| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Connective Tissue Disease-Associated Pulmonary Arterial Hypertension (WHO Group I CTD-PAH) |
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| E.1.1.1 | Medical condition in easily understood language |
| Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of bardoxolone methyl relative to placebo. |
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| E.2.2 | Secondary objectives of the trial |
| To assess the safety of bardoxolone methyl relative to placebo |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
a) Pulmonary Function Testing and Diffusion Capacity (DLco) assessments.
b) Additional PK testing.
The diffusion capacity (DLco) assessment will be performed on a subset of sites.
Similarly, although systemic exposure to bardoxolone methyl will be assessed in all patients, there will be a subgroup of patients that will participate on a more extensive PK testing.
Although the protocol refers to these as "substudies" separate sub-study protocols were not created to describe the procedures.
Please refer to study protocol section 9.10.12. for details of the Pulmonary Function Testing and Diffusion Capacity (DLco) testing and section 9.10.31. for details regarding the optional PK sub-study.
DLCO Substudy Objective: Evaluate the diffusion capacity for carbon monoxide in patients enrolled at sites that have the capability to perform this assessment and agree to participate in the substudy.
PK Substudy Objective: Collect additional serial blood samples to obtain more robust pharmacokinetic parameter estimates in patients that agree to participate in the substudy. |
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| E.3 | Principal inclusion criteria |
1. Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent;
2. BMI > 18.5 kg/m2;
3. Symptomatic pulmonary hypertension WHO/NYHA FC class II and III;
4. WHO Group I PAH associated with connective tissue disease;
5. Had a diagnostic right heart catheterization performed and documented within 36 months prior to Day 1 that confirmed a diagnosis of PAH according to all the following criteria:
a. Mean pulmonary artery pressure ≥ 25 mm Hg (at rest);
b. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg;
c. Pulmonary vascular resistance > 240 dyn•sec/cm5 or > 3 mm Hg/liter (L)/minute;
6. Has BNP level ≤ 400 pg/mL;
7. Had an average 6MWD ≥ 150 meters on two consecutive tests performed on different days prior to randomization, with with a percent difference ≤ 15% between tests;
8. Has been receiving no more than two (2) approved disease-specific PAH therapies. PAH therapy must have been at a stable dose for at least 90 days prior to Day 1. No additions or changes should be made to PAH therapies and doses should remain stable for the duration of the study;
9. Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following therapies that may affect walking distance, including but not limited to: vasodilators (including calcium channel blockers), digoxin, L-arginine supplementation, oxygen supplementation, diuretics, agents to treat neuropathic pain associated with peripheral neuropathy (such as pregabalin), and/or agents to treat anemia (such as supplemental iron, erythropoietin, or intravenous iron). If the patient receives intravenous iron therapy during Screening, the intravenous infusion must be performed at least 30 days prior to Day 1;
10. If receiving treatment for CTD with prednisone or any other drugs, the medications must remain the same for at least 90 days prior to Day 1. Doses for medications prescribed for the treatment of CTD must remain stable for at least 30 days prior to Day 1 and for the duration of the study;
11. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 with total lung capacity ≥ 65% (predicted);
12. Had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed tomography (CT), or pulmonary angiogram prior to Day 1 that shows no evidence of thromboembolic disease (i.e., should note normal or low probability for pulmonary embolism). If V/Q scan was abnormal (i.e., results other than normal or low probability), then a confirmatory CT or selective pulmonary angiography must exclude chronic thromboembolic pulmonary hypertension;
13. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 as measured by the central lab;
14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
15. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study prior to initiation of any patient-mandated procedures. |
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| E.4 | Principal exclusion criteria |
1. Participation in other investigational clinical studies involving interventional products being tested or used in a way different from the approved form or when used for an unapproved indication within 30 days prior to Day 1;
2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 90 days prior to Day 1 or planned initiation during the study;
3. Stopped receiving any PAH chronic therapy within 60 days prior to Day 1;
4. Received a dose of prednisone > 20 mg/day (or equivalent dose if other corticosteroid) within 30 days prior to Day 1;
5. Received intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues within 90 days prior to Day 1;
6. Received intravenous inotropes within 30 days prior to Day 1;
7. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period of rest;
8. Has systolic BP < 90 mm Hg during Screening after a period of rest;
9. Has a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: a. Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension; b. Pericardial constriction; c. Restrictive or congestive cardiomyopathy; d. Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 90 days of Day 1; e. Symptomatic coronary artery disease within the last 3 years;
10. Acutely decompensated heart failure within 30 days prior to Day 1, per investigator assessment;
11. Has more than two of the following clinical risk factors for left ventricular diastolic dysfunction: a. Age > 65 years; b. BMI ≥ 30 kg/m2; c. History of systemic hypertension; d. History of type 2 diabetes; e. History of atrial fibrillation;
12. History of atrial septostomy within 180 days prior to Day 1;
13. Uncontrolled obstructive sleep apnea;
14. Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to severe hepatic impairment (Child-Pugh Class A-C);
15. Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at Screening;
16. Hemoglobin (Hgb) concentration < 10.5 g/dL at Screening;
17. Diagnosis of Down syndrome;
18. History of malignancy within 5 years prior to Screening, with the exception of localized skin or cervical carcinomas;
19. Untreated or uncontrolled active bacterial, fungal, or viral infection;
20. Known or suspected active drug or alcohol abuse, per investigator judgment;
21. Use of inhaled nitric oxide within 7 days prior to Screening and Day 1 visits, excluding acute vasodilator testing during diagnostic cardiac catheterization;
22. Major surgery within 30 days prior to Day 1 or planned to occur during the course of the study;
23. Unwilling to practice acceptable methods of birth control (both males who have partners of childbearing 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;
24. Women who are pregnant or breastfeeding;
25. Any disability or impairment that would prohibit performance of the 6MWT;
26. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at risk by trial enrollment;
27. 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;
28. Known hypersensitivity to any component of the study drug;
29. Unable to communicate or cooperate with the investigator because of language problems, poor mental development, or impaired cerebral function.
30. Patient has active myositis;
31. Use of total parenteral nutrition within one year of the Day 1 study visit;
32. History of acute renal crisis within one year of the Day 1 study visit;
33. Patient has participated in investigational trials where bardoxolone methyl was administered.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in six-minute-walk distance (6MWD) relative to placebo at week 24. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Six minute walk test will be performed at screening, baseline, weeks 4, 8, 16, 24, End of treatment (if applicable) and Follow-up visit (week 28). Change from baseline will be calculated by comparing results at Day 1 and Week 24. |
|
| E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS
Time-to-first clinical improvement event consisting of a persistent change for any of the following:
• Improvement by at least one WHO functional class.
• Increase from baseline in 6 minute walk distance (6MWD) by at least 10%.
• Decrease from baseline in creatine kinase (as a surrogate biomarker for muscle injury and inflammation) by at least 10%.
OTHER
Exploratory Efficacy Endpoints:
Time-to-first clinical worsening event consisting of any of the following:
• Persistent worsening of WHO functional class due to worsening pulmonary hypertension
• Initiation of parenteral prostacyclin therapy due to worsening pulmonary hypertension
• Heart/lung transplantation or atrial septostomy
• All cause death
Safety Endpoints:
Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, and change from baseline in the following assessments: physical examinations, vital sign measurements, 12-lead electrocardiograms (ECGs), clinical laboratory measurements, and weight.
Additional Exploratory Endpoints
Change from baseline in the following assessments: parameters assessed with an optional wearable activity monitor; Borg dyspnea index at termination of 6MWT; WHO/NYHA functional class (FC); quality of life (SF-36); autoantibody levels; number of digital ulcers in scleroderma patients; and proportion of scleroderma patients with no new digital ulcers.
Pharmacokinetic Endpoints:
Systemic exposure to bardoxolone methyl will be assessed in all patients. Additional blood sampling will be performed in a subset of patients for the purpose of obtaining more robust pharmacokinetic (PK) parameter estimates (e.g., AUC, Cmax, Tmax) for bardoxolone methyl in the CTD-PAH population. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SECONDARY:
Whenever clinical improvement is observed (time to improvement constitute the endpoint).
Clinical exam and blood chemistry (including creatine kinase testing) will be performed at screening, baseline, weeks 1, 2, 4, 8, 16, 24, End of treatment (if applicable) and Follow-up visit (week 28).
6 minute walk and assesment of dyspnea and fatigue will be performed at screening, baseline, weeks 4, 8, 16, 24, End of treatment (if applicable) and Follow-up visit (week 28).
Other:
Exploratory and Ancillary Study Measures and Time Points for Exploratory Efficacy, Safety, additional exploratory and Pharmacokinetics are detailed in the study protocol. |
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| 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 | No |
| 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 | Yes |
| 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
| Information not present in EudraCT |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Czech Republic |
| Germany |
| Ireland |
| Israel |
| Japan |
| Mexico |
| Netherlands |
| Philippines |
| Spain |
| United Kingdom |
| United States |
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| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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