E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Kidney Disease Stage 4 |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10038359 |
E.1.2 | Term | Renal and urinary disorders |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 standard of care |
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E.2.2 | Secondary objectives of the trial |
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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) should have a documented medical contraindication (e.g., hyperkalemia, angioedema), which the investigator must discuss with the appropriate medical monitor;
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; |
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E.4 | Principal 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., known 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 395.5 mg/g;
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 contract agent that may induce nephropathy within 30 days prior to study randomisation 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 transfom into malignancy during the course of the study; |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to first event of the composite endpoint consisting of:
• ESRD (need for chronic dialysis or renal transplantation)
• Cardiovascular death
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Rate of change in eGFR over the duration of study
2. Tme to first hospitalization for heart failure or death due to heart failure
3. Tme to first event of the composite endpoint consisting of:
• Non-fatal myocardial infarction
• Non-fatal stroke
• Hospitalization for heart failure
• Cardiovascular death |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 125 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Israel |
Italy |
Mexico |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is defined as the last subjects last scheduled visit or the actual date of the follow-up contact, whichever is longer |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |