Bardoxolone Methyl Evaluation in Patients With Pulmonary Hypertension (PH) - LARIAT
Condition: Pulmonary Arterial Hypertension; Pulmonary Hypertension; Interstitial Lung Disease; Idiopathic Interstitial Pneumonia; Idiopathic Pulmonary Fibrosis; Sarcoidosis; Respiratory Bronchiolitis Associated Interstitial Lung Disease; Desquamative Interstitial Pneumonia; Cryptogenic Organizing Pneumonia; Acute Interstitial Pneumonitis; Idiopathic Lymphoid Interstitial Pneumonia; Idiopathic Pleuroparenchymal Fibroelastosis
MeSH terms: Pneumonia; Bronchiolitis; Lung Diseases; Hypertension, Pulmonary; Pulmonary Fibrosis; Pulmonary Arterial Hypertension; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Idiopathic Interstitial Pneumonias; Hamman-Rich Syndrome; Organizing Pneumonia; Cryptogenic Organizing Pneumonia; Hypertension; Sarcoidosis; Fibrosis
Intervention: Bardoxolone methyl; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Double (Participant, Investigator)
Enrollment: 166.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pulmonary Arterial Hypertension; PAH; Bardoxolone methyl; 6-minute walk distance; CDDO-me; RTA 402; Pulmonary Hypertension; Interstitial Lung Disease; Idiopathic Interstitial Pneumonia; Idiopathic Pulmonary Fibrosis; Sarcoidosis; Respiratory Bronchiolitis Associated ILD; Desquamative Interstitial Pneumonia; Cryptogenic Organizing Pneumonia; Acute Interstitial Pneumonitis; Idiopathic Lymphoid Interstitial Pneumonia; Idiopathic Pleuroparenchymal Fibroelastosis

Summary:

      This study assesses the safety and efficacy of bardoxolone methyl relative to placebo in
      patients with pulmonary hypertension to determine the recommended dose range, evaluate the
      change from baseline in 6-minute walk distance (6MWD) and determine the effect of Bardoxolone
      methyl in pulmonary hypertension associated with connective tissue disease, interstitial lung
      disease, and idiopathic etiologies, including subsets of patients with WHO Group III or WHO
      Group V PH following 16 weeks of study participation.
    

Eligibility criteria:

        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