Oral Treprostinil in Subjects With Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction

A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Oral Treprostinil in Subjects With Pulmonary Hypertension (PH) in Heart Failure With Preserved Ejection Fraction (HFpEF)

This was a multicenter, randomized (1:1; oral treprostinil to placebo), double-blind, placebo-controlled study in subjects with World Health Organization (WHO) Group 2 pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF). Once randomized, subjects took the initial dose of study drug at the study site on the day of randomization. Subjects returned to the study site for visits scheduled at Weeks 6, 12, 18, and 24. The duration of study participation was approximately 28 weeks from Screening until study completion (includes a 30-day Screening Phase and 24-week Treatment Phase).

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.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Hypertension; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Oral treprostinil; Drug: Placebo

Detailed Description

Study TDE-HF-301 was a multicenter, randomized, double-blind, placebo-controlled study designed to investigate the effect of oral treprostinil compared with placebo on exercise capacity in subjects with WHO Group 2 PH associated with HFpEF.

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner University Medical Center Phoenix
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Los Angeles, California, United States, 90211
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90073
      • VA Healthcare System of Greater Los Angeles
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles Pulmonary Division
    • Sacramento, California, United States, 95817
      • University of California - Davis Medical Center
    • Santa Barbara, California, United States, 93105
      • Santa Barbara Cottage Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
    • Aurora, Colorado, United States, 80012
      • Aurora Denver Cardiology Associates
    • Denver, Colorado, United States, 80206
      • National Jewish Health
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
    • Washington, District of Columbia, United States, 20037
      • Medical Faculty Associates, George Washington University
  • Florida
    • Brandon, Florida, United States, 33511
      • Bay Area Cardiology Associates
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
    • Jacksonville, Florida, United States, 33204
      • St. Vincent's Lung, Sleep, and Critical Care Specialists
    • Orlando, Florida, United States, 32803
      • Central Florida Pulmonary Group, P.A.
    • Orlando, Florida, United States, 32806
      • Florida Hospital
    • Tampa, Florida, United States, 33606
      • University of South Florida; Tampa General Hospital
    • Weston, Florida, United States, 33331
      • Cleveland Clinic of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Augusta, Georgia, United States, 30912
      • Augusta University
    • Austell, Georgia, United States, 30309
      • Piedmont Physicians Georgia Lung
    • Marietta, Georgia, United States, 30060
      • WellStar Medical Group
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
    • Peoria, Illinois, United States, 61614
      • OSF Healthcare
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Hospital and Health Services
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Methodist Research Institute, INC
    • Indianapolis, Indiana, United States, 46250
      • Community Physician Network, Heart and Vascular Care
  • Iowa
    • Iowa City, Iowa, United States, 55242
      • University of Iowa Hospitals and Clinics
    • West Des Moines, Iowa, United States, 50266
      • Iowa Heart Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Associates
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Physicians Outpatient Center
  • Maine
    • South Portland, Maine, United States, 04106
      • Chest Medicine Associates
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Brighton, Massachusetts, United States, 02135
      • St. Elizabeth's Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Medical Group
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • St. Luke's Hospital
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital of Kansas City
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Barnabas Health Lung Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Syracuse, New York, United States, 13066
      • Pulmonary Health Physicians, PC
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Asheville Cardiology Associates
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Pinehurst, North Carolina, United States, 28374
      • Pinehurst Medical Clinic
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Research Center The Christ Hospital Health Network
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
    • Toledo, Ohio, United States, 43614
      • University of Toledo Medical Center
  • Oregon
    • Portland, Oregon, United States, 97225
      • The Oregon Clinic
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17601
      • Lancaster General Hospital
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • Vitalink Research - Anderson
    • Anderson, South Carolina, United States, 29621
      • AnMed Health Pulmonary and Sleep Medicine
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Stern Cardiovascular Foundation
    • Knoxville, Tennessee, United States, 37909
      • Summit Medical Group
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Research Institute
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
    • Lubbock, Texas, United States, 79905
      • Texas Tech University Health Sciences Center
  • Utah
    • Murray, Utah, United States, 84157-7000
      • Intermountain Medical Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Heart and Vascular Institute
    • Norfolk, Virginia, United States, 23507
      • Sentara Cardiovascular Research Institute
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Roanoke, Virginia, United States, 24014
      • Carilion Clinic
  • Washington
    • Spokane, Washington, United States, 99204
      • Providence Medical Research Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The subject voluntarily gave informed consent to participate in the study.
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:

1. The subject was pregnant or lactating.
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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral treprostinil; Sustained-release oral tablets for TID administration	Drug: Oral treprostinil; Sustained-release oral tablets for TID administration; Other Names: Treprostinil diethanolamine, treprostinil diolamine
Placebo Comparator: Placebo; Placebo (sugar pill) for TID oral administration	Drug: Placebo; Placebo (sugar pill) for TID oral administration; Other Names: Matching placebo (sugar pill)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6MWD From Baseline to Week 24	The intent of the 6-Minute Walk Test (6MWT) is to evaluate exercise capacity associated with carrying out activities of daily living.	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NT-proBNP Levels From Baseline to Week 24	The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.	Baseline to Week 24
Number of Subjects With First Clinical Worsening Event From Baseline to Week 24	Clinical worsening was defined as the occurrence of any 1 of the following clinical worsening events: hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to PH and/or heart failure), outpatient administration of IV diuretics, death (all causes), decrease in 6MWD >15% from Baseline (or the subject was too ill to walk, and the cause was directly related to the disease under study) at 2 consecutive visits on different days (except Week 24).	Baseline to Week 24
Change in WHO FC From Baseline to Week 24	The WHO functional classification ranges from I (subject's disease does not affect daily activities) to IV (subject's disease causes severe impairment).	Baseline to Week 24

Collaborators and Investigators

• Sponsor: United Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2017
• Primary Completion (Actual): December 3, 2019
• Study Completion (Actual): December 3, 2019

Study Registration Dates

• First Submitted: January 27, 2017
• First Submitted That Met QC Criteria: January 30, 2017
• First Posted (Estimate): January 31, 2017

Study Record Updates

• Last Update Posted (Actual): November 10, 2020
• Last Update Submitted That Met QC Criteria: October 20, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; HFpEF; Oral Treprostinil; 6-Minute Walk Test
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Hypertension, Pulmonary; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: TDE-HF-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No