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: "2 × 2 factorial design. Included patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. Patients were allocated in a 1:2 ratio to anakinra or no IL-1 blockade. Simultaneously, patients were randomly assigned in a 1:1:1 ratio to siltuximab, tocilizumab, or no IL-6 blockade. Randomisation and subsequent data collection were done by means of the webbased system REDCap".
Comment: Allocation sequence random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: "open-label".
Comment: Unblinded study (participants and personnel/carers). Deviations from intended intervention arising because of the study context: No participant cross-over. Co-interventions of interest were balanced between groups: antivirals and corticosteroids. Biologics were part of the interventions evaluated. Hence, deviations did not arise because of the trial context. TIME TO CLINICAL IMPROVEMENT Participants were analyzed according to their randomized groups for the outcome. No participants were excluded from the analysis post-randomization. This method was considered appropriate to estimate the effect of assignment to intervention. Risk assessed to be low for the outcome: Time to clinical improvement MORTALITY, CLINICAL IMPROVEMENT, Our analysis for the 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 (D60 or more). Clinical improvement (D28). Clinical improvement (D60 or more). RoB assessment of the outcomes mortality (D28), time to death, score 7 and above D28 and serious adverse events for for the Tocilizumab arm and Siltuximab arm were consulted from The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499-518 due to unavailability of trial details. |
| Missing outcome data |
Low |
Comment: 342 participants randomized; 336 participants analyzed.
Data available for nearly all participants randomized. Risk assessed to be low for the outcomes: Mortality (D60 or more). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. RoB assessment of the outcomes mortality (D28), time to death, score 7 and above D28 and serious adverse events for the tocilizumab arm and siltuximab arm were consulted from The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499-518 due to unavailability of trial details. |
| 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 Observer-reported outcome not involving judgement. Risk assessed to be low for the outcome: Mortality (D60 or more). Time to death CLINICAL IMPROVEMENT Clinical improvement (defined as an increase of at least two points on a 6-category ordinal scale or discharge from the hospital alive) 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 outcome: Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. RoB assessment of the outcomes mortality (D28), time to death, score 7 and above D28 and serious adverse events for the tocilizumab arm and siltuximab arm were consulted from The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499-518 due to unavailability of trial details. |
| Selection of the reported results |
Low |
Comment: The protocol, statistical analysis plan, and registry were available (dated April 1, 2020).
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 (D60 or more). Clinical improvement (D28). Clinical improvement (D60 or more). Time to clinical improvement. RoB assessment of the outcomes mortality (D28), time to death, score 7 and above D28 and serious adverse events for the tocilizumab arm and siltuximab arm were consulted from The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499-518 due to unavailability of trial details. |
| Overall risk of bias |
Some concerns |