Efficacy and safety of riociguat in early pulmonary vascular disease (ESRA): a prospective, multicenter, randomized, double-blind, placebo-controlled phase IIa trial.

BACKGROUND Pulmonary arterial hypertension (PAH) therapies have not been systematically studied in early disease stages, despite potential benefit. RESEARCH QUESTION Is riociguat safe, well tolerated, and potentially effective in early pulmonary vascular disease (PVD)? STUDY DESIGN AND METHODS In this prospective, multicenter, double-blind phase IIa trial adults with early pulmonary vascular disease, defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg with pulmonary vascular resistance (PVR) ≥2 - <3 Wood Units (WU), or mPAP 21 - <25 mmHg with PVR ≥2 WU, were randomized and received 1:1 riociguat or placebo for 24 weeks. The primary endpoint was change in PVR from baseline to week 24. Secondary endpoints, evaluated hierarchically, comprised changes in cardiac index, total pulmonary resistance, diffusing capacity of the lung, six-minute walking distance, WHO functional class, quality of life (QoL). Complementary parameters were analyzed in an exploratory manner. Safety was monitored throughout. RESULTS Of 261 pre-screened patients, 35 eligible patients were randomized (97% female, 65.5±6.9 years; 77.1% connective tissue disease-associated PAH); 32 completed the trial. Reasons for ineligibility were documented. Riociguat significantly improved the primary endpoint PVR (riociguat -0.73±0.67 WU vs. placebo -0.02±0.67 WU, p=0.043; 27% placebo-adjusted reduction). No significant differences were observed in secondary endpoints. Of exploratory endpoints, only cardiac output showed a trend toward improvement under riociguat (0.35±0.86 l/min vs. placebo -0.19 ±0.75 l/min, p=0.084). Only mild to moderate adverse events were observed, serious events were not considered treatment related. INTERPRETATION Despite the limited number of participants, treatment with riociguat was safe and significantly improved the primary endpoint PVR over 24 weeks. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov, NCT05339087, available at https://clinicaltrials.gov/study/NCT05339087.