Kidney Week

Abstract: SA-OR122

Bardoxolone Methyl Improved GFR Measured by Standard Inulin Clearance: The TSUBAKI Study

Session Information

• High-Impact Clinical Trials
  November 02, 2017 | Location: Hall J, Morial Convention Center
  Abstract Time: 10:45 AM - 11:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 305 CKD: Clinical Trials and Tubulointerstitial Disorders

Authors

• Nangaku, Masaomi, the University of Tokyo School of Medicine, Tokyo, Japan

Masaomi Nangaku,

• Shimazaki, Ryutaro, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan

Ryutaro Shimazaki,

• Akizawa, Tadao, Showa University School of Medicine, Tokyo, Japan

Tadao Akizawa,

Background

Bardoxolone methyl (BARD), an Nrf2 activator, consistently and significantly increased the estimated glomerular filtration rate (eGFR) in multiple clinical studies in patients with diabetic kidney disease (DKD). A prior Phase 3 study (BEACON) was terminated prematurely due to early-onset fluid overload, however, post-hoc analyses identified risk factors for fluid overload. We have therefore conducted a study that excluded at-risk DKD patients, known as the TSUBAKI study. In the study, we used the inulin clearance method, which is the gold standard for measuring GFR, to determine if changes in eGFR were reflective of true changes in GFR.

Methods

This was a randomized, double-blind, placebo-controlled, multi-center Phase 2 trial in patients with stages G3 and G4 DKD without identified risk factors for fluid overload such as baseline BNP > 200 pg/ml and prior history of heart failure. Patients were administered BARD or placebo with a titration scheme from 5 to 15 mg orally once daily for 16 weeks. Primary efficacy endpoint was the change in GFR measured by standard inulin clearance after 16 weeks of treatment in patients with stage G3 in a pre-specified interim analysis. The safety of BARD was evaluated in patients with both stages.

Results

A total of 120 patients with stages G3 and G4 were treated. In patients with stage G3, 85 patients were randomly assigned to either BARD or placebo with a 1:1 allocation; three patients discontinued before treatment started. GFR was evaluated in 40 patients (BARD: n=17; placebo: n=23). The mean eGFR and GFR at baseline were 46.7 (32.9 to 58.8) and 48.5 (27.9 to 64.8) ml/min/1.73 m², respectively. A significant improvement in GFR was seen in the BARD compared to the placebo group (6.6 ml/min/1.73 m², p=0.008). Data also showed that BARD significantly improved eGFR compared to placebo. In patients with stage G4, all 38 patients completed their treatment period. For patients with both stages, BARD was well tolerated, and no signs or symptoms of fluid overload were observed.

Conclusion

BARD improved renal function assessed by inulin clearance. The results suggest among preselected patients, BARD may yield significant treatment benefits without safety concerns.