Subcutaneous treprostinil for the treatment of severe, non-operable chronic thromboembolic pulmonary hypertension: a randomized, double-blind, controlled study (CTREPH)

Abstract

Purpose: Treprostinil is a stable prostacyclin analogue approved for the treatment of pulmonary arterial hypertension. A short-term randomized, placebo-controlled trial reported that Treprostinil improved exercise capacity, indices of dyspnea, signs and symptoms, hemodynamics, and quality of life. Recent long-term data suggest that the treatment with subcutaneous Treprostinil (scTRE) is safe and efficacious over many years, in various forms of pre-capillary pulmonary hypertension (PH). The phase III, double-blind, randomized, controlled CTREPH study investigated the efficacy and safety of scTRE in patients with severe non-operable chronic thromboembolic pulmonary hypertension (CTEPH), a PH subset with no approved pharmacological treatment options. Methods: Patients with severe CTEPH classified as non-operable were assigned in a double-blinded fashion to low-dose scTRE (target dose 3 ng/kg/min - corresponding to a placebo dose) or high-dose scTRE (target dose 30 ng/kg/min at 12 weeks). Primary outcome was the change from baseline in 6-minute walking distance (6MWD) at week 24. Secondary endpoints included the change from baseline in pulmonary vascular resistance (PVR), NT-proBNP, WHO functional class (WHO FC), clinical worsening, quality of life (Minnesota questionnaire) and Borg dyspnea score. 92 patients were planned. Interim analysis was performed after 54 patients had been enrolled and subjected to study drug in four European expert centers (Prague, Vienna, Warsaw, Dresden). Results: Baseline 6MWD was 298.9±83.9 m, and PVR was 843±382 dynes.cm.s-5 (mean age 63.5 years, 48% female). 3 patients (5.5%) did not tolerate scTRE. 6 patients (11%) were withdrawn due to clinical worsening (n=4), and because of severe concomitant disease (ileus, aortic stenosis, n=2). 6MWD improved by 42.9 m from baseline (95% CI 11.1 to 74.8 m, intention-to-treat) in high-dose scTRE-treated patients, compared with a change of 4.5 m in subjects on low-dose scTRE (p= 0,059). PVR decreased by 211.6 dyn.s.cm-5 from baseline in patients on high-dose scTRE (95% -331.04 to -92.24) compared with an increase of 59.2 dyn.s.cm-5 (p=0.001) in the low-dose group. WHO FC significantly improved in patients on high-dose scTRE (p=0,01). Per protocol analysis demonstrated an increase of 6MWD by 57.4 m from baseline (95% CI 32.4 to 82.3 m, high-dose scTRE), compared with 5 m (p=0,0045, low-dose scTRE). Conclusions: In patients with non-operable CTEPH, scTRE significantly improved exercise capacity, WHO FC and PVR.