PURPOSE: There are no approved therapies for pulmonary arterial hypertension (PAH) in India, a situation similar to that in the United States when the initial studies of intravenous epoprostenol (prostacyclin) were conducted. Intravenous treprostinil, a stable prostacyclin analog, was tested in India in the first placebo-controlled study of intravenous therapy in PAH.
METHODS: This was a multicenter, placebo-controlled, 12-week study in NYHA Class III and IV patients with idiopathic/familial (IPAH) or collagen vascular disease- or HIV-associated PAH. Planned enrollment was up to 126 patients (2:1 active:placebo). Study drug was initiated at 4 ng/kg/min, with weekly increases of 8 ng/kg/min allowed. The primary endpoint was exercise capacity measured by the six-minute walk (6MW). Other endpoints included NYHA Class change, Borg dyspnea score, and dyspnea fatigue index. Rescue therapy with open-label treprostinil was allowed in cases of life-threatening deterioration, and all patients were eligible for lifelong open-label continuation treatment.
RESULTS: The safety committee suspended enrollment after 44 patients received study drug (30 treprostinil, 14 placebo) due to deaths (nine deaths, including six in patients randomized to placebo), catheter dislodgments (8 reported), and serious adverse events related to sepsis or infection (three treprostinil patients, six placebo patients). Pre-specified analyses were applied after all patients completed treatment. Most patients were female (61%), with IPAH (95%) and NYHA Class III disease severity (95%). The mean week 12 dose was 72.5 and 80.0 ng/kg/min in the treprostinil and placebo groups. Treprostinil improved 6MW by a median 83.0 meters and mean 92.7 ± 42.0 meters over placebo (p=0.0077 for both). Treprostinil improved 6MW/Borg score (combined assessment, p=0.0023), Borg score (median improvement -2.0, p=0.023), and NYHA class (median improvement -1.0, p=0.023).
CONCLUSION: Intravenous treprostinil therapy was highly effective in treating PAH symptoms in this placebo-controlled trial.
CLINICAL IMPLICATIONS: Intravenous treprostinil is efficacious in PAH, but may be an inappropriate therapy where local health care delivery systems and/or patient living conditions are unacceptable for chronic intravenous infusion via an indwelling catheter.
DISCLOSURE: Michael Wade, No Product/Research Disclosure Information; Employee M. Wade is an employee of United Therapeutics Corp.