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: "Participants were randomized via a centralized computer program"(report) "Randomization will be at the patient level and occur after data necessary to implement the inclusion and exclusion criteria have been entered into the secure randomization website" "Allocation concealment will be maintained by using centralized randomization that is remote from study sites"(protocol). Comment: Allocation sequence random. Allocation sequence concealed. Minor imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "Open-label design"
Comment: Unblinded study (participants and personnel/carers). No participant cross-over. No information on administration of co-interventions of interest, antivirals, biologics and corticosteroids were reported. Hence, no information on whether deviations arose because of the trial context. MORTALITY Our analysis for the binary outcome is an 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 outcome: Mortality (D60 or more). TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 9 (tocilizumab), 2 (sarilumab), 8 (anakinra) participants were excluded from the analysis post-randomization because outcome data were not available 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 some concerns for the outcomes: Time to death. Time to clinical improvement. |
| Missing outcome data |
Low |
Comment: 2216 participants randomized; 2188 to 2207 participants analyzed.
Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D60 or more). Time to death. Time to clinical improvement. |
| Measurement of the outcome |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome does not differ among groups. Unblinded study (outcome assessor) MORTALITY, TIME TO DEATH Mortality is an observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D60 or more). Time to death. TIME TO CLINICAL IMPROVEMENT Clinical improvement (defined as hospital discharge) require clinical judgement and could be affected by knowledge of intervention receipt. Risk assessed to be some concerns for the outcome: Time to clinical improvement. |
| Selection of the reported results |
Low |
Comment: The protocols (prospective core protocol dated July 10th, 2019 and retrospective pandemic appendix to core protocol dated May 18th, 2020), statistical analysis plan (retrospective: dated April 15th, 2021), and prospective registry (dated April 13th, 2016 up to version dated March 25th, 2020) 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 (D60 or more). Time to death. Time to clinical improvement. |
| Overall risk of bias |
Some concerns |