A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome - CARDINAL
NCT ID: NCT03019185
Last Updated: 2025-06-11
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2/PHASE3
187 participants
INTERVENTIONAL
2017-03-02
2020-10-30
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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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.
Bardoxolone Methyl
Bardoxolone methyl dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status.
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.
Bardoxolone Methyl
Bardoxolone methyl dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status.
Phase 3 Placebo
Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration.
Placebo Oral Capsule
Capsule containing an inert placebo
Interventions
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Placebo Oral Capsule
Capsule containing an inert placebo
Bardoxolone Methyl
Bardoxolone methyl dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
12 Years
60 Years
ALL
No
Sponsors
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Biogen
INDUSTRY
Responsible Party
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Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Arizona Kidney Disease and Hypertension Research Services, PLLC
Phoenix, Arizona, United States
Scripps Clinic, Nephrology
La Jolla, California, United States
Academic Medical Research Institute
Los Angeles, California, United States
David Geffen School of Medicine at UCLA
Los Angeles, California, United States
General Clinical Research Center - Parnassus
San Francisco, California, United States
University of California San Francisco - Children's Renal Center
San Francisco, California, United States
Denver Nephrologists PC
Denver, Colorado, United States
South Florida Research Institute
Lauderdale Lakes, Florida, United States
Emory University School of Medicine and Children's Healthcare of Atlanta
Atlanta, Georgia, United States
Boise Kidney & Hypertension Institute
Caldwell, Idaho, United States
Boise Kidney & Hypertension Institute
Meridian, Idaho, United States
NorthShore University Health System
Evanston, Illinois, United States
Biolab Research, LLC
Rockville, Maryland, United States
Tufts Medical Center
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
University of Minnesota - Division of Pediatric Nephrology
Minneapolis, Minnesota, United States
Children's Research Institute - The Children's Mercy Hospital
Kansas City, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
Hackensack Meridian School of Medicine
Hackensack, New Jersey, United States
Nephrology Associates, PC
Flushing, New York, United States
Columbia University Nephrology
New York, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
Brookview Hills Research Associates, PLLC
Winston-Salem, North Carolina, United States
Akron Nephrology Associates
Akron, Ohio, United States
Akron Children's Hospital
Akron, Ohio, United States
University of Cincinnati
Cincinnati, Ohio, United States
Cleveland Clinic
Cleveland, Ohio, United States
Oregon Health & Science University
Portland, Oregon, United States
Children's Hospital of Philadelphia (CHOP)
Philadelphia, Pennsylvania, United States
University of Pittsburgh School of Medicine - Division of Pediatric Nephrology
Pittsburgh, Pennsylvania, United States
The Warren Alpert Medical School of Brown University
Providence, Rhode Island, United States
South Carolina Nephrology & Hypertension Center, Inc
Orangeburg, South Carolina, United States
Renal Disease Research Institute
Dallas, Texas, United States
Southwest Houston Research
Houston, Texas, United States
Clinical Advancement Center
San Antonio, Texas, United States
University of Utah Health
Salt Lake City, Utah, United States
Advanced Clinical Research
West Jordan, Utah, United States
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia
Melbourne Renal Research Group
Melbourne, , Australia
John Hunter Hospital
New Lambton Heights, , Australia
Sydney Children's Hospital
Sydney, , Australia
The Children's Hospital at Westmead
Westmead, , Australia
CHU Grenoble- Grenoble France
La Tronche, , France
CHU Lyon-Hopital Edouard Herriot
Lyon, , France
Hopital Necker-Universite Paris Descartes
Paris, , France
University of Medicine Gottingen
Göttingen, , Germany
University Children's Hospital Heidelberg
Heidelberg, , Germany
St Marianna University Hospital
Kawasaki, , Japan
Kobe University Hospital
Kobe, , Japan
Japanese Red Cross Nagoya Daini Hospital
Nagoya, , Japan
JCHO Cyukyo Hospital
Nagoya, , Japan
Kitano Hospital
Osaka, , Japan
Saga University Hospital
Saga, , Japan
Saitama Children's Medical Center
Saitama, , Japan
JCHO Sendai Hospital
Sendai, , Japan
Juntendo University Hospital
Tokyo, , Japan
Tokyo Metropolitan Children's Medical Center
Tokyo, , Japan
Puerto Rico Clinical & Translational Research Center
Rio Piedras, , Puerto Rico
Servicio de Nefrologia pediatrica
Barcelona, , Spain
Fundacio Puigvert
Barcelona, , Spain
Hospital Virgen de la Arrixaca
El Palmar, , Spain
Royal Free Hospital
London, , United Kingdom
Countries
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References
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Warady BA, Pergola PE, Agarwal R, Andreoli S, Appel GB, Bangalore S, Block GA, Chapman AB, Chin MP, Gibson KL, Goldsberry A, Iijima K, Inker LA, Kashtan CE, Knebelmann B, Mariani LH, Meyer CJ, Nozu K, O'Grady M, Rheault MN, Silva AL, Stenvinkel P, Torra R, Chertow GM. Effects of Bardoxolone Methyl in Alport Syndrome. Clin J Am Soc Nephrol. 2022 Dec;17(12):1763-1774. doi: 10.2215/CJN.02400222. Epub 2022 Nov 21.
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.
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.
Provided Documents
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Document Type: Study Protocol: US Protocol
Document Type: Study Protocol: US Protocol Addendum
Document Type: Study Protocol: Europe Protocol
Document Type: Study Protocol: Germany Protocol
Document Type: Study Protocol: France Spain UK Protocol
Document Type: Study Protocol: France Spain UK Protocol Addendum
Document Type: Statistical Analysis Plan: Phase 2 SAP
Document Type: Statistical Analysis Plan: Phase 3 SAP
Related Links
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Website for the CARDINAL study
Other Identifiers
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RTA 402-C-1603
Identifier Type: -
Identifier Source: org_study_id
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