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Phase II Pharmacodynamic Trial to Determine the Effects of Bardoxolone Methyl on eGFR in Patients With Type 2 Diabetes and Chronic Kidney Disease

2014-08-27 03:16:28 | BioPortfolio

Summary

This study assesses the effects of a new formulation of bardoxolone methyl on eGFR in Patients with Chronic Kidney Disease and Type 2 Diabetes.

Description

Bardoxolone methyl (RTA 402) is an Antioxidant Inflammation Modulator (AIM) that is undergoing clinical testing in chronic kidney disease (CKD). Bardoxolone methyl and other AIMs inhibit immune-mediated inflammation by restoring redox homeostasis in inflamed tissues through the induction of the cytoprotective transcription factor Nrf2. In the diabetic population, adipocytes produce cytokines and mobilize free fatty acids which induce insulin resistance. Resultant hyperglycemia and increased cytokine production induces reactive oxygen and nitrogen species which in turn induce vascular inflammation and endothelial dysfunction. These stimuli cause further activation of NF-kB, promoting inflammation, mesangial cell contraction, mesangial expansion and endothelial dysfunction, the end result of which is decreased renal function. By inducing Nrf2 and suppressing redox-driven inflammation, we hypothesize that inflammation and resultant adverse renal functional changes in patients with chronic kidney disease resulting from diabetes can be suppressed.

In a Phase IIa open label study of patients with CKD and type 2 diabetes, treatment with bardoxolone methyl for 28 days resulted in significant improvements in renal function, including increases in eGFR, and decreases in serum creatinine, cystatin C, BUN, phosphorus, uric acid, creatinine clearance, and angiotensin II; improvements in glycemic control as assessed by hemoglobin A1c; and improvements in markers of endothelial dysfunction and systemic inflammation, such as circulating endothelial cells and adiponectin. These data are consistent with the hypothesis that bardoxolone methyl improves renal function through suppression of renovascular oxidative stress and inflammation.

A new formulation of bardoxolone methyl has been developed, which is the same chemical entity but manufactured to contain an amorphous dispersion rather than a crystalline solid state. The new amorphous dispersion formulation of bardoxolone methyl has been shown to be more orally bioavailable in non-human primates. The purpose of this study is to determine the appropriate dose of the new bardoxolone methyl formulation to use in future clinical studies by determining the dose response relationship on eGFR.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Renal Insufficiency, Chronic

Intervention

Bardoxolone methyl (amorphous dispersion)

Location

Montgomery
Alabama
United States
36106

Status

Recruiting

Source

Reata Pharmaceuticals, Inc.

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:16:28-0400

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Medical and Biotech [MESH] Definitions

Conditions in which the KIDNEYS perform below the normal level in the ability to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of PROTEINURIA) and reduction in GLOMERULAR FILTRATION RATE. The most severe form is KIDNEY FAILURE. Renal function may deteriorate slowly (RENAL INSUFFICIENCY, CHRONIC) or precipitously (RENAL INSUFFICIENCY, ACUTE).

Conditions in which the KIDNEYS perform below the normal level for more than three months. Chronic kidney insufficiency is classified by five stages according to the decline in GLOMERULAR FILTRATION RATE and the degree of kidney damage (as measured by the level of PROTEINURIA). The most severe form is the end-stage renal disease (CHRONIC KIDNEY FAILURE). (Kidney Foundation: Kidney Disease Outcome Quality Initiative, 2002)

A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for EDEMA and chronic RENAL INSUFFICIENCY.

The end-stage of CHRONIC RENAL INSUFFICIENCY. It is characterized by the severe irreversible kidney damage (as measured by the level of PROTEINURIA) and the reduction in GLOMERULAR FILTRATION RATE to less than 15 ml per min (Kidney Foundation: Kidney Disease Outcome Quality Initiative, 2002). These patients generally require HEMODIALYSIS or KIDNEY TRANSPLANTATION.

A condition characterized by calcification of the renal tissue itself. It is usually seen in distal RENAL TUBULAR ACIDOSIS with calcium deposition in the DISTAL KIDNEY TUBULES and the surrounding interstitium. Nephrocalcinosis causes RENAL INSUFFICIENCY.

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Nephrology - kidney function
Nephrology is a specialty of medicine and pediatrics that concerns itself with the study of normal kidney function, kidney problems, the treatment of kidney problems and renal replacement therapy (dialysis and kidney transplantation). Systemic conditions...


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