A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome - CARDINAL (CARDINAL)

A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome

This international, multi-center, Phase 2/3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with Alport syndrome. The Phase 2 portion of the trial will be open-label and enroll up to 30 patients. The Phase 3 portion of the trial will be double-blind, randomized, placebo-controlled and will enroll up to 180 patients.

Study Overview

• Status: Completed
• Conditions: Alport Syndrome
• Intervention / Treatment: Drug: Bardoxolone Methyl; Drug: Placebo Oral Capsule

Detailed Description

This international, multi-center, Phase 2/3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with Alport syndrome. The Phase 2 portion of the trial will be open-label and enroll up to 30 patients. The Phase 3 portion of the trial will be double-blind, randomized, placebo-controlled and will enroll up to 180 patients.

Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study. Patients in the Phase 3 cohort will be randomized 1:1 to either bardoxolone methyl or placebo and randomization will be stratified by baseline albumin to creatinine ratio (ACR). Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration.

All patients in the study will follow the same visit and assessment schedule. Following randomization on Day 1, patients will be scheduled to be assessed during treatment at Weeks 1, 2, 4, 6, 8, 12, 24, 36, 48, 52, 64, 76, 88, 100, and 104 and by telephone contact on Days 3, 10, 21, 31, 38, and 45. Patients will not receive study drug during a 4-week withdrawal period between Weeks 48 and 52. They will re-start treatment at Week 52 at the same dose they received at Week 48 and will continue study drug treatment through Week 100. Patients will also be scheduled to be assessed at an in person follow up visit at Week 104, 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): 187
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, VIC 3073
    • Melbourne Renal Research Group
  • New Lambton Heights, Australia, NSW 2305
    • John Hunter Hospital
  • Sydney, Australia, NSW 2031
    • Sydney Children's Hospital
  • Westmead, Australia, NSW 2145
    • The Children's Hospital at Westmead
  • Queensland
    • Herston, Queensland, Australia, 2145
      • Royal Brisbane and Women's Hospital
• France
  • La Tronche, France, 38700
    • CHU Grenoble- Grenoble France
  • Lyon, France, 69003
    • CHU Lyon-Hopital Edouard Herriot
  • Paris, France, 75015
    • Hopital Necker-Universite Paris Descartes
• Germany
  • Göttingen, Germany, 37075
    • University of Medicine Gottingen
  • Heidelberg, Germany, 69120
    • University Children's Hospital Heidelberg
• Japan
  • Kawasaki, Japan
    • St Marianna University Hospital
  • Kobe, Japan
    • Kobe University Hospital
  • Nagoya, Japan
    • Japanese Red Cross Nagoya Daini Hospital
  • Nagoya, Japan
    • JCHO Cyukyo Hospital
  • Osaka, Japan
    • Kitano Hospital
  • Saga, Japan
    • Saga University Hospital
  • Saitama, Japan
    • Saitama Children's Medical Center
  • Sendai, Japan
    • JCHO Sendai Hospital
  • Tokyo, Japan
    • Juntendo University Hospital
  • Tokyo, Japan
    • Tokyo Metropolitan Children's Medical Center
• Puerto Rico
  • Rio Piedras, Puerto Rico, 00935
    • Puerto Rico Clinical & Translational Research Center
• Spain
  • Barcelona, Spain, 119-08035
    • Servicio de Nefrologia pediatrica
  • Barcelona, Spain, 340-08025
    • Fundacio Puigvert
  • El Palmar, Spain, 30120
    • Hospital Virgen de la Arrixaca
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85308
      • Arizona Kidney Disease and Hypertension Research Services, PLLC
  • California
    • La Jolla, California, United States, 92037
      • Scripps Clinic, Nephrology
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA
    • Los Angeles, California, United States, 90022
      • Academic Medical Research Institute
    • San Francisco, California, United States, 94143
      • General Clinical Research Center - Parnassus
    • San Francisco, California, United States, 94143
      • University of California San Francisco - Children's Renal Center
  • Colorado
    • Denver, Colorado, United States, 80230
      • Denver Nephrologists PC
  • Florida
    • Lauderdale Lakes, Florida, United States, 33313
      • South Florida Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine and Children's Healthcare of Atlanta
  • Idaho
    • Caldwell, Idaho, United States, 83605
      • Boise Kidney & Hypertension Institute
    • Meridian, Idaho, United States, 83642
      • Boise Kidney & Hypertension Institute
  • Illinois
    • Evanston, Illinois, United States, 60201
      • NorthShore University Health System
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Biolab Research, LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota - Division of Pediatric Nephrology
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Research Institute - The Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack Meridian School of Medicine
  • New York
    • Flushing, New York, United States, 11355
      • Nephrology Associates, PC
    • New York, New York, United States, 10032
      • Columbia University Nephrology
  • North Carolina
    • Durham, North Carolina, United States, 27701
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27103
      • Brookview Hills Research Associates, PLLC
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Akron, Ohio, United States, 44302
      • Akron Nephrology Associates
    • Cincinnati, Ohio, United States, 45220
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia (CHOP)
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh School of Medicine - Division of Pediatric Nephrology
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • The Warren Alpert Medical School of Brown University
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • South Carolina Nephrology & Hypertension Center, Inc
  • Texas
    • Dallas, Texas, United States, 75235
      • Renal Disease Research Institute
    • Houston, Texas, United States, 77099
      • Southwest Houston Research
    • San Antonio, Texas, United States, 78215
      • Clinical Advancement Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health
    • West Jordan, Utah, United States, 84088
      • Advanced Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female patients 12 ≤ age ≤ 60 upon study consent;
• Diagnosis of Alport syndrome by genetic testing (documented mutation in a gene associated with Alport syndrome, including COL4A3, COL4A4, or COL4A5) or histologic assessment using electron microscopy;
• Screening eGFR ≥ 30 and ≤ 90 mL/min/1.73 m2. The two eGFR values collected at Screen A and Screen B visits used to determine eligibility must have a percent difference ≤ 25%;
• Albumin to creatinine ratio (ACR) ≤ 3500 mg/g at Screen B visit;
• If receiving an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB), the medications must remain the same for at least 6 weeks prior to the Screen A visit and during Screening. The dosage of ACE inhibitor and/or ARB must also be stable for 2 weeks prior to the Screen A visit and remain the same through Day 1 (i.e., no change in dosage or medication). Patients not taking an ACE inhibitor and/or ARB because of a medical contraindication must have discontinued treatment at least 8 weeks prior to the Screen A visit;
• Adequate bone marrow reserve and organ function at the Screen A visit
• Able to swallow capsules;
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;

Exclusion Criteria:

• Prior exposure to bardoxolone methyl;
• Ongoing chronic hemodialysis or peritoneal dialysis therapy;
• Renal transplant recipient;
• B-type natriuretic peptide (BNP) level > 200 pg/mL at Screen A visit;
• Uncontrolled diabetes (HbA1c > 11.0%) at Screen A visit;
• Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during Screening;
• Serum albumin < 3 g/dL at Screen A visit;
• History of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
• Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg at Screen A visit after a period of rest;
• Systolic BP < 90 mm Hg at Screen A visit after a period of rest;
• History of malignancy within 5 years prior to Screen A visit, with the exception of localized skin or cervical carcinomas;
• Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to randomization or anticipated need for immunosuppression during the study;
• Untreated or uncontrolled active bacterial, fungal, or viral infection;
• Participation in other interventional clinical studies within 30 days prior to Day 1;
• Unwilling to practice acceptable methods of birth control (both males who have partners of child-bearing 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;
• Women who are pregnant or breastfeeding;
• Known hypersensitivity to any component of the study drug

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 2 Bardoxolone Methyl; Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study. Patients with baseline ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline ACR > 300 mg/g will be titrated to a maximum dose of 30 mg. Adult patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if baseline ACR >300 mg/g) unless contraindicated clinically and approved by the medical monitor. Patients under the age of 18 receiving bardoxolone methyl will start 5 mg every other day during the first week and begin once-daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing following the same aforementioned dose titration scheme based on baseline ACR at Weeks 2, 4, and 6.	Drug: Bardoxolone Methyl; Bardoxolone methyl dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status.; Other Names: RTA 402
Active Comparator: Phase 3 Bardoxolone Methyl; Patients with baseline ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline ACR > 300 mg/g will be titrated to a maximum dose of 30 mg. Adult patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if baseline ACR >300 mg/g) unless contraindicated clinically and approved by the medical monitor. Patients under the age of 18 receiving bardoxolone methyl will start 5 mg every other day during the first week and begin once-daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing following the same aforementioned dose titration scheme based on baseline ACR at Weeks 2, 4, and 6.	Drug: Bardoxolone Methyl; Bardoxolone methyl dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status.; Other Names: RTA 402
Placebo Comparator: Phase 3 Placebo; Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration.	Drug: Placebo Oral Capsule; Capsule containing an inert placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 12 Weeks of Treatment (Phase 2)	To assess the change in eGFR from baseline to week 12 (Phase 2). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.	Baseline through 12 weeks after participant receives the first dose in the Phase 2 study
Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 3)	To assess the change in eGFR from baseline to week 48 (Phase 3). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.	Baseline through 48 weeks after participant receives the first dose in the Phase 3 study
Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 3)	To assess the change in eGFR from baseline to week 100 (Phase 3). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.	Baseline through 100 weeks after participant receives the first dose in the Phase 3 study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 2)	To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at Week 48. Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.	Baseline through 48 weeks after participant receives the first dose in the Phase 2 study
Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 2)	To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at Week 100. Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.	Baseline through 100 weeks after participant receives the first dose in the Phase 2 study
Change From Baseline in eGFR at Week 52 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)	To assess the change in eGFR from baseline to week 52 following a 4-week drug treatment withdrawal period (Phase 3). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.	Baseline through 52 weeks after participant receives the first dose in the Phase 3 study (or 4 weeks after last dose for patients who discontinued early in the first year)
Change From Baseline in eGFR at Week 104 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)	To assess the change in eGFR from baseline to week 104 following a 4-week drug treatment withdrawal period (Phase 3). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.	Baseline through 104 weeks after participant receives the first dose in the Phase 3 study (or 4 weeks after last dose for patients who discontinued early in the second year)

Collaborators and Investigators

• Sponsor: Reata, a wholly owned subsidiary of Biogen

Publications and helpful links

General Publications

• Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. 2021 Mar;36(3):711-719. doi: 10.1007/s00467-020-04819-6. Epub 2020 Nov 6. Erratum In: Pediatr Nephrol. 2021 Jan 12;:
• Chertow GM, Appel GB, Andreoli S, Bangalore S, Block GA, Chapman AB, Chin MP, Gibson KL, Goldsberry A, Iijima K, Inker LA, Knebelmann B, Mariani LH, Meyer CJ, Nozu K, O'Grady M, Silva AL, Stenvinkel P, Torra R, Warady BA, Pergola PE. Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome. Am J Nephrol. 2021;52(3):180-189. doi: 10.1159/000513777. Epub 2021 Mar 31.

Helpful Links

• Website for the CARDINAL study

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2017
• Primary Completion (Actual): October 6, 2020
• Study Completion (Actual): October 30, 2020

Study Registration Dates

• First Submitted: January 6, 2017
• First Submitted That Met QC Criteria: January 10, 2017
• First Posted (Estimated): January 12, 2017

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: February 1, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: RTA 402; Bardoxolone methyl; Alport Syndrome; CDDO-ME
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Urogenital Abnormalities; Congenital Abnormalities; Connective Tissue Diseases; Nephritis; Collagen Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Nephritis, Hereditary
• Other Study ID Numbers: RTA 402-C-1603

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/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes