Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR 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 study, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events (BEACON), 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 Phase 2 Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (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: A total of 40 patients were evaluated for the prespecified primary efficacy analysis. Mean change (95% confidence interval [CI]) from baseline in GFR was 5.95 (2.29 to 9.60) and -0.69 (-3.83 to 2.45) ml/min per 1.73 m² for patients randomized to bardoxolone methyl and placebo, respectively, with a significant intergroup difference of 6.64 ml/min per 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 aspartate aminotransferase, increased γ-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.

Keywords: bardoxolone methyl; chronic kidney disease; diabetic kidney disease; glomerular filtration rate; heart failure; inulin clearance.

Graphical abstract

Figure 1

Patient disposition in (a) cohort G3 and (b) cohort G4. FAS, full (safety) analysis set; PPS, per-protocol set.

Figure 2

Change from baseline in glomerular filtration rate (GFR) assessed by inulin clearance (interim per-protocol set). Data are least-squares mean (LSM) (95% confidence interval). P value indicates the difference between the LSM using the analysis of covariance model with treatment as a factor, and baseline values of GFR and log-transformed albumin/creatinine ratio as covariates,

Figure 3

Twenty-four-hour urine collection parameters (final per-protocol set) at week 16 in cohort G3: (a) creatinine clearance (CCr), (b) urine creatinine (Cr), (c) urine volume, and (d) urine sodium. Data for (a–d) are mean (95% confidence interval). P value is based on non−multiplicity-adjusted P value by t test and post hoc analyses.

Figure 4

Estimated glomerular filtration rate (eGFR) (full analysis set [FAS]) in (a) cohort G3 and (b) cohort G4; urinary albumin/creatinine ratio (ACR) (FAS) in (c) cohort G3 and (d) cohort G4; and baseline-adjusted ACR/eGFR in (e) cohort G3 and (f) cohort G4. Data are mean (95% confidence interval). P value is based on non−multiplicity-adjusted P value by t test and post hoc analyses. P value indicates the difference between the treatment groups at 16 weeks using the mixed-effects model with repeated measures with treatment and time as factors, treatment-by-visit interaction, and relevant baseline value as covariate.

Figure 5

Systolic and diastolic blood pressure (safety analysis set) in (a) cohort G3 and (b) cohort G4; B-type natriuretic peptide (BNP) levels (safety analysis set) in (c) cohort G3 and (d) cohort G4; and troponin T levels in (e) cohort G3 and (f) cohort G4. Data are mean (95% confidence interval). P value is based on non−multiplicity-adjusted P value by t test and post hoc analyses. P value indicates the difference between the treatment groups at 16 weeks using the mixed-effects model with repeated measures with treatment and time as factors, treatment-by-visit interaction, and relevant baseline value as covariate.

Figure 6

Change in body weight (safety analysis set) in (a) cohort G3 and (b) cohort G4 and change in creatine kinase (CK) in (c) cohort G3 and (d) cohort G4. Data are mean (95% confidence interval). P value is based on non−multiplicity-adjusted P value by t test and post hoc analyses.