FREEDOM-C: Oral Treprostinil in Combination With an Endothelin Receptor Antagonist (ERA) and/or a Phosphodiesterase-5 (PDE-5) Inhibitor for the Treatment of Pulmonary Arterial Hypertension (PAH)

A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Combination With an Endothelin Receptor Antagonist and/or a Phosphodiesterase-5 Inhibitor in Subjects With Pulmonary Arterial Hypertension

This study was an international, multi-center, randomized, double-blind, placebo-controlled study in subjects with PAH who were currently receiving approved therapy for their PAH (i.e., endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor). Study visits occurred at 4 week intervals for 16 weeks; the key measure of efficacy was the 6-minute walk test. Study procedures included routine blood tests, medical history, physical exams, disease evaluation, and exercise tests. One optional substudy was also a part of FREEDOM-C at select centers - a hemodynamic substudy with a right heart catheterization at Baseline and Week 16.

Patients who completed all assessments for 16-weeks were also eligible to enter an open-label, extension phase study (FREEDOM - EXT).

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Oral treprostinil (UT-15C) sustained release tablets; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 354
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia
    • The Prince Charles Hospital
  • Melbourne, Australia
    • The Alfred Hospital
  • Perth, Australia
    • Royal Perth Hospital
  • New South Wales
    • Sydney, New South Wales, Australia
      • St. Vincent's Hospital
• Austria
  • Innsbruck, Austria
    • Medizinische Universitat Innsbruck
  • Wien, Austria
    • Universitaet Wien
• Belgium
  • Brussels, Belgium
    • Hospital Erasme
  • Leuven, Belgium
    • University Hospital Gasthuisberg
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Respiratory Research
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 3J5
      • Vancouver Coastal Health Respiratory Clinic
  • Ontario
    • London, Ontario, Canada, N6A 4G5
      • Lab London Health Sciences Center
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • SMBD Jewish General Hospital
• France
  • Brest, France
    • Hospital Cavale Blanche
  • Clamart, France
    • Hospital Antoine Beclere
  • Lille Cedex, France
    • Hospital Claude Huriez
  • Lyon, France
    • Hopital Louis Pradel
• Germany
  • Hannover, Germany
    • Medizinische Hochschule Hannover
• Ireland
  • Dublin, Ireland
    • Mater Misericordiae University Hospital Ltd
• Israel
  • Jerusalem, Israel
    • Hadassah Ein-Kerem Medical Center
  • Petach Tikva, Israel
    • Rabin Medical Center
  • Ramat Gan, Israel
    • Tel Hashomer Medical Center
• Italy
  • Bologna, Italy
    • Universita degli Studi Bologna
  • Rome, Italy
    • universita "la Sapienza" Roma
• Netherlands
  • Amsterdam, Netherlands
    • Hospital Vrije Universiteit
• Poland
  • Warsaw, Poland
    • National Tuberculosis and Lung Disease Research Institute
• Spain
  • Barcelona, Spain
    • Hospital Valle Hebrón
  • Barcelona, Spain
    • Hospital Clinic of Barcelona
  • Madrid, Spain
    • Hospital 12 de Octubre
• United Kingdom
  • Cambridge, United Kingdom
    • Papworth Hospital
  • Glasgow, United Kingdom
    • Western Infirmary
  • London, United Kingdom
    • Royal Free Hospital
  • Newcastle, United Kingdom
    • Freeman Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama-Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Pulmonary Specialist
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Science Center
  • California
    • Los Angeles, California, United States, 90073
      • West Los Angeles VA Healthcare Center
    • Palo Alto, California, United States, 94305
      • Stanford University, Pulmonary and Critical Care
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Francisco, California, United States, 94143
      • University of California-San Francisco
    • Torrance, California, United States, 90502
      • Harbour-UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80218
      • The Children's Hospital
    • Aurora, Colorado, United States, 80262
      • Pulmonary Hypertension Clinic
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Iowa
    • Iowa, Iowa, United States, 52242
      • University of Iowa Health Care
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
    • Baltimore, Maryland, United States, 21205
      • John's Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia Presbyterian Medical Center
    • Rochester, New York, United States, 14643
      • Mary M Parkes Center for Asthma, Allergy and Pulmonary Care
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Legacy Clinic Northwest
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75235
      • UT Southwestern
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine, Pulmonary & Critical Care
    • San Antonio, Texas, United States, 78229
      • The University of Texas Health Science Center at San Antonio
  • Utah
    • Murray, Utah, United States, 84143
      • Intermountain Medical Center
  • Virginia
    • Fairfax, Virginia, United States, 22042
      • Inova Transplant Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Heart Care Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Between 12 and 70 years of age, inclusive.
• Body weight at least 45 kg (approximately 100 pounds).
• PAH that is either idiopathic/heritable (including PAH associated with appetite suppressant/toxin use); PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥ 5 years); PAH associated with collagen vascular disease; or PAH associated with HIV.
• Baseline 6-minute walk distance between 150 and 450 meters, inclusive.
• Currently receiving an approved endothelin receptor antagonist and/or an approved phosphodiesterase-5 inhibitor for at least 90 days and on a stable dose for at least the last 30 days.
• Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH.
• Reliable and cooperative with protocol requirements.

Exclusion Criteria:

• Nursing or pregnant.
• Received a prostacyclin within the past 30 days.
• PAH due to conditions other than noted in the above inclusion criteria.
• History of uncontrolled sleep apnea, renal insufficiency, anemia, left sided heart disease, uncontrolled systemic hypertension, or parenchymal lung disease.
• Use of an investigational drug within 30 days of Baseline.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active; Subjects assigned to active therapy with UT-15C 0.25, 0.5, 1, or 5 mg oral tablets.	Drug: Oral treprostinil (UT-15C) sustained release tablets; UT-15C 0.25, 0.5, 1, or 5 mg oral tablets by mouth every 12 hours
Placebo Comparator: Placebo Arm; Subjects assigned to placebo 0.25, 0.5, 1, or 5 mg oral tablets.	Drug: Placebo; Placebo 0.25, 0.5, 1, or 5 mg oral tablets by mouth every 12 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Six Minute Walk Distance (6MWD)	Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 16, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.	Baseline and 16 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Borg Dyspnea Score	The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 6-minute walk test. The Borg dyspnea score was assessed immediately following the 6-minute walk test. Scores ranged from 0 (for no shortness of breath) to 10 (for greatest shortness of breath ever experienced).	Baseline and 16 Weeks
Clinical Worsening Assessment	Definition of clinical worsening required one of the following: Death (all causes excluding accident); Transplantation or atrial septostomy; Clinical deterioration as defined by:Hospitalization as a result of PAH, or≥ 20% decrease in 6-minute walk distance from Baseline (or too ill to walk) and a decrease in WHO functional class AndInitiation of new PAH specific therapy (i.e., ERA, PDE5I, prostacyclin).	Baseline and 16 Weeks
Dyspnea-Fatigue Index	The dyspnea-fatigue index has three components, each rated on a scale of 0 to 4, for the magnitude of the task that evokes dyspnea or fatigue, the magnitude of the pace (or effort) with which the task is performed and the associated functional impairment in general activities. The ratings for each component were added to form an aggregate score, which could range from 0, for the worst condition, to 12, for the best.	Baseline and 16 Weeks
World Health Organization Functional Classification for PAH	Class I: Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II: Patients with pulmonary hypertension resulting in slight limitation of physical activity. These patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III: Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity.	Week 16
Six Minute Walk Distance (6MWD)	Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 12, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.	Baseline and 12 weeks
Six Minute Walk Distance (6MWD)	Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 8, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.	Baseline and 8 weeks
Six Minute Walk Distance (6MWD)	Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 4, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.	Baseline and 4 weeks
Change in Symptoms of PAH From Baseline to Week 16	Defined symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain, and orthopnea were assessed at Baseline prior to starting study drug and during the Treatment Phase at Week 16. Severity grade values (i.e., 0, 1, 2, or 3 in increasing severity) were assigned for each symptom. The outcome data describes the change in severity values from Baseline to Week 16 for each defined symptom of PAH.	Baseline and 16 weeks

Collaborators and Investigators

• Sponsor: United Therapeutics

Publications and helpful links

General Publications

• Tapson VF, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, Badesch DB, Frost AE, Shapiro SM, Laliberte K, Sigman J, Arneson C, Galie N. 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): a randomized controlled trial. Chest. 2012 Dec;142(6):1383-1390. doi: 10.1378/chest.11-2212.

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: May 11, 2006
• First Submitted That Met QC Criteria: May 11, 2006
• First Posted (Estimate): May 12, 2006

Study Record Updates

• Last Update Posted (Actual): August 2, 2017
• Last Update Submitted That Met QC Criteria: July 31, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: TDE-PH-301