A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome
Overview
- Phase
- Phase 2
- Intervention
- Placebo Oral Capsule
- Conditions
- Alport Syndrome
- Sponsor
- Biogen
- Enrollment
- 187
- Locations
- 62
- Primary Endpoint
- Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 12 Weeks of Treatment (Phase 2)
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
This international, multi-center, Phase 2/3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with Alport syndrome. The Phase 2 portion of the trial will be open-label and enroll up to 30 patients. The Phase 3 portion of the trial will be double-blind, randomized, placebo-controlled and will enroll up to 180 patients.
Detailed Description
This international, multi-center, Phase 2/3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with Alport syndrome. The Phase 2 portion of the trial will be open-label and enroll up to 30 patients. The Phase 3 portion of the trial will be double-blind, randomized, placebo-controlled and will enroll up to 180 patients. Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study. Patients in the Phase 3 cohort will be randomized 1:1 to either bardoxolone methyl or placebo and randomization will be stratified by baseline albumin to creatinine ratio (ACR). Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration. All patients in the study will follow the same visit and assessment schedule. Following randomization on Day 1, patients will be scheduled to be assessed during treatment at Weeks 1, 2, 4, 6, 8, 12, 24, 36, 48, 52, 64, 76, 88, 100, and 104 and by telephone contact on Days 3, 10, 21, 31, 38, and 45. Patients will not receive study drug during a 4-week withdrawal period between Weeks 48 and 52. They will re-start treatment at Week 52 at the same dose they received at Week 48 and will continue study drug treatment through Week 100. Patients will also be scheduled to be assessed at an in person follow up visit at Week 104, four weeks after the end of treatment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female patients 12 ≤ age ≤ 60 upon study consent;
- •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;
- •Screening eGFR ≥ 30 and ≤ 90 mL/min/1.73 m
- •The two eGFR values collected at Screen A and Screen B visits used to determine eligibility must have a percent difference ≤ 25%;
- •Albumin to creatinine ratio (ACR) ≤ 3500 mg/g at Screen B visit;
- •If receiving an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB), the medications must remain the same for at least 6 weeks prior to the Screen A visit and during Screening. The dosage of ACE inhibitor and/or ARB must also be stable for 2 weeks prior to the Screen A visit and remain the same through Day 1 (i.e., no change in dosage or medication). Patients not taking an ACE inhibitor and/or ARB because of a medical contraindication must have discontinued treatment at least 8 weeks prior to the Screen A visit;
- •Adequate bone marrow reserve and organ function at the Screen A visit
- •Able to swallow capsules;
- •Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
Exclusion Criteria
- •Prior exposure to bardoxolone methyl;
- •Ongoing chronic hemodialysis or peritoneal dialysis therapy;
- •Renal transplant recipient;
- •B-type natriuretic peptide (BNP) level \> 200 pg/mL at Screen A visit;
- •Uncontrolled diabetes (HbA1c \> 11.0%) at Screen A visit;
- •Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during Screening;
- •Serum albumin \< 3 g/dL at Screen A visit;
- •History of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
- •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;
- •Systolic BP \< 90 mm Hg at Screen A visit after a period of rest;
Arms & Interventions
Phase 3 Placebo
Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration.
Intervention: Placebo Oral Capsule
Phase 2 Bardoxolone Methyl
Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study. Patients with baseline ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline ACR \> 300 mg/g will be titrated to a maximum dose of 30 mg. Adult patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if baseline ACR \>300 mg/g) unless contraindicated clinically and approved by the medical monitor. Patients under the age of 18 receiving bardoxolone methyl will start 5 mg every other day during the first week and begin once-daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing following the same aforementioned dose titration scheme based on baseline ACR at Weeks 2, 4, and 6.
Intervention: Bardoxolone Methyl
Phase 3 Bardoxolone Methyl
Patients with baseline ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline ACR \> 300 mg/g will be titrated to a maximum dose of 30 mg. Adult patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if baseline ACR \>300 mg/g) unless contraindicated clinically and approved by the medical monitor. Patients under the age of 18 receiving bardoxolone methyl will start 5 mg every other day during the first week and begin once-daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing following the same aforementioned dose titration scheme based on baseline ACR at Weeks 2, 4, and 6.
Intervention: Bardoxolone Methyl
Outcomes
Primary Outcomes
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 12 Weeks of Treatment (Phase 2)
Time Frame: Baseline through 12 weeks after participant receives the first dose in the Phase 2 study
To assess the change in eGFR from baseline to week 12 (Phase 2). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.
Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 3)
Time Frame: Baseline through 48 weeks after participant receives the first dose in the Phase 3 study
To assess the change in eGFR from baseline to week 48 (Phase 3). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.
Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 3)
Time Frame: Baseline through 100 weeks after participant receives the first dose in the Phase 3 study
To assess the change in eGFR from baseline to week 100 (Phase 3). Estimated Glomerular filtration rate (eGFR) indicates how well the kidneys are filtering waste from the blood. The higher the eGFR number, the better the kidney function.
Secondary Outcomes
- Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 2)(Baseline through 48 weeks after participant receives the first dose in the Phase 2 study)
- Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 2)(Baseline through 100 weeks after participant receives the first dose in the Phase 2 study)
- Change From Baseline in eGFR at Week 52 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)(Baseline through 52 weeks after participant receives the first dose in the Phase 3 study (or 4 weeks after last dose for patients who discontinued early in the first year))
- Change From Baseline in eGFR at Week 104 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)(Baseline through 104 weeks after participant receives the first dose in the Phase 3 study (or 4 weeks after last dose for patients who discontinued early in the second year))