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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)?
Methods:
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.
Results:
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%).
Conclusions:
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.
Perspective:
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.
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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