ADPKD, Autosomal Dominant Polycystic Kidney
Conditions
Keywords
Bardoxolone Methyl, RTA 402, Autosomal Dominant Polycystic Kidney Disease, ADPKD
Brief summary
This international, multi-center, randomized, double-blind, placebo-controlled Phase 3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with ADPKD. Approximately 850 patients will be enrolled.
Detailed description
This international, multi-center, randomized, double-blind, placebo-controlled Phase 3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with ADPKD. Patients will be randomized 1:1 to either bardoxolone methyl or placebo. Patients 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. Dose de-escalation is permitted during the study if indicated clinically, and subsequent dose re-escalation is also permitted to meet the dosing objective of the highest tolerated dose. All patients in the study will follow the same visit and assessment schedule. Patients will continue to receive study drug or placebo through Week 100 and will not receive study drug or placebo during a 12-week off-treatment period between Weeks 100 and 112.
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
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients 12 ≤ age ≤ 70 upon study consent; * Diagnosis of ADPKD by modified Pei-Ravine criteria (for adults 18≤ age ≤70 years): 1) at least 3 cysts per kidney by sonography or at least 5 cysts by CT or MRI with family history of ADPKD or 2) at least 10 cysts per kidney by any radiologic method and exclusion of other cystic kidney diseases if without family history; * Screening eGFR (average of Screen A and Screen B eGFR values) ≥ 30 to≤ 90 mL/min/1.73 m2 (12 to 55 years) or ≥ 30 to ≤ 44 mL/min/1.73 m2 (56 to 70 years): 1\) Patients with either screening eGFR ≥ 60 to ≤ 90 mL/min/1.73 m2 or age 56 to 70 years, must have evidence of ADPKD progression (i.e., eGFR decline of ≥ 2.0 mL/min/1.73 m2 per year, based on historical eGFR data and medical monitor discretion); 2)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; * Systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg at Screen A or B visit after a period of rest.
Exclusion criteria
* History of administration of polycystic kidney disease-modifying agents (somatostatin analogues) within 2 months prior to the Screen A visit; * 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; * History of intracranial aneurysms; * 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 left-sided heart disease and/or clinically significant cardiac disease; * Systolic BP \< 90 mm Hg at Screen A visit after a period of rest; * BMI \< 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; * 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; * Concomitant use of tolvaptan is excluded. Patients previously treated with tolvaptan must have discontinued drug for at least 2 months prior to Screen A visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Off-treatment Period: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 108 | Baseline, Week 108 | Estimated Glomerular filtration rate (eGFR) is a measure of kidney function assessed through blood/serum. eGFR was measured in milliliters per minute per 1.73 meters square (mL/min/1.73 m\^2). Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function. Negative change from baseline in eGFR indicates worsened kidney function. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | From first dose of the study drug up to end of follow-up (up to Week 112) | AE:any untoward medical occurrence in a participant regardless of its causal relationship to study drug.AE can be any unfavorable & unintended sign,symptom/disease temporally associated with use of study drug,whether considered to be study-drug related/not.This includes clinically significant abnormal laboratory test result,any newly occurring events/previous conditions that have increased in severity/frequency since administration of study drug. SAE:any AE that at any dose results in death,life-threatening,requires hospitalization/prolongation of existing hospitalisation,substantial disruption of ability to conduct normal life functions,congenital anomaly or is an important medical event. AEs & SAEs that occurred during treatment and within 30 days after last dose were considered TE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Period: Change From Baseline in eGFR at Week 100 | Baseline, Week 100 | eGFR is a measure of kidney function assessed through blood/serum. eGFR was measured in mL/min/1.73 m\^2. Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function. A negative change from baseline in eGFR indicates worsened kidney function. |
Countries
Australia, Belgium, Czechia, France, Germany, Italy, Japan, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at the investigative sites in the United States, Australia, Belgium, Czech Republic, France, Germany, Italy, Japan, Spain, and United Kingdom beginning on 29 May 2019. The study completion date was 8 August 2023.
Pre-assignment details
A total of 667 participants were enrolled and randomized 1:1 to receive either bardoxolone methyl or placebo during the treatment period (up to Week 100) and continued to be assessed in the off-treatment period for 12 weeks (up to Week 112).
Participants by arm
| Arm | Count |
|---|---|
| Bardoxolone Methyl During the treatment period, the participants received bardoxolone methyl capsules, QD at a starting dose of 5 mg, followed by dose-escalation to 10 mg at Week 2, and to 20 mg at Week 4. If the eligibility UACR was \>300 mg/g, the dose was increased to 30 mg starting from Week 6 until Week 100. Participants continued to be assessed during the off-treatment period up to Week 112. | 334 |
| Placebo During the treatment period, participants received bardoxolone methyl matching-placebo capsules, orally, QD up to Week 100, with sham titration to maintain the blinding. Participants did not receive a bardoxolone methyl matching placebo capsule during the off-treatment period between Weeks 100 and 112. | 333 |
| Total | 667 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 13 | 6 |
| Overall Study | Reason not Specified | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 195 | 197 |
| Overall Study | Withdrawal by Subject | 19 | 17 |
Baseline characteristics
| Characteristic | Placebo | Total | Bardoxolone Methyl |
|---|---|---|---|
| Age, Continuous | 48.3 years STANDARD_DEVIATION 9.58 | 48.4 years STANDARD_DEVIATION 9.51 | 48.6 years STANDARD_DEVIATION 9.46 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 64 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 298 Participants | 603 Participants | 305 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 45 Participants | 79 Participants | 34 Participants |
| Race/Ethnicity, Customized Race Black or African American | 18 Participants | 41 Participants | 23 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 8 Participants | 14 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 261 Participants | 530 Participants | 269 Participants |
| Sex: Female, Male Female | 173 Participants | 361 Participants | 188 Participants |
| Sex: Female, Male Male | 160 Participants | 306 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 335 | 0 / 331 |
| other Total, other adverse events | 299 / 335 | 255 / 331 |
| serious Total, serious adverse events | 38 / 335 | 26 / 331 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
AE:any untoward medical occurrence in a participant regardless of its causal relationship to study drug.AE can be any unfavorable & unintended sign,symptom/disease temporally associated with use of study drug,whether considered to be study-drug related/not.This includes clinically significant abnormal laboratory test result,any newly occurring events/previous conditions that have increased in severity/frequency since administration of study drug. SAE:any AE that at any dose results in death,life-threatening,requires hospitalization/prolongation of existing hospitalisation,substantial disruption of ability to conduct normal life functions,congenital anomaly or is an important medical event. AEs & SAEs that occurred during treatment and within 30 days after last dose were considered TE.
Time frame: From first dose of the study drug up to end of follow-up (up to Week 112)
Population: Safety population included all enrolled participants who had received at least 1 dose of study drug. Participants who received 1 dose of bardoxolone methyl were classified in the bardoxolone methyl group. Participants who received at least 1 dose of placebo and no dose of bardoxolone methyl were classified in the placebo group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bardoxolone Methyl | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 314 Participants |
| Bardoxolone Methyl | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 38 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 296 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 26 Participants |
Primary
Off-treatment Period: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 108
Estimated Glomerular filtration rate (eGFR) is a measure of kidney function assessed through blood/serum. eGFR was measured in milliliters per minute per 1.73 meters square (mL/min/1.73 m\^2). Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function. Negative change from baseline in eGFR indicates worsened kidney function.
Time frame: Baseline, Week 108
Population: ITT population included all enrolled participants categorized by their randomized treatment group (whether or not they received study drug). 'Overall number of participants analyzed' indicates the number of participants with data available for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bardoxolone Methyl | Off-treatment Period: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 108 | -4.59 mL/min/1.73 m^2 | Standard Error 0.817 |
| Placebo | Off-treatment Period: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 108 | -5.56 mL/min/1.73 m^2 | Standard Error 0.769 |
Comparison: ANCOVA model with baseline eGFR as a covariate, and treatment group as fixed effects.p-value: =0.388695% CI: [-1.25, 3.19]ANCOVA
Secondary
Treatment Period: Change From Baseline in eGFR at Week 100
eGFR is a measure of kidney function assessed through blood/serum. eGFR was measured in mL/min/1.73 m\^2. Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function. A negative change from baseline in eGFR indicates worsened kidney function.
Time frame: Baseline, Week 100
Population: ITT included all enrolled participants categorized by their randomized treatment group (whether or not they received study drug). 'Overall number of participants analyzed' indicates the number of participants with an eGFR assessment at Week 100.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bardoxolone Methyl | Treatment Period: Change From Baseline in eGFR at Week 100 | 1.31 mL/min/1.73 m^2 | Standard Error 0.55 |
| Placebo | Treatment Period: Change From Baseline in eGFR at Week 100 | -6.64 mL/min/1.73 m^2 | Standard Error 0.549 |
Comparison: Mixed model repeated measure (MMRM) model used baseline eGFR as a covariate, and the following fixed factors: treatment group, time (Week 1 to 100, excluding Week 52), and the interaction between treatment and time. Within-participant errors are modeled using an unstructured covariance matrix.p-value: <0.000195% CI: [6.41, 9.47]MMRM