The Evaluation of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes

Conditions: Chronic Kidney Disease Stage 4
MedDRA version: 14.1Level: SOCClassification code 10038359Term: Renal and urinary disordersSystem Organ Class: 10038359 - Renal and urinary disorders
Therapeutic area: Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

Registration Number: EUCTR2010-022297-14-SE

Lead Sponsor: Reata Pharmaceuticals, Inc

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 2000

Inclusion Criteria

1. Screening eGFR = 15.0 and < 30.0 mL/min/1.73 m2; screening eGFR will be the average of the eGFR values collected during screening;
2. A history of type 2 diabetes; diagnosis should have been made at = 30 years of age (if diabetes developed at a younger age, C-peptide level must confirm type 2 diabetes);
3. Male or female patients at least 18 years of age;
4.Treatment with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB) for at least 6 weeks prior to Screening Visit A and during screening. The dosage of ACE inhibitor and/or ARB must be stable for 2 weeks prior to Screening Visit A and during screening (i.e., no change in dosage or medication). Patients not taking an ACE inhibitor and/or ARB, or taking an ACE inhibitor and/or ARB at levels below the goal dose set by K/DOQI guidelines (see Appendix A) must have a documented medical contraindication (e.g., hyperkalemia, hypotension), which the investigator must provide and discuss with a medical monitor prior to Screening Visit B. Patients not taking an ACE inhibitor and/or ARB because of a medical contraindication must have discontinued treatment at least 8 weeks prior to Screening Visit A;
5. Mean systolic blood pressure (SBP) must be = 160 mmHg and = 105 mmHg and mean diastolic blood pressure (DBP) must be < 90 mmHg during screening; both mean SBP and mean DBP (determined as the average of three readings) must be within the described range at two separate time points, which must occur at least 4 days apart during the screening period(blood pressure may be re-evaluated once as part of an unscheduled visit);
6. Serum magnesium level must be greater than or equal to 1.3 mEq/L (0.65 mmol/L) at screen B or during a subsequent unscheduled visit during screening (serum magnesium level may be reevaluated
once during an unscheduled visit);
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1200
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 800

Exclusion Criteria

1. Type 1 diabetes mellitus (juvenile onset). If a history of diabetic ketoacidosis exists, a C-peptide level must confirm type 2 diabetes;
2.Known non-diabetic renal disease (e.g., polycystic kidney disease, focal segmental glomerulosclerosis) [nephrosclerosis superimposed on diabetic kidney disease is acceptable];
3. Ongoing clinical investigation with evidence (e.g., unexplained hematuria or red blood cell or white blood cell casts) suggesting non-diabetic renal disease other than nephrosclerosis;
4. History of a renal transplant or a planned transplant from a living donor during the study;
5. Albumin to creatinine ratio (ACR) at Screening Visit B greater than 3500 mg/g (395.5 mg/mmol);
6. Hemoglobin A1c level > 11.0% (97 mmol/mol) during screening;
7. Acute dialysis or acute kidney injury within 12 weeks prior to screening or during screening;
8. Clinical signs and/or symptoms of uremia and expected need for renal replacement therapy within 12 weeks following randomization, as assessed by the investigator;
9. Recently active cardiovascular disease defined as:
• Unstable angina pectoris within 12 weeks before study randomization;
• Myocardial infarction, coronary artery bypass graft surgery, or percutaneous transluminal coronary angioplasty/stent within 12 weeks before study randomization;
• Cerebrovascular accident, including transient ischemic attack within 12 weeks before study randomization;
• Current diagnosis of Class III or IV NYHA congestive heart failure (Appendix B);
10. Clinical diagnosis of severe obstructive valvular heart disease or severe obstructive hypertrophic cardiomyopathy;
11. Atrioventricular block, 2o or 3o, not successfully treated with a pacemaker;
12.Administration of a contrast agent that may induce nephropathy within 30 days prior to study randomization or planned during the study;
13. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to randomization or anticipated need for immunosuppression during the study;
14. Total bilirubin, aspartate transaminase (AST), or alanine transaminase (ALT) level greater than the upper limit of normal (ULN) or alkaline phosphatase level greater than two times the ULN on ANY screening laboratory test result;
15. Female patients who are pregnant, intend to become pregnant during the study, or are nursing;
16. BMI < 18.5 kg/m2;
17. Known hypersensitivity to any component of the study drug;
18. Current history of drug or alcohol abuse, as assessed by the investigator;
19. Clinically significant infection requiring intravenous administration of antibiotics or hospitalization within 6 weeks prior to Screening Visit A or during screening;
20.Hepatitis B surface antigen positive;
21.Diagnosis or treatment of a malignancy in the past 5 years, excluding non-melanoma skin cancer and carcinoma in situ of the cervix or a condition highly likely to transform into a malignancy during the course of the study;

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the efficacy of bardoxolone methyl relative to placebo in delaying progression to end-stage renal disease (ESRD) and cardiovascular death in patients with Stage 4 CKD and type 2 diabetes receiving the standard of care;Secondary Objective: To assess the safety of bardoxolone methyl relative to placebo in patients with Stage 4 CKD and type 2 diabetes receiving the standard of care;Primary end point(s): Time to first event of the composite endpoint consisting of:<br>• ESRD<br>• Cardiovascular death<br>;Timepoint(s) of evaluation of this end point: Throughout the trial

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Rate of change in eGFR over the duration of study<br>2. Time to first hospitalization for heart failure or death due to heart failure<br>3. Time to first event of the composite endpoint consisting of: <br>• Non-fatal myocardial infarction<br>• Non-fatal stroke<br>• Hospitalization for heart failure<br>• Cardiovascular death;Timepoint(s) of evaluation of this end point: Throughout the trial

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