FREEDOM - M: Oral Treprostinil as Monotherapy for the Treatment of Pulmonary Arterial Hypertension (PAH)

December 12, 2023 updated by: United Therapeutics

A 12-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Subjects With Pulmonary Arterial Hypertension

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

349

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Wien, Austria
        • Universitaet Wien
  • Belgium
      • Brussels, Belgium
        • Hospital Erasme
      • Leuven, Belgium
        • University Hospital Gasthuisberg
  • Canada
    • Alberta
      • Calgary, Alberta, Canada
        • Peter Lougheed Centre
    • Ontario
      • London, Ontario, Canada
        • London Health Science Centre
    • Quebec
      • Montreal, Quebec, Canada
        • SMBD Jewish General Hospital
  • China
      • Beijing, China
        • Peking Union Medical College Hospital
      • Beijing, China
        • Beijing Shijitan Hospital
      • Shanghai, China
        • Shanghai Pulmonary Hospital
  • France
      • Clamart, France
        • Hospital Antoine Beclere
  • India
      • Chennai, Tamil Nadu, India
        • K. S. Hospital
      • New Delhi, India
        • Sir Ganga Ram Hospital
      • Pune, India
        • Ruby Hall Clinic
      • Visakhapatnam, Andra Pradesh, India
        • Care Hospital
    • Andhra Pradesh
      • Hyderbad, Andhra Pradesh, India
        • PRIME Hospitals
    • Gujarat
      • Ahmedabad, Gujarat, India
        • Care Institute of Medical Science
      • Ahmedabad, Gujarat, India
        • Lifecare Institute of Medical Sciences & Research
    • Karnataka
      • Bangalore, Karnataka, India
        • Narayana Hrudayalaya Institute of Medical Sciences
    • Maharashtra
      • Parel Mumbai, Maharashtra, India
        • Asian Heart Institute and Research Centre
      • Pune, Maharashtra, India
        • Poona hospital and research centre
    • Tamil Nadu
      • Chennai, Tamil Nadu, India
        • Sri Ramachandra Medical College
      • Coimbatore, Tamil Nadu, India
        • G. Kuppuswamy Naidu Memorial Hospital
  • 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
  • Mexico
      • Monterrey, Mexico
        • Unidad de Investigacion Clinica en Medicina (UDICEM)
    • DF
      • Mexico City, DF, Mexico
        • Instituto Nacional de Cardiologia
    • NL
      • Monterrey, NL, Mexico
        • Hospital Universitario UANL
  • Netherlands
      • Amsterdam, Netherlands
        • VU Medisch Centrum (VUCM)
  • Poland
      • Kraków, Poland
        • Krakowski Szpital Specjalistyczny im. (Kraków Specialist Hospital)
      • Warsaw, Poland
        • National Tuberculosis and Lung Disease Research Institute
      • Wroclaw, Poland
        • Wojewódzki Szpital Specjalistyczny we Wroclawiu (Provincial Specialist Hospital in Wrocław)
  • Puerto Rico
      • Guaynabo, Puerto Rico
        • Auxilio Mutuo Hospital
  • United States
    • Alabama
      • Birmingham, Alabama, United States
        • University of Alabama-Birmingham
    • Arizona
      • Phoenix, Arizona, United States
        • Mayo Clinic Arizona
      • Phoenix, Arizona, United States
        • Arizona Pulmonary Specialist
    • California
      • Fresno, California, United States
        • University of California, San Francisco-Fresno
      • Los Angeles, California, United States
        • West Los Angeles VA Healthcare Center
      • Sacramento, California, United States
        • UC Davis Medical Center
      • Torrance, California, United States
        • Harbor-UCLA Medical Center
    • Colorado
      • Aurora, Colorado, United States
        • University of Colorado Health Science Center
    • Florida
      • Jacksonville, Florida, United States
        • University of Florida - Shands Hospital
      • Weston, Florida, United States
        • Cleveland Clinic Florida
    • Georgia
      • Atlanta, Georgia, United States
        • Emory University Hospital
    • Illinois
      • Chicago, Illinois, United States
        • University of Chicago Hospitals
    • Iowa
      • Iowa City, Iowa, United States
        • University of Iowa Hospital and Clinics
    • Kentucky
      • Louisville, Kentucky, United States
        • Kentuckiana Pulmonary Associates
    • Louisiana
      • Alexandria, Louisiana, United States
        • Alexandria Cardiology Clinic
    • Maine
      • Portland, Maine, United States
        • Maine Medical Center
    • Maryland
      • Baltimore, Maryland, United States
        • University of Maryland School of Medicine
    • Massachusetts
      • Boston, Massachusetts, United States
        • Brigham and Women's Hospital
      • Boston, Massachusetts, United States
        • Tufts Medical Center
    • Michigan
      • Ann Arbor, Michigan, United States
        • University of Michigan
    • Minnesota
      • Rochester, Minnesota, United States
        • Mayo Clinic
    • Missouri
      • Saint Louis, Missouri, United States
        • Washington University Hospital
    • Nebraska
      • Omaha, Nebraska, United States
        • Nebraska Medical Center
    • New Jersey
      • Newark, New Jersey, United States
        • Newark Beth Israel Medical Center
    • New York
      • Mineola, New York, United States
        • Winthrop University Hospital
      • New York, New York, United States
        • Columbia Presbyterian Medical Center
      • Rochester, New York, United States
        • Mary M Parkes Center for Asthma, Allergy and Pulmonary Care - University of Rochester
    • Ohio
      • Cincinnati, Ohio, United States
        • University of Cincinnati
      • Cincinnati, Ohio, United States
        • The Lindner Center
      • Cleveland, Ohio, United States
        • University Hospitals of Cleveland
      • Cleveland, Ohio, United States
        • The Cleveland Clinic Foundation
      • Columbus, Ohio, United States
        • Ohio State University
    • Oregon
      • Portland, Oregon, United States
        • Oregon Health and Science University
      • Portland, Oregon, United States
        • Legacy Clinic Northwest
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States
        • University of Pittsburgh Medical Center
      • Pittsburgh, Pennsylvania, United States
        • Allegheny General Hospital
    • South Carolina
      • Charleston, South Carolina, United States
        • Medical University of South Carolina
    • Texas
      • Dallas, Texas, United States
        • University of Texas Southwestern
      • Houston, Texas, United States
        • Baylor College of Medicine, Pulmonary & Critical Care
      • San Antonio, Texas, United States
        • University of Texas Health Science Center at San Antonio
    • Virginia
      • Falls Church, Virginia, United States
        • Inova Fairfax Hospital
    • Washington
      • Seattle, Washington, United States
        • University of Washington Medical Center
    • Wisconsin
      • Milwaukee, Wisconsin, United States
        • Heart Care Associates

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years to 75 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: UT-15C (oral treprositnil)
Subjects receive UT-15C (oral treprostinil) twice daily.
Drug: Oral treprostinil (UT-15C) Sustained Release Tablets
Sustained release oral tablet, twice daily
Other Names:
  • treprostinil diethanolamine
Placebo Comparator: Placebo
Subjects receive placebo (sugar pill) twice daily.
Other: Placebo
Placebo oral tablet twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Six Minute Walk Distance (6MWD)
Time Frame: 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.
Baseline and Week 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Six Minute Walk Distance (6MWD)
Time Frame: Baseline and Week 11

Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 11, a time expected to correlate with trough treprostinil concentration.

The six minute walk test was to be conducted 8 to 13 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 11. 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.
Baseline and Week 11
Six Minute Walk Distance (6MWD)
Time Frame: Baseline and Week 8

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.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 8. 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.
Baseline and Week 8
Six Minute Walk Distance (6MWD)
Time Frame: 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.
Baseline and Week 4
Clinical Worsening Assessment
Time Frame: 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)
Baseline and Week 12
World Health Organization Functional Classification for PAH
Time Frame: 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.
Baseline and Week 12
Borg Dyspnea Score
Time Frame: 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).
Baseline and Week 12
Dyspnea-Fatigue Index
Time Frame: 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.
Baseline and Week 12
Symptoms of PAH
Time Frame: 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.
Baseline and Week 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

United Therapeutics

Investigators

  • Study Director: Kevin Laliberte, PharmD, United Therapeutics

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2006

Primary Completion (Actual)

April 1, 2011

Study Completion (Actual)

April 1, 2011

Study Registration Dates

First Submitted

May 11, 2006

First Submitted That Met QC Criteria

May 11, 2006

First Posted (Estimated)

May 12, 2006

Study Record Updates

Last Update Posted (Estimated)

January 3, 2024

Last Update Submitted That Met QC Criteria

December 12, 2023

Last Verified

February 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TDE-PH-302

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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