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Original Research: Pulmonary Vascular Disease |

Oral Treprostinil for the Treatment of Pulmonary Arterial Hypertension in Patients on Background Endothelin Receptor Antagonist and/or Phosphodiesterase Type 5 Inhibitor Therapy (The FREEDOM-C Study)Oral Treprostinil for Pulmonary Hypertension: A Randomized Controlled Trial

Victor F. Tapson, MD, FCCP; Fernando Torres, MD; Fiona Kermeen, MD; Anne M. Keogh, MD; Roblee P. Allen, MD, FCCP; Robert P. Frantz, MD; David B. Badesch, MD, FCCP; Adaani E. Frost, MD, FCCP; Shelley M. Shapiro, MD; Kevin Laliberte, PharmD; Jeffrey Sigman, BA; Carl Arneson, MStat; Nazzareno Galiè, MD
Author and Funding Information

From the Division of Pulmonary, Allergy, and Critical Care Medicine (Dr Tapson), Duke University Medical Center, Durham, NC; the Division of Pulmonary and Critical Care Medicine (Dr Torres), University of Texas Southwestern Medical Center, Dallas, TX; the Prince Charles Hospital (Dr Kermeen), Brisbane, QLD, Australia; St. Vincent’s Hospital (Dr Keogh), Sydney, NSW, Australia; the UC Davis Medical Center (Dr Allen), Sacramento, CA; the Division of Cardiovascular Disease (Dr Frantz), Mayo Clinic, Rochester, MN; the Divisions of Pulmonary Sciences and Critical Care Medicine and Cardiology (Dr Badesch), University of Colorado Denver, Denver, CO; the Section of Pulmonary and Critical Care Medicine (Dr Frost), Baylor College of Medicine, Houston, TX; the West Los Angeles Veterans Administration Healthcare Center (Dr Shapiro), Los Angeles, CA; the United Therapeutics Corporation (Dr Laliberte and Messrs Sigman and Arneson), Research Triangle Park, NC; and the Department of Medicine (Dr Galiè), Institute of Cardiology, Bologna, Italy.

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


For editorial comment see page 1363

Funding/Support: This study 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. 2012;142(6):1383-1390. doi:10.1378/chest.11-2212
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Background:  Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor.

Methods:  A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score.

Results:  Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m).

Conclusions:  The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies.

Trial registry:  ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov

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