Sample size and multiplicity strategy
HO
SECONDARY
The sample size estimation for at least 24 patients (12 patients per treatment group) with active HO at baseline and classic ACVR1(R206H) mutation was based on statistical considerations for the following efficacy end points: percent change from baseline in (1) TLA by In period 1, testing of the primary and key secondary efficacy end points followed a hierarchical testing procedure to address multiplicity at an overall two-sided α = 0.05 significance level. Testing of the key secondary efficacy end points would follow a hierarchical testing sequence only if statistical significance was established for all primary end points. No further adjustments were made for other secondary and exploratory end points, for which nominal In period 2, the evaluation of these prospectively specified redefined primary and key secondary end points relating to new heterotopic bone formation warranted new analyses, which were independent from that of period 1 and required their own overall type I error rate of 10% (α of 0.1). To control the type I error rate at 0.10 for the primary and key secondary null hypotheses in period 2, a hierarchical testing procedure was applied at a two-sided 10% significant level as detailed. No further adjustments were made for other secondary and exploratory end points in period 2, for which estimates, 95% CI and/or nominal 