Oral Treprostinil in Subjects With Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction
NCT ID: NCT03037580
Last Updated: 2020-11-10
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE3
84 participants
INTERVENTIONAL
2017-08-15
2019-12-03
Brief Summary
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The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only a small portion of the anticipated total subjects had been enrolled, with many terminating early due to the study termination, there was a limited ability to explore the effect of oral treprostinil in this indication in this study.
Detailed Description
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Once randomized, subjects were dispensed study drug and took an initial dose (0.125 mg) at the study site on the day of randomization. Dosing of study drug continued at 0.125 mg 3 times daily (TID; every 6 to 8 hours) with food. Dose increases could occur in 0.125-mg increments every 72 hours at the discretion of the Investigator up to a maximum allowable dose of 6 mg TID. Subjects received oral treprostinil as 0.125, 0.25, 1.0, or 2.5 mg sustained-release osmotic tablets (maximum dose 6 mg TID) or matching placebo. Doses of study drug were to be increased in the absence of dose-limiting drug-related adverse events (AEs) to ensure that each subject received the optimal dose throughout the study. Subjects returned for visits at Weeks 6, 12, 18, and 24. Subjects who terminated study drug early were asked to complete all remaining study visits. The study had an adaptive design where the maximum allowable dose was 2 mg until the Data Monitoring Committee had confirmed a satisfactory safety profile. After this confirmation, the maximum allowable dose was increased to 4 mg TID. This occurred after 45 subjects had been enrolled. A subsequent Data Monitoring Committee meeting, which occurred after 75 subjects had been enrolled, increased the maximum allowable dose to 6 mg TID.
Efficacy assessments consisted of 6-Minute Walk Distance (6MWD), blood collection for N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, clinical worsening, WHO Functional Class (FC), Borg dyspnea score, glycated hemoglobin (HbA1c), and Kansas City Cardiomyopathy Questionnaire (KCCQ).
Safety assessments consisted of AEs, physical examinations, vital signs, 12-lead electrocardiograms (ECGs), echocardiograms (ECHOs), heart failure signs and symptoms, pregnancy testing, clinical laboratory tests, hospitalizations due to cardiopulmonary indication, and worsening heart failure as demonstrated by outpatient administration of intravenous (IV) diuretics. Subjects could have optionally provided samples for the evaluation of biomarkers and pharmacogenomics.
Subjects that completed the 24-week treatment period on study drug were permitted to enter the open-label extension study (Study TDE-HF-302).
The study was discontinued by the Sponsor on 14 October 2019 due to slow enrollment. As only a small portion of the anticipated total subjects had been enrolled, with many terminating early due to the study termination, there was a limited ability to explore the effect of oral treprostinil in this indication in this study.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Oral treprostinil
Sustained-release oral tablets for TID administration
Oral treprostinil
Sustained-release oral tablets for TID administration
Placebo
Placebo (sugar pill) for TID oral administration
Placebo
Placebo (sugar pill) for TID oral administration
Interventions
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Oral treprostinil
Sustained-release oral tablets for TID administration
Placebo
Placebo (sugar pill) for TID oral administration
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. The subject was 18 to 85 years of age (inclusive) at Screening (ie, date of providing written informed consent).
3. A subject could qualify if they had undergone a right heart catheterization (RHC) within 180 days of Baseline.
4. The subject had a diagnosis of heart failure with a left ventricular ejection fraction (LVEF) ≥45% by ECHO completed during Screening (prior to randomization).
5. The subject's baseline 6MWD was at least 150 meters.
6. The subject had pulmonary function tests conducted within 6 months of Screening or during the Screening Phase.
7. Subjects on a chronic medication for heart failure were on a stable dose for ≥30 days prior to randomization.
8. In the opinion of the Investigator, the subject was able to communicate effectively with study personnel, and was considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.
9. Women of childbearing potential, including any female who had experienced menarche and who had not undergone successful surgical sterilization or was not postmenopausal, must have practiced true abstinence from intercourse when it was in line with their preferred and usual lifestyle, or have used 2 different forms of highly effective contraception for the duration of the study, and for at least 30 days after discontinuing study drug. Male subjects with a partner of childbearing potential must have used a condom during the length of the study, and for at least 48 hours after discontinuing study drug.
10. Subjects on chronic medications (eg, inhaled corticosteroids, long-acting beta2 adrenergic agonist, long acting muscarinic antagonists, combination inhaled drugs, anti-inflammatory drugs, oral/parenteral corticosteroids, or biologic agents) for any underlying respiratory condition were on a stable dose for ≥30 days prior to randomization.
Exclusion Criteria
2. In the opinion of the Principal Investigator, the subject had a primary diagnosis of PH other than WHO Group 2 PH.
3. The subject had shown intolerance or significant lack of efficacy to a prostacyclin or prostacyclin analogue that resulted in discontinuation of therapy or inability to effectively titrate that therapy.
4. The subject had received any approved pulmonary arterial hypertension (PAH) therapies within 30 days of randomization. Chronic use of an approved phosphodiesterase type 5 inhibitor (PDE5-I) was allowed as long as the subject has been on a stable dose for at least 90 days prior to randomization and had a RHC confirming the parameters necessary for inclusion in the study after being on a stable PDE5-I dose for at least 30 days.
5. The subject had been hospitalized for a cardiopulmonary indication within 30 days of randomization.
6. The subject had a myocardial infarction within 90 days of randomization.
7. The subject had cardiac resynchronization therapy within 90 days of randomization or anticipated resynchronization therapy during the study treatment period.
8. The subject had liver function tests greater than 3 times the upper limit of normal at Screening, clinically significant liver disease/dysfunction, known Child-Pugh Class C hepatic disease, or noncirrhotic portal hypertension.
9. The subject had uncontrolled systemic hypertension, systolic blood pressure \<100 mmHg, or a resting heart rate \>100 beats per minute at Baseline.
10. The subject had known genetic hypertrophic cardiomyopathy, sarcoidosis, or cardiac amyloidosis.
11. The subject had a known history of any LVEF less than 40% by ECHO within 3 years of randomization. Note: a transient decline in LVEF below 40% that occurred and recovered more than 6 months before the start of Screening and was associated with an acute intercurrent condition (eg, atrial fibrillation) was allowed.
12. The subject had hemodynamically significant valvular heart disease as determined by the Investigator, including: greater than mild aortic and/or mitral stenosis or severe mitral and/or aortic regurgitation (\>Grade 3)
13. The subject had a Body Mass Index \>45 kg/m\^2.
14. The subject had any musculoskeletal disorder, or had any other condition that limited ambulation.
15. The subject had end-stage renal disease requiring/receiving dialysis.
16. The subject participated in an investigational drug or device study within 30 days prior to the first dose of study drug.
18 Years
85 Years
ALL
No
Sponsors
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United Therapeutics
INDUSTRY
Responsible Party
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Principal Investigators
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Mardi Gomberg-Maitland, MD
Role: PRINCIPAL_INVESTIGATOR
George Washington University
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Banner University Medical Center Phoenix
Phoenix, Arizona, United States
University of Arizona
Tucson, Arizona, United States
VA Healthcare System of Greater Los Angeles
Los Angeles, California, United States
University of California Los Angeles Pulmonary Division
Los Angeles, California, United States
Cedars-Sinai Medical Center
Los Angeles, California, United States
University of California - Davis Medical Center
Sacramento, California, United States
Santa Barbara Cottage Hospital
Santa Barbara, California, United States
Aurora Denver Cardiology Associates
Aurora, Colorado, United States
University of Colorado Denver
Aurora, Colorado, United States
National Jewish Health
Denver, Colorado, United States
South Denver Cardiology
Littleton, Colorado, United States
MedStar Georgetown University Hospital
Washington D.C., District of Columbia, United States
Medical Faculty Associates, George Washington University
Washington D.C., District of Columbia, United States
Bay Area Cardiology Associates
Brandon, Florida, United States
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States
St. Vincent's Lung, Sleep, and Critical Care Specialists
Jacksonville, Florida, United States
Central Florida Pulmonary Group, P.A.
Orlando, Florida, United States
Florida Hospital
Orlando, Florida, United States
University of South Florida; Tampa General Hospital
Tampa, Florida, United States
Cleveland Clinic of Florida
Weston, Florida, United States
Emory University Hospital
Atlanta, Georgia, United States
Augusta University
Augusta, Georgia, United States
Piedmont Physicians Georgia Lung
Austell, Georgia, United States
WellStar Medical Group
Marietta, Georgia, United States
University of Illinois at Chicago Hospital
Chicago, Illinois, United States
Loyola University Medical Center
Maywood, Illinois, United States
Advocate Christ Medical Center
Oak Lawn, Illinois, United States
OSF HealthCare
Peoria, Illinois, United States
Indiana University Health Methodist Research Institute, INC
Indianapolis, Indiana, United States
Community Physician Network, Heart and Vascular Care
Indianapolis, Indiana, United States
Saint Vincent Hospital and Health Services
Indianapolis, Indiana, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States
Iowa Heart Center
West Des Moines, Iowa, United States
University of Kansas Medical Center
Kansas City, Kansas, United States
University of Kentucky Medical Center
Lexington, Kentucky, United States
Kentuckiana Pulmonary Associates
Louisville, Kentucky, United States
University of Louisville Physicians Outpatient Center
Louisville, Kentucky, United States
Chest Medicine Associates
South Portland, Maine, United States
Tufts Medical Center
Boston, Massachusetts, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
St. Elizabeth's Medical Center
Brighton, Massachusetts, United States
Henry Ford Health System
Detroit, Michigan, United States
Spectrum Health Medical Group
Grand Rapids, Michigan, United States
University of Minnesota
Minneapolis, Minnesota, United States
St. Luke's Hospital
Chesterfield, Missouri, United States
Saint Luke's Hospital of Kansas City
Kansas City, Missouri, United States
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, United States
Barnabas Health Lung Center
Newark, New Jersey, United States
Albany Medical College
Albany, New York, United States
Mount Sinai Medical Center
New York, New York, United States
Pulmonary Health Physicians, PC
Syracuse, New York, United States
Montefiore Medical Center
The Bronx, New York, United States
Asheville Cardiology Associates
Asheville, North Carolina, United States
Duke University Medical Center
Durham, North Carolina, United States
Pinehurst Medical Clinic
Pinehurst, North Carolina, United States
The Lindner Research Center The Christ Hospital Health Network
Cincinnati, Ohio, United States
Cleveland Clinic
Cleveland, Ohio, United States
The Ohio State University Wexner Medical Center
Columbus, Ohio, United States
University of Toledo Medical Center
Toledo, Ohio, United States
The Oregon Clinic
Portland, Oregon, United States
Lancaster General Hospital
Lancaster, Pennsylvania, United States
Allegheny General Hospital
Pittsburgh, Pennsylvania, United States
AnMed Health Pulmonary and Sleep Medicine
Anderson, South Carolina, United States
VitaLink Research - Anderson
Anderson, South Carolina, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Stern Cardiovascular Foundation
Germantown, Tennessee, United States
Summit Medical Group
Knoxville, Tennessee, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Baylor University Medical Center
Dallas, Texas, United States
Houston Methodist Research Institute
Houston, Texas, United States
The University of Texas Health Science Center at Houston
Houston, Texas, United States
Texas Tech University Health Sciences Center
Lubbock, Texas, United States
Intermountain Medical Center
Murray, Utah, United States
Inova Heart and Vascular Institute
Falls Church, Virginia, United States
Sentara Cardiovascular Research Institute
Norfolk, Virginia, United States
Virginia Commonwealth University
Richmond, Virginia, United States
Carilion Clinic
Roanoke, Virginia, United States
Providence Medical Research Center
Spokane, Washington, United States
West Virginia University Hospital
Morgantown, West Virginia, United States
Aurora St. Luke's Medical Center
Milwaukee, Wisconsin, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Countries
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Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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TDE-HF-301
Identifier Type: -
Identifier Source: org_study_id