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 randomized (2:1) to receive intravenous tocilizumab (8 mg/kg infusion, maximum 800 mg) or placebo plus standard care using an interactive voice or web-based response system and permuted-block randomization. Randomization was stratified by geographic region (North America, Europe) and mechanical ventilation (yes, no)."
Comment: Allocation sequence random. Allocation sequence concealed. Any differences in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: "Masking: Double (Participant, Investigator)"
Comment: Blinded study (participants and personnel/carers) MORTALITY. CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE. ADVERSE AND SERIOUS ADVERSE EVENT. 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 low for outcome: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO VIRAL NEGATIVE CONVERISON. TIME TO DEATH. TIME TO CLINICAL IMPROVEMENT. Participants were analyzed according to their randomized groups for the time-to-event outcome. Of note, 2 vs 1 participants were excluded from the (time to clinical improvement) analysis post-randomization for reasons other than missing data. 1 vs 1 were excluded from the (time to death) analysis post randomization because of a randomization error. 11 vs 12 participants were excluded from the (time to viral negative conversion) analysis post-randomization because they did not have at least one virology assessment. 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 outcome: Time to viral negative conversion. Time to death. Time to clinical improvement. |
| Missing outcome data |
Low |
Comment: 452 patients randomized; 429 analyzed for viral negative conversion, 438 patients analyzed for all other outcomes.
Data available for all or nearly all participants. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement of outcome probably does not differ between groups. Blinded study (outcome assessor) Risk assessed to be low for the outcomes: Mortality (D28). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The protocol (dated 18 March, 2020), statistical analysis plan and prospective registry (dated March 23, 2020 were available).
MORTALITY. TIME TO DEATH. WHO SCORE 7 AND ABOVE. ADVERSE AND SERIOUS ADVERSE EVENTS. Outcome 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 (D28). Mortality (D60 or more). Time to death. WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO VIRAL NEGATIVE CONVERSION. TIME TO CLINICAL IMPROVEMENT. Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcome: Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. |
| Overall risk of bias |
Some concerns |