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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02036970
Recruitment Status : Completed
First Posted : January 15, 2014
Last Update Posted : January 3, 2019
Sponsor:
Information provided by (Responsible Party):
Reata Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE January 13, 2014
First Posted Date  ICMJE January 15, 2014
Last Update Posted Date January 3, 2019
Study Start Date  ICMJE May 2014
Actual Primary Completion Date January 19, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 13, 2014)
Change from baseline in 6-Minute Walk Distance (6MWD) [ Time Frame: 16 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bardoxolone Methyl Evaluation in Patients With Pulmonary Hypertension (PH) - LARIAT
Official Title  ICMJE A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Pulmonary Hypertension
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: Bardoxolone methyl
    Other Name: RTA 402 capsules
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Dose-Ranging Phase: Dose 1
    Bardoxolone methyl [Dose 1] mg capsules or placebo by mouth once daily x 16 weeks
    Interventions:
    • Drug: Bardoxolone methyl
    • Drug: Placebo
  • Experimental: Dose-Ranging Phase: Dose 2
    Bardoxolone methyl [Dose 2] mg capsules or placebo by mouth once daily x 16 weeks
    Interventions:
    • Drug: Bardoxolone methyl
    • Drug: Placebo
  • Experimental: Dose-Ranging Phase: Dose 3
    Bardoxolone methyl [Dose 3] mg capsules or placebo by mouth once daily x 16 weeks
    Interventions:
    • Drug: Bardoxolone methyl
    • Drug: Placebo
  • Experimental: Dose-Ranging Phase: Dose 4
    Bardoxolone methyl [Dose 4] mg capsules or placebo by mouth once daily x 16 weeks
    Interventions:
    • Drug: Bardoxolone methyl
    • Drug: Placebo
  • Experimental: Dose-Titration Phase

    Bardoxolone methyl [Dose 2] mg capsules or placebo by mouth once daily x 3 weeks, escalating to [Dose 3] mg or placebo by mouth once daily at Week 4 for 13 weeks

    If a patient experiences a dose-limiting toxicity, the investigator may de-escalate the dose.

    Interventions:
    • Drug: Bardoxolone methyl
    • Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 18, 2018)
166
Original Estimated Enrollment  ICMJE
 (submitted: January 13, 2014)
112
Actual Study Completion Date  ICMJE May 16, 2018
Actual Primary Completion Date January 19, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   United States
Removed Location Countries Spain,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT02036970
Other Study ID Numbers  ICMJE RTA 402-C-1302
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Reata Pharmaceuticals, Inc.
Study Sponsor  ICMJE Reata Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Reata Pharmaceuticals, Inc.
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP