Bardoxolone Methyl Evaluation in Patients With Pulmonary Hypertension (PH) - LARIAT

Inclusion Criteria:

   1. Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent;

   2. BMI > 18.5 kg/m²

   3. Symptomatic pulmonary hypertension WHO class II and III;

   4. WHO Group I, III, or V PH according to the following criteria:

      1. If diagnosed with WHO Group I PAH, then on of the following subtypes:

         - Idiopathic or heritable PAH;

         - PAH associated with connective tissue disease;

         - PAH associated with simple, congenital systemic-to-pulmonary shunts at least
         1 year following shunt repair;

         - PAH associated with anorexigen or drug-induced toxicity;

         - PAH associated with human immunodeficiency virus (HIV); or

      2. If WHO Group III PH then primary diagnosis must be one of the following subtypes:

         - Connective tissue disease associated ILD (CTD-ILD);

         - Idiopathic pulmonary fibrosis (IPF);

         - Nonspecific interstitial pneumonia (NSIP); or

      3. If WHO Group V PH then patient must be diagnosed with sarcoidosis;

   5. Had a diagnostic right heart catheterization performed and documented within 36 months
   prior to Day 1 that confirmed a diagnosis of PH

   6. If WHO Group I, has been receiving no more than three (3) FDA-approved
   disease-specific PAH therapies except for intravenous (iv) prostacyclin/prostacyclin
   analogues. PAH therapy must be at a stable dose for at least 90 days prior to Day 1;

   7. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR)
   ≥ 45 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable
   formula;

Exclusion Criteria:

   1. Participation in other interventional clinical studies involving pharmaceutical
   products being tested or used in a way different from the approved form or when used
   for an unapproved indication within 30 days prior to Day 1;

   2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 3 months
   (90 days) prior to Day 1 or planned initiation during Part 1 of the study;

   3. Stopped receiving any PH chronic therapy within 60 days prior to Day 1;

   4. Requirement for receipt of intravenous inotropes within 30 days prior to Day 1;

   5. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure
   (BP) > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening
   after a period of rest;

   6. Has systolic BP < 90 mm Hg during Screening after a period of rest;

   7. WHO Group III or V patients who at rest require supplemental oxygen at a rate of >4
   L/min and have peripheral capillary oxygen saturation levels <92%;

   8. Has a history of clinically significant left-sided heart disease and/or clinically
   significant cardiac disease,including but not limited to any of the following:

      1. Congenital or acquired valvular disease if clinically significant apart from
      tricuspid valvular insufficiency due to pulmonary hypertension;

      2. Pericardial constriction;

      3. Restrictive or congestive cardiomyopathy;

      4. Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 60 days
      of Day 1;

      5. Any current or prior history of symptomatic coronary disease (prior myocardial
      infarction, percutaneous coronary intervention, coronary artery bypass graft
      surgery, or anginal chest pain);

   9. Acutely decompensated heart failure within 30 days prior to Day 1, as per Investigator
   assessment;

10. History of atrial septostomy within 180 days prior to Day 1;

11. History of obstructive sleep apnea that is untreated;

12. Has a 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);

13. Serum aminotransferase (ALT or AST) levels > the upper limit of normal (ULN) at
   Screening;

14. For patients with HIV-associated PAH, any of the following:

      1. Concomitant active opportunistic infections within 180 days prior to Screening;

      2. Detectable viral load within 90 days prior to Screening;

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

      4. Changes in antiretroviral regimen within 90 days prior to Screening;

      5. Using inhaled pentamidine