Rodatristat ethyl decreases activity in pulmonary arterial hypertension: results from the ELEVATE-2 trial

RATIONALE: Wearable devices provide an objective measurement of activity in the home setting and are complementary to 6-minute walk distance. Patients with pulmonary arterial hypertension (PAH) have low daily activity time, which is likely related to physiologic impairment and behavioral changes. Actigraphy may be a functional outcome assessment capable of detecting changes in activity mediated by improvement in physiology in a therapy trial. OBJECTIVES: ELEVATE-2 was a phase 2 trial evaluating rodatristat ethyl versus placebo in PAH. We hypothesized rodatristat ethyl would improve measures of activity, specifically peak steps, at week 24, and further that changes in actigraphy measures would correlate with changes in stroke volume index. METHODS: ELEVATE-2 was a randomized, double-blinded, placebo-controlled trial. All participants wore an ActiGraph on their wrist. We compared changes in average peak 5-minute steps (steps during the most active 5 minutes of a day, whether or not consecutive), daily steps, moderate activity time, and vigorous activity time at baseline, week 12, and week 24. Linear mixed methods with repeated measures were performed to assess treatment-time interaction at week 24, and least squares means were used to compare groups. Linear regression was performed to evaluate the changes in stroke volume index on activity parameters. RESULTS: Of the 108 participants, 100 were included in the analysis. Adjusted least squares mean showed that peak 5-minute steps (-49 steps [95% CI, -80 to -18]), moderate activity time (-17.3 minutes/day [95% CI, -29.3 to -5.3]), and daily steps (-656 [95% CI, -1171 to -140]) all decreased at week 24 after treatment with rodatristat ethyl compared to placebo. Peak 5-minute steps were weakly associated with changes in stroke volume index (0.74 [95% CI, 0.11-1.37]). CONCLUSIONS: Rodatristat ethyl reduced multiple activity parameters in this small, randomized multicenter study. Peak steps, daily steps, and moderate activity time seem to capture different aspects of movement in the home setting. Activity parameters were not strongly associated with resting hemodynamics, underscoring the influence of behavioral and external factors on activity. CLINICAL TRIALS REGISTRATION: NCT04712669.