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:"Eligible patients were randomly assigned in a 2:1 ratio using an interactive web-based response system and a permuted block method to receive blinded treatment with tocilizumab plus remdesivir or placebo plus remdesivir. Randomization was stratified by geographic region (North America, Europe, other) and by a 2-level factor based on clinical status at screening (ordinal scale categories 4–5, category 6) on a 7-category ordinal scale."
Comment: Allocation sequence random. Allocation sequence probably concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "Study site personnel and patients will be blinded to TCZ treatment assignment during
the study." (protocol)
Comment: Blinded study (participants and personnel/carers) MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS Our analysis is an intention-to-treat analysis. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). Clinical improvement (D60 or more). WHO score 7 and above (D28). Serious adverse events. TIME TO CLINICAL IMPROVEMENT, TIME TO DEATH, TIME TO SCORE 7+ Participants were analyzed according to their randomized groups for the outcome. Of note, 4 vs 5 participants were excluded from the analysis post-randomization because they did not receive tocilizumab or placebo. This method was considered inappropriate to estimate the effect of assignment to intervention for this outcome. There was probably no substantial impact of failure to analyze participants according to their randomized groups. Risk assessed to be some concerns for the outcomes: Time to clinical improvement. Time to death. Time to WHO score 7 and above. |
| Missing outcome data |
Low |
Comment: 649 participants randomized; 640 participants analyzed for efficacy outcomes; 642 participants analyzed for safety outcomes.
Data available for all or nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60). Time to death. Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan and registry were available (dated June 1, 2020).
MORTALITY, TIME TO DEATH, CLINICAL IMPROVEMENT D28, TIME TO CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, ADVERSE AND SERIOUS ADVERSE EVENTS Outcome pre-specified in the registry/protocol. 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). 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. CLINICAL IMPROVEMENT D60, TIME TO WHO SCORE 7 AND ABOVE. Outcome not pre-specified in the registry/protocol. No information on whether the result was selected from multiple outcome measurements or analyses of the data. Trial probably not analyzed as pre-specified. Risk assessed to be some concerns for the outcome: Clinical improvement (D60 or more). Time to WHO score 7 and above. |
| Overall risk of bias |
Some concerns |