Study design rationale and prespecified interim analysis
EVENT
Four initial tropifexor doses of 10–90 μg were assessed in Part A based on preclinical results, safety and pharmacological activity (elevation of FGF19 up to 6 h after dosing) in this first-in-human studyFollowing DMC recommendation, randomization to Part B began with the tropifexor 90-μg (found to be safe and efficacious) dose and tropifexor 60 μg (the next highest dose). A second analysis was performed after all patients in Part A completed the week 16 visit. A third analysis of complete Part A and B data (pooled) was performed when all patients randomized to Part B completed the end-of-study visit (week 16) or prematurely discontinued the study. An interim analysis of Part C data (fourth planned reporting event) was performed when all patients completed the week 12 visit (time of primary endpoint) or prematurely discontinued the study. The final data analysis was carried out when all patients in Part C completed the week 52 visit.Part C was introduced based on DMC recommendation to pursue tropifexor doses >90 μg. Randomization into Part C began after completion of Part B randomization. An exploratory exposure–response analysis of the Part A biomarker data (ALT, AST, FGF19 and GGT) at week 8 suggested investigation of area under the curve (AUC) > 40 ng × h mlThe timepoint for week 8 interim analysis in Part A and the treatment duration (12 weeks) for Parts A and B were selected based on internal recommendations. This treatment duration was also supported by Good Laboratory Practice toxicology studies (13 weeks). Further longer-term Good Laboratory Practice toxicology studies (26 weeks in rats and 39 weeks in dogs) enabled tropifexor treatment for 48 weeks in Part C to allow for evaluation of histologic endpoints and long-term safety and efficacy.