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

• ClinicalTrials.gov Identifier: NCT02036970
• Recruitment Status: Completed
• First Posted: January 15, 2014
• Results First Posted: July 23, 2021
• Last Update Posted: December 7, 2021
• Sponsor: Reata Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Reata Pharmaceuticals, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
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	Drug: Bardoxolone methyl; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 166 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Pulmonary Hypertension
• Study Start Date: May 2014
• Actual Primary Completion Date: January 19, 2018
• Actual Study Completion Date: May 16, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 Dose-Ranging Bardoxolone methyl 2.5 mg/Part 2: Open-Label; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules
Experimental: Part 1: Dose-Ranging Bardoxolone methyl 5 mg/Part 2: Open-Label; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules
Experimental: Part 1: Dose-Ranging Bardoxolone methyl 10 mg/Part 2: Open-Label; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules
Experimental: Part 1: Dose-Ranging Bardoxolone methyl 20 mg/Part 2: Open-Label; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules
Placebo Comparator: Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone methyl 2.5 mg; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules; Drug: Placebo
Placebo Comparator: Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone methyl 5 mg; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules; Drug: Placebo
Placebo Comparator: Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules; Drug: Placebo
Placebo Comparator: Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone methyl 20 mg; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules; Drug: Placebo
Experimental: Part 1: Dose Titration: Bardoxolone methyl 10 mg/Part 2: Bardoxolone methyl 10 mg; 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)	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules
Placebo Comparator: Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg; 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	Drug: Bardoxolone methyl; Other Name: RTA 402 capsules; Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arizona

Banner University Medical Center, Phoenix Advanced Lung Disease Institute

Phoenix, Arizona, United States, 85004

Arizona Pulmonary Specialists

Phoenix, Arizona, United States, 85012

United States, California

Cedars Sinai Medical Center

Beverly Hills, California, United States, 90211

VA Healthcare System of Greater Los Angeles

Los Angeles, California, United States, 90073

University of California Davis Medical Center - Division of Pulmonary and Critical Care

Sacramento, California, United States, 95817

Harbor - UCLA Medical Center

Torrance, California, United States, 90502

United States, Colorado

University of Colorado Denver - Division of Pulmonary Sciences

Aurora, Colorado, United States, 80045

South Denver Cardiology Associates, P.C

Littleton, Colorado, United States, 80120

United States, District of Columbia

Georgetown University Medical Center - Department of Rheumatology

Washington, District of Columbia, United States, 20007

United States, Florida

Cleveland Clinic of Florida

Weston, Florida, United States, 33331

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

United States, Maine

Maine Medical Center - Division of Pulmonary and Critical Care Medicine

Portland, Maine, United States, 04102

United States, Massachusetts

Tufts Medical Center

Boston, Massachusetts, United States, 02111

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Boston University School of Medicine

Boston, Massachusetts, United States, 02118

United States, New York

Winthrop University Hospital

Mineola, New York, United States, 11501

Mount Sinai, Beth Israel Medical Center

New York, New York, United States, 10003

Weill Cornell Medical Center

New York, New York, United States, 10021

University of Rochester - University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, Ohio

The Lindner Clinical Trial Center

Cincinnati, Ohio, United States, 45219

University of Cincinnati - Department of Internal Medicine Pulmonary, Critical Care & Sleep Medicine

Cincinnati, Ohio, United States, 45267

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States, 43210

United States, Oklahoma

Oklahoma Heart Hospital

Oklahoma City, Oklahoma, United States, 73120

United States, Pennsylvania

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

BreatheAmerica El Paso, Inc.

El Paso, Texas, United States, 79912

Houston Methodist Research Institute

Houston, Texas, United States, 77030

The University of Texas - Health Science Center & Medical School at Houston

Houston, Texas, United States, 77030

University of Texas Houston - Division of Rheumatology and Clinical Immunogenetics

Houston, Texas, United States, 77030

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

Germany

University Clinic Carl Gustav Carus

Dresden, Germany, 01304

Universitaetsklinikum Hamburg-Eppendorf

Hamburg, Germany, 20246

Sponsors and Collaborators

Reata Pharmaceuticals, Inc.

  Study Documents (Full-Text)

Documents provided by Reata Pharmaceuticals, Inc.:

Study Protocol  [PDF] January 26, 2017

Statistical Analysis Plan  [PDF] June 14, 2018

More Information

• Responsible Party: Reata Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02036970
• Other Study ID Numbers: RTA 402-C-1302
• First Posted: January 15, 2014
• Results First Posted: July 23, 2021
• Last Update Posted: December 7, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Reata Pharmaceuticals, Inc.:

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

Additional relevant MeSH terms:

Pneumonia; Bronchiolitis; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Idiopathic Interstitial Pneumonias; Hamman-Rich Syndrome; Organizing Pneumonia; Cryptogenic Organizing Pneumonia; Hypertension; Sarcoidosis; Fibrosis; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Bronchitis; Bronchial Diseases; Lung Diseases, Obstructive; Lymphoproliferative Disorders; Lymphatic Diseases; Hypersensitivity, Delayed; Hypersensitivity; Immune System Diseases; Bronchiolitis Obliterans