Oral Treprostinil in Subjects With Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction
Condition: Pulmonary Hypertension; Heart Failure With Preserved Ejection Fraction
MeSH terms: Hypertension, Pulmonary; Hypertension; Heart Failure
Intervention: Oral treprostinil; Placebo
Intervention description: Sustained-release oral tablets for TID administration; Placebo (sugar pill) for TID oral administration
Intervention MeSH terms: Treprostinil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 84.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Pulmonary Hypertension; 6-Minute Walk Test; HFpEF; Oral Treprostinil

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.
    

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.