A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome - CARDINAL (CARDINAL)
Alport Syndrome
About this trial
This is an interventional treatment trial for Alport Syndrome focused on measuring Alport Syndrome, Bardoxolone methyl, CDDO-ME, RTA 402
Eligibility Criteria
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
Sites / Locations
- University of Alabama at Birmingham
- Arizona Kidney Disease and Hypertension Research Services, PLLC
- Scripps Clinic, Nephrology
- Academic Medical Research Institute
- David Geffen School of Medicine at UCLA
- General Clinical Research Center - Parnassus
- University of California San Francisco - Children's Renal Center
- Denver Nephrologists PC
- South Florida Research Institute
- Emory University School of Medicine and Children's Healthcare of Atlanta
- Boise Kidney & Hypertension Institute
- Boise Kidney & Hypertension Institute
- NorthShore University Health System
- Biolab Research, LLC
- Tufts Medical Center
- University of Michigan
- University of Minnesota - Division of Pediatric Nephrology
- Children's Research Institute - The Children's Mercy Hospital
- Washington University School of Medicine
- Hackensack Meridian School of Medicine
- Nephrology Associates, PC
- Columbia University Nephrology
- Duke University Medical Center
- Brookview Hills Research Associates, PLLC
- Akron Nephrology Associates
- Akron Children's Hospital
- University of Cincinnati
- Cleveland Clinic
- Oregon Health & Science University
- Children's Hospital of Philadelphia (CHOP)
- University of Pittsburgh School of Medicine - Division of Pediatric Nephrology
- The Warren Alpert Medical School of Brown University
- South Carolina Nephrology & Hypertension Center, Inc
- Renal Disease Research Institute
- Southwest Houston Research
- Clinical Advancement Center
- University of Utah Health
- Advanced Clinical Research
- Royal Brisbane and Women's Hospital
- Melbourne Renal Research Group
- John Hunter Hospital
- Sydney Children's Hospital
- The Children's Hospital at Westmead
- CHU Grenoble- Grenoble France
- CHU Lyon-Hopital Edouard Herriot
- Hopital Necker-Universite Paris Descartes
- University of Medicine Gottingen
- University Children's Hospital Heidelberg
- St Marianna University Hospital
- Kobe University Hospital
- Japanese Red Cross Nagoya Daini Hospital
- JCHO Cyukyo Hospital
- Kitano Hospital
- Saga University Hospital
- Saitama Children's Medical Center
- JCHO Sendai Hospital
- Juntendo University Hospital
- Tokyo Metropolitan Children's Medical Center
- Puerto Rico Clinical & Translational Research Center
- Servicio de Nefrologia pediatrica
- Fundacio Puigvert
- Hospital Virgen de la Arrixaca
- Royal Free Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Experimental
Active Comparator
Placebo Comparator
Phase 2 Bardoxolone Methyl
Phase 3 Bardoxolone Methyl
Phase 3 Placebo
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.
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.
Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration.