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: "Patients were randomized through permuted-block randomization and an interactive voice or web-based response system"
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Some concerns |
Quote: “double-blind, placebo-controlled trial”
"A site blinding plan was established at each site to identify which personnel would be blinded or unblinded at a site level. A pharmacy manual and specific training in addition to completion of a site blinding plan was provided to each site. Each site had an unblinded pharmacist that randomized the patient and prepared and labeled study medication in the same method for both tocilizumab and placebo. The remainder of the study team was blinded to treatment assignment. There was no communication during the study between unblinded and blinded members. In addition, there was an unblinded medical monitor available to answer questions from the unblinded site staff. Placebo was not provided and consisted of an unaltered saline infusion bag, the same as would be used to prepare tocilizumab. The volume of tocilizumab diluted in saline appears colorless and matches saline." Comment: Blinded study. Participants were blinded. Carers were probably blinded. MORTALITY. CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE. ADVERSE AND SERIOUS ADVERSE EVENTS. 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 the outcome: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. TIME TO CLINICAL IMPROVEMENT. TIME TO WHO SCORE 7 AND ABOVE. Participants were analyzed according to their randomized groups for the outcome. Of note, 10 vs 1 participants were excluded from the analysis post-randomization because they did not receive the drug. This method was considered inappropriate to estimate the effect of assignment to intervention for this time-to-event 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 outcome: Time to clinical improvement. Time to WHO score 7 and above. |
| Missing outcome data |
Low |
Comment: 388 patients randomized; 377 patients analyzed.
Data available for all or nearly all participants. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). 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 the outcome probably does not differ between groups. Quote: "double-blind, placebo- controlled"; "Each site had an unblinded pharmacist that randomized the patient and prepared and labeled study medication in the same method for both tocilizumab and placebo. The remainder of the study team was blinded to treatment assignment." Comment: Outcome assessor probably blinded. Risk assessed to be low for the outcome: Mortality (D28). Mortality (D60 or more). Clinical improvement (D28). 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 |
Low |
Comment: The protocol, statistical analysis plan and registry were available.
Outcomes reported as 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). Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |