Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome
Por:
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
Publicada:
1 may 2021
Ahead of Print:
1 mar 2021
Resumen:
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 m(2), 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 m(2), 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 m(2) 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.
Filiaciones:
Chertow, GM:
Stanford Univ, Sch Med, Dept Med, Div Nephrol, Palo Alto, CA 94304 USA
Appel, GB:
Columbia Univ Coll Phys & Surg, Dept Med, Div Nephrol, New York, NY USA
Andreoli, S:
Indiana Univ Sch Med, Riley Hosp Children, Indianapolis, IN 46202 USA
Bangalore, S:
NYU, Sch Med, Cardiovasc Clin Res Ctr, New York, NY USA
Block, GA:
US Renal Care Inc, Dept Clin Res & Med Affairs, Plano, TX USA
Chapman, AB:
Univ Chicago, Sect Nephrol, Chicago, IL 60637 USA
Chin, MP:
Reata Pharmaceut, Prod Dev Dept, Plano, TX USA
Gibson, KL:
Univ N Carolina, Kidney Ctr, Chapel Hill, NC 27515 USA
Goldsberry, A:
Reata Pharmaceut, Prod Dev Dept, Plano, TX USA
Iijima, K:
Kobe Univ, Grad Sch Med, Dept Pediat, Kobe, Hyogo, Japan
Inker, LA:
Tufts Med Ctr, Div Nephrol, Boston, MA 02111 USA
Knebelmann, B:
Univ Paris, Necker Hosp, AP HP, Dept Nephrol, Paris, France
Mariani, LH:
Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA
Meyer, CJ:
Reata Pharmaceut, Prod Dev Dept, Plano, TX USA
Nozu, K:
Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA
O'Grady, M:
Reata Pharmaceut, Prod Dev Dept, Plano, TX USA
Silva, AL:
Boise Kidney & Hypertens Inst, Meridian, ID USA
Stenvinkel, P:
Karolinska Inst, Dept Clin Sci Technol & Intervent, Div Renal Med & Baxter Novum, Stockholm, Sweden
Torra, R:
Univ Autonoma Barcelona, Inst Invest Carlos III, Fundacio Puigvert, Inherited Kidney Disorders,Nephrol Dept, Barcelona, Spain
Warady, BA:
Childrens Mercy Kansas City, Div Pediat Nephrol, Kansas City, MO USA
Pergola, PE:
Renal Associates PA, San Antonio, TX USA
Green Published, hybrid
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