Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension: A Randomized Controlled Trial

Study Questions:

What is the safety and efficacy of the oral prostacyclin analogue, treprostinil diolamine, as initial treatment for de novo pulmonary arterial hypertension (PAH)?


Three hundred and forty-nine patients with PAH (intent-to-treat population [ITT]) not receiving an endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n = 233; placebo, n = 116). The primary analysis population (modified ITT [mITT]) included 228 patients (treprostinil, n = 151; placebo, n = 77) with access to 0.25 mg treprostinil tablets at randomization. Study drug was administered every 12 hours with dose escalation of an additional 0.25-0.5 mg BID every 3 days and a maximum possible dose of 12 mg BID. The primary endpoint was change from baseline in 6-minute walk distance (6MWD) at week 12. Secondary endpoints included Borg dyspnea index, clinical worsening, and symptoms of PAH.


For the mITT population, the mean age was 39.4 years (range 12-73 years). The majority were Asian (71%) and female (73%), with a diagnosis of idiopathic PAH/hereditable PAH (75%) or connective tissue disease (20%), 66% World Health Organization functional class III, and mean 6MWD 330 m. For the mITT population, the mean dose of treprostinil for patients completing the week 12 assessments was 3.4 ± 1.9 mg BID. The week 12 treatment effect for 6MWD (mITT population) was 23.0 m (p = 0.0125). For the ITT population, 6MWD improvements were observed at peak (26.0 m; p = 0.0001) and trough plasma study drug concentrations (17.0 m; p = 0.0025). Other than an improvement in the combined 6MWD/Borg dyspnea score, there were no significant changes in secondary endpoints. Oral treprostinil therapy was generally well tolerated; most common adverse events (ITT) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%).


Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy.


Overall, the results from this study with respect to 6MWD are similar to those seen in the placebo-controlled studies for currently approved PAH oral therapies (both ERA and phosphodiesterase-5 inhibitor). However, most studies have shown a decrease in percentage of clinical worsening. The side effects were high and typical of the prostacyclins. The oral treprostinil dose of 3.5 mg BID produced plasma levels between 2 and 8 hours post-dose, which is comparable to parenteral infusion rates of 10-30 ng/kg/min. However, the average patient dose for parenteral treprostinil in clinical practice is at least 50 ng/kg/min.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Lipid Metabolism, Acute Heart Failure, Pulmonary Hypertension, Exercise, Hypertension

Keywords: Connective Tissue Diseases, Phosphodiesterase Inhibitors, Nausea, Mandible, Epoprostenol, Exercise, Diarrhea, Pain, Dyspnea, Headache, Vasodilator Agents, Heart Failure, Hypertension, Pulmonary, Prostaglandins I, Hypertension, Diabetes Mellitus, Tablets, Ethanolamines

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