Alport Syndrome
Conditions
Keywords
Alport Syndrome, Bardoxolone methyl, CDDO-ME, RTA 402
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.
Interventions
DRUGPlacebo Oral Capsule
Capsule containing an inert placebo
Bardoxolone methyl dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status.
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 60 Years
Healthy volunteers
No
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 m2. 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; * History of malignancy within 5 years prior to Screen A visit, with the exception of localized skin or cervical carcinomas; * Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to randomization or anticipated need for immunosuppression during the study; * Untreated or uncontrolled active bacterial, fungal, or viral infection; * Participation in other interventional clinical studies within 30 days prior to Day 1; * Unwilling to practice acceptable methods of birth control (both males who have partners of child-bearing 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; * Women who are pregnant or breastfeeding; * Known hypersensitivity to any component of the study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 12 Weeks of Treatment (Phase 2) | 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) | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at Week 48. 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 2) | Baseline through 100 weeks after participant receives the first dose in the Phase 2 study | To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at Week 100. 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 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) | To assess the change in eGFR from baseline to week 52 following a 4-week drug treatment withdrawal period (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 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) | To assess the change in eGFR from baseline to week 104 following a 4-week drug treatment withdrawal period (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. |
Countries
Australia, France, Germany, Japan, Puerto Rico, Spain, United Kingdom, United States
Participant flow
Recruitment details
CARDINAL Phase 2 and Phase 3 were conducted under the same protocol. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3.
Participants by arm
| Arm | Count |
|---|---|
| Phase 2 Bardoxolone Methyl Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 2 Study | 30 |
| Phase 3 Placebo Participants who received placebo (with sham titration) in the Cardinal Phase 3 Study | 80 |
| Phase 3 Bardoxolone Methyl Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 3 Study | 77 |
| Total | 187 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | ESKD Resulting in Kidney Transplant | 1 | 0 | 0 |
| Overall Study | Inability to continue due to increased serum creatinine | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 3 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase 3 Placebo | Phase 3 Bardoxolone Methyl | Total | Phase 2 Bardoxolone Methyl |
|---|---|---|---|---|
| Age, Continuous | 39.6 years STANDARD_DEVIATION 16.03 | 38.8 years STANDARD_DEVIATION 14.55 | 39.9 years STANDARD_DEVIATION 14.94 | 43.63 years STANDARD_DEVIATION 12.557 |
| Baseline estimated glomerular filtration rate (eGFR) | 62.63 mL/min/1.73 m^2 STANDARD_DEVIATION 18.234 | 62.74 mL/min/1.73 m^2 STANDARD_DEVIATION 17.719 | 61.32 mL/min/1.73 m^2 STANDARD_DEVIATION 19.227 | 54.17 mL/min/1.73 m^2 STANDARD_DEVIATION 24.075 |
| Baseline urine albumin-to-creatinine ratio (UACR) | 134.45 mg/g | 148.09 mg/g | 142.05 mg/g | 147.83 mg/g |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 9 Participants | 22 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 70 Participants | 68 Participants | 165 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 14 Participants | 27 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 6 Participants | 0 Participants |
| Race (NIH/OMB) White | 63 Participants | 55 Participants | 144 Participants | 26 Participants |
| Region of Enrollment Australia | 1 participants | 4 participants | 5 participants | 0 participants |
| Region of Enrollment France | 5 participants | 2 participants | 7 participants | 0 participants |
| Region of Enrollment Germany | 3 participants | 2 participants | 5 participants | 0 participants |
| Region of Enrollment Japan | 9 participants | 12 participants | 21 participants | 0 participants |
| Region of Enrollment Spain | 5 participants | 3 participants | 8 participants | 0 participants |
| Region of Enrollment United States | 57 participants | 54 participants | 141 participants | 30 participants |
| Sex: Female, Male Female | 48 Participants | 43 Participants | 109 Participants | 18 Participants |
| Sex: Female, Male Male | 32 Participants | 34 Participants | 78 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 80 | 0 / 77 |
| other Total, other adverse events | 29 / 30 | 76 / 80 | 75 / 77 |
| serious Total, serious adverse events | 6 / 30 | 15 / 80 | 8 / 77 |
Outcome results
Primary
Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 3)
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.
Time frame: Baseline through 100 weeks after participant receives the first dose in the Phase 3 study
Population: Intent-to-treat population (all randomized patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2 Bardoxolone Methyl | Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 3) | -8.45 mL/min/1.73 m^2 | Standard Error 1.478 |
| Phase 3 Bardoxolone Methyl | Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 3) | -0.81 mL/min/1.73 m^2 | Standard Error 1.556 |
p-value: 0.000595% CI: [3.41, 11.89]Mixed Models Analysis
Primary
Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 3)
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.
Time frame: Baseline through 48 weeks after participant receives the first dose in the Phase 3 study
Population: Intent-to-treat population (all randomized patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2 Bardoxolone Methyl | Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 3) | -4.77 mL/min/1.73 m^2 | Standard Error 1.248 |
| Phase 3 Bardoxolone Methyl | Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 3) | 4.71 mL/min/1.73 m^2 | Standard Error 1.307 |
p-value: <0.000197.5% CI: [5.38, 13.6]Mixed Models Analysis
Primary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 12 Weeks of Treatment (Phase 2)
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.
Time frame: Baseline through 12 weeks after participant receives the first dose in the Phase 2 study
Population: Intent-to-treat population (all enrolled patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2 Bardoxolone Methyl | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) After 12 Weeks of Treatment (Phase 2) | 13.37 mL/min/1.73 m^2 | Standard Error 1.4111 |
p-value: <0.000195% CI: [10.48, 16.27]Mixed Models Analysis
Secondary
Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 2)
To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at Week 100. 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.
Time frame: Baseline through 100 weeks after participant receives the first dose in the Phase 2 study
Population: Intent-to-treat population (all enrolled patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2 Bardoxolone Methyl | Change From Baseline in eGFR After 100 Weeks of Treatment (Phase 2) | 4.28 mL/min/1.73 m^2 | Standard Error 1.7484 |
p-value: 0.01595% CI: [0.84, 7.72]Mixed Models Analysis
Secondary
Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 2)
To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at Week 48. 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.
Time frame: Baseline through 48 weeks after participant receives the first dose in the Phase 2 study
Population: Intent-to-treat population (all enrolled patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2 Bardoxolone Methyl | Change From Baseline in eGFR After 48 Weeks of Treatment (Phase 2) | 7.4 mL/min/1.73 m^2 | Standard Error 1.9451 |
p-value: 0.000895% CI: [3.4, 11.39]Mixed Models Analysis
Secondary
Change From Baseline in eGFR at Week 104 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)
To assess the change in eGFR from baseline to week 104 following a 4-week drug treatment withdrawal period (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.
Time frame: 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)
Population: Intent-to-treat population (all randomized patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2 Bardoxolone Methyl | Change From Baseline in eGFR at Week 104 Following a 4-week Drug Treatment Withdrawal Period (Phase 3) | -8.84 mL/min/1.73 m^2 | Standard Error 1.353 |
| Phase 3 Bardoxolone Methyl | Change From Baseline in eGFR at Week 104 Following a 4-week Drug Treatment Withdrawal Period (Phase 3) | -4.52 mL/min/1.73 m^2 | Standard Error 1.395 |
p-value: 0.023295% CI: [0.58, 7.94]ANCOVA
Secondary
Change From Baseline in eGFR at Week 52 Following a 4-week Drug Treatment Withdrawal Period (Phase 3)
To assess the change in eGFR from baseline to week 52 following a 4-week drug treatment withdrawal period (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.
Time frame: 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)
Population: Intent-to-treat population (all randomized patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2 Bardoxolone Methyl | Change From Baseline in eGFR at Week 52 Following a 4-week Drug Treatment Withdrawal Period (Phase 3) | -6.08 mL/min/1.73 m^2 | Standard Error 1.243 |
| Phase 3 Bardoxolone Methyl | Change From Baseline in eGFR at Week 52 Following a 4-week Drug Treatment Withdrawal Period (Phase 3) | -0.99 mL/min/1.73 m^2 | Standard Error 1.253 |
p-value: 0.002197.5% CI: [1.37, 8.8]ANCOVA