Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension - CATALYST
- Conditions
- Connective Tissue Disease-Associated Pulmonary Arterial Hypertension
- Interventions
- Drug: Placebo capsules
- Registration Number
- NCT02657356
- 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 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.
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 202
-
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
-
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo capsules Placebo capsules Placebo capsules will be administered orally once a day for 24 weeks. Bardoxolone methyl capsules 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.
- Primary Outcome Measures
Name Time Method Change From Baseline in Six-minute-walk Distance (6MWD) Relative to Placebo at Week 24 Baseline through 24 weeks after participant receives the first dose
- Secondary Outcome Measures
Name Time Method Time to First Persistent Clinical Improvement Event 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.
Trial Locations
- Locations (106)
Wexner Medical Center at The Ohio State University
🇺🇸Columbus, Ohio, United States
University of Illinois at Chicago
🇺🇸Chicago, Illinois, United States
Boston University School of Medicine
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Pacific Pulmonary Research, Inc.
🇺🇸San Diego, California, United States
University of Miami Miller School of Medicine
🇺🇸Miami, Florida, United States
University of Texas Health Science Center at Houston
🇺🇸Houston, Texas, United States
University of Rochester - University of Rochester Medical Center
🇺🇸Rochester, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Universitätsklinikum Carl Gustav Carus an der TU Dresden
🇩🇪Dresden, Germany
Peter Lougheed Centre
🇨🇦Calgary, Alberta, Canada
Instituto do Coração - HCFMUSP
🇧🇷São Paulo, Brazil
Hospital Británico de Buenos Aires
🇦🇷Buenos Aires, Ciudad Autónoma De BuenosAires, Argentina
Institut klinicke a experimentalni mediciny
🇨🇿Prague, Czechia
Nippon Medical School Hospital
🇯🇵Tokyo, Bunkyo-ku, Japan
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
The Methodist Hospital Research Institute
🇺🇸Houston, Texas, United States
Piedmont-Georgia Lung
🇺🇸Austell, Georgia, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Fundación Favaloro
🇦🇷Buenos Aires, Ciudad Autónoma De BuenosAires, Argentina
Hospital Privado Centro Médico de Córdoba
🇦🇷Cordoba, Argentina
Kentuckiana Pulmonary Associates
🇺🇸Louisville, Kentucky, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
Centro Médico Dra de Salvo
🇦🇷Buenos Aires, Ciudad Autónoma De BuenosAires, Argentina
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
Kitasato University Hospital
🇯🇵Sagamihara, Kanagawa, Japan
Vseobecna fakultni nemocnice v Praze
🇨🇿Prague, Czechia
Hospital Cordoba
🇦🇷Cordoba, Argentina
NYU Langone Health
🇺🇸New York, New York, United States
Universitätsklinikum Hamburg Eppendorf
🇩🇪Hamburg, Germany
Hospital São Paulo
🇧🇷Sao Paulo, Brazil
Gunma University School of Medicine
🇯🇵Gunma, Japan
Hadassah University Hospital Ein Kerem
🇮🇱Jerusalem, Israel
Hospital Dia do Pulmão
🇧🇷Blumenau, Santa Catarina, Brazil
Princess Alexandra Hospital
🇦🇺Brisbane, Queensland, Australia
Hôpital Erasme
🇧🇪Brussels, Belgium
Universitätsklinikum Köln
🇩🇪Köln, Germany
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Kurume University Medical Center
🇯🇵Sendai-shi, Japan
Thorax Klinik
🇩🇪Heidelberg, Germany
DRK Kliniken Berlin Westend
🇩🇪Berlin, Germany
London Health Sciences Centre
🇨🇦London, Ontario, Canada
Centre Hospitalier de l'Université Laval
🇨🇦Sainte Foy, Quebec, Canada
National Hospital Organization Okayama Medical Center
🇯🇵Okayama-shi, Okayama, Japan
Makati Medical Center (MMC)
🇵🇭Makati, Philippines
University of California San Diego
🇺🇸La Jolla, California, United States
Philippine Heart Center (PHC)
🇵🇭Quezon City, Philippines
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Banner University Medical Center, Phoenix Advanced Lung Disease Institute
🇺🇸Phoenix, Arizona, United States
Arizona Pulmonary Specialists
🇺🇸Phoenix, Arizona, United States
Integris Nazih Zuhdi Transplant Institute
🇺🇸Oklahoma City, Oklahoma, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Instituto de Investigaciones Clínicas Mar Del Plata
🇦🇷Buenos Aires, Mar Del Plata, Argentina
Georgetown University Medical Center - Department of Rheumatology
🇺🇸Washington, District of Columbia, United States
Regents of The University of California
🇺🇸Fresno, California, United States
Augusta University
🇺🇸Augusta, Georgia, United States
David Geffen School of Medicine UCLA
🇺🇸Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸Beverly Hills, California, United States
Cleveland Clinic Florida
🇺🇸Weston, Florida, United States
Santa Barbara Pulmonary Associates
🇺🇸Santa Barbara, California, United States
Harbor - UCLA Medical Center
🇺🇸Torrance, California, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Instituto De Enfermedades Respiratorias E Investigacion Medica
🇦🇷Buenos Aires, Villa Vatteone, Argentina
Instituto de Cardiologia de Corrientes Juana Francisca Cabral
🇦🇷Corrientes, Argentina
John Hunter Hospital
🇦🇺New Lambton, New South Wales, Australia
St Vincent's Hospital Sydney
🇦🇺Darlinghurst, New South Wales, Australia
Hospital de Alta Complejidad "Pte. J. D. Perón"
🇦🇷Formosa, Argentina
Irmandade Da Santa Casa de Misericordia de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital de Messejana
🇧🇷Fortaleza, Ceara, Brazil
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
Universitätsklinikum Freiburg
🇩🇪Freiburg im Breisgau, Baden-Württemberg, Germany
Universitatsklinkum Erlangen
🇩🇪Erlangen, Bayern, Germany
Rabin Medical Center
🇮🇱Petah Tikva, Israel
Tohoku University Hospital
🇯🇵Sendai, Miyagi, Japan
Chiba University Hospital
🇯🇵Chiba, Japan
Nagoya Medical Center
🇯🇵Nagoya, Japan
Kobe University Hospital
🇯🇵Kobe, Japan
Hospital Civil Fray Antonio Alcalde
🇲🇽Guadalajara, Jalisco, Mexico
Unidad de Investigación Clínica En Medicina SC
🇲🇽Monterrey, Nuevo Leon, Mexico
Fujita Health University Hospital
🇯🇵Toyoake, Japan
Hokkaido University Hospital
🇯🇵Sapporo, Japan
National Cerebral and Cardiovascular Center
🇯🇵Suita, Japan
Vrije Universiteit Amsterdam
🇳🇱Amsterdam, Noord-Holland, Netherlands
Angeles University Foundation Medical Center (AUFMC)
🇵🇭Angeles City, Philippines
Mary Mediatrix Medical Center (MMMC)
🇵🇭Lipa, Philippines
Philippine General Hospital (PGH)
🇵🇭Manila, Philippines
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Puerta de Hierro
🇪🇸Majadahonda, Spain
Royal Free Hospital
🇬🇧London, United Kingdom
Hospital de Gran Canaria Doctor Negrin
🇪🇸Las Palmas de Gran Canaria, Spain
Hospital Virgen de La Salud
🇪🇸Toledo, Spain
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Golden Jubilee National Hospital
🇬🇧Glasgow, United Kingdom
Hospital Universitario Marques de Valdecilla
🇪🇸Santander, Cantabria, Spain
UZ Leuven
🇧🇪Leuven, Vlaams Brabant, Belgium
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
🇲🇽Mexico City, Distrito Federal, Mexico
Hospital Universitario Dr. Jose Eleuterio González
🇲🇽Monterrey, Nuevo Leon, Mexico
University of New Mexico
🇺🇸Albuquerque, New Mexico, United States
Instituto Nacional de Cardiologia Dr. Ignacio Chavez
🇲🇽Ciudad de Mexico, Distrito Federal, Mexico
Universität Greifswald
🇩🇪Greifswald, Mecklenburg-Vorpommern, Germany
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States