FREEDOM - M: Oral Treprostinil as Monotherapy for the Treatment of Pulmonary Arterial Hypertension (PAH)
- Conditions
- Pulmonary Hypertension
- Interventions
- Other: PlaceboDrug: Oral treprostinil (UT-15C) Sustained Release Tablets
- Registration Number
- NCT00325403
- Lead Sponsor
- United Therapeutics
- Brief Summary
This study was an international, multicenter, randomized (2:1 active:placebo), double-blind, placebo-controlled study in subjects with PAH who were NOT currently receiving approved therapy for their PAH. Study visits occurred at 4 week intervals for 12 weeks (with an additional visit at Week 11) with the key measure of efficacy being the 6-minute walk test. Study procedures included routine blood tests, medical history, physical exams, disease evaluation, and exercise tests. Two optional substudies were also a part of FREEDOM-M at select centers - a hemodynamic substudy with a right heart catheterization at Baseline and Week 12 and a genetics and biomarkers substudy with blood samples collected at Baseline and Week 12.
Patients who completed all assessments for 12 weeks were also eligible to enter an open-label, extension phase study (FREEDOM - EXT).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 349
- Between 12 and 75 years of age, inclusive.
- Body weight at least 40 kg with a Body Mass Index < 45
- PAH that is either idiopathic/heritable; associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥ 5 years); associated with collagen vascular disease; associated with HIV.
- Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH.
- Baseline 6-minute walk distance between 200 and 425 meters, inclusive.
- Reliable and cooperative with protocol requirements.
- Nursing or pregnant.
- Currently receiving an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, or prostacyclin within 30 days of Baseline.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Subjects receive placebo (sugar pill) twice daily. UT-15C (oral treprositnil) Oral treprostinil (UT-15C) Sustained Release Tablets Subjects receive UT-15C (oral treprostinil) twice daily.
- Primary Outcome Measures
Name Time Method Six Minute Walk Distance (6MWD) Baseline and Week 12 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.
The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 12. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.
- Secondary Outcome Measures
Name Time Method Symptoms of PAH Baseline and Week 12 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 12. Severity grade values (i.e., 0, 1, 2, or 3 in increasing severity) were assigned for each symptom.
Six Minute Walk Distance (6MWD) Baseline and Week 4 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.
The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 4. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.Clinical Worsening Assessment Baseline and Week 12 Definition of clinical worsening included patients who met at least one of the following criteria during the 12 weeks of the study:
1. Death (all causes excluding accident)
2. Transplantation or atrial septostomy
3. Clinical deterioration as defined by:
1. Hospitalization as a result of PAH, or
2. greater than or equal to 20% decrease in 6MWD from Baseline (or too ill to walk) and a decrease in WHO functional class And
3. Initiation of new PAH specific therapy (i.e., ERA, PDE5-I, prostacyclin)Borg Dyspnea Score Baseline and Week 12 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).
Dyspnea-Fatigue Index Baseline and Week 12 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.
World Health Organization Functional Classification for PAH Baseline and Week 12 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.
Trial Locations
- Locations (77)
Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
Emory University Hospital
🇺🇸Atlanta, Georgia, United States
University of Chicago Hospitals
🇺🇸Chicago, Illinois, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Universitaet Wien
🇦🇹Wien, Austria
SMBD Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Care Hospital
🇮🇳Visakhapatnam, Andra Pradesh, India
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Hospital Antoine Beclere
🇫🇷Clamart, France
Maine Medical Center
🇺🇸Portland, Maine, United States
Legacy Clinic Northwest
🇺🇸Portland, Oregon, United States
University Hospital Gasthuisberg
🇧🇪Leuven, Belgium
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
London Health Science Centre
🇨🇦London, Ontario, Canada
Care Institute of Medical Science
🇮🇳Ahmedabad, Gujarat, India
Hospital Erasme
🇧🇪Brussels, Belgium
Narayana Hrudayalaya Institute of Medical Sciences
🇮🇳Bangalore, Karnataka, India
K. S. Hospital
🇮🇳Chennai, Tamil Nadu, India
Unidad de Investigacion Clinica en Medicina (UDICEM)
🇲🇽Monterrey, Mexico
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Beijing Shijitan Hospital
🇨🇳Beijing, China
Peking Union Medical College Hospital
🇨🇳Beijing, China
University of California, San Francisco-Fresno
🇺🇸Fresno, California, United States
University of Iowa Hospital and Clinics
🇺🇸Iowa City, Iowa, United States
Columbia Presbyterian Medical Center
🇺🇸New York, New York, United States
Washington University Hospital
🇺🇸Saint Louis, Missouri, United States
Winthrop University Hospital
🇺🇸Mineola, New York, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
Baylor College of Medicine, Pulmonary & Critical Care
🇺🇸Houston, Texas, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
West Los Angeles VA Healthcare Center
🇺🇸Los Angeles, California, United States
University of Maryland School of Medicine
🇺🇸Baltimore, Maryland, United States
Mary M Parkes Center for Asthma, Allergy and Pulmonary Care - University of Rochester
🇺🇸Rochester, New York, United States
The Lindner Center
🇺🇸Cincinnati, Ohio, United States
University Hospitals of Cleveland
🇺🇸Cleveland, Ohio, United States
University of Texas Southwestern
🇺🇸Dallas, Texas, United States
Peter Lougheed Centre
🇨🇦Calgary, Alberta, Canada
Inova Fairfax Hospital
🇺🇸Falls Church, Virginia, United States
Shanghai Pulmonary Hospital
🇨🇳Shanghai, China
PRIME Hospitals
🇮🇳Hyderbad, Andhra Pradesh, India
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Hospital Universitario UANL
🇲🇽Monterrey, NL, Mexico
National Tuberculosis and Lung Disease Research Institute
🇵🇱Warsaw, Poland
Wojewódzki Szpital Specjalistyczny we Wroclawiu (Provincial Specialist Hospital in Wrocław)
🇵🇱Wroclaw, Poland
Auxilio Mutuo Hospital
🇵🇷Guaynabo, Puerto Rico
G. Kuppuswamy Naidu Memorial Hospital
🇮🇳Coimbatore, Tamil Nadu, India
Sri Ramachandra Medical College
🇮🇳Chennai, Tamil Nadu, India
Arizona Pulmonary Specialist
🇺🇸Phoenix, Arizona, United States
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
University of Alabama-Birmingham
🇺🇸Birmingham, Alabama, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
UC Davis Medical Center
🇺🇸Sacramento, California, United States
University of Colorado Health Science Center
🇺🇸Aurora, Colorado, United States
Kentuckiana Pulmonary Associates
🇺🇸Louisville, Kentucky, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Heart Care Associates
🇺🇸Milwaukee, Wisconsin, United States
Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Krakowski Szpital Specjalistyczny im. (Kraków Specialist Hospital)
🇵🇱Kraków, Poland
Lifecare Institute of Medical Sciences & Research
🇮🇳Ahmedabad, Gujarat, India
Asian Heart Institute and Research Centre
🇮🇳Parel Mumbai, Maharashtra, India
Poona Hospital and Research Centre
🇮🇳Pune, Maharashtra, India
Hadassah Ein-Kerem Medical Center
🇮🇱Jerusalem, Israel
Rabin Medical Center
🇮🇱Petach Tikva, Israel
Tel Hashomer Medical Center
🇮🇱Ramat Gan, Israel
Universita degli Studi Bologna
🇮🇹Bologna, Italy
Instituto Nacional de Cardiologia
🇲🇽Mexico City, DF, Mexico
VU Medisch Centrum (VUCM)
🇳🇱Amsterdam, Netherlands
University of Florida - Shands Hospital
🇺🇸Jacksonville, Florida, United States
Cleveland Clinic Florida
🇺🇸Weston, Florida, United States
Sir Ganga Ram Hospital
🇮🇳New Delhi, India
Alexandria Cardiology Clinic
🇺🇸Alexandria, Louisiana, United States
Ruby Hall Clinic
🇮🇳Pune, India