Pulmonary Hypertension MedDRA version: 20.0 Level: HLT Classification code 10037401 Term: Pulmonary hypertensions System Organ Class: 100000004855
Conditions
Interventions
Product Name: Bardoxolone methyl
Product Code: RTA 402
Pharmaceutical Form: Capsule
INN or Proposed INN: bardoxolone methyl
Current Sponsor code: RTA 402
Other descriptive name: BARDOXOLONE METHYL
Co
Sponsors
Reata Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 (TL
Exclusion criteria
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 4 L/min or have peripheral capillary oxygen saturation (SpO2) levels 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the recommended dose range for further study of bardoxolone methyl. ;Secondary Objective: 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. ;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. ;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. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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. ;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. | — |
Countries
Germany, Spain, United Kingdom, United States
Contacts
Public ContactClinical team
Reata Pharmaceuticals, Inc.
Outcome results
None listed