Glenn M Chertow1, Gerald B Appel2, Sharon Andreoli3, Sripal Bangalore4, Geoffrey A Block5, Arlene B Chapman6, Melanie P Chin7, Keisha L Gibson8, Angie Goldsberry7, Kazumoto Iijima9, Lesley A Inker10, Bertrand Knebelmann11, Laura H Mariani12, Colin J Meyer7, Kandai Nozu9, Megan O'Grady7, Arnold L Silva13, Peter Stenvinkel14, Roser Torra15, Bradley A Warady16, Pablo E Pergola17. 1. Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA. 2. Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA. 3. Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA. 4. Cardiovascular Clinical Research Center, New York University School of Medicine, New York, New York, USA. 5. Department of Clinical Research and Medical Affairs, US Renal Care, Inc., Plano, Texas, USA. 6. Section of Nephrology, University of Chicago, Chicago, Illinois, USA. 7. Department of Product Development, Reata Pharmaceuticals, Plano, Texas, USA. 8. University of North Carolina Kidney Center at Chapel Hill, Chapel Hill, North Carolina, USA. 9. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan. 10. Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA. 11. Department of Nephrology, Necker Hospital, AP-HP, Université de Paris, Paris, France. 12. Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA. 13. Boise Kidney and Hypertension Institute, Meridian, Idaho, USA. 14. Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and Intervention, Karolinska Institutet, Stockholm, Sweden. 15. Inherited Kidney Disorders, Nephrology Department, Fundacio Puigvert, Instituto de Investigacion Carlos III, Universitat Autonoma de Barcelona, Barcelona, Spain. 16. Division of Pediatric Nephrology, Children's Mercy Kansas City, Kansas City, Missouri, USA. 17. Renal Associates PA, San Antonio, Texas, USA.
Abstract
INTRODUCTION: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. METHODS: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. RESULTS: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/ CONCLUSION: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.
INTRODUCTION: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. METHODS: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12-70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30-90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. RESULTS: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/ CONCLUSION: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.
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