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

Alport Syndrome Clinical Trial

— CARDINAL  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03019185
• Other study ID #: RTA 402-C-1603
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: March 2, 2017
• Est. completion date: October 30, 2020

Study information

• Verified date: February 2024
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 187
• Est. completion date: October 30, 2020
• Est. primary completion date: October 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Alport Syndrome
• Nephritis, Hereditary
• Syndrome

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
Australia	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
France	CHU Grenoble- Grenoble France	La Tronche
France	CHU Lyon-Hopital Edouard Herriot	Lyon
France	Hopital Necker-Universite Paris Descartes	Paris
Germany	University of Medicine Gottingen	Göttingen
Germany	University Children's Hospital Heidelberg	Heidelberg
Japan	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
Puerto Rico	Puerto Rico Clinical & Translational Research Center	Rio Piedras
Spain	Fundacio Puigvert	Barcelona
Spain	Servicio de Nefrologia pediatrica	Barcelona
Spain	Hospital Virgen de la Arrixaca	El Palmar
United Kingdom	Royal Free Hospital	London
United States	Akron Children's Hospital	Akron	Ohio
United States	Akron Nephrology Associates	Akron	Ohio
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University School of Medicine and Children's Healthcare of Atlanta	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Tufts Medical Center	Boston	Massachusetts
United States	Boise Kidney & Hypertension Institute	Caldwell	Idaho
United States	University of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Renal Disease Research Institute	Dallas	Texas
United States	Denver Nephrologists PC	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	NorthShore University Health System	Evanston	Illinois
United States	Nephrology Associates, PC	Flushing	New York
United States	Hackensack Meridian School of Medicine	Hackensack	New Jersey
United States	Southwest Houston Research	Houston	Texas
United States	Children's Research Institute - The Children's Mercy Hospital	Kansas City	Missouri
United States	Scripps Clinic, Nephrology	La Jolla	California
United States	South Florida Research Institute	Lauderdale Lakes	Florida
United States	Academic Medical Research Institute	Los Angeles	California
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	Boise Kidney & Hypertension Institute	Meridian	Idaho
United States	University of Minnesota - Division of Pediatric Nephrology	Minneapolis	Minnesota
United States	Columbia University Nephrology	New York	New York
United States	South Carolina Nephrology & Hypertension Center, Inc	Orangeburg	South Carolina
United States	Children's Hospital of Philadelphia (CHOP)	Philadelphia	Pennsylvania
United States	Arizona Kidney Disease and Hypertension Research Services, PLLC	Phoenix	Arizona
United States	University of Pittsburgh School of Medicine - Division of Pediatric Nephrology	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	The Warren Alpert Medical School of Brown University	Providence	Rhode Island
United States	Biolab Research, LLC	Rockville	Maryland
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah Health	Salt Lake City	Utah
United States	Clinical Advancement Center	San Antonio	Texas
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	Advanced Clinical Research	West Jordan	Utah
United States	Brookview Hills Research Associates, PLLC	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Reata, a wholly owned subsidiary of Biogen

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Japan,  Puerto Rico,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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)

External Links

•   Website for the CARDINAL study