Clinical trial NCT02657356: Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension - CATALYST
Official title: A Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Connective Tissue Disease-Associated Pulmonary Arterial Hypertension
Keywords: Pulmonary Hypertension
Pulmonary Arterial Hypertension
Connective Tissue Disease-Associated Pulmonary Arterial Hypertension
Bardoxolone methyl
PAH
RTA 402
6-minute walk distance
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2016-01-15
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

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