Statistical analysis
PD, death, TTP
REGRESSION, EVENTS, TTP
The sample size was determined based on a conservative estimation of the median PFS of 5.0 months in the aponermin group and 3.5 months in the placebo group. According to ethical opinion, the proportion of patients in the aponermin and placebo groups was 2:1. It was estimated that a total of 286 events of PD or death over a 30-months enrollment period and a 6-months follow-up would be required to have a statistical power of 80%. This is to show superiority at a hazard ratio (HR) of 0.70 using a log-rank test (one-sided alpha is 0.025). A total of 313 patients were needed based on the calculation before factoring in the dropout rate. However, considering a 25% dropout rate, at least 417 patients were required (278 in the aponermin group and 139 in the placebo group).No interim analyse was done in this trial. A final analysis was performed when the last participant had been enrolled for 6 months.In this study, all efficacy analyses were based on the modified intention-to-treat population (mITT), including all randomized patients who received at least one dose of the trial treatment. The primary endpoint, PFS, was compared using a prespecified stratified log-rank test. The Kaplan–Meier method was used to estimate the median PFS and depict the curve. The 95% confidence interval (CI) was estimated using the Brookmeyer-Crowley formula. HR and 95% CI were estimated using a stratified Cox proportional hazards model. The proportional hazards assumption was assessed and met by the Cox regression model, using time-dependent explanatory variables. The aforementioned strata variables were the same as those used in the randomization. Other time-to-event data, including OS, DOR, TTR, TTP, and subgroup analyses of PFS and OS, were analysed using a method similar to PFS. The ORR, clinical benefit rate and the rate of each response were compared between the groups using chi-squared tests. The Clopper–Pearson method was used to calculate the 95% CI. Subgroup analyses of ORR were performed using similar method. Scores for the EORTC QLQ-30 and MY20 were calculated according to the developer's scoring manual. The raw scores from the scales in both questionnaires were standardized by linear transformation to range 0–100. Descriptive statistics for the baseline scores for each domain were summarized, and the differences between groups were assessed using a group t-test. A mixed-model measure analysis was used to estimate the treatment effects over time for each domain (longitudinal analysis) and assess the differences between groups. The safety analysis included all patients who received at least one dose of the trial treatment. AEs were coded using MedDRA version 22.1. The frequency of AEs was reported.All statistical analyses were conducted using SAS software (version 9.4). Two-sided 