E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Alport syndrome is a rare genetic disorder characterized by progressive kidney disease and abnormalities of the ears and eyes. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001843 |
E.1.2 | Term | Alport's syndrome |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase 2: - To assess the change from baseline in estimated glomerular filtration rate (eGFR) in bardoxolone methyl-treated patients after 12 weeks of treatment. - To assess the safety of bardoxolone methyl after 12 weeks of treatment. Phase 3: - To assess the change from baseline in estimated glomerular filtration rate (eGFR) in bardoxolone methyl-treated patients relative to placebo after 48 weeks of treatment. - To assess the safety of bardoxolone methyl relative to placebo after 48 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
Phase 2: - To assess the safety and efficacy of bardoxolone methyl after 48 and 100 weeks of treatment. Exploratory - to assess the safety and efficacy of bardoxolone methyl at Week 52 following a 4-week drug treatment withdrawal period Phase 3: Key Secondary - To assess the change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo at Week 52 following a 4-week drug treatment withdrawal period. Secondary - To assess the change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo after 100 weeks of treatment. - To assess the safety of bardoxolone methyl relative to placebo after 100 weeks of treatment. - To assess the change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo at Week 104 following a 4-week drug treatment withdrawal period. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients 18 ≤ age ≤ 60 upon study consent; 2. Diagnosis of Alport syndrome by genetic testing (documented mutation in a gene associated with Alport syndrome, including COL4A3, COL4A4, or COL4A5) or histologic assessment using electron microscopy; 3. Screening eGFR (average of Screen A and Screen B eGFR values) ≥ 30 and ≤ 90 mL/min/1.73 m2. The two eGFR values collected at Screen A and Screen B visits used to determine eligibility must have a percent difference ≤ 25%; 4. Albumin to creatinine ratio (ACR) ≤ 3500 mg/g at Screen B visit; 5. Receiving an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB), at the maximally tolerated labeled daily dose (MTLDD), as defined in Section 9.1.7, for at least 6 weeks prior to the Screen A visit. The dosage of ACE inhibitor and/or ARB should remain the same throughout the remainder of the study (i.e., no change in dosage or medication), and any potential changes should be discussed with the medical monitor. Patients not taking an ACE inhibitor and/or ARB because of a medical contraindication may be eligible if they have discontinued treatment at least 8 weeks prior to the Screen A visit (these patients must be discussed with medical monitor prior to enrollment); 6. Adequate bone marrow reserve and organ function at the Screen A visit as follows: a. Hematologic: Absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L, hemoglobin (Hgb) ≥ 9 g/dL; b. Hepatic: Total bilirubin (TBL) ≤ 1.5X the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5X ULN; 7. Able to swallow capsules; 8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures; 9. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study prior to initiation of any patient-mandated procedures. |
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E.4 | Principal exclusion criteria |
1. Prior exposure to bardoxolone methyl; 2. Ongoing chronic hemodialysis or peritoneal dialysis therapy; 3. Renal transplant recipient; 4. B-type natriuretic peptide (BNP) level >200 pg/mL at Screen A visit; 5. Uncontrolled diabetes (HbA1c >11.0%) at Screen A visit; 6. Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during Screening; 7. Serum albumin < 3 g/dL at Screen A visit; 8. History of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: a. Clinically significant congenital or acquired valvular disease; b. Left ventricular ejection fraction < 40% (based on echocardiogram performed at Screen A visit or within 6 months prior to Day 1); c. Pericardial constriction (based on echocardiogram performed at Screen A visit or within 6 months prior to Day 1); d. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at Screen A visit or within 6 months prior to Day 1); e. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or angina); f. History of hospitalization for heart failure; g. Cardiac insufficiency, defined as New York Heart Association Class >2; h. History of atrial fibrillation; i. History of unstable arrhythmias; 9. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg at Screen A visit after a period of rest; 10. Systolic BP < 90 mm Hg at Screen A visit after a period of rest; 11. History of malignancy within 5 years prior to Screen A visit, with the exception of localized skin or cervical carcinomas; 12. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to randomization or anticipated need for immunosuppression during the study. 13. Untreated or uncontrolled active bacterial, fungal, or viral infection; 14. Participation in other investigational clinical studies within 30 days prior to Day 1; 15. Unwilling to practice acceptable methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during Screening, while taking study drug, and for at least 30 days after the last dose of study drug is ingested; 16. Women who are pregnant or breastfeeding; 17. Known hypersensitivity to any component of the study drug; 18. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at risk by trial enrollment; 19. Patient is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 2 Change from baseline in eGFR at Week 12.
Phase 3 Change from baseline in eGFR relative to placebo at Week 48. |
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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) |
Phase 3 Key Secondary Efficacy Endpoint The change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo at Week 52 following a 4-week drug treatment withdrawal period. Secondary Efficacy Endpoints - The change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo at Week 100. - The change from baseline in eGFR in bardoxolone methyl-treated patients relative to placebo at Week 104 following a 4-week drug treatment withdrawal period. Exploratory Efficacy Endpoints -The percentage of bardoxolone methyl versus placebo patients with an increase/decrease from baseline in eGRF of 30% or more after 48 weeks of treatment. -The percentage of bardoxolone methyl versus placebo patients with an increase/decrease from baseline in eGRF of 30% or more after 100 weeks of treatment. -The distribution of changes from baseline in eGFR in bardoxolone methyl versus placebo after 48 weeks and 100 weeks of treatment. -The Patient Global Impression of CHange (PGIC) scores in bardoxolone methyl-treated patients relative to placebo after 48 weeks and 100 weeks of treatment - The Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone methyl-treated patients relative to placebo after 48 weeks and 100 weeks of treatment. Safety Endpoints Frequency, intensity, and relationship to study drug of AEs and SAEs, and change from baseline in the following assessments: vital sign measurements, 12-lead ECGs, clinical laboratory measurements, and weight. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key Secondary Efficacy Endpoint Week 52
Secondary Efficacy Endpoints Week 100 - Week 104
Explorative Efficacy Endpoints Week 48 and Week 100
Safety Endpoints Duration of the study |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
Canada |
France |
Germany |
Spain |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |