• Dick de Zeeuw, Tadao Akizawa, Paul Audhya, George L Bakris, Melanie Chin, Heidi Christ-Schmidt, Angie Goldsberry, Mark Houser, Melissa Krauth, Lambers HeerspinkHiddo JHJ, John J McMurray, Colin J Meyer, Hans-Henrik Parving, Giuseppe Remuzzi, Robert D Toto, Nosratola D Vaziri, Christoph Wanner, Janet Wittes, Danielle Wrolstad, Glenn M Chertow, and BEACON Trial Investigators.
• From the University of Groningen, Groningen, the Netherlands (D.Z., H.J.L.H.); Showa University School of Medicine, Tokyo (T.A.); Reata Pharmaceuticals, Irving, TX (P.A., M.C., A.G., M.K., C.J.M.); University of Chicago (G.L.B.) and AbbVie Pharmaceuticals (M.H.) - both in Chicago; Statistics Collaborative, Washington, DC (H.C.-S., J.W., D.W.); University of Glasgow, Glasgow, United Kingdom (J.J.M.); Rigshospitalet, University of Copenhagen, Copenhagen (H.-H.P.); Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy (G.R.); University of Texas Southwestern Medical Center, Dallas (R.D.T.); University of California, Irvine (N.D.V.); University of Würzburg, Würzburg, Germany (C.W.); and Stanford University, Palo Alto, CA (G.M.C.).
• N. Engl. J. Med. 2013 Dec 26; 369 (26): 2492-503.

BackgroundAlthough inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown.MethodsWe randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes.ResultsThe sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group.ConclusionsAmong patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).

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