28). Incidence of viral negative conversion (D7). Time to viral negative conversion. WHO score 7 and above (D28). The authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected events. All these outcomes 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 outcomes: Adverse events. Serious adverse events. |
Selection of the reported results |
Low |
Comment: The protocol and statistical analysis plan were available.
ADVERSE and SERIOUS ADVERSE EVENTS Outcome pre-specified. 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 outcome: Adverse events. Serious adverse events. MORTALITY Mortality outcome was not pre-specified, 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 (D28). VIRAL NEGATIVE CONVERSION, WHO SCORE 7 AND ABOVE Outcome data acquired from contact with authors. 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: Incidence of viral negative conversion (D7). WHO score 7 and above (D28). TIME TO VIRAL NEGATIVE CONVERSION 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 outcomes: Time to viral negative conversion. |
Overall risk of bias |
Some concerns |