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)

Pulmonary Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00325442
• Other study ID #: TDE-PH-301
• Status: Completed
• Phase: Phase 3
• First received: May 11, 2006
• Last updated: July 31, 2017
• Start date: October 2006
• Est. completion date: December 2010

Study information

• Verified date: July 2017
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 354
• Est. completion date: December 2010
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

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
Placebo 0.25, 0.5, 1, or 5 mg oral tablets by mouth every 12 hours

Locations

Country	Name	City	State
Australia	The Prince Charles Hospital	Brisbane
Australia	The Alfred Hospital	Melbourne
Australia	Royal Perth Hospital	Perth
Australia	St. Vincent's Hospital	Sydney	New South Wales
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Universitaet Wien	Wien
Belgium	Hospital Erasme	Brussels
Belgium	University Hospital Gasthuisberg	Leuven
Canada	Respiratory Research	Calgary	Alberta
Canada	Lab London Health Sciences Center	London	Ontario
Canada	SMBD Jewish General Hospital	Montreal	Quebec
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Vancouver Coastal Health Respiratory Clinic	Vancouver	British Columbia
France	Hospital Cavale Blanche	Brest
France	Hospital Antoine Beclere	Clamart
France	Hospital Claude Huriez	Lille Cedex
France	Hôpital Louis Pradel	Lyon
Germany	Medizinische Hochschule Hannover	Hannover
Ireland	Mater Misericordiae University Hospital Ltd	Dublin
Israel	Hadassah Ein-Kerem Medical Center	Jerusalem
Israel	Rabin Medical Center	Petach Tikva
Israel	Tel Hashomer Medical Center	Ramat Gan
Italy	Universita degli Studi Bologna	Bologna
Italy	Universita "La Sapienza" Roma	Rome
Netherlands	Hospital Vrije Universiteit	Amsterdam
Poland	National Tuberculosis and Lung Disease Research Institute	Warsaw
Spain	Hospital Clinic of Barcelona	Barcelona
Spain	Hospital Valle Hebron	Barcelona
Spain	Hospital 12 de Octubre	Madrid
United Kingdom	Papworth Hospital	Cambridge
United Kingdom	Western Infirmary	Glasgow
United Kingdom	Royal Free Hospital	London
United Kingdom	Freeman Hospital	Newcastle
United States	University of Michigan	Ann Arbor	Michigan
United States	Pulmonary Hypertension Clinic	Aurora	Colorado
United States	The Children's Hospital	Aurora	Colorado
United States	John's Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	University of Alabama-Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Chicago	Chicago	Illinois
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	UT Southwestern	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Inova Transplant Center	Fairfax	Virginia
United States	Baylor College of Medicine, Pulmonary & Critical Care	Houston	Texas
United States	University of Iowa Health Care	Iowa	Iowa
United States	West Los Angeles VA Healthcare Center	Los Angeles	California
United States	Heart Care Associates	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia Presbyterian Medical Center	New York	New York
United States	Stanford University, Pulmonary and Critical Care	Palo Alto	California
United States	Arizona Pulmonary Specialist	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Legacy Clinic Northwest	Portland	Oregon
United States	Maine Medical Center	Portland	Maine
United States	Mary M Parkes Center for Asthma, Allergy and Pulmonary Care	Rochester	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	UC Davis Medical Center	Sacramento	California
United States	Washington University Hospital	Saint Louis	Missouri
United States	The University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	University of California-San Francisco	San Francisco	California
United States	University of Washington Medical Center	Seattle	Washington
United States	Harbour-UCLA Medical Center	Torrance	California
United States	University of Arizona Health Science Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Ireland,  Israel,  Italy,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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 And; Initiation of new PAH specific therapy (i.e., ERA, PDE5I, prostacyclin).	Baseline and 16 Weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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