LARIAT

Principal Investigator: John  Ryan
Keywords: pulmonary hypertension Department: Cardiovascular Medicine
IRB Number: 00088526 Co Investigator: John  Ryan
Specialty: Cardiology
Sub Specialties: General Cardiology
Recruitment Status: Completed

Contact Information

John Kirk
john.kirk@hsc.utah.edu
801-585-2944

Brief Summary

Objectives:
 
Primary:
  • To determine the recommended dose range for further study of bardoxolone methyl.
Secondary:
  • 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.
  • 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.

Detailed Description

Objectives: For patients enrolled in this study, the objectives are as follows: Primary: o To determine the recommended dose range for further study of bardoxolone methyl. Secondary: 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 methylversus 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.

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 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 (IPF) according to the American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines;
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:
     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,
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 (6MWDs) ≥ 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 no more than two (2) approved disease-specific PAH therapies.  Cohort 3b WHO Group I PAH patients enrolled outside the United States must be receiving zero (0) or one (1) PAH therapies. 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 connective tissue disease (CTD) with any other drugs, doses should remain stable for the duration of the study;
12. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 that meet the following criteria:
           a. For WHO Group I PAH patients with connective tissue disease, total lung capacity ≥ 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 Group III or V PH patients, total lung capacity (TLC) between 50 - 90%; and predicted; 
13. For WHO Group I patients, had a ventilation-perfusion (V/Q) lung scan or spiral/helical/electron beam computed tomography (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 Group III or V PH patients, the presence of ILD must be confirmed by a diagnostic high resolution computed tomography (HRCT) scan or biopsy performed and documented prior to Day 1.

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 of 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.