Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes

The Occurrence of Renal Events (BEACON)

Dick De Zeeuw, Tadao Akizawa, Rajiv Agarwal, Paul Audhya, George L. Bakris, Melanie Chin, Melissa Krauth, Hiddo J. Lambers Heerspink, Colin J. Meyer, John J. McMurray, Hans Henrik Parving, Pablo E. Pergola, Giuseppe Remuzzi, Robert D. Toto, Nosratola D. Vaziri, Christoph Wanner, David G. Warnock, Janet Wittes, Glenn M. Chertow

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.

Original languageEnglish
Pages (from-to)212-222
Number of pages11
JournalAmerican Journal of Nephrology
Volume37
Issue number3
DOIs
StatePublished - Apr 2013

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Chronic Renal Insufficiency
Type 2 Diabetes Mellitus
Kidney
Renin-Angiotensin System
Glomerular Filtration Rate
Anti-Inflammatory Agents
Antioxidants
Morbidity
Mortality
Chronic Kidney Failure
Oxidative Stress
Placebos
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Inflammation
Therapeutics
Pharmaceutical Preparations

Keywords

  • Bardoxolone methyl
  • Cardiovascular death
  • Chronic kidney disease
  • Clinical trial
  • Diabetes mellitus
  • End-stage renal disease
  • Glomerular filtration rate
  • Nrf2
  • Trial design

ASJC Scopus subject areas

  • Nephrology

Cite this

Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes : The Occurrence of Renal Events (BEACON). / De Zeeuw, Dick; Akizawa, Tadao; Agarwal, Rajiv; Audhya, Paul; Bakris, George L.; Chin, Melanie; Krauth, Melissa; Lambers Heerspink, Hiddo J.; Meyer, Colin J.; McMurray, John J.; Parving, Hans Henrik; Pergola, Pablo E.; Remuzzi, Giuseppe; Toto, Robert D.; Vaziri, Nosratola D.; Wanner, Christoph; Warnock, David G.; Wittes, Janet; Chertow, Glenn M.

In: American Journal of Nephrology, Vol. 37, No. 3, 04.2013, p. 212-222.

Research output: Contribution to journalArticle

De Zeeuw, D, Akizawa, T, Agarwal, R, Audhya, P, Bakris, GL, Chin, M, Krauth, M, Lambers Heerspink, HJ, Meyer, CJ, McMurray, JJ, Parving, HH, Pergola, PE, Remuzzi, G, Toto, RD, Vaziri, ND, Wanner, C, Warnock, DG, Wittes, J & Chertow, GM 2013, 'Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes: The Occurrence of Renal Events (BEACON)', American Journal of Nephrology, vol. 37, no. 3, pp. 212-222. https://doi.org/10.1159/000346948
De Zeeuw, Dick ; Akizawa, Tadao ; Agarwal, Rajiv ; Audhya, Paul ; Bakris, George L. ; Chin, Melanie ; Krauth, Melissa ; Lambers Heerspink, Hiddo J. ; Meyer, Colin J. ; McMurray, John J. ; Parving, Hans Henrik ; Pergola, Pablo E. ; Remuzzi, Giuseppe ; Toto, Robert D. ; Vaziri, Nosratola D. ; Wanner, Christoph ; Warnock, David G. ; Wittes, Janet ; Chertow, Glenn M. / Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes : The Occurrence of Renal Events (BEACON). In: American Journal of Nephrology. 2013 ; Vol. 37, No. 3. pp. 212-222.
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T1 - Rationale and trial design of bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes

T2 - The Occurrence of Renal Events (BEACON)

AU - De Zeeuw, Dick

AU - Akizawa, Tadao

AU - Agarwal, Rajiv

AU - Audhya, Paul

AU - Bakris, George L.

AU - Chin, Melanie

AU - Krauth, Melissa

AU - Lambers Heerspink, Hiddo J.

AU - Meyer, Colin J.

AU - McMurray, John J.

AU - Parving, Hans Henrik

AU - Pergola, Pablo E.

AU - Remuzzi, Giuseppe

AU - Toto, Robert D.

AU - Vaziri, Nosratola D.

AU - Wanner, Christoph

AU - Warnock, David G.

AU - Wittes, Janet

AU - Chertow, Glenn M.

PY - 2013/4

Y1 - 2013/4

N2 - Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.

AB - Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.

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KW - Clinical trial

KW - Diabetes mellitus

KW - End-stage renal disease

KW - Glomerular filtration rate

KW - Nrf2

KW - Trial design

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