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 concealed online randomization system"
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "the interventions were given as open-label drugs"
Comment: Unblinded study (participants and personnel/carers) Deviations from intended intervention arising because of the study context: No participant cross-over. Co-interventions of interest: antivirals, biologics, and corticosteroids were reported and proportions of patients receiving these different drug categories were not balanced between groups. This deviation 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 (available case) analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be some concerns for the outcomes: Time to death. Time to clinical improvement. WHO score 7 and above (D60 or more). Serious adverse events. |
| Missing outcome data |
Some concerns |
Comment: 726 participants randomized; 694 participants analyzed for SAEs; 677 participants analyzed for time to event outcomes; 453 participants analyzed for WHO score 7 and above.
Data for safety available for nearly all participants randomized. Risk assessed to be low for the outcome: Serious adverse events. Data for time to event outcomes were not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: Withdrawal of consent (4.9%, 3.8%, 6.8%, 4.0%) and missing outcome data (2.2%, 1.9%, 3.4%, 2.4%). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome. Risk assessed to be some concerns for the outcomes: Time to death. Time to clinical improvement. Data for WHO score 7 and above not available for all or nearly all participants randomized; 38% (34 vs 54 vs 52 vs 37%) missing data. No evidence that the result is not biased. Reasons: as above, and Already with outcome (invasive ventilation) at baseline (27%, 50%, 45%, 30%). Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome. Risk assessed to be some concerns for the outcome: WHO score 7 and above (D60 or more). |
| 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). TIME TO DEATH Mortality is an observer-reported outcome not involving judgement. Risk assessed to be low for the outcome: Time to death. 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 (D60 or more). TIME TO CLINICAL IMPROVEMENT Clinical improvement (defined as hospital discharge) requires clinical judgement and could be affected by knowledge of intervention receipt, but it not considered likely to in the context of a pandemic. Risk assessed to be some concerns for the outcome: Time to clinical improvement. SERIOUS ADVERSE EVENTS The authors reported on 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 outcome: Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and registry (dated 13 April 2016) 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: Time to death. Time to clinical improvement. WHO score 7 and above (D60 or more). Serious adverse events. |
| Overall risk of bias |
Some concerns |