title: 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.
abstract: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, NC. Electronic address: tapso001@mc.duke.edu.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Tapson
authors.affiliation: Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Jing
authors.affiliation: Peking Union Medical College Hospital, Beijing, China.
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Xu
authors.affiliation: Department of Pulmonary Vascular Disease, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: Arizona Pulmonary Specialists Ltd, Phoenix, AZ.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Feldman
authors.affiliation: Cardiovascular Biomedical Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England; National Institutes of Health Research, and Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England.
authors.forename: David G
authors.initials: DG
authors.lastname: Kiely
authors.affiliation: Heart Lung Clinic, St Vincent's Hospital, Sydney, NSW, Australia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Kotlyar
authors.affiliation: United Therapeutics Corporation, Research Triangle Park, NC.
authors.forename: C Shane
authors.initials: CS
authors.lastname: McSwain
authors.affiliation: United Therapeutics Corporation, Research Triangle Park, NC.
authors.forename: Kevin
authors.initials: K
authors.lastname: Laliberte
authors.affiliation: United Therapeutics Corporation, Research Triangle Park, NC.
authors.forename: Carl
authors.initials: C
authors.lastname: Arneson
authors.affiliation: UC San Diego Medical Center, San Diego, CA.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Rubin
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D017079:Exercise Tolerance / Q000187:drug effects*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; D011464:Epoprostenol; C427248:treprostinil