Statistical analysis
death
REGRESSION, SECONDARY, RECRUITMENT, POSITIVE
The statistical analysis plan was finalized prior to recruitment of the first patient. Sample size was calculated based on two approaches: the classical conventional approach and the adaptive design approach.Related to clinical experience and pre-trial data the usual care group was expected to reach the primary outcome after a mean of 15 +/- 6 days. Based on published literature and off-label experience of tocilizumab in Karolinska University Hospital Huddinge, we expected the time for reaching the primary outcome to decrease to 11 days in the anakinra and tocilizumab treatment arms.Taking the significance level at 5% and Type II error as 20% and an expected mean difference of 4 days, assuming a standard deviation of 6, 36 subjects were required per group to obtain 80% power. Given an anticipated dropout rate of 10%, a total of 40 subjects per group allocated 1:1:1 to UC, anakinra and tocilizumab (120 patients in all) was needed to obtain 80% power.Since the available data on covid-19 and potential effects of interventions to date was sparse, we expected that small variations in the magnitude of difference between intervention groups and control group in reaching the primary outcome could result in decreased power of the analysis. Therefore, an adaptive design was employed, allowing re-estimation of sample size at an interim point, when about 50% of the patients had been included. The interim analysis was performed by a statistician blinded to treatment assignment after recruitment of 74 patients. It found larger variance in the primary outcome than anticipated, 60 and 63 in the study arms with the largest between-group difference of mean days to recovery. This indicated that at least 61 patients had to be included per arm to maintain power. Given possible dropouts, decision was taken to increase sample size to 195 (65 patients per arm).The data were summarized as means (standard deviations (SD)) for symmetrically distributed numerical variables and medians (interquartile ranges (IQR)) for numerical variables with skewed distributions or categorical ordinal variables. Positive counts and percentages were presented for binary variables. Missing data were handled as missing at random.Analyses were performed by intention-to-treat, i e patients were analyzed as randomized. For the primary analysis of time to recovery, rate ratios stratified by time were calculated using the Mantel-Cox method. A corresponding log-rank test was conducted comparing anakinra or tocilizumab with usual care. Kaplan-Meier estimates of cumulative recoveries were estimated. Time was censored for patients who died at their day of death. For patients who had not recovered by then, time was censored at day 29. In a sensitivity analysis, hazard ratios were estimated using Cox proportional hazard regression models either crude, adjusted for age and sex or adjusted for age, sex and BMI.For the secondary analysis, differences in mortality were assessed using the Chi-squared test. Median time-to-event and confidence intervals were estimated. Differences in median time-to-event were calculated and confidence intervals estimated using bootstrap. Rate ratios were estimated and compared as in the primary analysis. Confidence intervals for proportions or pairwise differences of proportions were obtained and percentage point differences evaluated under a binomial distribution assumption. Confidence intervals for number of days or pairwise difference in mean number of days were estimated and differences evaluated according to the assumptions of a t-test. In sensitivity analyses of the main outcome, crude age and sex adjusted regression analyses were conducted using a Cox proportional hazard model. The purpose of the sensitivity analyses was to explore potential effects of age and sex on hazard ratios, between treatment groups due to the discontinuation of the recruitment.A significance level of 0.05 was chosen and two-sided p-values were reported. The robust sandwich estimator was used to estimate standard errors for all regression models. All analyses were conducted in STATA version 16.1 (StataCorp, College Station, TX).