Dataset Information

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 ?-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.

SUBMITTER: Nangaku M

PROVIDER: S-EPMC7271944 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR in Diabetic Kidney Disease Patients (TSUBAKI Study).

Nangaku Masaomi M Kanda Hironori H Takama Hirotaka H Ichikawa Tomohiro T Hase Hiroki H Akizawa Tadao T

Kidney international reports 20200414 6

<h4>Introduction</h4>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 b ...[more]

PMID: 32518870

Similar Datasets

Project description:Although 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.We 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.The 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.Among 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.).

Project description:BackgroundDiabetic kidney disease (DKD) is a serious complication that begins with albuminuria and often leads to a rapid progressive decline in renal function. Niclosamide is a potent inhibitor of the Wnt/β-catenin pathway, which controls the expression of multiple genes of the renin-angiotensin-aldosterone system (RAAS), which in turn is influences the progression of DKD. This study was conducted to evaluate the effect of niclosamide as adjuvant therapy on DKD.MethodsOut of 127 patients screened for eligibility, 60 patients completed the study. After randomization, 30 patients in the niclosamide arm received ramipril plus niclosamide, and 30 patients in the control arm received ramipril only for 6 months. The primary outcomes were the changes in urinary albumin to creatinine ratio (UACR), serum creatinine, and estimated glomerular filtration rate (eGFR). The secondary outcomes were measurements of urinary matrix metalloproteinase-7 (MMP-7), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and podocalyxin (PCX). Comparisons between the two arms were done using student t-test. Correlation analysis was done using Pearson correlation.ResultsNiclosamide decreased UACR by 24% (95% CI - 30 to - 18.3%) while there was a rise in UACR in the control arm by 11% (95% CI 4 to 18.2%) after 6 months (P < 0.001). Moreover, a significant reduction in MMP-7 and PCX was noticed in the niclosamide arm. Regression analysis revealed a strong association between MMP-7, which is a noninvasive biomarker predicting the activity of the Wnt/β-catenin signaling, and UACR. A 1 mg/dL decline in MMP-7 level was associated with a 25 mg/g lowering in UACR (B = 24.95, P < 0.001).ConclusionThe addition of niclosamide to patients with diabetic kidney disease receiving an angiotensin-converting enzyme inhibitor significantly reduces albumin excretion. Further larger-scale trials are needed to confirm our results.Trial registrationThe study was prospectively registered on clinicaltrial.gov on March 23, 2020, with identification code NCT04317430.

Project description:Assessment of GFR is central to clinical practice, research, and public health. Current Kidney Disease Improving Global Outcomes guidelines recommend measurement of serum creatinine to estimate GFR as the initial step in GFR evaluation. Serum creatinine is influenced by creatinine metabolism as well as GFR; hence, all equations to estimate GFR from serum creatinine include surrogates for muscle mass, such as age, sex, race, height, or weight. The guideline-recommended equation in adults (the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation) includes a term for race (specified as black versus nonblack), which improves the accuracy of GFR estimation by accounting for differences in non-GFR determinants of serum creatinine by race in the study populations used to develop the equation. In that study, blacks had a 16% higher average measured GFR compared with nonblacks with the same age, sex, and serum creatinine. The reasons for this difference are only partly understood, and the use of race in GFR estimation has limitations. Some have proposed eliminating the race coefficient, but this would induce a systematic underestimation of measured GFR in blacks, with potential unintended consequences at the individual and population levels. We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group. We suggest full disclosure of use of race in GFR estimation, accommodation of those who decline to identify their race, and shared decision making between health care providers and patients. We also suggest mindful use of cystatin C as a confirmatory test as well as clearance measurements. It would be preferable to avoid specification of race in GFR estimation if there was a superior, evidence-based substitute. The goal of future research should be to develop more accurate methods for GFR estimation that do not require use of race or other demographic characteristics.

Project description:IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as novel therapeutics to treat diabetic kidney disease (DKD). Although the beneficial effects of SGLT2i have been demonstrated, their target mechanisms on kidney function are unknown. The current study aimed to elucidate these mechanisms by studying SGLT2i-induced changes in the urinary proteome of persons with type 2 diabetes (T2D) and DKD.MethodsA total of 40 participants with T2D were enrolled in a double-blinded randomized cross-over trial at the Steno Diabetes Center Copenhagen, Denmark. They were treated with 10 mg of dapagliflozin for 12 weeks. Thirty-two participants with complete urinary proteomics measures before and after the trial were included. All participants received renin-angiotensin system blockade and had albuminuria, (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g). A type 1 diabetes (T1D) cohort consisting of healthy controls and persons with DKD was included for validation. Urinary proteome changes were analyzed using Wilcoxon signed-rank test. Functional enrichment analysis was conducted to discover affected biological processes.ResultsDapagliflozin treatment significantly (Padjusted < 0.05) affected 36 urinary peptide fragments derived from 19 proteins. Eighteen proteins were correspondingly reflected in the validation cohort. A multifold change in peptide abundance was observed in many proteins (A1BG, urinary albumin [ALB], Caldesmon 1, COLCRNN, heat shock protein 90-β [HSP90AB1], IGLL5, peptidase inhibitor 16 [PI16], prostaglandin-H2-D-isomerase [PTGDS], SERPINA1). These also included urinary biomarkers of kidney fibrosis and function (type I and III collagens and albumin). Biological processes relating to inflammation, wound healing, and kidney fibrosis were enriched.ConclusionThe current study discovers the urinary proteome impacted by the SGLT2i, thereby providing new potential target sites and pathways, especially relating to wound healing and inflammation.

Project description:Background and objectivesImpaired nitric oxide signaling through soluble guanylate cyclase has been implicated in the pathophysiology of diabetic kidney disease. Praliciguat, a soluble guanylate cyclase stimulator that amplifies nitric oxide signaling, inhibited kidney inflammation and fibrosis in animal models.Design, setting, participants, & measurementsIn a phase 2 trial, 156 adults with type 2 diabetes, eGFR 30-75 ml/min per 1.73 m2, and urine albumin-creatinine ratio 200-5000 mg/g treated with renin-angiotensin system inhibitors were randomly allocated 1:1:1 to placebo, 20 mg praliciguat, or 40 mg praliciguat daily for 12 weeks. The primary efficacy and safety outcomes were change from baseline to weeks 8 and 12 in urine albumin-creatinine ratio and treatment-emergent adverse events, respectively. Other outcomes assessed were 24-hour ambulatory BP and metabolic parameters.ResultsOf 156 participants randomized, 140 (90%) completed the study. The primary efficacy analysis demonstrated a mean change from baseline in urine albumin-creatinine ratio of -28% (90% confidence interval, -36 to -18) in the pooled praliciguat group and -15% (-28 to 0.4) in the placebo group (difference -15%; -31 to 4; P=0.17). Between-group decreases from baseline to week 12 for praliciguat versus placebo were seen in mean 24-hour systolic BP (-4 mm Hg; -8 to -1), hemoglobin A1c (-0.3%; -0.5 to -0.03), and serum cholesterol (-10 mg/dl; -19 to -1). The incidence of treatment-emergent adverse events was similar in the pooled praliciguat and placebo groups (42% and 44%, respectively). Serious adverse events, events leading to study drug discontinuation, and events potentially related to BP lowering were reported at higher frequency in the 40-mg group but were similar in 20-mg and placebo groups.ConclusionsPraliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease.Clinical trial registry name and registration numberA Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy/Diabetic Kidney Disease as Measured by Albuminuria, NCT03217591.

Dataset Information

Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR in Diabetic Kidney Disease Patients (TSUBAKI Study).

Publications

Randomized Clinical Trial on the Effect of Bardoxolone Methyl on GFR in Diabetic Kidney Disease Patients (TSUBAKI Study).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets