Autosomal Dominant Polycystic Kidney, CKD Associated With Type 1 Diabetes, Focal Segmental Glomerulosclerosis, IgA Nephropathy
Conditions
Keywords
IgA Nephropathy, CKD associated with type 1 diabetes, Focal segmental glomerulosclerosis, Autosomal dominant polycystic kidney disease, IgAN, FSGS, ADPKD, Bardoxolone methyl, CDDO-ME, RTA 402
Brief summary
This multi-center, open-label Phase 2 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with the following rare chronic kidney diseases (CKD): CKD associated with type 1 diabetes (T1D), IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), and autosomal dominant polycystic kidney disease (ADPKD). Patients will be enrolled in disease specific cohorts within the trial, and effectiveness of bardoxolone methyl in treating CKD will be assessed separately by cohort for each rare CKD. 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, and 12, and by telephone contact on Days 3, 10, 21, 31, 38, and 45. Patients will also be scheduled to be assessed at an in-person follow-up visit at Week 16, four weeks after the end of treatment.
Interventions
Bardoxolone 5 mg capsules
Sponsors
Biogen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients 18 ≤ age ≤ 65 upon study consent; * 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%; * Albumin to creatinine ratio (ACR) ≤ 2500 mg/g at Screen B visit; * If receiving an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB), patients should be prescribed the maximally tolerated labeled daily dose (MTLDD) for at least 6 weeks prior to the Screen A visit; * For patients enrolling in T1D Cohort: Diagnosis of type 1 diabetes confirmed by fasting C-peptide level. Diagnosis must have been made ≤ 35 years of age; and prescribed stable dose of insulin to maintain adequate glucose control for at least 6 months prior to the Screen A visit; * For patients enrolling in IgAN Cohort: Biopsy-confirmed IgA nephropathy; * For patients enrolling in FSGS Cohort: Biopsy-confirmed FSGS that is not due to known secondary causes including morbid obesity, decreased renal mass, viral infections, drug-induced nephrotoxicity, or prior history of vasculitis; * For patients enrolling in ADPKD Cohort: Genetic confirmation of PKD1 mutation; * Adequate bone marrow reserve and organ function at the Screen A visit as follows: Hematologic: Absolute neutrophil count \> 1.5 x 109/L, platelets \> 100 x 109/L, hemoglobin (Hgb) ≥ 9 g/dL; and Hepatic: Total bilirubin (TBL) ≤ 1.5 times the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 times ULN.
Exclusion criteria
* Kidney or any other solid organ transplant recipient or a planned transplant during the study; * B-type natriuretic peptide (BNP) level \> 200 pg/mL 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; * Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to randomization or anticipated need for immunosuppression during the study; * For patients enrolling in IgAN Cohort: Systemic manifestations of Henoch-Schonlein purpura within 1 year prior to Screen A visit; or have used belimumab, eculizumab, or rituximab within 6 months prior to Screen A visit; * For patients enrolling in ADPKD Cohort: Receiving tolvaptan; * Cerebrovascular event (stroke, transient ischemic attack) or aneurysm within 6 months prior to Screen A visit or during Screening; * History of clinically significant left-sided heart disease and/or clinically significant cardiac disease; * Uncontrolled systemic hypertension; * Systolic BP \< 90 mm Hg at Screen A visit after a period of rest; * History of malignancy within 2 years prior to Screen A visit, with the exception of localized skin or cervical carcinomas; * Uncontrolled diabetes (HbA1c \> 10.0%) at Screen A visit; * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 | 12 weeks after participant receives the first dose | To assess the change in eGFR from baseline to week 12. eGFR is a measure of kidney function assessed through blood/serum. Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bardoxolone Methyl - ADPKD Participants with autosomal polycystic kidney disease (ADPKD) who received bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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.
Bardoxolone methyl capsules: Bardoxolone 5 mg capsules | 31 |
| Bardoxolone Methyl - IgAN Participants with IgA nephropathy (IgAN) who received bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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.
Bardoxolone methyl capsules: Bardoxolone 5 mg capsules | 26 |
| Bardoxolone Methyl - T1D Participants with Type 1 diabetes (T1D) who received bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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.
Bardoxolone methyl capsules: Bardoxolone 5 mg capsules | 28 |
| Bardoxolone Methyl - FSGS Participants with focal segmental glomerulosclerosis (FSGS) who received bardoxolone methyl capsules at a starting dose of 5 mg and titrate 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.
Bardoxolone methyl capsules: Bardoxolone 5 mg capsules | 18 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Bardoxolone Methyl - IgAN | Bardoxolone Methyl - T1D | Bardoxolone Methyl - FSGS | Bardoxolone Methyl - ADPKD | Total |
|---|---|---|---|---|---|
| Age, Continuous | 48.5 years STANDARD_DEVIATION 9.53 | 49 years STANDARD_DEVIATION 9.91 | 48.6 years STANDARD_DEVIATION 12.79 | 47.4 years STANDARD_DEVIATION 9.49 | 48.3 years STANDARD_DEVIATION 10.12 |
| Baseline estimated glomerular filtration rate (eGFR) | 46.19 mL/min/1.73 m^2 STANDARD_DEVIATION 12.576 | 67.52 mL/min/1.73 m^2 STANDARD_DEVIATION 17.059 | 51.66 mL/min/1.73 m^2 STANDARD_DEVIATION 18.144 | 47.69 mL/min/1.73 m^2 STANDARD_DEVIATION 13.63 | 53.39 mL/min/1.73 m^2 STANDARD_DEVIATION 17.427 |
| Baseline urine albumin-to-creatinine ratio (UACR) | 104.03 mg/g | 30.88 mg/g | 184.30 mg/g | 44.40 mg/g | 63.95 mg/g |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 26 Participants | 17 Participants | 28 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 5 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 27 Participants | 11 Participants | 25 Participants | 85 Participants |
| Sex: Female, Male Female | 11 Participants | 21 Participants | 10 Participants | 21 Participants | 63 Participants |
| Sex: Female, Male Male | 15 Participants | 7 Participants | 8 Participants | 10 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 26 | 0 / 28 | 0 / 18 |
| other Total, other adverse events | 30 / 31 | 22 / 26 | 25 / 28 | 16 / 18 |
| serious Total, serious adverse events | 2 / 31 | 0 / 26 | 0 / 28 | 1 / 18 |
Outcome results
Primary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12
To assess the change in eGFR from baseline to week 12. eGFR is a measure of kidney function assessed through blood/serum. Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function.
Time frame: 12 weeks after participant receives the first dose
Population: Intent-to-treat population (all enrolled patients)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bardoxolone Methyl - ADPKD | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 | 9.31 mL/min/1.73 m^2 | Standard Error 1.3743 |
| Bardoxolone Methyl - IgAN | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 | 8.00 mL/min/1.73 m^2 | Standard Error 1.57 |
| Bardoxolone Methyl - T1D | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 | 5.46 mL/min/1.73 m^2 | Standard Error 2.2792 |
| Bardoxolone Methyl - FSGS | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 | 7.83 mL/min/1.73 m^2 | Standard Error 2.216 |
p-value: <0.000195% CI: [6.5, 12.13]Mixed Models Analysis
p-value: <0.000195% CI: [4.75, 11.25]Mixed Models Analysis
p-value: 0.024795% CI: [0.76, 10.16]Mixed Models Analysis
p-value: 0.00395% CI: [3.11, 12.55]Mixed Models Analysis