Outcome Assessment and Statistical Analysis
cough
SECONDARY
The primary endpoint was the ratio of the number of coughs/h in 24 h at Week 4 to that at baseline. Secondary efficacy endpoints included the ratio of the number of coughs/h while awake/asleep to that at baseline and change from baseline in cough severity (VAS; 0–100 mm; 0: no cough, 100: worst cough ever) [The previous phase 2a study observed a mean ± standard deviation (SD) log-transformed ratio of coughs/h in 24 h after 2 weeks of treatment to that at baseline of − 0.327 ± 0.379 with sivopixant 150 mg and − 0.160 ± 0.363 with placebo. The effect size between the placebo and sivopixant groups was assumed to be − 0.44 and the same at 4 weeks. Based on that, the sample size in the current study (80% power using a 2-sided 5% significance level) was calculated as 83 patients per group. By allowing a dropout rate of 10%, 93 patients per treatment group would be needed. Thus, the planned sample size at randomization was 372 patients.All efficacy analyses were performed in the full analysis set (FAS), and safety analysis was performed in the safety population. The primary endpoint analysis was additionally performed in the per-protocol set (PPS) as supplemental analysis. The analysis sets have been described in e-Appendix 3 (Online Resource).For the analysis of the primary efficacy endpoint, the ratio of the number of coughs/h in 24 h at each visit to that at baseline was transformed using the common logarithm. The primary endpoints were assessed using a mixed-effects model, with treatment group, week, and the interaction between treatment group and week as fixed effects; patient as random effect; and region and log-transformed coughs/h in 24 h at baseline as covariates. Missing data for cough frequency were not imputed, and observed data were used for the model. Baseline value was defined as the last valid assessment recorded prior to first administration of the study medication. The primary analysis summarized each of the three 2-way comparisons with placebo and presented the estimate for the difference in treatment effect at Week 4 and 95% confidence interval (CI) for this difference. The In the proof-of-concept study, four patients with baseline hourly cough count values < 10 were included. However, the placebo-adjusted change in cough count was highly variable in this subgroup, and for this reason, patients with cough count < 10 at Visit 1 were excluded from this phase 2b trial. However, we did undertake a post hoc subgroup analysis for the primary and some secondary endpoints in patients with ≥ 10 and < 10 coughs/h in 24 h at Visit 2. All analyses and tabulations were performed using SAS, version 9.2 or higher.