Study assessments and statistical analyses
toxicities, AML, OS
ADVERSE EVENT, ADVERSE EVENT, AML, REGRESSION, EVENTS
Statistical analyses were performed according to the principles of the ICH-guideline E9 “Statistical Principles for Clinical Trials.” The primary outcome was OS. A sample size of 100 patients was initially planned to provide a sufficiently precise 95% CI for the hazard ratio (HR, nintedanib vs placebo) of OS. With the initial assumptions of exponential-distributed OS (median OS 176 days in the nintedanib arm vs 110 days in the placebo arm, HR 0.625, 80 events in total), the probability to observe a confirmatory 95% CI for the HR with half-width ≤ 0.34 was 80%. Patients were randomly assigned to treatment of either LDAC plus nintedanib or LDAC plus placebo in a 1:1 ratio. Randomization was stratified by AML status (newly diagnosed and r/r AML). A block randomization was used with a block length of 4.Data base closure was on July 27, 2021. Measurements were summarized by descriptive statistics. Statistical analyses for time-to-event endpoints included the Kaplan–Meier estimator, log-rank test, Cox proportional hazard regression model, and competing risk approach. In the primary analysis, a confirmatory two-sided 95% confidence interval (CI) for the HR of nintedanib vs placebo adjusted for AML status was established in the full-analysis-set using the intention-to-treat (ITT) principle. The Cox model included OS as dependent variable and the main effect of the AML status variable and the treatment arm variable as covariates. The primary analysis was calculated by a 95% CI for the HR by using a Cox regression with treatment arm and AML status (newly diagnosed vs r/r) as independent variables. For sensitivity analysis, the unadjusted 95% CI was computed using a Cox model including the treatment arm variable as the only covariate and both arms were compared using a log-rank test. In addition, analyses were repeated in the per-protocol collective (results not shown).For safety analyses, patients were analyzed according to the received study treatment (as treated). All patients who received any dose of either nintedanib or placebo were included in the safety and efficacy analyses. Adverse events (AE) and laboratory abnormalities were based on Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) and were coded according to Medical Dictionary for Regulatory Activities (MedDRA, version 21.1). AEs were summarized by type, frequency, severity, relatedness, and seriousness. The numbers of patients who developed toxicities within a system organ class were compared between the two groups using Fisher’s exact tests. All 