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

Connective Tissue Disease-Associated Pulmonary Arterial Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02657356
• Other study ID #: RTA 402-C-1504
• Status: Terminated
• Phase: Phase 3
• Start date: October 4, 2016
• Est. completion date: May 7, 2020

Study information

• Verified date: February 2024
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 202
• Est. completion date: May 7, 2020
• Est. primary completion date: May 7, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Connective Tissue Disease-Associated Pulmonary Arterial Hypertension
• Connective Tissue Diseases
• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Placebo capsules

• Bardoxolone methyl capsules

Locations

Country	Name	City	State
Argentina	Centro Médico Dra de Salvo	Buenos Aires	Ciudad Autónoma De BuenosAires
Argentina	Fundación Favaloro	Buenos Aires	Ciudad Autónoma De BuenosAires
Argentina	Hospital Británico de Buenos Aires	Buenos Aires	Ciudad Autónoma De BuenosAires
Argentina	Instituto De Enfermedades Respiratorias E Investigacion Medica	Buenos Aires	Villa Vatteone
Argentina	Instituto de Investigaciones Clínicas Mar Del Plata	Buenos Aires	Mar Del Plata
Argentina	Hospital Cordoba	Cordoba
Argentina	Hospital Privado Centro Médico de Córdoba	Cordoba
Argentina	Instituto de Cardiologia de Corrientes Juana Francisca Cabral	Corrientes
Argentina	Hospital de Alta Complejidad "Pte. J. D. Perón"	Formosa
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	St Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	John Hunter Hospital	New Lambton	New South Wales
Belgium	Hôpital Erasme	Brussels
Belgium	UZ Leuven	Leuven	Vlaams Brabant
Brazil	Hospital Dia do Pulmão	Blumenau	Santa Catarina
Brazil	Hospital de Messejana	Fortaleza	Ceara
Brazil	Irmandade Da Santa Casa de Misericordia de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital São Paulo	Sao Paulo
Brazil	Instituto do Coração - HCFMUSP	São Paulo
Canada	Peter Lougheed Centre	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	London Health Sciences Centre	London	Ontario
Canada	Centre Hospitalier de l'Université Laval	Sainte Foy	Quebec
Canada	Vancouver General Hospital	Vancouver	British Columbia
Czechia	Institut klinicke a experimentalni mediciny	Prague
Czechia	Vseobecna fakultni nemocnice v Praze	Prague
Germany	DRK Kliniken Berlin Westend	Berlin
Germany	Universitätsklinikum Carl Gustav Carus an der TU Dresden	Dresden
Germany	Universitatsklinkum Erlangen	Erlangen	Bayern
Germany	Universitätsklinikum Freiburg	Freiburg im Breisgau	Baden-Württemberg
Germany	Universität Greifswald	Greifswald	Mecklenburg-Vorpommern
Germany	Universitätsklinikum Hamburg Eppendorf	Hamburg
Germany	Thorax Klinik	Heidelberg
Germany	Universitätsklinikum Köln	Köln
Israel	Hadassah University Hospital Ein Kerem	Jerusalem
Israel	Rabin Medical Center	Petah Tikva
Japan	Chiba University Hospital	Chiba
Japan	Gunma University School of Medicine	Gunma
Japan	Kobe University Hospital	Kobe
Japan	Nagoya Medical Center	Nagoya
Japan	National Hospital Organization Okayama Medical Center	Okayama-shi	Okayama
Japan	Kitasato University Hospital	Sagamihara	Kanagawa
Japan	Hokkaido University Hospital	Sapporo
Japan	Tohoku University Hospital	Sendai	Miyagi
Japan	Kurume University Medical Center	Sendai-shi
Japan	National Cerebral and Cardiovascular Center	Suita
Japan	Nippon Medical School Hospital	Tokyo	Bunkyo-ku
Japan	Fujita Health University Hospital	Toyoake
Mexico	Instituto Nacional de Cardiologia Dr. Ignacio Chavez	Ciudad de Mexico	Distrito Federal
Mexico	Hospital Civil Fray Antonio Alcalde	Guadalajara	Jalisco
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Mexico City	Distrito Federal
Mexico	Hospital Universitario Dr. Jose Eleuterio González	Monterrey	Nuevo Leon
Mexico	Unidad de Investigación Clínica En Medicina SC	Monterrey	Nuevo Leon
Netherlands	Vrije Universiteit Amsterdam	Amsterdam	Noord-Holland
Philippines	Angeles University Foundation Medical Center (AUFMC)	Angeles City
Philippines	Mary Mediatrix Medical Center (MMMC)	Lipa
Philippines	Makati Medical Center (MMC)	Makati
Philippines	Philippine General Hospital (PGH)	Manila
Philippines	Philippine Heart Center (PHC)	Quezon City
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital de Gran Canaria Doctor Negrin	Las Palmas de Gran Canaria
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda
Spain	Hospital Universitario Marques de Valdecilla	Santander	Cantabria
Spain	Hospital Virgen de La Salud	Toledo
United Kingdom	Golden Jubilee National Hospital	Glasgow
United Kingdom	Royal Free Hospital	London
United States	University of New Mexico	Albuquerque	New Mexico
United States	University of Michigan	Ann Arbor	Michigan
United States	Augusta University	Augusta	Georgia
United States	Piedmont-Georgia Lung	Austell	Georgia
United States	Cedars Sinai Medical Center	Beverly Hills	California
United States	Boston University School of Medicine	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Illinois at Chicago	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Wexner Medical Center at The Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Regents of The University of California	Fresno	California
United States	The Methodist Hospital Research Institute	Houston	Texas
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	University of California San Diego	La Jolla	California
United States	David Geffen School of Medicine UCLA	Los Angeles	California
United States	Kentuckiana Pulmonary Associates	Louisville	Kentucky
United States	University of Miami Miller School of Medicine	Miami	Florida
United States	NYU Langone Health	New York	New York
United States	Integris Nazih Zuhdi Transplant Institute	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Arizona Pulmonary Specialists	Phoenix	Arizona
United States	Banner University Medical Center, Phoenix Advanced Lung Disease Institute	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	University of Rochester - University of Rochester Medical Center	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Pacific Pulmonary Research, Inc.	San Diego	California
United States	Santa Barbara Pulmonary Associates	Santa Barbara	California
United States	Harbor - UCLA Medical Center	Torrance	California
United States	Georgetown University Medical Center - Department of Rheumatology	Washington	District of Columbia
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Reata, a wholly owned subsidiary of Biogen

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  Czechia,  Germany,  Israel,  Japan,  Mexico,  Netherlands,  Philippines,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Time to First Persistent Clinical Improvement Event	At least one of the following four criteria must have been met: Improvement by at least one WHO functional class coupled with no more than a 15% decrease from baseline in 6MWT; Increase from baseline in 6MWT by at least 10% and stability or improvement in the WHO functional class; 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; 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