Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension - CATALYST

February 1, 2024 updated by: Reata, a wholly owned subsidiary of Biogen

A Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension

This study assesses the safety and efficacy of bardoxolone methyl relative to placebo in patients with connective tissue disease-associated pulmonary arterial hypertension to determine the recommended dose range and evaluate the change from baseline in 6-minute walk distance (6MWD) following 24 weeks of study participation.

Study Overview

Detailed Description

This double-blind, randomized, placebo-controlled trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with World Health Organization Group I Connective Tissue Disease Pulmonary Arterial Hypertension (WHO Group I CTD-PAH).

Qualified patients will be randomized 1:1 to either bardoxolone methyl or placebo to be administered once daily for 24 weeks. Patients randomized to placebo will remain on placebo throughout the study. Patients randomized to bardoxolone methyl will start at 5 mg and will dose-escalate to 10 mg at Week 4 unless contraindicated clinically. Dose de-escalation is permitted during the study if indicated clinically.

All patients in the study will follow the same visit and assessment schedule. Following randomization, patients will be scheduled to be assessed in person during treatment at Weeks 1, 2, 4, 6, 8, 16, and 24 and by telephone contact on Days 3, 10, 21, 31, 38, 84, and 140. Patients will also be scheduled to be assessed at an in person follow up visit at Week 28, four weeks after the end of treatment.

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

Study Type

Interventional

Enrollment (Actual)

202

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Cordoba, Argentina, X5016KEH
        • Hospital Privado Centro Medico de Cordoba
      • Cordoba, Argentina, X5004CDP
        • Hospital Cordoba
      • Corrientes, Argentina, W3400AMZ
        • Instituto de Cardiologia de Corrientes Juana Francisca Cabral
      • Formosa, Argentina, 3600
        • Hospital de Alta Complejidad "Pte. J. D. Perón"
    • Ciudad Autónoma De BuenosAires
      • Buenos Aires, Ciudad Autónoma De BuenosAires, Argentina, C1426ABP
        • Centro Medico Dra de Salvo
      • Buenos Aires, Ciudad Autónoma De BuenosAires, Argentina, C1093AAS
        • Fundacion Favaloro
      • Buenos Aires, Ciudad Autónoma De BuenosAires, Argentina, C1280AEB
        • Hospital Britanico de Buenos Aires
    • Mar Del Plata
      • Buenos Aires, Mar Del Plata, Argentina, B7600FZN
        • Instituto de Investigaciones Clinicas Mar del Plata
    • Villa Vatteone
      • Buenos Aires, Villa Vatteone, Argentina, B1853AIK
        • Instituto De Enfermedades Respiratorias E Investigacion Medica
    • New South Wales
      • Camperdown, New South Wales, Australia, 2050
        • Royal Prince Alfred Hospital
      • Darlinghurst, New South Wales, Australia, 2010
        • St Vincent's Hospital Sydney
      • New Lambton, New South Wales, Australia, 2305
        • John Hunter Hospital
    • Queensland
      • Brisbane, Queensland, Australia, 4102
        • Princess Alexandra Hospital
    • Tasmania
      • Hobart, Tasmania, Australia, 7000
        • Royal Hobart Hospital
      • Brussels, Belgium, 1070
        • Hopital Erasme
    • Vlaams Brabant
      • Leuven, Vlaams Brabant, Belgium, 3000
        • UZ Leuven
      • Sao Paulo, Brazil, 04023-900
        • Hospital Sao Paulo
      • São Paulo, Brazil, 05403-900
        • Instituto do Coração - HCFMUSP
    • Ceara
      • Fortaleza, Ceara, Brazil, 60864-190
        • Hospital de Messejana
    • Rio Grande Do Sul
      • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-074
        • Irmandade Da Santa Casa de Misericordia de Porto Alegre
    • Santa Catarina
      • Blumenau, Santa Catarina, Brazil, 89010-000
        • Hospital Dia do Pulmao
    • Alberta
      • Calgary, Alberta, Canada, T1Y 6J4
        • Peter Lougheed Centre
      • Edmonton, Alberta, Canada, T6G 2B7
        • University of Alberta
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 1M9
        • Vancouver General Hospital
    • Ontario
      • London, Ontario, Canada, N6A 5W9
        • London Health Sciences Centre
    • Quebec
      • Sainte Foy, Quebec, Canada, G1V 4G5
        • Centre Hospitalier de l'Universite Laval
      • Prague, Czechia, 128 00
        • Vseobecna fakultni nemocnice v Praze
      • Prague, Czechia, 140 00
        • Institut klinicke a experimentalni mediciny
      • Berlin, Germany, 14050
        • DRK Kliniken Berlin Westend
      • Dresden, Germany, 01307
        • Universitätsklinikum Carl Gustav Carus an der TU Dresden
      • Hamburg, Germany, 20246
        • Universitätsklinikum Hamburg Eppendorf
      • Heidelberg, Germany, 69126
        • Thorax Klinik
      • Köln, Germany, 50937
        • Universitätsklinikum Köln
    • Baden-Württemberg
      • Freiburg im Breisgau, Baden-Württemberg, Germany, 79106
        • Universitatsklinikum Freiburg
    • Bayern
      • Erlangen, Bayern, Germany, 91054
        • Universitatsklinkum Erlangen
    • Mecklenburg-Vorpommern
      • Greifswald, Mecklenburg-Vorpommern, Germany, 17475
        • Universitat Greifswald
      • Jerusalem, Israel, 91120
        • Hadassah University Hospital Ein Kerem
      • Petah Tikva, Israel, 49100
        • Rabin Medical Center
      • Chiba, Japan, 260-8677
        • Chiba University Hospital
      • Gunma, Japan, 371-8510
        • Gunma University School of Medicine
      • Kobe, Japan, 6500017
        • Kobe University Hospital
      • Nagoya, Japan, 460-0001
        • Nagoya Medical Center
      • Sapporo, Japan, 0608648
        • Hokkaido University Hospital
      • Sendai-shi, Japan, 980-8574
        • Kurume University Medical Center
      • Suita, Japan, 5658565
        • National Cerebral and Cardiovascular Center
      • Toyoake, Japan, 470-1192
        • Fujita Health University Hospital
    • Bunkyo-ku
      • Tokyo, Bunkyo-ku, Japan, 113-8603
        • Nippon Medical School Hospital
    • Kanagawa
      • Sagamihara, Kanagawa, Japan, 252-0375
        • Kitasato University Hospital
    • Miyagi
      • Sendai, Miyagi, Japan, 980-8574
        • Tohoku University Hospital
    • Okayama
      • Okayama-shi, Okayama, Japan, 701-1192
        • National Hospital Organization Okayama Medical Center
    • Distrito Federal
      • Ciudad de Mexico, Distrito Federal, Mexico, 14080
        • Instituto Nacional de Cardiologia Dr. Ignacio Chavez
      • Mexico City, Distrito Federal, Mexico, 14000
        • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
    • Jalisco
      • Guadalajara, Jalisco, Mexico, 44280
        • Hospital Civil Fray Antonio Alcalde
    • Nuevo Leon
      • Monterrey, Nuevo Leon, Mexico, 64460
        • Hospital Universitario Dr. Jose Eleuterio González
      • Monterrey, Nuevo Leon, Mexico, 64718
        • Unidad de Investigación Clínica En Medicina SC
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1007 MB
        • Vrije Universiteit Amsterdam
      • Angeles City, Philippines
        • Angeles University Foundation Medical Center (AUFMC)
      • Lipa, Philippines
        • Mary Mediatrix Medical Center (MMMC)
      • Makati, Philippines
        • Makati Medical Center (MMC)
      • Manila, Philippines
        • Philippine General Hospital (PGH)
      • Quezon City, Philippines, 1100
        • Philippine Heart Center (PHC)
      • Barcelona, Spain, 08035
        • Hospital Universitario Vall d'Hebron
      • Las Palmas de Gran Canaria, Spain, 35010
        • Hospital de Gran Canaria Doctor Negrin
      • Madrid, Spain, 28041
        • Hospital Universitario 12 de Octubre
      • Majadahonda, Spain
        • Hospital Universitario Puerta de Hierro
      • Toledo, Spain, 45004
        • Hospital Virgen de la Salud
    • Cantabria
      • Santander, Cantabria, Spain
        • Hospital Universitario Marques de Valdecilla
      • Glasgow, United Kingdom, G81 4HX
        • Golden Jubilee National Hospital
      • London, United Kingdom, NW3 2QG
        • Royal Free Hospital
    • 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
      • Fresno, California, United States, 93701
        • Regents of the University of California
      • La Jolla, California, United States, 92093
        • University Of California San Diego
      • Los Angeles, California, United States, 90095
        • David Geffen School of Medicine UCLA
      • San Diego, California, United States, 92103
        • Pacific Pulmonary Research, Inc.
      • Santa Barbara, California, United States, 93105
        • Santa Barbara Pulmonary Associates
      • Torrance, California, United States, 90502
        • Harbor - UCLA Medical Center
    • District of Columbia
      • Washington, District of Columbia, United States, 20007
        • Georgetown University Medical Center - Department of Rheumatology
    • Florida
      • Miami, Florida, United States, 33136
        • University of Miami Miller School of Medicine
      • Weston, Florida, United States, 33331
        • Cleveland Clinic Florida
    • Georgia
      • Augusta, Georgia, United States, 30912
        • Augusta University
      • Austell, Georgia, United States, 30106
        • Piedmont-Georgia Lung
    • Illinois
      • Chicago, Illinois, United States, 60612
        • University of Illinois at Chicago
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • Kentuckiana Pulmonary Associates
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
      • Boston, Massachusetts, United States, 02118
        • Boston University School of Medicine
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine
    • Nebraska
      • Omaha, Nebraska, United States, 68131
        • University of Nebraska Medical Center
    • New Mexico
      • Albuquerque, New Mexico, United States, 87131
        • University of New Mexico
    • New York
      • New York, New York, United States, 10003
        • NYU Langone Health
      • Rochester, New York, United States, 14642
        • University of Rochester - University of Rochester Medical Center
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • University of Cincinnati
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic
      • Columbus, Ohio, United States, 43210
        • Wexner Medical Center at the Ohio State University
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73120
        • Integris Nazih Zuhdi Transplant Institute
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health & Science University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Thomas Jefferson University
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina
    • Texas
      • Dallas, Texas, United States, 75390
        • University of Texas Southwestern Medical Center
      • Houston, Texas, United States, 77030
        • The Methodist Hospital Research Institute
      • Houston, Texas, United States, 77030
        • University of Texas Health Science Center at Houston
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • University of Utah

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • BMI > 18.5 kg/m2;
  • Symptomatic pulmonary hypertension WHO/NYHA FC class II and III;
  • WHO Group I PAH associated with connective tissue disease;
  • Had a diagnostic right heart catheterization performed and documented within 36 months prior to Day 1 that confirmed a diagnosis of PAH according to all the following criteria:

    • Mean pulmonary artery pressure ≥ 25 mm Hg (at rest);
    • Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg;
    • Pulmonary vascular resistance > 240 dyn.sec/cm5 or > 3 mm Hg/liter (L)/minute;
  • Has BNP level ≤ 400 pg/mL;
  • Had an average 6MWD ≥ 150 meters on two consecutive tests performed on different days prior to randomization, with both tests measuring within 15% of one another;
  • Has been receiving no more than two (2) approved disease-specific PAH therapies. PAH therapy must have been at a stable dose for at least 90 days prior to Day 1. No additions or changes should be made to PAH therapies and doses should remain stable for the duration of the study;
  • Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following therapies that may affect PAH: vasodilators (including calcium channel blockers), digoxin, L-arginine supplementation, or oxygen supplementation. No additions or changes should be made to therapies and doses should remain stable for the duration of the study;
  • If receiving treatment for CTD with prednisone or any other drugs, doses must remain stable for at least 30 days prior to Day 1 and for the duration of the study Had pulmonary function tests (PFTs) within 90 days prior to Day 1 with total lung capacity ≥ 65% (predicted);
  • Had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed tomography (CT), or pulmonary angiogram prior to Day 1 that shows no evidence of thromboembolic disease (i.e., should note normal or low probability for pulmonary embolism). If V/Q scan was abnormal (i.e., results other than normal or low probability), then a confirmatory CT or selective pulmonary angiography must exclude chronic thromboembolic pulmonary hypertension;
  • Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 as measured by the central lab;
  • Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
  • Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study prior to initiation of any patient-mandated procedures

Exclusion Criteria:

  • Participation in other investigational clinical studies involving interventional 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;
  • Initiation of an exercise program for cardio-pulmonary rehabilitation within 90 days prior to Day 1 or planned initiation during the study;
  • Stopped receiving any PAH chronic therapy within 60 days prior to Day 1;
  • Received a dose of prednisone > 20 mg/day (or equivalent dose if other corticosteroid) within 30 days prior to Day 1;
  • Received intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues within 90 days prior to Day 1;
  • Received intravenous inotropes within 30 days prior to Day 1;
  • Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period of rest;
  • Has systolic BP < 90 mm Hg during Screening after a period of rest;
  • 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:

    • Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension;
    • Pericardial constriction;
    • Restrictive or congestive cardiomyopathy;
    • Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 90 days of Day 1;
    • Symptomatic coronary artery disease within the last 3 years;
  • Acutely decompensated heart failure within 30 days prior to Day 1, per investigator assessment;
  • Has more than two of the following clinical risk factors for left ventricular diastolic dysfunction:

    • Age > 65 years;
    • BMI ≥ 30 kg/m2;
    • History of systemic hypertension;
    • History of type 2 diabetes;
    • History of atrial fibrillation;
    • History of atrial septostomy within 180 days prior to Day 1;
    • History of uncontrolled obstructive sleep apnea;
  • 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);
  • Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at Screening;
  • Hemoglobin (Hgb) concentration < 8.5 g/dL at Screening;
  • Diagnosis of Down syndrome;
  • History of malignancy within 5 years prior to screening, with the exception of localized skin or cervical carcinomas;
  • Untreated or uncontrolled active bacterial, fungal, or viral infection;
  • Known or suspected active drug or alcohol abuse, per investigator judgment;
  • Use of Herbalife supplements within 14 days prior to Day 1;
  • Major surgery within 30 days prior to Day 1 or planned to occur during the course of the study;
  • Unwilling to practice acceptable methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during screening, while taking study drug, and for at least 30 days after the last dose of study drug is ingested;
  • Use of inhaled nitric oxide within 7 days prior to Screening and Day 1 visits, excluding acute vasodilator testing during diagnostic cardiac catheterization;
  • Women who are pregnant or breastfeeding;
  • Any disability or impairment that would prohibit performance of the 6MWT;
  • Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at risk by trial enrollment;
  • Patient is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason;
  • Known hypersensitivity to any component of the study drug;
  • Unable to communicate or cooperate with the investigator because of language problems, poor mental development, or impaired cerebral function.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo capsules
Placebo capsules will be administered orally once a day for 24 weeks.
Experimental: Bardoxolone methyl capsules
Each patient will receive bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient is 5 mg and will dose-escalate to 10 mg at Week 4, unless contraindicated clinically.
Other Names:
  • RTA 402 capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change From Baseline in Six-minute-walk Distance (6MWD) Relative to Placebo at Week 24
Time Frame: Baseline through 24 weeks after participant receives the first dose
Baseline through 24 weeks after participant receives the first dose

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to First Persistent Clinical Improvement Event
Time Frame: Baseline through the end of the study

At least one of the following four criteria must have been met:

  1. Improvement by at least one WHO functional class coupled with no more than a 15% decrease from baseline in 6MWT
  2. Increase from baseline in 6MWT by at least 10% and stability or improvement in the WHO functional class
  3. Decrease from baseline in creatine kinase (a surrogate biomarker for muscle injury and inflammation) by at least 10% and no worsening in WHO functional class and no more than a 15% decrease from baseline in 6MWT
  4. Improvement in estimated glomerular filtration rate eGFR ≥10% of baseline The persistence of the change in WHO functional class, 6MWT, eGFR, or creatine kinase must be confirmed by a subsequent assessment at least 14 days after the initial assessment, or at the next scheduled assessment. If persistent improvement is confirmed, the date of the event was considered the initial assessment of improved WHO functional class, 6MWT, eGFR, or creatine kinase.
Baseline through the end of the study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 4, 2016

Primary Completion (Actual)

May 7, 2020

Study Completion (Actual)

May 7, 2020

Study Registration Dates

First Submitted

January 13, 2016

First Submitted That Met QC Criteria

January 14, 2016

First Posted (Estimated)

January 15, 2016

Study Record Updates

Last Update Posted (Estimated)

February 6, 2024

Last Update Submitted That Met QC Criteria

February 1, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

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/

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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