Rodatristat Ethyl Decreases Activity in Pulmonary Arterial Hypertension: Results from the ELEVATE-2 Trial

Abstract Rationale Wearable devices provide an objective measurement of activity in the home setting and are complementary to 6-minute walk distance. Pulmonary arterial hypertension (PAH) patients 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. Objective 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 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 Peak 5-minute steps (-49 steps (-80 to -18)), moderate activity time (-17.3 minutes/day (-29.3 to -5.3)), and daily steps (-656 (-1,171 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 (0.11 to 1.37). Conclusion Rodatristat ethyl reduced multiple activity parameters in this small but randomized, multi-center 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.