| Bias | Author's judgement | Support for judgement |
| Randomization |
Low |
Quote: “Participants were randomly assigned (1:1) using a web-based secure centralised system to either usual care plus anakinra or usual care alone. An independent statistician provided a computer-generated assignment randomisation list stratified by centre and blocked with varying block sizes (randomly of sizes two or four) unknown to the investigators.”
Comment: Allocation sequence random. Allocation sequence concealed. |
| Deviations from intervention |
Low |
Quote: “Open-label”
Comment: Unblinded study. No participant cross-over. Administration of co-interventions of interest was reported and was balanced between groups: antivirals, corticosteroids, biologics. Overall, there were no deviations that arose due to the trial context. Data were analyzed using intention-to-treat analysis for both efficacy and safety outcomes, which, to estimate the effect of assignment to intervention, was considered appropriate; participants analyzed according to their randomized assignment. Of note, 5 vs 2 patients were excluded from analysis. This is accounted for in ROB domain 3. Risk assessed to be low for outcomes: Mortality (D28). Mortality (D60). Time to death. 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. |
| Missing outcome data |
Low |
Comment: 116 patients randomized; 114 patients analyzed.
Data available for > 95% of population. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60). Time to death. 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 |
Some concerns |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Unblinded study Mortality is an observer-reported outcome not involving judgement. For WHO score 7 and above, we consider that the assessment cannot possibly be influenced by knowledge of intervention assignment. Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60). Time to death. WHO score 7 and above (D28). Time to WHO score 7 and above. Clinical improvement (defined as discharge by day 28) requires clinical judgement and could be affected by knowledge of intervention receipt. Also, the authors reported on adverse events and serious adverse events that may contain both clinically- and laboratory-detected outcomes. All these outcomes can be influenced by knowledge of the intervention assignment. Risk assessed to be some concerns for the outcomes: Clinical improvement (D28). Time to clinical improvement. Adverse events. Serious adverse events. |
| Selection of the reported results |
Some concerns |
Comment: The protocol, statistical analysis plan (SAP) and trial registry were available.
Mortality and WHO score 7 and above outcomes analyzed as pre-specified. Time to hospital discharge (taken as clinical improvement) was pre-specified in the protocol with no timepoint (as is typical) and in the registry at a timepoint of 90 days, however, in the report "it was assessed at day 28 because this was the latest timepoint when data were complete for almost all patients". Following contact with the authors, it was determined that this was done on the recommendations of the DSMB; to analyze trials when 28 days follow-up had been achieved. 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). Time to death. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). Time to WHO score 7 and above. Adverse events and serious adverse events were not pre-specified. No information on whether the results were selected from multiple outcome measurements or analyses of the data. Risk assessed to be some concerns for the outcomes: Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |