Efficacy and Safety of Oral UT-15C Tablets to Treat Pulmonary Arterial Hypertension (FREEDOM-C2)

A 16-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Subjects With Pulmonary Arterial Hypertension

This study is an international, multi-center, randomized, double-blind, placebo-controlled study in subjects with PAH who are currently receiving approved therapy for their PAH (i.e., endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor). Study visits will occur at 4 week intervals for 16 weeks with the key measure of efficacy being the 6-minute walk test. Study procedures include routine blood tests, medical history, physical exams, disease evaluation, and exercise tests.

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

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: UT-15C SR

• Study Type: Interventional
• Enrollment (Actual): 310
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • University Hospital Gasthuisberg
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • University of Calgary
    • Edmonton, Alberta, Canada, T6G 2B7
      • University Of Alberta Hospitals
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver Coastal Health Respiratory Clinic
  • Ontario
    • London, Ontario, Canada, N6A 4G5
      • London Health Sciences Center
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
• France
  • Brest, France, 29609
    • Hospital Cavale Blanche
  • Cedex
    • Lille, Cedex, France, 59037
      • Hospital Claude Huriez
    • Pessac, Cedex, France, 33604
      • Hospital Haut levêque
• Germany
  • Dresden, Germany, 01307
    • Universitaetsklinikum Dresden
  • Greifswald, Germany, 17475
    • University Hospital Greifswald
  • Heidelberg, Germany, 69120
    • Universitaetsklinikum Heidelberg
• Israel
  • Haifa, Israel, 34362
    • Lady Davis Carmel Medical Centre
  • Haifa, Israel, 31096
    • Pulmonology Department Rambam Medical Center
  • Ramat Gan, Israel, 52621
    • Pulmonary Institute
• Italy
  • Naples, Italy
    • Azienda Ospedaliera Universitaria
• Netherlands
  • Amsterdam, Netherlands, 1007
    • VUMC
• Portugal
  • Lisboa, Portugal, 1160-024
    • Hospital De Santa Marta
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
• Sweden
  • Lund, Sweden, 221 85
    • Lund University Hospital
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital NHS Trust
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0006
      • University of Alabama-Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Pulmonary Specialist, Ltd
  • California
    • Fresno, California, United States, 93701
      • University of California, San Francisco-Fresno
    • La Jolla, California, United States, 92037
      • UCSD Medical Center
    • Los Angeles, California, United States, 90073
      • West Los Angeles VA Healthcare Center
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • Torrance, California, United States, 90502
      • Harbor-UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Science Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida-Jacksonville
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospitals
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Kansas University Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Associates
  • Maine
    • Portland, Maine, United States, 04102-3175
      • Maine Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02115
      • Pulmonary Critical Care Medicine, Brigham and Women's Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • Mayo Clinic
  • Missouri
    • St. Louis, Missouri, United States, 63110-1093
      • Washington University Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-5300
      • University of Nebraska Medical Center
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10032
      • Columbia University Presbyterian Medical Center
    • Rochester, New York, United States, 14623
      • Mary M Parkes Center for Asthma, Allergy and Pulmonary Care
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0564
      • University of Cincinnati
    • Cincinnati, Ohio, United States, 45219
      • Lindner Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University
    • Toledo, Ohio, United States, 43614
      • The University of Toledo
  • Oregon
    • Portland, Oregon, United States, 97239
      • OHSU
    • Portland, Oregon, United States, 97210
      • Legacy Pulmonary Northwest
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
  • Utah
    • Murray, Utah, United States, 84157-7000
      • Intermountain Medical Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Transplant Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• A subject is eligible for inclusion in this study if all of the following criteria apply:
• Between 18 and 75 years of age, inclusive.
• Body weight at least 40 kg (approximately 90 lbs.)
• PAH that is either idiopathic/heritable; associated with appetite suppressant or toxin use; associated with collagen vascular disease; associated with repaired congenital shunts; associated with HIV.
• 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.
• Baseline six-minute walk distance (6MWD) between 150-425 meters
• Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH.
• Reliable and cooperative with protocol requirements.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Identical placebo tablets to UT-15C, doses were titrated in the same manner	Drug: Placebo
Experimental: UT-15C SR; Doses were initiated at 0.25 mg BID and increased by 0.25 mg BID every three days (as clinically indicated based on tolerability and symptoms of PAH), to a max dose of 16 mg BID.	Drug: UT-15C SR; treprostinil diolamine sustained release tablets; Other Names: treprostinil diolamine, treprostinil diethanolamine, UT-15C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-minute Walk Distance (6MWD)	Placebo-corrected change in 6MWD from Baseline to Week 16, correlates with the current 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 6MWD was to be assessed between 3 and 6 hours after the morning dose of study drug and background therapy(ies).	Baseline and 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Worsening Assessment	Definition of clinical worsening included patients who met at least one of the following criteria during the 16 weeks of study: Death (all causes excluding accident); Transplantation; Atrial septostomy; Hospitalization as a result of right heart failure; Greater than or equal to a 20% decrease in 6MWD from Baseline (or too ill to walk) AND addition of an inhaled prostacyclin analogue, ERA, or PDE-5i; Initiation of parenteral prostacyclin therapy (i.e., epoprostenol, iloprost, or treprostinil) for the treatment of PAH	Baseline and 16 Weeks
Borg Dyspnea Score	The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the six-minute walk test (6MWT). The Borg dyspnea score was assessed immediately following the 6MWT. Scores ranged from 0 (for no shortness of breath) to 10 (for the greatest shortness of breath ever experienced).	Baseline and 16 Weeks
World Health Organization (WHO) Functional Class	Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms.	Baseline and 16 Weeks
Symptoms of PAH	Symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain and orthopnea were assessed by the physician at Baseline and Week 16. Severity grade values (i.e., 0, 1, 2 or 3) for each symptom were provided each subject. A severity of 0 indicated no symptoms, the maximum severity was 3, indicating severe symptoms. Mean change in symptom severity from Baseline to Week 16 is described.	Baseline and 16 Weeks
Dyspnea Fatigue Index	The dyspnea-fatigue index was assessed at Baseline and Week 16. Each of the three components of the dyspnea-fatigue index were rated on a scale 0 to 4, with 0 being the worst condition and 4 being the best condition for each component. The dyspnea-fatigue index is computed by summing the three component scores.	Baseline and 16 Weeks
N-terminal proBNP (NT-proBNP)	Serum N-terminal pro-BNP concentration was assessed at Baseline and Week 16.	Baseline and 16 Weeks
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)	Change in CAMPHOR Scores from Baseline to Week 16. The CAMPHOR is a health related quality of life instrument validated for pulmonary hypertension that assesses impairment (symptoms), disability (activities) and quality of life. The questionnaire is divided into three sections; Symptoms (Scores 0-25; high scores indicate more symptoms), Activity (Score 0-30; low score indicates good functioning)and Quality of Life (0-25; high scores indicate poor QoL). The sum of these scores equates to the Total score (0-80). In the CAMPHOR scores, lower scores indicate improvements.	Baseline and 16 Weeks

Collaborators and Investigators

• Sponsor: United Therapeutics
• Investigators: Study Chair: Lewis Rubin, MD, University of California, San Diego

Publications and helpful links

General Publications

• Richter MJ, Schermuly R, Seeger W, Rao Y, Ghofrani HA, Gall H. Relevance of angiopoietin-2 and soluble P-selectin levels in patients with pulmonary arterial hypertension receiving combination therapy with oral treprostinil: a FREEDOM-C2 biomarker substudy. Pulm Circ. 2016 Dec;6(4):516-523. doi: 10.1086/688671.
• Tapson VF, Jing ZC, Xu KF, Pan L, Feldman J, Kiely DG, Kotlyar E, McSwain CS, Laliberte K, Arneson C, Rubin LJ; FREEDOM-C2 Study Team. 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. Chest. 2013 Sep;144(3):952-958. doi: 10.1378/chest.12-2875.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: April 23, 2009
• First Submitted That Met QC Criteria: April 23, 2009
• First Posted (Estimate): April 24, 2009

Study Record Updates

• Last Update Posted (Estimate): January 15, 2013
• Last Update Submitted That Met QC Criteria: December 7, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• 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-308