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 (protocol): “Randomization will be centralized
and thus will be completely independent from patients and physicians participating in the study ensuring allocation concealment.”
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: No participant cross-over. No information on administration of co-interventions of interest: biologics and corticosteroids. Antivirals were co-administered in 2 vs 1 participants (TCZ+DEX vs DEX). Hence, no information on whether deviations arose because of the trial context. MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE Our analysis for the binary outcomes 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 outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. Of note, 2 vs 1 participants were excluded from the analysis post-randomization due to no consent. This is considered missing data and 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: 453 participants randomized; 450 participants analyzed.
Of note 2 vs 1 participants were excluded from analysis due to no consent. Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Time to clinical improvement. 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, TIME TO DEATH Observer-reported outcomes not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). 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 outcomes: WHO score 7 and above (D28). CLINICAL IMPROVEMENT Clinical improvement (defined as 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 outcomes: Clinical improvement (D28). Time to clinical improvement. 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 |
Some concerns |
Comment: The prospective registry (dated July 16th, 2020) and protocol (dated July, 17th, 2020) were available.
MORTALITY, TIME TO DEATH, (TIME TO) CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, SERIOUS ADVERSE EVENTS Outcomes pre-specified. Results were not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified for clinical outcomes and serious adverse events. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Serious adverse events. ADVERSE EVENTS Outcome adverse events was 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 for safety. Risk assessed to be some concerns for the outcomes: Adverse events. |
| Overall risk of bias |
Some concerns |