Pulmonary HypertensionPhase 3FREEDOM-C2NCT00887978
Efficacy and Safety of Oral UT-15C Tablets to Treat Pulmonary Arterial Hypertension
A Phase 3 study testing UT-15C SR in people with Pulmonary Hypertension, run by United Therapeutics at 62 sites in 12 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Pulmonary Hypertension
- What is being tested?
- UT-15C SR
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 310 participants
- Where
- 62 sitesin 12 countries
- Study dates
- Jun 2009to Jul 2011
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
None listed.
Trial locations and contacts
62 sites in 12 countries.
62 sites in 12 countries
United States40 sites
Emory University School of Medicine
Atlanta, Georgia, 30322
University of Colorado Health Science Center
Aurora, Colorado, 80045
University of Alabama-Birmingham
Birmingham, Alabama, 35294-0006
Tufts Medical Center
Boston, Massachusetts, 02111
Pulmonary Critical Care Medicine, Brigham and Women's Hospital
Boston, Massachusetts, 02115
University of Chicago Hospitals
Chicago, Illinois, 60637
Lindner Center
Cincinnati, Ohio, 45219
University of Cincinnati
Cincinnati, Ohio, 45267-0564
University Hospitals Case Medical Center
Cleveland, Ohio, 44106
Ohio State University
Columbus, Ohio, 43210
UT Southwestern
Dallas, Texas, 75390
Duke University Medical Center
Durham, North Carolina, 27710
Inova Transplant Center
Falls Church, Virginia, 22042
University of California, San Francisco-Fresno
Fresno, California, 93701
The University of Texas Health Science Center at Houston
Houston, Texas, 77030
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
University of Florida-Jacksonville
Jacksonville, Florida, 32209
Kansas University Medical Center
Kansas City, Kansas, 66160
UCSD Medical Center
La Jolla, California, 92037
West Los Angeles VA Healthcare Center
Los Angeles, California, 90073
Kentuckiana Pulmonary Associates
Louisville, Kentucky, 40202
Winthrop University Hospital
Mineola, New York, 11501
Intermountain Medical Center
Murray, Utah, 84157-7000
Columbia University Presbyterian Medical Center
New York, New York, 10032
Newark Beth Israel Medical Center
Newark, New Jersey, 07112
University of Nebraska Medical Center
Omaha, Nebraska, 68198-5300
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Arizona Pulmonary Specialist, LTD
Phoenix, Arizona, 85013
Allegheny General Hospital
Pittsburgh, Pennsylvania, 15212
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213
Maine Medical Center
Portland, Maine, 04102-3175
Legacy Pulmonary Northwest
Portland, Oregon, 97210
OHSU
Portland, Oregon, 97239
Mayo Clinic
Rochester, Minnesota, 55902
Mary M Parkes Center for Asthma, Allergy and Pulmonary Care
Rochester, New York, 14623
UC Davis Medical Center
Sacramento, California, 95817
Washington University Hospital
St Louis, Missouri, 63110-1093
The University of Toledo
Toledo, Ohio, 43614
Harbor-UCLA Medical Center
Torrance, California, 90502
Cleveland Clinic Florida
Weston, Florida, 33331
Canada5 sites
University of Calgary
Calgary, Alberta, T1Y 6J4
University of Alberta Hospitals
Edmonton, Alberta, T6G 2B7
London Health Sciences Center
London, Ontario, N6A 4G5
Toronto General Hospital
Toronto, Ontario, M5G 2N2
Vancouver Coastal Health Respiratory Clinic
Vancouver, British Columbia, V5Z 1M9
France3 sites
Hospital Cavale Blanche
Brest, 29609
Hospital Claude Huriez
Lille, Cedex, 59037
Hospital Haut Leveque
Pessac, Cedex, 33604
Germany3 sites
Universitaetsklinikum Dresden
Dresden, 01307
University Hospital Greifswald
Greifswald, 17475
Universitaetsklinikum Heidelberg
Heidelberg, 69120
Israel3 sites
Pulmonology Department Rambam Medical Center
Haifa, 31096
Lady Davis Carmel Medical Centre
Haifa, 34362
Pulmonary institute
Ramat Gan, 52621
Spain2 sites
Hospital Clinic I Provincial de Barcelona
Barcelona, 08036
Hospital 12 de Octubre
Madrid, 28041
About this study
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
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).
- Conditions
- Pulmonary Hypertension
- Being tested
- UT-15C SR, Placebo
- Medical subject headings
- Hypertension, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
UT-15C SRDrug
Also called treprostinil diolamine, treprostinil diethanolamine, UT-15C
treprostinil diolamine sustained release tablets
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Identical placebo tablets to UT-15C, doses were titrated in the same manner Receives: Drug: Placebo |
| UT-15C SR | Experimental | 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. Receives: Drug: UT-15C SR |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline and 16 weeks
Secondary outcomes (7)
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
Measured: Baseline and 16 Weeks
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).
Measured: Baseline and 16 Weeks
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.
Measured: Baseline and 16 Weeks
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.
Measured: Baseline and 16 Weeks
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.
Measured: Baseline and 16 Weeks
N-terminal proBNP (NT-proBNP)
Serum N-terminal pro-BNP concentration was assessed at Baseline and Week 16.
Measured: Baseline and 16 Weeks
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.
Measured: Baseline and 16 Weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2009 (estimated)
- Study startJun 2009
- Primary completionJul 2011
- Study completionJul 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Pulmonary HypertensionStudies of the same condition, open and under way.
- More trials run by United TherapeuticsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 310 participants (actual)
Sponsor and investigators
- Lead sponsor
- United Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Lewis Rubin, MD, Study chair, University of California, San Diego
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00887978
- Sponsor's protocol ID
- TDE-PH-308
- Acronym
- FREEDOM-C2
- Status last verified
- Dec 2012
- First submitted
- 23 Apr 2009
- Last updated
- 15 Jan 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Lachant D, Raina A, Krishnan M, Sood N, Balasubramanian V, Barbera JA, Kiely DG, Lee D, Wu B, Hwang S, Seaman S, Broderick M, Elwing J. Efficacy and Safety of Oral Treprostinil in Patients with Pulmonary Arterial Hypertension on Background Monotherapy or Dual Therapy. Adv Ther. 2026 Mar;43(3):1308-1326. doi: 10.1007/s12325-026-03497-4. Epub 2026 Feb 2.
PubMed 41627369Richter 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.
PubMed 28090293Tapson 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.
PubMed 23669822
Study at a glance
From the registry record, last updated by the sponsor on 15 Jan 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00887978
- Acronym / sponsor ID
- FREEDOM-C2 / TDE-PH-308
- Conditions
- Pulmonary Hypertension
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 310 participants (actual)
- Lead sponsor
- United TherapeuticsIndustry (pharma, biotech, devices)
- Study start
- Jun 2009
- Primary completion
- Jul 2011 (actual)
- Study completion
- Jul 2011 (actual)
- First posted
- 24 Apr 2009 (estimated)
- Results
- Posted 15 Jan 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboIdentical placebo tablets to UT-15C, doses were titrated in the same manner |
| UT-15C SR | Experimental | Drug: UT-15C SRDoses 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| UT-15C SRAlso: treprostinil diolamine, treprostinil diethanolamine, UT-15Ctreprostinil diolamine sustained release tablets | Drug | UT-15C SR |
| Placebo | Drug | Placebo |
Primary outcome
6-minute Walk Distance (6MWD)
Time frame: Baseline and 16 weeks
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).
7 secondary outcomes
Clinical Worsening Assessment
Time frame: Baseline and 16 Weeks
Borg Dyspnea Score
Time frame: Baseline and 16 Weeks
World Health Organization (WHO) Functional Class
Time frame: Baseline and 16 Weeks
Symptoms of PAH
Time frame: Baseline and 16 Weeks
Dyspnea Fatigue Index
Time frame: Baseline and 16 Weeks
N-terminal proBNP (NT-proBNP)
Time frame: Baseline and 16 Weeks
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
Time frame: Baseline and 16 Weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jan 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41627369Lachant D, Raina A, Krishnan M, Sood N, Balasubramanian V, Barbera JA, Kiely DG, Lee D, Wu B, Hwang S, Seaman S, Broderick M, Elwing J. Efficacy and Safety of Oral Treprostinil in Patients with Pulmonary Arterial Hypertension on Background Monotherapy or Dual Therapy. Adv Ther. 2026 Mar;43(3):1308-1326. doi: 10.1007/s12325-026-03497-4. Epub 2026 Feb 2.
- Derived from this study: PubMed 28090293Richter 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.
- Derived from this study: PubMed 23669822Tapson 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lewis Rubin, MD study chair
University of California, San Diego
62 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing UT-15C SR in people with Pulmonary Hypertension, run by United Therapeutics at 62 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Jan 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 62 sites in United States, Canada, France, Germany, Israel and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Jan 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
6-minute Walk Distance (6MWD) (time frame: Baseline and 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00887978, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jan 2013.