Clinical trial NCT03019185: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome - CARDINAL
Official title: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Alport Syndrome
Keywords: Alport Syndrome
Bardoxolone methyl
CDDO-ME
RTA 402
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2017-01-12
Enrollment: 187
Sex: ALL
Minimum age (years): 12
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

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

Primary outcomes:
measure: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 12 Weeks of Treatment (Phase 2)
timeFrame: Baseline through 12 weeks after participant receives the first dose in the Phase 2 study
measure: Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 3)
timeFrame: Baseline through 48 weeks after participant receives the first dose in the Phase 3 study
measure: Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 3)
timeFrame: Baseline through 100 weeks after participant receives the first dose in the Phase 3 study
Secondary outcomes:
measure: Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 2)
timeFrame: Baseline through 48 weeks after participant receives the first dose in the Phase 2 study
measure: Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 2)
timeFrame: Baseline through 100 weeks after participant receives the first dose in the Phase 2 study
measure: Change From Baseline in eGFR at Week 52 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)
timeFrame: 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)
measure: Change From Baseline in eGFR at Week 104 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)
timeFrame: 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)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Arizona Kidney Disease and Hypertension Research Services, PLLC
state: Arizona
city: La Jolla
country: United States
facility: Scripps Clinic, Nephrology
state: California
city: Los Angeles
country: United States
facility: Academic Medical Research Institute
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: San Francisco
country: United States
facility: General Clinical Research Center - Parnassus
state: California
city: San Francisco
country: United States
facility: University of California San Francisco - Children's Renal Center
state: California
city: Denver
country: United States
facility: Denver Nephrologists PC
state: Colorado
city: Lauderdale Lakes
country: United States
facility: South Florida Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine and Children's Healthcare of Atlanta
state: Georgia
city: Caldwell
country: United States
facility: Boise Kidney & Hypertension Institute
state: Idaho
city: Meridian
country: United States
facility: Boise Kidney & Hypertension Institute
state: Idaho
city: Evanston
country: United States
facility: NorthShore University Health System
state: Illinois
city: Rockville
country: United States
facility: Biolab Research, LLC
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota - Division of Pediatric Nephrology
state: Minnesota
city: Kansas City
country: United States
facility: Children's Research Institute - The Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack Meridian School of Medicine
state: New Jersey
city: Flushing
country: United States
facility: Nephrology Associates, PC
state: New York
city: New York
country: United States
facility: Columbia University Nephrology
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Brookview Hills Research Associates, PLLC
state: North Carolina
city: Akron
country: United States
facility: Akron Nephrology Associates
state: Ohio
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh School of Medicine - Division of Pediatric Nephrology
state: Pennsylvania
city: Providence
country: United States
facility: The Warren Alpert Medical School of Brown University
state: Rhode Island
city: Orangeburg
country: United States
facility: South Carolina Nephrology & Hypertension Center, Inc
state: South Carolina
city: Dallas
country: United States
facility: Renal Disease Research Institute
state: Texas
city: Houston
country: United States
facility: Southwest Houston Research
state: Texas
city: San Antonio
country: United States
facility: Clinical Advancement Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Health
state: Utah
city: West Jordan
country: United States
facility: Advanced Clinical Research
state: Utah
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Melbourne Renal Research Group
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
city: Sydney
country: Australia
facility: Sydney Children's Hospital
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
city: La Tronche
country: France
facility: CHU Grenoble- Grenoble France
city: Lyon
country: France
facility: CHU Lyon-Hopital Edouard Herriot
city: Paris
country: France
facility: Hopital Necker-Universite Paris Descartes
city: Göttingen
country: Germany
facility: University of Medicine Gottingen
city: Heidelberg
country: Germany
facility: University Children's Hospital Heidelberg
city: Kawasaki
country: Japan
facility: St Marianna University Hospital
city: Kobe
country: Japan
facility: Kobe University Hospital
city: Nagoya
country: Japan
facility: Japanese Red Cross Nagoya Daini Hospital
city: Nagoya
country: Japan
facility: JCHO Cyukyo Hospital
city: Osaka
country: Japan
facility: Kitano Hospital
city: Saga
country: Japan
facility: Saga University Hospital
city: Saitama
country: Japan
facility: Saitama Children's Medical Center
city: Sendai
country: Japan
facility: JCHO Sendai Hospital
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Children's Medical Center
city: Rio Piedras
country: Puerto Rico
facility: Puerto Rico Clinical & Translational Research Center
city: Barcelona
country: Spain
facility: Servicio de Nefrologia pediatrica
city: Barcelona
country: Spain
facility: Fundacio Puigvert
city: El Palmar
country: Spain
facility: Hospital Virgen de la Arrixaca
city: London
country: United Kingdom
facility: Royal Free Hospital
Study officials:
References:
citation: 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.
citation: 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.