Clinical Trials

Inclusion Criteria:

• The subject voluntarily gives informed consent to participate in the study.
• The subject is 18 to 85 years of age (inclusive) at Screening (i.e., date of providing written informed consent).
• A subject can qualify if they have undergone a RHC within 180 days of Baseline and either of the following conditions (regular criterion or fluid challenge criterion) are met:
• Regular criterion:
  • A PAPm ≥ 25 mmHg;
  • A PCWP >15 mmHg but ≤ 30 mmHg. In cases where a PCWP is not available or deemed unreliable, a left ventricular end-diastolic pressure (LVEDP) obtained within the 180-day window may be used. Note that a subject would be eligible to participate in the trial if they have a PAPm > 25 mmHg, a PVR > 3 wood units, and a PCWP < 15 mmHg from a RHC conducted during the Screening period if they had a PCWP >15 mmHg (with no upper limit) associated with a diagnosis of HFpEF on the preceding RHC (done within 180 days of Baseline);
  • A PVR of ≥ 3.0 Wood units (≥ 240 dynes*s/cm^5) calculated using thermodilution or Fick technique.
• Fluid challenge criterion:
  • A PAPm ≥ 25 mmHg;
  • A positive fluid challenge, namely a PCWP ≥ 16 mmHg after ~500 ml saline infused via IV over approximately 5 minutes;
  • A PVR of ≥ 3.0 Wood units (≥ 240 dynes*s/cm5) calculated using thermodilution or Fick technique;
  • 3 or more of the following risk factors for PH associated with HFpEF:
    • Hypertension;
    • Type 2 diabetes mellitus;
    • Hyperlipidemia;
    • Atrial fibrillation;
    • Age > 65 years old;
    • Sleep apnea;
    • Left atrial volume index > 32 ml/m^2 (transthoracic echocardiogram);
    • Body mass index > 30 kg/m^2;
• The subject has a diagnosis of heart failure with a LVEF ≥ 45% by ECHO completed during Screening (prior to randomization).
• The subject’s baseline 6MWD must be at least 150 meters.
• The subject has pulmonary function tests conducted within 6 months of Screening or during the Screening phase to confirm the following:
  • Total lung capacity is ≥ 60% of the predicted value;
  • Forced expiratory volume at 1 second (FEV1) is ≥ 50% of the predicted value;
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) is ≥ 40% of the predicted value (unadjusted, or adjusted for alveolar volume).
• Subjects on a chronic medication for heart failure (e.g., ACE inhibitors, ARBs, and beta blockers) must be on a stable dose for ≥ 30 days prior to randomization. The exception is with changes of anticoagulants and/or diuretics; these medications should not be newly started or stopped within 30 days of randomization and no healthcare provider prescribed dose change should occur within 7 days of randomization, with the exception of the withholding of doses of anticoagulants for the conduct of the RHC, when required.
• In the opinion of the Investigator, the subject is able to communicate effectively with study personnel, and is considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.
• WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months). WOCBP must practice true abstinence from intercourse when it is in line with their preferred and usual lifestyle, or use 2 different forms of highly effective contraception for the duration of the study, and for at least 30 days after discontinuing study drug. Medically acceptable forms of effective contraception include:
  • approved hormonal contraceptives (such as birth control pills);
  • barrier methods (such as a condom or diaphragm) used with a spermicide;
  • an intrauterine device;
  • partner vasectomy.
  • For WOCBP, a negative urine pregnancy test is required at Screening and Baseline prior to initiating study drug. Male subjects with a partner of childbearing potential must use a condom during the length of the study, and for at least 48 hours after discontinuing study drug.
• Subjects on chronic medications (e.g., 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 must be on a stable dose for ≥ 30 days prior to randomization.

Exclusion Criteria:

• The subject is pregnant or lactating.
• In the opinion of the Principal Investigator, the subject has a primary diagnosis of PH other than WHO Group 2 PH.
• The subject has 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.
• The subject has received PAH therapies, including prostacyclin therapy (i.e., epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity testing), nonprostanoid IP receptor agonist (selexipag), ERA, or soluble guanylate cyclase stimulator, within 30 days of randomization. Chronic use of an approved phosphodiesterase type 5 inhibitor (PDE5-I) is allowed as long as the subject has been on a stable dose for at least 90 days prior to randomization and has had an RHC confirming the parameters necessary for inclusion in the study after being on a stable PDE5-I dose for at least 30 days. If the Investigator does not intend to keep a subject on their PDE5-I therapy, it must be stopped at least 30 days prior to randomization. Intermittent use of a PDE5-I (≤ 3 times per week) to treat erectile dysfunction is permitted.
• The subject has been hospitalized for a cardiopulmonary indication within 30 days of randomization.
• The subject had a myocardial infarction within 90 days of randomization.
• The subject had cardiac resynchronization therapy within 90 days of randomization or anticipated resynchronization therapy during the study treatment period.
• The subject has liver function tests (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) greater than 3 times the upper limit of normal at Screening, clinically significant liver disease/dysfunction per Investigator’s clinical judgement, known Child-Pugh Class C hepatic disease, or noncirrhotic portal hypertension.
• The subject has uncontrolled systemic hypertension, defined as a systolic blood pressure > 160 mmHg or a diastolic blood pressure > 110 mmHg at Baseline.
• The subject has a systolic blood pressure < 100 mmHg at Baseline.
• The subject has a resting heart rate > 100 beats per minute at Baseline.
• The subject has known genetic hypertrophic cardiomyopathy.
• The subject has sarcoidosis or cardiac amyloidosis.
• The subject has 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 (e.g., atrial fibrillation) is allowed.
• The subject has hemodynamically significant valvular heart disease as determined by the Investigator, including:
  • Greater than mild aortic and/or mitral stenosis;
  • Severe mitral and/or aortic regurgitation (> Grade 3).
• The subject has a body mass index > 45 kg/m2.
• The subject has any musculoskeletal disorder (e.g., arthritis affecting the lower limbs, recent hip or knee joint replacement, artificial leg), or has any other condition that would likely be the primary limit to ambulation as opposed to the  disease under study.
• The subject has end-stage renal disease requiring/receiving dialysis.
• The subject has used any investigational drug/device, or participated in any investigational study, within 30 days prior to the first dose of study drug.