Strengths and Limitations
death
SECONDARY
The strengths of this trial include its randomized design in a very representative sample of the Spanish population during the first waves of the COVID-19 pandemic. In addition, the baseline characteristics were generally well-balanced between groups, and the post hoc adjusted analyses yielded similar results as the unadjusted analyses regarding the risk of mechanical ventilation and death.One of the main limitations of the study is its open-label design. It is not expected that this influenced the risk of bias in the measurement of the outcomes, because they are objective or very protocoled measures, but it could have had some influence on the deviations from the intended interventions, such as a differential use of cointerventions. The need for prohibited medication was higher in the SoC group, which may have induced an underestimation of the benefit of anakinra. Another limitation is that, although the analysis was conducted in an ITT basis, there were some missing data for principal and secondary outcomes that may be lost to follow-up for nonrandom reasons. We consider that this did not bias the results, because the percentage of missing data is not high (5%) and the sensitivity analysis for different scenarios suggests stability of the results regardless the assumptions. Another limitation is that the hospital effect has not been included in the analysis, although we consider that this has not had an important effect because we did not expect high heterogeneity among centers. Regarding randomization, the proportion of patients requiring oxygen supplementation at baseline was significantly higher in the anakinra group, but we think that it is related to chance and does not imply a bias in the randomization procedure, so no adjustment for it has been conducted. Furthermore, the sample size was not high enough to detect moderate differences between groups in primary and secondary outcomes, but we consider this information useful for future studies and meta-analyses.