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

Pulmonary Hypertension Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03037580
• Other study ID #: TDE-HF-301
• Status: Terminated
• Phase: Phase 3
• Start date: August 15, 2017
• Est. completion date: December 3, 2019

Study information

• Verified date: October 2020
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 84
• Est. completion date: December 3, 2019
• Est. primary completion date: December 3, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Oral treprostinil
Sustained-release oral tablets for TID administration
• Placebo
Placebo (sugar pill) for TID oral administration

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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