Statistical analysis
toxicity, ICH
REGRESSION, EVENTS, SECONDARY, REMISSION
The primary analysis will be performed according to the intention-to-treat (ITT) principle in the full analysis set (FAS). The FAS includes all randomized patients in whom therapy after randomization was started. Patients will be analysed in the treatment arms to which they were randomized, irrespective of whether they refused or discontinued the treatment or whether other protocol deviations are known.The analysis of the primary endpoint PFS will be conducted in the FAS according to the intention-to-treat principle. The treatment effect will be estimated and tested by Cox regression. The regression model will include treatment and, for adjustment, the stratification variable ECOG (0/1 vs. ≥ 2) as independent variables. As estimate of the effect size, the hazard ratio (arm A vs. arm B) will be calculated with a corresponding asymptotic two-sided 95% confidence interval (CI). The two-sided test on the difference between the experimental arm A and the control arm B at two-sided significance level of 5% will be based on the corresponding asymptotic two-sided 95% CI from the Cox regression model.Additionally, PFS rates in the two treatment arms will be estimated by the Kaplan-Meier method.The primary analysis is conducted irrespective of the occurrence of intercurrent events, consistent with the treatment policy strategy of the estimands framework described in the ICH E9 (R1) addendum. Intercurrent events comprise early termination of treatment due to toxicity, treatment failure or patient´s wish. These events are captured in the secondary endpoint EFS in accordance with the composite strategy.As a sensitivity analysis, the analysis will be repeated in the per-protocol (PP) set, excluding patients with major protocol violations.Secondary endpoints will be analyzed descriptively. EFS and OS will be analyzed in the same way as described for PFS. Remission after 2 cycles of induction treatment will be determined after the 2nd cycle of R-MP in arm A and after the 2nd cycle of MARTA in arm B (= RA I in both arms). The endpoint remission after completion of the 3rd cycle of R-MP (arm A) / consolidating HCT-ASCT (arm B) will be determined within 25–35 days after the start of the 3rd cycle of R-MP (arm A) / on day 30 after ASCT (arm B).Sensitivity analyses will be performed by additionally including other relevant prognostic variables: gender, LDH level (≤ vs. > above upper normal limit), involvement of deep structures of the brain (yes vs. no) and protein count of cerebrospinal fluid (≤ vs. > above upper normal limit), to adjust for potential confounding in the regression models proposed above for the primary and the secondary endpoints.Safety analyses will be performed in the safety population (SAF). Patients in the SAF are analyzed as belonging to the treatment arm defined by treatment received. Patients are included in the respective treatment arm, if treatment was started.