| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| High blood pressure in the lungs. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10037401 |
| E.1.2 | Term | Pulmonary hypertensions |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 determine the recommended dose range for further study of bardoxolone methyl.
|
|
| E.2.2 | Secondary objectives of the trial |
o To assess the change from baseline in 6-minute walk distance (6MWD) in those patients
treated with bardoxolone methyl versus patients given placebo for 16 weeks.
o To assess the safety and tolerability of 16 weeks of treatment with bardoxolone methyl
versus 16 weeks of administration of placebo.
Exploratory:
o To determine the effect of bardoxolone methyl in pulmonary hypertension (PH) associated
with connective tissue disease, interstitial lung disease, and idiopathic etiologies, including
subsets of patients with World Health Organization (WHO) Group III or WHO Group V PH. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent;
2. MI > 18.5 kg/m2;
3.Symptomatic pulmonary hypertension WHO Functional Class II and III;
4.WHO Group I, III, or V PH according to the following criteria:
a.If diagnosed with WHO Group I PAH, then one of the following subtypes:
i.Idiopathic or heritable PAH;
ii.PAH associated with connective tissue disease;
iii.PAH associated with simple, congenital systemic-to-pulmonary shunts at
least 1 year following shunt repair;
iv.PAH associated with anorexigen or drug-induced toxicity;
v.PAH associated with human immunodeficiency virus (HIV); or
b.If WHO Group III PH, then primary diagnosis must be one of the following subtypes:
i.Connective tissue disease associated ILD (CTD-ILD);
ii.Idiopathic pulmonary fibrosis according to the American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines (Raghu 2011);
iii.Nonspecific interstitial pneumonia (NSIP) or the following idiopathic interstitial pneumonia subtypes, according to the American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines (Travis 2013):
1.Respiratory bronchiolitis-associated interstitial lung disease;
2.Desquamative interstitial pneumonia;
3.Cryptogenic organizing pneumonia;
4.Acute interstitial pneumonitis;
5.Idiopathic lymphoid interstitial pneumonia;
6.Idiopathic pleuroparenchymal fibroelastosis;
7.Unclassifiable idiopathic interstitial pneumonia, including patients who have not had a lung biopsy; or
c.If WHO Group V PH, then patient must be diagnosed with sarcoidosis;
5.Had a diagnostic right heart catheterization performed and documented prior to Day 1 that confirmed a diagnosis of PH according to all the following criteria:
a.If diagnosed with WHO Group I PAH, then:
i.Mean pulmonary artery pressure ≥ 25 mm Hg (at rest);
ii.Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg;
iii.Pulmonary vascular resistance > 240 dyn.sec/cm5 or > 3 mm Hg/Liter (L)/minute;
b.If not diagnosed with WHO Group I PAH, then:
i.Mean pulmonary artery pressure ≥ 21 mm Hg (at rest);
ii.Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg;
iii.Pulmonary vascular resistance > 160 dyn.sec/cm5
6.Has BNP level ≤ 400 pg/mL;
7.Has an average 6-minute walk distance ≥ 150 meters on two consecutive tests
performed on different days prior to randomization, with both tests measuring within 15% of one another;
8.Has been receiving one (1) or two (2) approved disease-specific PAH therapies. Cohort
3b WHO Group I PAH patients enrolled outside the United States must be receiving one (1) PAH therapy. PAH therapy must be at a stable dose for at least 90 days prior to Day 1;
9.If WHO Group III or WHO Group V, disease-specific therapy must be at a stable dose for 30 days;
10.Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following
therapies that may affect PH: vasodilators (including calcium channel blockers), digoxin,
L-arginine supplementation, or oxygen supplementation;
11.If receiving prednisone, has maintained a stable dose of ≤ 20 mg/day (or equivalent dose if other corticosteroid) for at least 30 days prior to Day 1. If receiving treatment for
CTD with any other drugs, doses should remain stable for the duration of the study;
12.Had PFTs within 90 days prior to Day 1 that meet the following criteria:
a.For WHO GroupI PAH patients with connective tissue disease, total lung capacity (TLC) ≥ 65% (predicted);
b.For all other WHO Group I PAH patients,
i.Forced expiratory volume in 1 second (FEV1 ) ≥ 65% (predicted); or
ii.FEV1/forced vital capacity ratio (FEV1/FVC) ≥ 65%;
c.For WHO GroupIII or V PH patients, total lung capacity (TLC) between 50-90% (predicted);
13.or WHO Group I patients, had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam CT or pulmonary angiogram prior to
Screening 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 disease;
14.Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable
formula;
15.Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
16.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;
17.For WHO GroupIII or V PH patients, the presence of ILD must be confirmed by a diagnostic high resolution computed tomography scan or biopsy performed and documented prior to Day1. |
|
| E.4 | Principal exclusion criteria |
1. Participation in other investigational clinical studies involving pharmaceutical 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 3 months
(90 days) prior to Day 1 or planned initiation during Part 1 of the study;
3. Stopped receiving any PH chronic therapy within 60 days prior to Day 1;
4. Requirement for receipt of intravenous inotropes within 30 days prior to Day 1;
5. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening after a
period of rest;
6. Has systolic BP < 90 mm Hg during Screening after a period of rest;
7. WHO Group III patients with pulmonary hypertension primarily associated with chronic
obstructive pulmonary disease, sleep-disordered breathing, and/or alveolar hypoventilation
disorders;
8. WHO Group III or V patients who at rest require supplemental oxygen at a rate > 4 L/min or have peripheral capillary oxygen saturation (SpO2) levels < 92%;
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 60 days of Day 1;
e. Any current or prior history of symptomatic coronary disease (prior myocardial
infarction, percutaneous coronary intervention, coronary artery bypass graft surgery,
or anginal chest pain);
10. Clinical instability within 8 weeks prior to Day 1, such as hospitalization due to respiratory or cardiac symptoms, acutely decompensated heart failure, syncope, or other events that in the investigator’s opinion would suggest the patient is an inappropriate candidate for the study;
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. Obstructive sleep apnea that is untreated;
14. For patients with HIV-associated PAH, any of the following:
a. Concomitant active opportunistic infections within 180 days prior to Screening;
b. Detectable viral load within 90 days prior to Screening;
c. Cluster designation 4 (CD4+) T-cell count < 200 mm3 within 90 days prior to Screening;
d. Changes in antiretroviral regimen within 90 days prior to Screening;
e. Using inhaled pentamidine;
15. 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);
16. Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at
Screening;
17. Hemoglobin (Hgb) concentration < 10.5 g/dL at Screening;
18. Diagnosis of Down syndrome;
19. History of malignancy within 5 years prior to screening, with the exception of localized skin or cervical carcinomas;
20. Active bacterial, fungal, or viral infection, incompatible with the study;
21. Known or suspected active drug or alcohol abuse, per Investigator judgment;
22. Major surgery within 30 days prior to Screening or planned to occur during the course of the study;
23. Unwilling to practice 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 due to language problems, poor mental development, or impaired cerebral function;
30. Use of intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues;
31. Prior exposure to bardoxolone methyl. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Change from baseline in 6-minute walk distance (6MWD) through Week 16.
Safety: Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, concomitant medications, and change from baseline in the following assessments: physical examinations, vital sign measurements, 24-hour ambulatory blood pressure monitoring (ABPM; Cohorts 1 and 2 only), 12-lead electrocardiograms (ECGs), clinical laboratory measurements, and weight. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoint will be evaluated on screening and days 1 (cohort 3 and 4 only), 28, 56, 84, 112.
Safety endpoints will be evaluated on every study visit, ECG on screening, day 112, end of treatment visit and F/U, clinical labs and weight will be done on screening and days 1, 7, 14, 28, 42 (cohort 3 and 4 only), 56, 84, 112, end of treatment, F/U visits and for cohort 3 and 4 also on weeks 18, 20, 22, 24, 32. Cohorts 1 and 2 also have 24-hour ambulatory blood pressure monitoring done on days screening, days 28 and 112.
|
|
| E.5.2 | Secondary end point(s) |
| Change from baseline in the following assessments: N-terminal pro-B-type natriuretic peptide (NT-Pro BNP); Borg dyspnea index; WHO/NYHA pulmonary arterial hypertension (PAH) functional class (FC); parameters collected during Doppler echocardiography (ECHO; Cohorts 1 and 2 only), optional cardiopulmonary exercise testing (CPET), optional magnetic resonance imaging (MRI), optional near-infrared spectroscopy (NIRS) muscle tests, and optional muscle biopsy; clinical worsening; autoantibody levels in connective tissue disease patients (Cohorts 3a and 4a); change in lung function parameters in patients with connective tissue disease and/or interstitial lung disease (Cohorts 3a and 4); number of digital ulcers in scleroderma patients (Cohorts 3a and 4a); and proportion of scleroderma patients with no new digital ulcers (Cohorts 3a and 4a); changes from baseline in sarcoidosis patients (Cohort 4d) for parameters collected during chest x-rays, PET/HRCT scans, inflammatory mediator panels, King’s Sarcoidosis Questionnaire, and Sarcoidosis Organ Assessment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| NT-Pro BNP on: screening(S),days(D)1,7,14,28,56,84,112, weeks(W)18,20,32,56, EOT,FU and for cohorts(C) 3,4 also:D42,W22,24:Borg dysp.index on:D1(C 3,4),28,56,84,112,W20,32,56,EOT,FU. WHO/NYHA PAH FC:S,D1,112,W32,EOT,FU and for C 3,4 on W16,20. DopplerECHO (C1,2) on:S,D1,28,112/EOT. Optional:- CPET on:S D1,28,112,EOT,FU and W18,20,32,56, for C1,2. –MRI and NIRS muscle tests on:D1,28,112/EOT. -muscle biopsy on: D1,112/EOT. Autoantib. levels in CTDP (C3a,4a) on: S, D112/EOT. Change in lung fun. parameters in CTDP and/or ILD (C3a,4):S,D1,28,56,84,112/EOT, FU. No digital ulcers in scleroderma pts (C3a,4a) on: S,D112/EOT. Proportion of scleroderma pts w/o new digital ulcers (C3a,4a) on: S,D112/EOT. Changes in sarcoidosis pts (C4d) for para. in chest x-rays, PET/HRCT,KSQ,SOA on: S,D112/EOT. |
|
| 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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
| 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 | 8 |
| 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 |
| Germany |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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