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 1:1 through permuted-block randomization to receive SOC and 1 dose of tocilizumab 4 or 8 mg/kg (maximum 800 mg) intravenously. An interactive voice or web-based response system provided sites with treatment assignments. Randomization was stratified by pneumonia severity (moderate or severe).
Comment: Allocation sequence random Allocation sequence concealed |
| 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. Administration of co-interventions of interest, antivirals and corticosteroids, were reported and balanced. Biologics were the intervention. Hence, deviations did not arise because of the trial context. 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 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, 1 vs 2 participants were excluded from the analysis post-randomization because they did not receive the treatment. 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 outcome: Time to death. Time to clinical improvement. (TIME TO) VIRAL NEGATIVE CONVERSION Participants were analyzed according to their randomized groups for the outcome. Of note, 21 vs 22 participants were excluded from the analysis post-randomization because it was not possible to collect sample from all patients randomized at all timepoints. This will be assessed in ROB 3 domain. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcome: Incidence of viral negative conversion. Time to viral negative conversion. |
| Missing outcome data |
Low |
Comment: 100 participants randomized; 57 patients analyzed for viral negative conversion; 97 participants analyzed for all other outcomes.
MORTALITY. TIME TO DEATH. (TIME TO) CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE. ADVERSE AND SERIOUS ADVERSE EVENTS Data available for all or nearly all participants randomized. Of note, the exclusions were already accounted for in domain 2 for the time to death and time to clinical improvement outcomes. 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. Adverse events. Serious adverse events. (TIME TO) VIRAL NEGATIVE CONVERSION. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: According to the authors, due to the conditions at the time of study it was not possible to collect nasopharyngeal swabs samples from all patients at all timepoints. Missingness probably could not depend on the true value of the outcome. Risk assessed to be low for the outcomes: Incidence of viral negative conversion. Time to viral negative conversion. |
| 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. (TIME TO) VIRAL NEGATIVE CONVERSION Observer-reported outcome not involving judgement. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Incidence of viral negative conversion. Time to viral negative conversion. WHO SCORE 7 AND ABOVE For this outcome, 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). (TIME TO) CLINICAL IMPROVEMENT Clinical improvement (defined as discharge (score of 1 on the 7 category WHO ordinal scale)) 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 |
Low |
Comment: The protocol, statistical analysis plan and registry (dated April 27, 2020) were available.
MORTALITY. TIME TO VIRAL NEGATIVE CONVERSION. 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 outcome: Mortality (D28). Mortality (D60 or more). Time to viral negative conversion. Clinical improvement (D28). Adverse events. Serious adverse events. TIME TO DEATH. VIRAL NEGATIVE CONVERSION. (TIME TO) CLINICAL IMPROVEMENT. WHO SCORE 7 AND ABOVE. Outcome data acquired from direct contact with authors. Analysis performed by the COVID-NMA. Risk assessed to be low for the outcome: Time to death. Incidence of viral negative conversion (D7). Time to clinical improvement. WHO score 7 and above (D28). |
| Overall risk of bias |
Some concerns |