Statistical analysis
REGRESSION, SECONDARY
The study was powered to detect an absolute increase of 20% in the rate of patients discharged alive at day 15 with a power of 90% and a two-sided 0.05 significance level, assuming a 50% rate in the control group. Accordingly, the sample size was 124 patients per group. To account for potential errors in the administration of the allocated treatment, this number was increased to 150 per group.The analysis followed the intention to treat (ITT) principle, and all randomised participants were analysed in the group allocated by randomisation, regardless of the actual treatment received or other protocol deviations. Only participants withdrawing their consent during the study and opposing analysis of their data were excluded from the analysis. The Statistical Analysis Plan was developed blinded to treatment assignment (i.e. without knowledge of group allocation), except for the last amendment concerning fallback solutions when some models did not converge. When drafting the first version of the Statistical Analysis Plan, some changes were made compared to the original protocol: (1) the last observation carried forward approach to handle supplemented by multiple imputation for missing data, given that the primary outcome was missing for two participants only; (2) the analytic model for binary outcomes changed from logistic regression with random centre effects to a log-binomial model with robust standard errors in order to directly estimate relative risks (RRs) instead of odds ratios and limit issues with convergence of binomial generalised linear mixed models [Missing primary outcome data were treated as failures, and sensitivity analyses with the worst-case scenario imputation (imputing a failure in the experimental group but a success in the control group) or available data analysis were carried out. No imputation was performed for secondary efficacy and safety outcomes.Binary outcomes were analysed with a log-binomial model adjusted for the randomisation strata, with robust standard errors to account for centre [No correction for multiplicity and no hierarchical testing procedures were used in analysing secondary outcomes, which should be regarded as exploratory. Analyses were performed using R 4.0.5 software (The R Foundation for Statistical Computing, Vienna, Austria).