| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Autosomal dominant polycystic kidney disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Autosomal dominant polycystic kidney disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036046 |
| E.1.2 | Term | Polycystic kidney, autosomal dominant |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess the off-treatment change from baseline in estimated glomerular filtration rate (eGFR) at Week 52 or following a 4-week drug treatment withdrawal period in the first year of treatment.
- To assess safety and tolerability of bardoxolone methyl.
|
|
| E.2.2 | Secondary objectives of the trial |
- To assess the off-treatment change from baseline in eGFR at Week 104 or following a 4-week drug treatment withdrawal period in the second year of treatment.
- To assess the change from baseline in eGFR after 48 weeks of treatment.
- To assess the change from baseline in eGFR after 100 weeks of treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients 18 ≤ age ≤ 70 upon study consent;
2. Diagnosis of ADPKD by modified Pei-Ravine criteria: 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 10cysts per kidney by any radiologic method and exclusion of other cystic kidney diseases if without family history;
3. Screening eGFR (average of Screen A and Screen B eGFR values) ≥ 30 to ≤ 90 mL/min/1.73 m2 (18 to 55 years) or ≥ 30 to ≤ 44 mL/min/1.73 m2 (56 to 70 years):
a. 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);
b. The two eGFR values collected at Screen A and Screen B visits used to determine eligibility must have a percent difference ≤ 25%;
4. Albumin to creatinine ratio (ACR) ≤ 2500 mg/g at Screen B visit;
5. Systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg at Screen A visit after a period of rest. Patients receiving an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB) must be on a stable dose for at least 6 weeks prior to the Screen A visit;
6. Adequate bone marrow reserve and organ function at the Screen A visit as follows:
a. Hematologic: Absolute neutrophil count > 1.5 x 10^9/L, platelets > 100 x 10^9/L, hemoglobin (Hgb) ≥ 9 g/dL;
b. Hepatic: Total bilirubin (TBL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN);
7. Able to swallow capsules;
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
9. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study prior to initiation of any protocol-mandated procedures. |
|
| E.4 | Principal exclusion criteria |
1. Prior exposure to bardoxolone methyl;
2. Concomitant use of tolvaptan is excluded. Patients previously treated with tolvaptan must have discontinued drug for at least 3 months prior to Screen A visit. Initiation of concomitant tolvaptan use during the study is not permitted;
3. History of administration of polycystic kidney disease-modifying agents (somatostatin analogues) within 3 months prior to the Screen A visit.
4. B-type natriuretic peptide (BNP) level > 200 pg/mL at Screen A visit;
5. Uncontrolled diabetes (HbA1c > 11.0%) at Screen A visit;
6. Serum albumin < 3 g/dL at Screen A visit;
7. History of intracranial aneurysms;
8. Kidney or any other solid organ transplant recipient or a planned transplant during the study;
9. Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during Screening;
10. History of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
a. Clinically significant congenital or acquired valvular disease;
b. Left ventricular ejection fraction < 40% (based on echocardiogram performed at Screen A visit or within 6 months prior to Day 1);
c. Pericardial constriction (based on echocardiogram performed at Screen A visit or within 6 months prior to Day 1);
d. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at Screen A visit or within 6 months prior to Day 1);
e. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or angina);
f. History of hospitalization for heart failure;
g. Cardiac insufficiency, defined as New York Heart Association Class III or IV;
h. History of untreated atrial fibrillation;
i. History of unstable arrhythmias;
11. Systolic BP < 90 mm Hg at Screen A visit after a period of rest;
12. BMI < 18.5 kg/m2 at the Screen A visit;
13. History of malignancy within 5 years prior to Screen A visit, with the exception of localized skin or cervical carcinomas;
14. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to randomization or anticipated need for immunosuppression during the study;
15. Untreated or uncontrolled active bacterial, fungal, or viral infection;
16. Participation in other interventional clinical studies within 30 days prior to Day 1;
17. 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;
18. Women who are pregnant or breastfeeding;
19. Known hypersensitivity to any component of the study drug;
20. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at risk by trial enrollment;
21. Patient is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Off-treatment change from baseline in eGFR at Week 52 (or following a 4-week drug treatment withdrawal period in the first year of treatment)
Safety and Tolerability:
Frequency, intensity, and relationship to study drug of AEs and SAEs, and change from baseline in the following assessments: vital sign measurements, 12-lead ECGs, clinical laboratory measurements, and weight. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy endpoint will be analyzed after all patients have completed their Week 52 visit.
The primary safety endpoint will be assessed throughout the clinical trial. |
|
| E.5.2 | Secondary end point(s) |
- Off-treatment change from baseline in eGFR at Week 104 (or following a 4-week drug treatment withdrawal period in the second year of treatment)
- Change from baseline in eGFR at Week 48.
- Change from baseline in eGFR at Week 100. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be scheduled to be assessed during treatment at Weeks 1, 2, 4, 6, 8, 12, 24, 36, 48, 52(A), 52(B), 64, 76, 88, 100, 104(A) and 104(B).
The off-treatment change from baseline in eGFR at Week 104 (or following a 4-week drug treatment withdrawal period in the second will be analyzed after all patients have completed their Week 104 visit. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Czech Republic |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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