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

Primary Purpose

Pulmonary Hypertension

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
UT-15C SR
Placebo
Sponsored by
United Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Hypertension

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama-Birmingham
  • Arizona Pulmonary Specialist, LTD
  • University of California, San Francisco-Fresno
  • UCSD Medical Center
  • West Los Angeles VA Healthcare Center
  • UC Davis Medical Center
  • Harbor-UCLA Medical Center
  • University of Colorado Health Science Center
  • University of Florida-Jacksonville
  • Cleveland Clinic Florida
  • Emory University School of Medicine
  • University of Chicago Hospitals
  • University of Iowa Hospitals and Clinics
  • Kansas University Medical Center
  • Kentuckiana Pulmonary Associates
  • Maine Medical Center
  • Tufts Medical Center
  • Pulmonary Critical Care Medicine, Brigham and Women's Hospital
  • Mayo Clinic
  • Washington University Hospital
  • University of Nebraska Medical Center
  • Newark Beth Israel Medical Center
  • Winthrop University Hospital
  • Columbia University Presbyterian Medical Center
  • Mary M Parkes Center for Asthma, Allergy and Pulmonary Care
  • Duke University Medical Center
  • Lindner Center
  • University of Cincinnati
  • University Hospitals Case Medical Center
  • Ohio State University
  • The University of Toledo
  • Legacy Pulmonary Northwest
  • OHSU
  • University of Pennsylvania
  • Allegheny General Hospital
  • University of Pittsburgh Medical Center
  • UT Southwestern
  • The University of Texas Health Science Center at Houston
  • Intermountain Medical Center
  • Inova Transplant Center
  • University Hospital Gasthuisberg
  • University of Calgary
  • University of Alberta Hospitals
  • Vancouver Coastal Health Respiratory Clinic
  • London Health Sciences Center
  • Toronto General Hospital
  • Hospital Claude Huriez
  • Hospital Haut Leveque
  • Hospital Cavale Blanche
  • Universitaetsklinikum Dresden
  • University Hospital Greifswald
  • Universitaetsklinikum Heidelberg
  • Pulmonology Department Rambam Medical Center
  • Lady Davis Carmel Medical Centre
  • Pulmonary institute
  • Azienda Ospedaliera Universitaria
  • VUMC
  • Hospital de Santa Marta
  • Hospital Clinic I Provincial de Barcelona
  • Hospital 12 de Octubre
  • Lund University Hospital
  • Royal Free Hospital NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

UT-15C SR

Arm Description

Identical placebo tablets to UT-15C, doses were titrated in the same manner

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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
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).
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.
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.
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.
N-terminal proBNP (NT-proBNP)
Serum N-terminal pro-BNP concentration was assessed at Baseline and Week 16.
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.

Full Information

First Posted
April 23, 2009
Last Updated
December 7, 2012
Sponsor
United Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT00887978
Brief Title
Efficacy and Safety of Oral UT-15C Tablets to Treat Pulmonary Arterial Hypertension
Acronym
FREEDOM-C2
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2012
Overall Recruitment Status
Completed
Study Start Date
June 2009 (undefined)
Primary Completion Date
July 2011 (Actual)
Study Completion Date
July 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
United Therapeutics

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
310 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Identical placebo tablets to UT-15C, doses were titrated in the same manner
Arm Title
UT-15C SR
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
UT-15C SR
Other Intervention Name(s)
treprostinil diolamine, treprostinil diethanolamine, UT-15C
Intervention Description
treprostinil diolamine sustained release tablets
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
6-minute Walk Distance (6MWD)
Description
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).
Time Frame
Baseline and 16 weeks
Secondary Outcome Measure Information:
Title
Clinical Worsening Assessment
Description
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
Time Frame
Baseline and 16 Weeks
Title
Borg Dyspnea Score
Description
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).
Time Frame
Baseline and 16 Weeks
Title
World Health Organization (WHO) Functional Class
Description
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.
Time Frame
Baseline and 16 Weeks
Title
Symptoms of PAH
Description
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.
Time Frame
Baseline and 16 Weeks
Title
Dyspnea Fatigue Index
Description
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.
Time Frame
Baseline and 16 Weeks
Title
N-terminal proBNP (NT-proBNP)
Description
Serum N-terminal pro-BNP concentration was assessed at Baseline and Week 16.
Time Frame
Baseline and 16 Weeks
Title
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
Description
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.
Time Frame
Baseline and 16 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lewis Rubin, MD
Organizational Affiliation
University of California, San Diego
Official's Role
Study Chair
Facility Information:
Facility Name
University of Alabama-Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294-0006
Country
United States
Facility Name
Arizona Pulmonary Specialist, LTD
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Facility Name
University of California, San Francisco-Fresno
City
Fresno
State/Province
California
ZIP/Postal Code
93701
Country
United States
Facility Name
UCSD Medical Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Facility Name
West Los Angeles VA Healthcare Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90073
Country
United States
Facility Name
UC Davis Medical Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Harbor-UCLA Medical Center
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
University of Colorado Health Science Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Florida-Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Cleveland Clinic Florida
City
Weston
State/Province
Florida
ZIP/Postal Code
33331
Country
United States
Facility Name
Emory University School of Medicine
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Chicago Hospitals
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Iowa Hospitals and Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Kansas University Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
Kentuckiana Pulmonary Associates
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
Maine Medical Center
City
Portland
State/Province
Maine
ZIP/Postal Code
04102-3175
Country
United States
Facility Name
Tufts Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Pulmonary Critical Care Medicine, Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55902
Country
United States
Facility Name
Washington University Hospital
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110-1093
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198-5300
Country
United States
Facility Name
Newark Beth Israel Medical Center
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07112
Country
United States
Facility Name
Winthrop University Hospital
City
Mineola
State/Province
New York
ZIP/Postal Code
11501
Country
United States
Facility Name
Columbia University Presbyterian Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Mary M Parkes Center for Asthma, Allergy and Pulmonary Care
City
Rochester
State/Province
New York
ZIP/Postal Code
14623
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Lindner Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267-0564
Country
United States
Facility Name
University Hospitals Case Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
The University of Toledo
City
Toledo
State/Province
Ohio
ZIP/Postal Code
43614
Country
United States
Facility Name
Legacy Pulmonary Northwest
City
Portland
State/Province
Oregon
ZIP/Postal Code
97210
Country
United States
Facility Name
OHSU
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Allegheny General Hospital
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15212
Country
United States
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
UT Southwestern
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
The University of Texas Health Science Center at Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Intermountain Medical Center
City
Murray
State/Province
Utah
ZIP/Postal Code
84157-7000
Country
United States
Facility Name
Inova Transplant Center
City
Falls Church
State/Province
Virginia
ZIP/Postal Code
22042
Country
United States
Facility Name
University Hospital Gasthuisberg
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
University of Calgary
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T1Y 6J4
Country
Canada
Facility Name
University of Alberta Hospitals
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2B7
Country
Canada
Facility Name
Vancouver Coastal Health Respiratory Clinic
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 1M9
Country
Canada
Facility Name
London Health Sciences Center
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 4G5
Country
Canada
Facility Name
Toronto General Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2N2
Country
Canada
Facility Name
Hospital Claude Huriez
City
Lille
State/Province
Cedex
ZIP/Postal Code
59037
Country
France
Facility Name
Hospital Haut Leveque
City
Pessac
State/Province
Cedex
ZIP/Postal Code
33604
Country
France
Facility Name
Hospital Cavale Blanche
City
Brest
ZIP/Postal Code
29609
Country
France
Facility Name
Universitaetsklinikum Dresden
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
University Hospital Greifswald
City
Greifswald
ZIP/Postal Code
17475
Country
Germany
Facility Name
Universitaetsklinikum Heidelberg
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Pulmonology Department Rambam Medical Center
City
Haifa
ZIP/Postal Code
31096
Country
Israel
Facility Name
Lady Davis Carmel Medical Centre
City
Haifa
ZIP/Postal Code
34362
Country
Israel
Facility Name
Pulmonary institute
City
Ramat Gan
ZIP/Postal Code
52621
Country
Israel
Facility Name
Azienda Ospedaliera Universitaria
City
Naples
Country
Italy
Facility Name
VUMC
City
Amsterdam
ZIP/Postal Code
1007
Country
Netherlands
Facility Name
Hospital de Santa Marta
City
Lisboa
ZIP/Postal Code
1160-024
Country
Portugal
Facility Name
Hospital Clinic I Provincial de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Lund University Hospital
City
Lund
ZIP/Postal Code
221 85
Country
Sweden
Facility Name
Royal Free Hospital NHS Trust
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
28090293
Citation
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.
Results Reference
derived
PubMed Identifier
23669822
Citation
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.
Results Reference
derived

Learn more about this trial

Efficacy and Safety of Oral UT-15C Tablets to Treat Pulmonary Arterial Hypertension

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