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

Pulmonary Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00325403
• Other study ID #: TDE-PH-302
• Status: Completed
• Phase: Phase 3
• Start date: October 2006
• Est. completion date: April 2011

Study information

• Verified date: February 2013
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 349
• Est. completion date: April 2011
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Arterial Hypertension
• Pulmonary Hypertension

Intervention

Drug:
• Oral treprostinil (UT-15C) Sustained Release Tablets
Sustained release oral tablet, twice daily

Other:
• Placebo
Placebo oral tablet twice daily

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  China,  France,  India,  Israel,  Italy,  Mexico,  Netherlands,  Poland,  Puerto Rico, 

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 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	Six Minute Walk Distance (6MWD)	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
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.; 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
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.; 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
Secondary	Clinical Worsening Assessment	Definition of clinical worsening included patients who met at least one of the following criteria during the 12 weeks of the study: Death (all causes excluding accident); Transplantation or atrial septostomy; Clinical deterioration as defined by: Hospitalization as a result of PAH, or; greater than or equal to 20% decrease in 6MWD from Baseline (or too ill to walk) and a decrease in WHO functional class And; Initiation of new PAH specific therapy (i.e., ERA, PDE5-I, prostacyclin)	Baseline and Week 12
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.	Baseline and Week 12
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 Week 12
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 Week 12
Secondary	Symptoms of PAH	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

External Links

•   FREEDOM Studies Website