Randomized clinical trial on the effect of bardoxolone methyl on glomerular filtration rate in diabetic kidney disease patients (TSUBAKI study)

Abstract Introduction Bardoxolone methyl significantly increases estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD). However, the phase 3 BEACON study was terminated prematurely because bardoxolone methyl increased the risk for early-onset fluid overload in patients with identifiable risk factors for heart failure (elevated baseline B-type natriuretic peptide levels >200 pg/ml and prior history of hospitalization for heart failure). The TSUBAKI study aimed to determine if patients without risk factors can mitigate the risk for fluid overload and whether changes in eGFR with bardoxolone methyl reflect true increases in GFR. Methods This phase 2, randomized, multicenter, double-blind, placebo-controlled study enrolled patients with type 2 diabetes and stage 3-4 CKD. Patients were randomized 1:1 to bardoxolone methyl (n=41) or placebo (n=41) (cohort G3), or 2:1 to bardoxolone methyl (n=24) or placebo (n=14) (cohort G4), administered orally once daily for 16 weeks using a dose-titration scheme. The primary efficacy endpoint was change from baseline in GFR measured by inulin clearance at week 16 in the cohort G3. Results Forty patients were evaluated for the prespecified primary efficacy analysis. Mean change (95% CI) from baseline in GFR was 5.95 (2.29 to 9.60) and −0.69 (−3.83 to 2.45) ml/min/1.73 m2 for patients randomized to bardoxolone methyl and placebo, respectively, with a significant intergroup difference of 6.64 ml/min/1.73 m2 (P=0.008). Increases in the albumin/creatinine ratio were observed in the bardoxolone methyl group vs the placebo group. The most common adverse events (≥15% in either group) were viral upper respiratory tract infection, increased alanine aminotransferase, increased alanine aminotransferase, increased gamma-glutamyltransferase, and constipation. Peripheral edema was reported by 4 patients receiving bardoxolone methyl and by 1 patient receiving placebo; all events were mild and self-limiting. No patient died or experienced heart failure. The study discontinuation rate was higher in the bardoxolone methyl group (cohort G3; n=8; cohort G4: n=7) than the placebo group (cohort G3; n=1; cohort G4: n=0). Conclusion Bardoxolone methyl significantly increased measured GFR, and further investigation is ongoing to evaluate whether it provides clinical benefit without major safety concerns in selected patients with CKD.