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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)Treprostinil for Pulmonary Arterial Hypertension: A Randomized Controlled Trial

Victor F. Tapson, MD, FCCP; Zhi-Cheng Jing, MD, FCCP; Kai-Feng Xu, MD; Lei Pan, MD; Jeremy Feldman, MD, FCCP; David G. Kiely, MD; Eugene Kotlyar, MD; C. Shane McSwain, MS; Kevin Laliberte, PharmD; Carl Arneson, MSTAT; Lewis J. Rubin, MD, FCCP; on behalf of the FREEDOM-C2 Study Team
Author and Funding Information

From the Division of Pulmonary, Allergy, and Critical Care Medicine (Dr Tapson), Duke University Medical Center, Durham, NC; United Therapeutics Corporation (Dr Laliberte and Messrs McSwain and Arneson), Research Triangle Park, NC; Shanghai Pulmonary Hospital (Dr Jing), Tongji University School of Medicine, Shanghai, China; Peking Union Medical College Hospital (Dr Xu), Beijing, China; Department of Pulmonary Vascular Disease (Dr Pan), Beijing Shijitan Hospital, Capital Medical University, Beijing, China; Arizona Pulmonary Specialists Ltd (Dr Feldman), Phoenix, AZ; Cardiovascular Biomedical Research Unit (Dr Kiely), National Institutes of Health Research, and Sheffield Pulmonary Vascular Disease Unit (Dr Kiely), Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England; Heart Lung Clinic (Dr Kotlyar), St Vincent’s Hospital, Sydney, NSW, Australia; and UC San Diego Medical Center (Dr Rubin), San Diego, CA.

Correspondence to: Victor F. Tapson, MD, FCCP, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Box 102351, Durham, NC 27710; e-mail: tapso001@mc.duke.edu


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

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(3):952-958. doi:10.1378/chest.12-2875
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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.

Trial registry:  ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov

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