LARIAT

Inclusion Criteria

  • Male and female patients ≥ 18 to ≤ 75 years of age upon study consent;
  • BMI > 18.5kg/m2
  • Symptomatic pulmonary arterial hypertension WHO/NYHA FC class II and III;
  • Patients with WHO Group 1 PAH (idiopathic; heritable; drug or toxin induced; connective tissue disease; congenital heart disease; HIV)
  • RHC confirmeing a diagnosis of PAH according to all the following criteria:  mPAP ≥ 25 mm Hg (at rest); PCWP ≤ 15 mm Hg; PVR > 240 dyn.sec/cm5 or > 3 mm Hg/Liter (L)/minute
  • BNP level ≤ 200 pg/mL
  • 6MWD ≥ 150 and ≤ 450 meters performed on different days during Screening
  • On oral, disease-specific PAH therapy consisting of an ERA and/or a PDE5i
  • Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following therapies that may affect PAH: vasodilators (including calcium channel blockers), digoxin, L-arginine supplementation, or oxygen supplementation
  • If receiving prednisone, has maintained a stable dose of ≤ 20 mg/day (or equivalent dose if other corticosteroid) for at least 30 days prior to Day 1
  • If receiving treatment for CTD with any other drugs, doses should remain stable for the duration of the study
  • Had PFTs showing FEV1 ≥ 65% (predicted); FEV1/FVC ≥ 65%; or TLC ≥ 65% (predicted)
  • Had a V/Q lung scan, CT or pulmonary angiogram prior to Screening that shows no evidence of thromboembolic disease
  • Adequate kidney function defined as an eGFR ≥ 60 mL/min/1.73 m2

 Exclusion Criteria:

  • Participation in an intensive exercise training program for pulmonary rehabilitation within 90 days prior to Screening
  • Receiving chronic treatment with a prostacyclin/prostacyclin analogue or riociguat within 60 days prior to Day 1
  • Requirement for receipt of intravenous inotropes within 30 days prior to Day 1
  • Has uncontrolled systemic hypertension (SBP > 160 mm Hg or DBP > 100 mm )
  • Has systolic BP < 90 mm Hg during Screening after a period of rest
  • History of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:  Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension; pericardial constriction; restrictive or congestive cardiomyopathy; LVEF< 40% at the Screen echo; symptomatic coronary disease
  • Acutely decompensated heart failure within 30 days prior to Day 1, as per Investigator assessment
  • Has more than two of the following clinical risk factors for left ventricular diastolic dysfunction:  Age > 65 years; BMI ≥ 30 kg/m2; history of systemic hypertension; history of type 2 diabetes; history of atrial fibrillation
  • History of atrial septostomy within 180 days prior to Day 1
  • History of obstructive sleep apnea that is untreated
  • For patients with HIV-associated PAH, any of the following:

–  Concomitant active opportunistic infections within 180 days prior to Screening

–  Detectable viral load within 90 days prior to Screening

–  Cluster designation (CD+) T-cell count < 200 mm3 within 90 days prior to Screening

–  Changes in antiretroviral regimen within 90 days prior to Screening

–  Using inhaled pentamidine

  • History of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C)
  • ALT or AST levels > ULN at Screening
  • Hgb concentration < 8.5 g/dL at Screening
  • Diagnosis of Down syndrome
  • History of malignancy within 5 years prior to screening, with the exception of localized skin or cervical carcinomas
  • Active bacterial, fungal, or viral infection, incompatible with the study