Exercise treadmill testing for efficacy evaluation in randomized, controlled trials

Abstract

Exercise treadmill testing measures functional capacity and inducible myocardial ischemia and has historically served as an endpoint in phase 2 trials. The Precision Medicine with Zibotentan in Microvascular Angina trial evaluated the selective endothelin-A receptor antagonist zibotentan as a potential disease-modifying therapy for microvascular angina. The trial had a randomized, double-blind, cross-over design and the primary outcome was exercise duration. Compared with placebo, zibotentan at a dose of 10-mg daily for 12-weeks did not improve exercise duration or angina symptoms. In this prespecified analysis, exercise duration was compared across four sequential study visits and the factors associated with within-trial changes were evaluated. Exercise test duration increased progressively in all participants during sequential trial phases, independent of treatment with either zibotentan or placebo. This improvement in exercise duration was associated with female sex (interaction p-value = .0213; effect estimate [95% confidence interval]) 34.95 [13.99, 55.78] seconds, P = .002). In conclusion, the exercise test has limitations as an objective endpoint of efficacy in randomized trials. PRIZE; https://clinicaltrials.gov/study/NCT04097314 Clinicaltrials.gov Registration: NCT04097314.