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

A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Pulmonary Hypertension

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.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis; Pulmonary Arterial Hypertension; Pulmonary Hypertension; Interstitial Lung Disease; Sarcoidosis; Idiopathic Interstitial Pneumonia; Cryptogenic Organizing Pneumonia; Desquamative Interstitial Pneumonia; Respiratory Bronchiolitis Associated Interstitial Lung Disease; Acute Interstitial Pneumonitis; Idiopathic Lymphoid Interstitial Pneumonia; Idiopathic Pleuroparenchymal Fibroelastosis
• Intervention / Treatment: Drug: Placebo; Drug: Bardoxolone methyl

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 Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Dresden, Germany, 01304
    • University Clinic Carl Gustav Carus
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Arizona Pulmonary Specialists
    • Phoenix, Arizona, United States, 85004
      • Banner University Medical Center, Phoenix Advanced Lung Disease Institute
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars Sinai Medical Center
    • Los Angeles, California, United States, 90073
      • VA Healthcare System of Greater Los Angeles
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center - Division of Pulmonary and Critical Care
    • Torrance, California, United States, 90502
      • Harbor - UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver - Division of Pulmonary Sciences
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology Associates, P.C
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center - Department of Rheumatology
  • Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic of Florida
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center - Division of Pulmonary and Critical Care Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10021
      • Weill Cornell Medical Center
    • New York, New York, United States, 10003
      • Mount Sinai, Beth Israel Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester - University of Rochester Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Clinical Trial Center
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati - Department of Internal Medicine Pulmonary, Critical Care & Sleep Medicine
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Oklahoma Heart Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • El Paso, Texas, United States, 79912
      • BreatheAmerica El Paso, Inc.
    • Houston, Texas, United States, 77030
      • 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
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

10

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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: Placebo; Drug: Bardoxolone methyl; Other Names: RTA 402 capsules
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: Placebo; Drug: Bardoxolone methyl; Other Names: RTA 402 capsules
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: Placebo; Drug: Bardoxolone methyl; Other Names: RTA 402 capsules
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: Placebo; Drug: Bardoxolone methyl; Other Names: RTA 402 capsules
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 Names: 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: Placebo; Drug: Bardoxolone methyl; Other Names: RTA 402 capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo	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.	Baseline through Week 16

Collaborators and Investigators

• Sponsor: Reata, a wholly owned subsidiary of Biogen

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2014
• Primary Completion (Actual): January 19, 2018
• Study Completion (Actual): May 16, 2018

Study Registration Dates

• First Submitted: January 13, 2014
• First Submitted That Met QC Criteria: January 13, 2014
• First Posted (Estimated): January 15, 2014

Study Record Updates

• Last Update Posted (Actual): February 5, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Pulmonary Arterial Hypertension; PAH; Sarcoidosis; RTA 402; Bardoxolone methyl; Idiopathic Pulmonary Fibrosis; Interstitial Lung Disease; Idiopathic Interstitial Pneumonia; 6-minute walk distance; CDDO-me; Respiratory Bronchiolitis Associated ILD; Desquamative Interstitial Pneumonia; Cryptogenic Organizing Pneumonia; Acute Interstitial Pneumonitis; Idiopathic Lymphoid Interstitial Pneumonia; Idiopathic Pleuroparenchymal Fibroelastosis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Hypersensitivity; Hypersensitivity, Delayed; Bronchitis; Bronchiolitis Obliterans; Fibrosis; Hypertension; Lung Diseases; Pneumonia; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Lung Diseases, Interstitial; Bronchiolitis; Sarcoidosis; Idiopathic Interstitial Pneumonias; Hamman-Rich Syndrome; Cryptogenic Organizing Pneumonia; Organizing Pneumonia
• Other Study ID Numbers: RTA 402-C-1302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/