Chest
Volume 144, Issue 3, September 2013, Pages 952-958
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Original Research
Pulmonary Vascular Disease
Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients Receiving Background Endothelin Receptor Antagonist and Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C2 Study): A Randomized Controlled Trial

https://doi.org/10.1378/chest.12-2875Get rights and content

Background

Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) as parenteral or inhaled therapy. Treprostinil diolamine, a sustained-release oral formulation of treprostinil, was studied to determine whether it could provide a more convenient prostacyclin treatment option for patients with less severe PAH. The objective of this study was to evaluate the efficacy and safety of oral treprostinil in patients with PAH receiving stable background endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I) therapy, or both.

Methods

A 16-week, multicenter, double-blind, placebo-controlled study in 310 patients with PAH compared bid administration of oral treprostinil (n = 157) with placebo (n = 153). The primary end point was change in 6-min walk distance at week 16. Secondary efficacy end points were World Health Organization functional class, Borg dyspnea score, dyspnea-fatigue index, signs and symptoms of PAH, and clinical worsening.

Results

One hundred thirty-two patients (84%) receiving oral treprostinil and 138 (90%) receiving placebo completed the study. The mean ± SD dose of oral treprostinil at week 16 was 3.1 ± 1.9 mg bid. The Hodges-Lehmann placebo-corrected median difference in 6MWD at week 16 was 10.0 m (95% CI, −2 to 22 m; P = .089). There were no significant changes in secondary end points. The most common adverse events associated with oral treprostinil were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), and jaw pain (25%).

Conclusions

The addition of oral treprostinil to background ERA and PDE-5I therapy did not result in a statistically significant improvement in exercise capacity. Side effects were common but tolerated by most subjects.

Section snippets

Patient Population

Eligible patients were aged 18 to 75 years with idiopathic PAH (IPAH) (including PAH associated with appetite suppressant or toxin use), familial PAH (FPAH), or PAH associated with congenital heart disease (repaired congenital systemic-to-pulmonary shunts for ≥ 5 years); connective tissue disease; or HIV. Diagnosis of PAH required a mean pulmonary arterial pressure of > 25 mm Hg, pulmonary capillary wedge pressure or left ventricular end-diastolic pressure of ≤ 15 mm Hg, pulmonary vascular

Patient Demographics and Disposition

A total of 310 patients (oral treprostinil, 157; placebo, 153) were randomized and received the study drug between June 15, 2009, and July 22, 2011 (Fig 1). The mean age for the study population was 51 years (range, 18-76 years). Patients were primarily women (78%) with IPAH or FPAH (65%) and World Health Organization functional class III (73%) symptoms (Table 1). At baseline, 53 patients (17%) were receiving ERA therapy alone, 132 (43%) were receiving PDE-5I therapy alone, and 125 (40%) were

Discussion

Sixteen weeks of oral treprostinil in combination with stable background therapy of ERA, PDE-5I, or both failed to improve exercise capacity in patients with PAH. There were no significant improvements in secondary end points. Although adverse events were common with oral treprostinil, it was well tolerated by most patients; the most frequent side effects were consistent with prostacyclin therapy.

For the primary end point, the change in 6MWD from baseline to week 16 was 10 m; this was not

Conclusions

Sixteen weeks of oral treprostinil therapy did not significantly improve 6MWD in patients with PAH receiving background therapy of ERA, PDE-5I, or both. Oral treprostinil therapy in combination with ERA and PDE-5I therapy appeared to be safe. Although side effects were common, they were tolerated by most patients. Additional studies of longer duration would be required to fully evaluate the clinical benefit of oral treprostinil therapy at higher doses in combination with ERA or PDE-5I

Acknowledgments

Author contributions: Dr Tapson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Tapson: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and final approval of the manuscript.

Dr Jing: contributed to the data collection, analysis, and interpretation and critical review and final approval of the manuscript.

Dr Xu: contributed to the data

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Funding/Support: This research was funded by United Therapeutics Corporation.

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