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: "stratified randomization"
From contact with authors: "The Allocations Portal The logic of the Allocations portal is quite simple and straightforward. Once a patient is successfully enrolled, he/she is automatically made visible in the Allocations Portal, 6 6 waiting to be allocated by the unblinded pharmacist. Once allocation is requested the process is automatic. The software finds the first not allocated slot in the Randomization table according to the combination of the patient’s strata (initial WHO classification, dexamethasone intake and BMI classification), assign this slot to the patient’s primary key and reports back to the main table (only for the allocators eyes) the allocation assigned to the patient (placebo or anakinra)." Comment: Allocation sequence probably random. Allocation sequence concealed. Imbalances in baseline characteristics appear to be compatible with chance. |
| Deviations from intervention |
Low |
Quote: "double-blind" "Study drug was prepared by an unblinded pharmacist with access to the electronic study system using a separate username and a password. Administration was done by a blind study nurse" (report) "Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)" (registry)
Comment: Blinded study (participants and personnel/carers) MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE, AE, SAE 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). WHO score 7 and above (D60 or more). Adverse events. Serious adverse events. TIME TO DEATH, (TIME TO) VIRAL NEGATIVE CONVERSION, TIME TO CLINICAL IMPROVEMENT, TIME TO WHO SCORE 7 AND ABOVE Participants were analyzed according to their randomized groups for the outcome. Of note, 7 vs 5 participants (viral negative conversion) and 24 vs 14 (time to death, time to clinical improvement and time to WHO score 7 and above) were excluded from the analysis post-randomization due to missing data which is accounted for in domain 3. This method was considered appropriate to estimate the effect of assignment to intervention for this outcome. Risk assessed to be low for the outcomes: Time to death. Incidence of viral negative conversion (D7). Time to viral negative conversion. Time to clinical improvement. Time to WHO score 7 and above. |
| Missing outcome data |
Some concerns |
MORTALITY (D28), (TIME TO) VIRAL NEGATIVE CONVERSION, CLINICAL IMPROVEMENT, WHO SCORE 7 AND ABOVE (D28), AE, SAE
Comment: 606 participants randomized; 594 participants analyzed. Data available for nearly all participants randomized. Of note, 7 vs 5 participants were excluded due to withdrawal of consent. Risk assessed to be low for the outcomes: Mortality (D28). Incidence of viral negative conversion (D7). Time to viral negative conversion. Clinical improvement (D28). WHO score 7 and above (D28). Adverse events. Serious adverse events. MORTALITY (D60 OR MORE), TIME TO DEATH, TIME TO CLINICAL IMPROVEMENT, (TIME TO) WHO SCORE 7 AND ABOVE (D60 OR MORE) Comment: 606 participants randomized; 568 participants analyzed. Data not available for all or nearly all participants randomized. No evidence that the result is not biased. Reasons: lost to follow-up (24 vs 14) Missingness could depend on the true value of the outcome. Not likely that missingness depended on the true value of the outcome (same reasons and equal proportion of missingness between arms). Risk assessed to be some concerns for the outcomes: Mortality (D60 or more). Time to death. Time to clinical improvement. WHO score 7 and above (D60 or more). Time to WHO score 7 and above. |
| Measurement of the outcome |
Low |
Comment: Method of measuring the outcome probably appropriate.
Measurement or ascertainment of outcome probably does not differ between groups. Blinded study (outcome assessor). Risk assessed to be low for the outcomes: Mortality (D28). Mortality (D60 or more). Time to death. Incidence of viral negative conversion (D7). Time to viral negative conversion. Clinical improvement (D28). Time to clinical improvement. WHO score 7 and above (D28). WHO score 7 and above (D60 or more). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Selection of the reported results |
Low |
Comment: The statistical analysis plan (dated April 26th, 2021) and the prospective protocol (dated December 5th, 2020) and registries were available (dated December 23rd, 2020 (NCT04680949) and December 9th, 2020 (EudraCT 2020-005828-11)).
MORTALITY, CLINICAL IMPROVEMENT, WHO SCORE 7 OR ABOVE (D28 OUTCOMES) Outcome pre-specified (as part of the WHO-CPS 11-point ordinal scale). 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). Clinical improvement (D28). WHO score 7 and above (D28). VIRAL NEGATIVE CONVERSION Outcome data acquired from contact with authors. Results were probably not selected from multiple outcome measurements or analyses of the data. Trial analyzed as pre-specified. Risk assessed to be low for the outcome: Incidence of viral negative conversion (D7). Time to viral negative conversion. MORTALITY, TIME TO CLINICAL IMPROVEMENT, WHO SCORE 7 OR ABOVE, AE, SAE (D60 0R MORE OUTCOMES) Outcome data acquired from contact with authors but also pre-specified in the registry at day 90 timepoint. 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). Time to death. Time to clinical improvement. WHO score 7 and above (D60 or more). Time to WHO score 7 and above. Adverse events. Serious adverse events. |
| Overall risk of bias |
Some concerns |