Clinical trial NCT03037580: Oral Treprostinil in Subjects With Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Pulmonary Hypertension
Heart Failure With Preserved Ejection Fraction
Keywords: Pulmonary Hypertension
6-Minute Walk Test
HFpEF
Oral Treprostinil
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2017-01-31
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in 6MWD From Baseline to Week 24
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Change in NT-proBNP Levels From Baseline to Week 24
timeFrame: Baseline to Week 24
measure: Number of Subjects With First Clinical Worsening Event From Baseline to Week 24
timeFrame: Baseline to Week 24
measure: Change in WHO FC From Baseline to Week 24
timeFrame: Baseline to Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner University Medical Center Phoenix
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Los Angeles
country: United States
facility: VA Healthcare System of Greater Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Pulmonary Division
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Sacramento
country: United States
facility: University of California - Davis Medical Center
state: California
city: Santa Barbara
country: United States
facility: Santa Barbara Cottage Hospital
state: California
city: Aurora
country: United States
facility: Aurora Denver Cardiology Associates
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Littleton
country: United States
facility: South Denver Cardiology
state: Colorado
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: Medical Faculty Associates, George Washington University
state: District of Columbia
city: Brandon
country: United States
facility: Bay Area Cardiology Associates
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: St. Vincent's Lung, Sleep, and Critical Care Specialists
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group, P.A.
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Tampa
country: United States
facility: University of South Florida; Tampa General Hospital
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic of Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Austell
country: United States
facility: Piedmont Physicians Georgia Lung
state: Georgia
city: Marietta
country: United States
facility: WellStar Medical Group
state: Georgia
city: Chicago
country: United States
facility: University of Illinois at Chicago Hospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Christ Medical Center
state: Illinois
city: Peoria
country: United States
facility: OSF HealthCare
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Methodist Research Institute, INC
state: Indiana
city: Indianapolis
country: United States
facility: Community Physician Network, Heart and Vascular Care
state: Indiana
city: Indianapolis
country: United States
facility: Saint Vincent Hospital and Health Services
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: West Des Moines
country: United States
facility: Iowa Heart Center
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville Physicians Outpatient Center
state: Kentucky
city: South Portland
country: United States
facility: Chest Medicine Associates
state: Maine
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Brighton
country: United States
facility: St. Elizabeth's Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Medical Group
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Chesterfield
country: United States
facility: St. Luke's Hospital
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Newark
country: United States
facility: Barnabas Health Lung Center
state: New Jersey
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Syracuse
country: United States
facility: Pulmonary Health Physicians, PC
state: New York
city: Asheville
country: United States
facility: Asheville Cardiology Associates
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Pinehurst
country: United States
facility: Pinehurst Medical Clinic
state: North Carolina
city: Cincinnati
country: United States
facility: The Lindner Research Center The Christ Hospital Health Network
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Toledo
country: United States
facility: University of Toledo Medical Center
state: Ohio
city: Portland
country: United States
facility: The Oregon Clinic
state: Oregon
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Anderson
country: United States
facility: AnMed Health Pulmonary and Sleep Medicine
state: South Carolina
city: Anderson
country: United States
facility: VitaLink Research - Anderson
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Germantown
country: United States
facility: Stern Cardiovascular Foundation
state: Tennessee
city: Knoxville
country: United States
facility: Summit Medical Group
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Research Institute
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Lubbock
country: United States
facility: Texas Tech University Health Sciences Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Falls Church
country: United States
facility: Inova Heart and Vascular Institute
state: Virginia
city: Norfolk
country: United States
facility: Sentara Cardiovascular Research Institute
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Roanoke
country: United States
facility: Carilion Clinic
state: Virginia
city: Spokane
country: United States
facility: Providence Medical Research Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Hospital
state: West Virginia
city: Milwaukee
country: United States
facility: Aurora St. Luke's Medical Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: George Washington University
name: Mardi Gomberg-Maitland, MD
role: PRINCIPAL_INVESTIGATOR
References: