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.
Exercise treadmill testing provides information on functional capacity and inducible myocardial ischemia reflected by ST-segment deviation and chest discomfort limiting exercise. In phase 2 clinical trials, the exercise treadmill test has served as an intermediate endpoint for Food and Drug Administration (FDA) licensing of medicines for angina. Exercise testing is also used as an intermediate endpoint in randomized trials in other patient populations, including those with heart failure and pulmonary hypertension.
Microvascular angina is defined by symptoms, evidence of myocardial ischemia, no obstructive coronary artery disease, and abnormal coronary microvascular function. The exercise treadmill test is useful for the diagnosis of ischemia and nonobstructive coronary arteries (INOCA), but it also has limitations particularly in individuals with comorbidity and a noncardiovascular reason for exercise impairment e.g. arthritis. Patients with INOCA may experience exercise-limiting symptoms and disease-modifying therapy is limited. The exercise treadmill test has been considered as an intermediate endpoint in INOCA trials, however the utility of the exercise test as an efficacy endpoint in trials involving patients with INOCA remains uncertain
The Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial evaluated the selective endothelin-A receptor antagonist zibotentan as a potential disease-modifying therapy for microvascular angina Compared with placebo, zibotentan did not improve exercise duration or angina symptoms.
Methods
The PRIZE trial was approved by the UK National Research Ethics Service (reference 19/NE/0110), cosponsored by NHS Greater Glasgow & Clyde and the University of Glasgow. The study adhered to the principles of the Declaration of Helsinki and the CONSORT 2010 statement for randomized clinical trials.
PRIZE was a multicenter, double-blind, placebo-controlled, sequential crossover trial of zibotentan 10-mg once daily over twelve weeks in 118 participants randomized to receive zibotentan followed by placebo, or vice versa.
The participants completed four sequential exercise treadmill tests. They underwent Bruce protocol exercise testing at enrolment (screening visit), at baseline (after a 3-week single-blind placebo run-in), and at the end of each of the sequential treatment phases, reflecting the randomized cross-over design. In this prespecified analysis, factors associated with within-trial changes in the duration of exercise were evaluated. The study was publicly registered at ClinicalTrials.gov (NCT04097314). Trial conduct was overseen by a Steering Committee and an Independent Data and Monitoring Committee. Because the crossover design did not involve adjudication of between-group clinical endpoints, a Clinical Event Committee was not required.
Results
Main trial results
In this trial, zibotentan 10-mg once daily for twelve weeks did not improve exercise duration (primary outcome) compared with placebo (mean difference −4.26 seconds; 95% CI −19.60 to 11.06; P =.5871), and zibotentan did not improve symptoms, physical activity or health-related quality of life as reflected by validated patient reported outcome measures.
Pharmacodynamics
Compared to placebo, zibotentan reduced systolic blood pressure ( n = 117, effect estimate (95% confidence interval −5.49 (−8.49, −2.50) mmHg; P <.001) and hemoglobin level ( n = 116, −7.73 g/L (−9.43, −6.01) mm Hg; P <.001), consistent with vasodilation and hemodilution, respectively.
Exercise duration
Exercise duration improved progressively in all participants during the clinical trial period but not during the preceding screening phase ( Figure and Table ). Screening lasted 62.0 [45.0, 84.0] days and no difference in exercise duration occurred between the first and second exercise tests (screening and baseline visits: median difference: 3.0 seconds [interquartile range −27.0 to 41.0]; P =.726). Similarly, no significant improvement occurred during phase 1 (from runin to the end of the first treatment phase), with a median change of 1.0 second [interquartile range −28.0 to 51.0] ( P =.113). By contrast, compared to the exercise duration at the end of phase 1, exercise duration at the end of phase 2 (end of trial visit) was significantly increased (median change: 22.0 seconds [interquartile range −19.0 to 58.0]; P =.009), and exercise duration at the end of phase 2 was also significantly longer compared to baseline (second exercise test) (26.0 seconds [interquartile range −26.0 to 77.0]; P =.002). The durations of exercise at the end of phase 1 and phase 2 exceeded the durations of exercise before treatment with zibotentan or placebo, regardless of the randomized treatment sequence ( Figure ). The progressive improvement in exercise duration during treatment phases was unrelated to the randomized sequence of zibotentan and placebo.
Exercise treadmill test duration in the PRIZE clinical trial. A. Line plot showing mean total exercise duration (seconds) at each study visit for 118 randomi z ed participants (black dots and line), placebo-first group (blue squares and interrupted line), and zibotentan-first group (red asterisks and dotted line). No significant change in exercise time was observed between screening (first exercise test) and baseline (second exercise test), with both exercise tests occurring before treatment allocation, or at the end of phase 1 (third exercise test). However, a significant improvement in exercise duration occurred at the end of phase 2 (fourth exercise test), regardless of treatment order. Missing exercise test data are shown in the Table . B. Exercise test time differences (seconds) between visits of the randomized participants (n and missing).
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