Chronic Kidney Diseases
Conditions
Keywords
Advanced CKD, Chronic Kidney Disease, Bardoxolone methyl, RTA 402, eGFR, Advanced Chronic Kidney Disease
Brief summary
This multi-center, randomized, double-blind, placebo-controlled, Phase 2 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with CKD due to multiple etiologies at risk of rapid disease progression. Approximately 70 patients will be enrolled and randomized 1:1 to either bardoxolone methyl or placebo. Patients with CKD secondary to varying etiologies will be enrolled from age 18-70 years with eGFR ≥ 20 to \< 60 mL/min/1.73 m2, and other risk factors for rapid progression of kidney disease. The maximum target dose will be determined by baseline proteinuria status. Patients with baseline urine albumin to creatinine ratio (UACR) ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline UACR \> 300 mg/g will be titrated to a maximum dose of 30 mg. Qualified patients will be randomized 1:1 to receive either bardoxolone methyl or placebo once daily (preferably in the morning) throughout a 12-week dosing period. Patients in the study will follow the same visit and assessment schedule. Patients will be assessed during treatment at Day 1, Weeks 1, 2, 4, 6, 8, and 12 and by telephone contact on Days 3, 10, 21, 31, 35, and 45. Date of last dose and the end-of-treatment assessments mark the end of the treatment period. Patients will not receive study drug during a 5-week off-treatment period between Weeks 12 and 17. The off-treatment (OT) period includes 5 visits requiring various assessments to characterize eGFR from the time of study drug discontinuation through Day 35 off-treatment.
Interventions
Bardoxolone methyl capsules dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status
DRUGPlacebo oral capsule
Capsule containing an inert placebo
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of CKD with screening eGFR (average of Screen A and Screen B eGFR values) ≥ 20 to \< 60 mL/min/1.73 m2 * Patient must meet at least one of the following criteria: 1. UACR ≥ 300 mg/g; OR 2. eGFR decline at a rate of ≥ 4 mL/min/1.73 m2 in prior year; OR 3. Hematuria defined as \> 5-10 red blood cells (RBCs) per high power field (HPF, manual method), or documented history of positive urinary dipstick for blood in prior year, or macroscopic hematuria in prior 3 years; * Systolic blood pressure ≤ 150 mmHg and diastolic blood pressure ≤ 90 mmHg at Screen A visit after a period of rest (≥ 5 minutes); * Treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or an angiotensin II receptor blocker (ARB) at the maximally tolerated labeled daily dose for at least 6 weeks prior to the Screen A visit and with no anticipated changes to dose(s) during study participation. * Able to swallow capsules -
Exclusion criteria
* Prior exposure to bardoxolone methyl; * CKD secondary to or associated with any of the following: 1. History of rapidly progressive glomerulonephritis (RPGN) 2. Glomerulonephritis requiring immunosuppression in the last 6 months prior to Screen A; * Concomitant use of tolvaptan. * Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to Day 1 or anticipated need for immunosuppression during the study; * Patients currently taking a sodium/glucose cotransporter-2 inhibitor (SGLT2i), requiring dose adjustments within 12 weeks prior to Day 1 or if dose is anticipated to change during study participation; * B-type natriuretic peptide (BNP) level \> 200 pg/mL at Screen A visit; * Uncontrolled diabetes (HbA1c \> 11.0%) at Screen A visit; * Serum albumin \< 3 g/dL at Screen A visit; * Kidney or any other solid organ transplant recipient or a planned transplant during the study; * Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during Screening; * History of clinically significant cardiac disease; * Systolic blood pressure \< 90 mmHg at Screen A visit after a period of rest; * Body mass index \< 18.5 kg/m2 at the Screen A visit; * History of malignancy within 5 years prior to Screen A visit, with the exception of localized skin or cervical carcinomas; * Coronavirus disease 2019 (COVID-19) diagnosis within 3 months prior to Screen A or have ever required COVID-19 related hospitalization; * Participation in other interventional clinical studies within 3 months (or if relevant 5 half-lives of that study medication, whichever is the longer) prior to Screen B; * Unwilling to practice acceptable methods of birth control; * 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 | Baseline through 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 Bardoxolone methyl capsules administered orally once daily for 12 weeks 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) | 39 |
| Placebo Placebo capsules administered orally once daily for 12 weeks, with sham titration to maintain the blind | 42 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Bardoxolone Methyl | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56.4 years STANDARD_DEVIATION 13.5 | 59.8 years STANDARD_DEVIATION 12.66 | 58.2 years STANDARD_DEVIATION 13.11 |
| Baseline estimated glomerular filtration rate (eGFR) | 36.563 mL/min/1.73 m^2 STANDARD_DEVIATION 9.8465 | 34.883 mL/min/1.73 m^2 STANDARD_DEVIATION 10.1765 | 35.692 mL/min/1.73 m^2 STANDARD_DEVIATION 9.9921 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 10 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 31 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 39 Participants | 71 Participants |
| Region of Enrollment United States | 39 participants | 42 participants | 81 participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Male | 23 Participants | 26 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 42 |
| other Total, other adverse events | 31 / 39 | 30 / 42 |
| serious Total, serious adverse events | 3 / 39 | 1 / 42 |
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: Baseline through 12 weeks after participant receives the first dose
Population: Intent-to-treat population (all enrolled patients whether or not they received the study drug)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bardoxolone Methyl | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 | 6.79 mL/min/1.73 m^2 | Standard Error 0.925 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 12 | -0.92 mL/min/1.73 m^2 | Standard Error 0.868 |
p-value: <0.000195% CI: [5.18, 10.24]Mixed Models Analysis