Trial NCT04322123
Publication Cavalcanti AB, N Engl J Med (2020) (published paper)
Primary outcome on the report: Clinical status at 15 days, evaluated with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition)

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 was performed in blocks of six and was stratified according to the use or nonuse of supplemental oxygen at the time of randomization. Randomization was performed centrally by means of an electronic case-report form system (RedCap)".
Quote from Supplementary Appendix: "The trial statistician, not involved with patient enrolment or care, generated the rndomization table in R software (R Core Team, 2019) and implemented in the RedCap. The study treatment was revealed to investigators only after patients were registered in the RedCap, ensuring proper concealment of the allocation sequence."
Comment: Allocation sequence random. Allocation sequence concealed.
Imbalances in baseline characteristics appear to be compatible with chance
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:
In the HCQ+AZM arm, 3 did not receive HCQ. In the HCQ arm, 21 received HCQ+AZM. In the control arm, 7 received HCQ and 17 received HCQ+AZM.
Deviations too small to affect the outcome.
No information on administration of review co-intervention of interest: biologics. Antivirals and corticosteroids were reported.
Hence, no information on whether deviations arose because of the trial context.

MORTLAITY, 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 some concerns for the outcomes: Mortality (D28). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events.
Missing outcome data
Low 		Comment: 667 participants randomized, 665 participants analyzed.
Data available for all or nearly all participants randomized.
2 patients were also excluded from analysis due to consent withdrawal after randomization (n=1) and duplicated randomization (n=1).
Risk assessed to be low for outcomes: Mortality (D28). Clinical improvement (D28). 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
Mortality is an observer-reported outcome not involving judgement.
Risk assessed to be low for outcomes: Mortality (D28).

WHO SCORE 7 AND ABOVE
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: WHO score 7 and above (D28).

CLINICAL IMPROVEMENT
Clinical improvement (defined as discharge from the hospital) requires clinical judgement and could be affected by knowledge of intervention receipt, but is not likely in the context of the pandemic.
Risk assessed to be some concerns for the outcomes: Clinical improvement (D28).

ADVERSE and SERIOUS ADVERSE EVENTS
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
Low 		Comment: The protocol, statistical analysis plan and prospective registry were available.
Outcomes 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 outcomes: Mortality (D28). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events.
Overall risk of bias
Some concerns