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

Phase 2

Completed

• Conditions: 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
• Interventions: Drug: Bardoxolone methyl; Drug: Placebo

• Registration Number: NCT02036970
• Lead Sponsor: Reata, a wholly owned subsidiary of Biogen

Brief 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.

Detailed Description

The molecular and pharmacological effects of bardoxolone methyl are broad through its induction of Nrf2 and suppression of NF-κB. Bardoxolone methyl may therefore address multiple facets of the pathophysiology of PH because it suppresses activation of proinflammatory mediators, enhances endothelial NO bioavailability, improves metabolic dysfunction, suppresses vascular proliferation, and prevents maladaptive remodeling. Furthermore, while existing therapies primarily target only smooth muscle cells, bardoxolone methyl targets multiple cell types relevant to PH, including endothelial cells, smooth muscle cells, and macrophages.

This is a two-part study.

Part 1: Part 1 of the study will include a dose-ranging phase and a dose-titration phase.

Part 2 (extension period): All patients from Part 1 who complete the 16-week treatment period as planned will be eligible to continue directly into the extension period to evaluate the intermediate and long-term safety and efficacy of bardoxolone methyl.

Study Sponsor, originally Reata Pharmaceuticals, Inc., is now Reata Pharmaceuticals, Inc., a wholly owned subsidiary of Biogen.

Study Timeline

• Study First Submitted: 2014-01-13
• Study First Submitted QC: 2014-01-13
• Study First Posted: 2014-01-15
• Study Start: 2014-05-31
• Primary Completion: 2018-01-19
• Study Completion: 2018-05-16
• Disposition First Submitted: 2019-01-02
• Disposition First Submitted QC: 2019-01-02
• Disposition First Posted: 2019-01-03
• Results First Submitted: 2020-12-31
• Results First Submitted QC: 2021-06-28
• Results First Posted: 2021-07-23
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-01
• Last Update Posted: 2024-02-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 166

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1 Dose-Ranging Bardoxolone methyl 2.5 mg/Part 2: Open-Label	Bardoxolone methyl	Participants received bardoxolone methyl 2.5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Bardoxolone methyl 20 mg/Part 2: Open-Label	Bardoxolone methyl	Participants received bardoxolone methyl 20 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone methyl 2.5 mg	Placebo	Participants received bardoxolone methyl 2.5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone methyl 5 mg	Placebo	Participants received bardoxolone methyl 5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg	Placebo	Participants received bardoxolone methyl 10 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone methyl 20 mg	Placebo	Participants received bardoxolone methyl 20 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg	Placebo	Participants in Part 1 received Placebo once-daily from Day 1 thru Week 16. Participants who continued to Part 2 initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from week 20 onwards
Part 1: Dose-Ranging Bardoxolone methyl 5 mg/Part 2: Open-Label	Bardoxolone methyl	Participants received bardoxolone methyl 5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Bardoxolone methyl 10 mg/Part 2: Open-Label	Bardoxolone methyl	Participants received bardoxolone methyl 10 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone methyl 2.5 mg	Bardoxolone methyl	Participants received bardoxolone methyl 2.5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone methyl 5 mg	Bardoxolone methyl	Participants received bardoxolone methyl 5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg	Bardoxolone methyl	Participants received bardoxolone methyl 10 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone methyl 20 mg	Bardoxolone methyl	Participants received bardoxolone methyl 20 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose Titration: Bardoxolone methyl 10 mg/Part 2: Bardoxolone methyl 10 mg	Bardoxolone methyl	Participants in Part 1 started with bardoxolone methyl 5 mg once-daily from Day 1 and escalated to bardoxolone methyl 10 mg once-daily starting at Week 4 thru Week 16. Participants who continued to Part 2 continued to receive the same bardoxolone methyl dose once-daily in Part 2 (Week 16 and onwards)
Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg	Bardoxolone methyl	Participants in Part 1 received Placebo once-daily from Day 1 thru Week 16. Participants who continued to Part 2 initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from week 20 onwards

Primary Outcome Measures

Name	Time	Method
Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo	Baseline through Week 16	Overall treatment effect in exercise capacity, as measured by the total distance walked in 6 minutes (6MWD) mean change from baseline though Week 16. A lower 6MWD reflects greater severity thus, a positive change from baseline suggests an improvement.

Trial Locations

Locations (32)

Mount Sinai, Beth Israel Medical Center; 🇺🇸 New York, New York, United States

University of California Davis Medical Center - Division of Pulmonary and Critical Care; 🇺🇸 Sacramento, California, United States

Cedars Sinai Medical Center; 🇺🇸 Beverly Hills, California, United States

University of Colorado Denver - Division of Pulmonary Sciences; 🇺🇸 Aurora, Colorado, United States

BreatheAmerica El Paso, Inc.; 🇺🇸 El Paso, Texas, United States

University Clinic Carl Gustav Carus; 🇩🇪 Dresden, Germany

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

VA Healthcare System of Greater Los Angeles; 🇺🇸 Los Angeles, California, United States

University of Chicago; 🇺🇸 Chicago, Illinois, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

Brigham and Women's Hospital; 🇺🇸 Boston, Massachusetts, United States

Houston Methodist Research Institute; 🇺🇸 Houston, Texas, United States

The Lindner Clinical Trial Center; 🇺🇸 Cincinnati, Ohio, United States

Banner University Medical Center, Phoenix Advanced Lung Disease Institute; 🇺🇸 Phoenix, Arizona, United States

Arizona Pulmonary Specialists; 🇺🇸 Phoenix, Arizona, United States

Oklahoma Heart Hospital; 🇺🇸 Oklahoma City, Oklahoma, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Harbor - UCLA Medical Center; 🇺🇸 Torrance, California, United States

Georgetown University Medical Center - Department of Rheumatology; 🇺🇸 Washington, District of Columbia, United States

Boston University School of Medicine; 🇺🇸 Boston, Massachusetts, United States

Weill Cornell Medical Center; 🇺🇸 New York, New York, United States

University of Rochester - University of Rochester Medical Center; 🇺🇸 Rochester, New York, United States

University of Cincinnati - Department of Internal Medicine Pulmonary, Critical Care & Sleep Medicine; 🇺🇸 Cincinnati, Ohio, United States

The University of Texas - Health Science Center & Medical School at Houston; 🇺🇸 Houston, Texas, United States

The Ohio State University Wexner Medical Center; 🇺🇸 Columbus, Ohio, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

Cleveland Clinic of Florida; 🇺🇸 Weston, Florida, United States

Maine Medical Center - Division of Pulmonary and Critical Care Medicine; 🇺🇸 Portland, Maine, United States

University of Texas Houston - Division of Rheumatology and Clinical Immunogenetics; 🇺🇸 Houston, Texas, United States

Winthrop University Hospital; 🇺🇸 Mineola, New York, United States

Universitaetsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

South Denver Cardiology Associates, P.C; 🇺🇸 Littleton, Colorado, United States