| 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 randomization 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: Baseline characteristics between intervention groups were comparable; any differences appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Comment: Unblinded study.
In the HCQ and AZM arm, 3 did not receive HCQ. In the HCQ arm, 21 received HCQ and AZM. In the control arm, 7 received HCQ and 17 received HCQ and AZM. Deviations too small to affect the outcome. No information on review co-intervention of interest: biologics. Antivirals and corticosteroids were reported. Outcome data were analyzed using intention-to-treat analysis. |
| Missing outcome data |
Low |
Comment: 2 patients were also excluded from analysis due to consent withdrawal after randomization (n=1) and duplicated randomization (n=1). Therefore, 667 randomized, 665 analyzed. All missing data occurred due to documented reasons unrelated to the outcome. Risk assessed to be low for outcomes: Mortality. Time to death. Clinical improvement. WHO score 6 and above. WHO score 7 and above. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Some concerns |
Comment: Mortality is an observer-reported outcome not involving judgement. WHO score 7 and above is an outcome that reflects decisions made by the intervention provider. However, we consider that the assessment of these outcomes cannot possibly be influenced by knowledge of the intervention assignment. Risk assessed to be low for outcomes: Mortality. Time to death. WHO score 7 and above. For Score 6 and above, although the assessment could possibly be influenced by knowledge of the intervention assignment, we did not consider this likely to have happened in the context of a pandemic. Clinical improvement (the definition is discharge from the hospital) reflects a decision made by the intervention provider where the assessment could also possibly be influenced by knowledge of the intervention assignment however we did not consider this likely in the context of a pandemic. Adverse events and serious adverse events may contain both clinically- and laboratory-detected outcomes, therefore it can be influenced by knowledge of the intervention assignment, but is not likely to. Risk assessed to be some concerns for outcomes: WHO score 6 and above. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol and statistical analysis plan were available.
Trial analyzed as pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Risk assessed to be low for the outcomes: Mortality. Time to death. Clinical improvement. WHO score 6 and above. WHO score 7 and above. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |