Acute Interstitial Pneumonitis, Cryptogenic Organizing Pneumonia, Desquamative Interstitial Pneumonia, Idiopathic Interstitial Pneumonia, Idiopathic Lymphoid Interstitial Pneumonia, Idiopathic Pleuroparenchymal Fibroelastosis, Idiopathic Pulmonary Fibrosis, Interstitial Lung Disease, Pulmonary Arterial Hypertension, Pulmonary Hypertension, Respiratory Bronchiolitis Associated Interstitial Lung Disease, Sarcoidosis
Conditions
Keywords
Pulmonary Arterial Hypertension, PAH, Bardoxolone methyl, 6-minute walk distance, CDDO-me, RTA 402, Pulmonary Hypertension, Interstitial Lung Disease, Idiopathic Interstitial Pneumonia, Idiopathic Pulmonary Fibrosis, Sarcoidosis, Respiratory Bronchiolitis Associated ILD, Desquamative Interstitial Pneumonia, Cryptogenic Organizing Pneumonia, Acute Interstitial Pneumonitis, Idiopathic Lymphoid Interstitial Pneumonia, Idiopathic Pleuroparenchymal Fibroelastosis
Brief summary
This study assesses the safety and efficacy of bardoxolone methyl relative to placebo in patients with pulmonary hypertension to determine the recommended dose range, evaluate the change from baseline in 6-minute walk distance (6MWD) and determine the effect of Bardoxolone methyl in pulmonary hypertension associated with connective tissue disease, interstitial lung disease, and idiopathic etiologies, including subsets of patients with WHO Group III or WHO Group V PH following 16 weeks of study participation.
Detailed description
The molecular and pharmacological effects of bardoxolone methyl are broad through its induction of Nrf2 and suppression of NF-κB. Bardoxolone methyl may therefore address multiple facets of the pathophysiology of PH because it suppresses activation of proinflammatory mediators, enhances endothelial NO bioavailability, improves metabolic dysfunction, suppresses vascular proliferation, and prevents maladaptive remodeling. Furthermore, while existing therapies primarily target only smooth muscle cells, bardoxolone methyl targets multiple cell types relevant to PH, including endothelial cells, smooth muscle cells, and macrophages. This is a two-part study. Part 1: Part 1 of the study will include a dose-ranging phase and a dose-titration phase. Part 2 (extension period): All patients from Part 1 who complete the 16-week treatment period as planned will be eligible to continue directly into the extension period to evaluate the intermediate and long-term safety and efficacy of bardoxolone methyl.
Interventions
DRUGPlacebo
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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 class II and III; 4. WHO Group I, III, or V PH according to the following criteria: 1. If diagnosed with WHO Group I PAH, then on of the following subtypes: * Idiopathic or heritable PAH; * PAH associated with connective tissue disease; * PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair; * PAH associated with anorexigen or drug-induced toxicity; * PAH associated with human immunodeficiency virus (HIV); or 2. If WHO Group III PH then primary diagnosis must be one of the following subtypes: * Connective tissue disease associated ILD (CTD-ILD); * Idiopathic pulmonary fibrosis (IPF); * Nonspecific interstitial pneumonia (NSIP); or 3. If WHO Group V PH then patient must be diagnosed with sarcoidosis; 5. Had a diagnostic right heart catheterization performed and documented within 36 months prior to Day 1 that confirmed a diagnosis of PH 6. If WHO Group I, has been receiving no more than three (3) FDA-approved disease-specific PAH therapies except for intravenous (iv) prostacyclin/prostacyclin analogues. PAH therapy must be at a stable dose for at least 90 days prior to Day 1; 7. 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;
Exclusion criteria
1. Participation in other interventional 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 or V patients who at rest require supplemental oxygen at a rate of \>4 L/min and have peripheral capillary oxygen saturation levels \<92%; 8. 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: 1. Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension; 2. Pericardial constriction; 3. Restrictive or congestive cardiomyopathy; 4. Left ventricular ejection fraction \< 40% per echocardiogram (ECHO) within 60 days of Day 1; 5. Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or anginal chest pain); 9. Acutely decompensated heart failure within 30 days prior to Day 1, as per Investigator assessment; 10. History of atrial septostomy within 180 days prior to Day 1; 11. History of obstructive sleep apnea that is untreated; 12. 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); 13. Serum aminotransferase (ALT or AST) levels \> the upper limit of normal (ULN) at Screening; 14. For patients with HIV-associated PAH, any of the following: 1. Concomitant active opportunistic infections within 180 days prior to Screening; 2. Detectable viral load within 90 days prior to Screening; 3. Cluster designation (CD+) T-cell count \< 200 mm3 within 90 days prior to Screening; 4. Changes in antiretroviral regimen within 90 days prior to Screening; 5. Using inhaled pentamidine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Baseline through Week 16 | Overall treatment effect in exercise capacity, as measured by the total distance walked in 6 minutes (6MWD) mean change from baseline though Week 16. A lower 6MWD reflects greater severity thus, a positive change from baseline suggests an improvement. |
Countries
Germany, United States
Participant flow
Pre-assignment details
Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16). Part 2: Open-label extension period (Week 16 onwards). Part 2 is the extension period and patients were to stay until study drug became available through extended access program \[Study 402-C-1602\]. Each participant in Part 2 was also in Part 1.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label Part 1: Participants were randomized to receive bardoxolone methyl 2.5 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 2.5 mg once-daily from Week 16 onwards. | 6 |
| Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label Part 1: Participants were randomized to receive bardoxolone methyl 5 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 5 mg once-daily from Week 16 onwards. | 12 |
| Part 1: Dose-Ranging Bardoxolone Methly 10 mg/Part 2: Open-Label Part 1: Participants were randomized to receive bardoxolone methyl 10 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 wer eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 10 mg once-daily from Week 16 onwards. | 11 |
| Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label Part 1: Participants were randomized to receive bardoxolone methyl 20 mg once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and continued to receive the same bardoxolone methyl 20 mg once-daily from Week 16 onwards. | 12 |
| Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 2.5 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 2.5 mg once-daily from Week 16 and onwards. | 2 |
| Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 5 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 5 mg once-daily from Week 16 and onwards. | 4 |
| Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 10 mg once-daily from Week 16 and onwards. | 3 |
| Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 20 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received bardoxolone methyl 20 mg once-daily from Week 16 and onwards. | 4 |
| Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Participants were randomized to receive bardoxolone methyl 10 mg capsules. Participants initially started with bardoxolone methyl 5 mg once-daily from Day 1 and titrated to bardoxolone methyl 10 mg once-daily starting at Week 4 up to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and received the same bardoxolone methyl dose once-daily from Week 16 and onwards. | 74 |
| Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg Part 1: Participants were randomized to receive bardoxolone methyl matching placebo 10 mg capsules once-daily from Day 1 to Week 16. Part 2: Participants who completed treatment in Part 1 were eligible to continue to the extension Part 2 and initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from Week 20 and onwards. | 38 |
| Total | 166 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1: Day 1 Through Week 16 | Adverse Event | 0 | 0 | 3 | 2 | 0 | 1 | 0 | 1 | 3 | 1 |
| Part 1: Day 1 Through Week 16 | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 1: Day 1 Through Week 16 | Progressive Disease | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1: Day 1 Through Week 16 | Protocol Violation | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Part 1: Day 1 Through Week 16 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 4 |
| Part 2: Week 16 Onwards | Adverse Event | 0 | 2 | 1 | 1 | 1 | 0 | 1 | 0 | 6 | 3 |
| Part 2: Week 16 Onwards | Progressive Disease | 0 | 2 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 2 |
| Part 2: Week 16 Onwards | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 2: Week 16 Onwards | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Total | Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg | Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg | Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg | Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg | Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg | Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg | Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label | Part 1: Dose-Ranging Bardoxolone Methly 10 mg/Part 2: Open-Label | Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label | Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 6-Minute Walk Test (6MWT) | 396.2 meters STANDARD_DEVIATION 88.32 | 395.2 meters STANDARD_DEVIATION 84.99 | 380.8 meters STANDARD_DEVIATION 96.46 | 449.3 meters STANDARD_DEVIATION 84.64 | 367 meters STANDARD_DEVIATION 46.02 | 418.9 meters STANDARD_DEVIATION 71.18 | 358 meters STANDARD_DEVIATION 96.17 | 454.5 meters STANDARD_DEVIATION 93.01 | 385.7 meters STANDARD_DEVIATION 55.45 | 425.8 meters STANDARD_DEVIATION 81 | 412 meters STANDARD_DEVIATION 19.7 |
| Age, Continuous Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) | 54.3 years STANDARD_DEVIATION 12.8 | 55.6 years STANDARD_DEVIATION 12.7 | 56.4 years STANDARD_DEVIATION 12.41 | 51.3 years STANDARD_DEVIATION 8.54 | 54.7 years STANDARD_DEVIATION 0.58 | 39.5 years STANDARD_DEVIATION 11.27 | 53 years STANDARD_DEVIATION 15.56 | 49.6 years STANDARD_DEVIATION 13.06 | 50.6 years STANDARD_DEVIATION 16.33 | 52.8 years STANDARD_DEVIATION 14.84 | 52.5 years STANDARD_DEVIATION 7.15 |
| Age, Continuous Part 2: Open-label extension period (Week 16 and onwards) | 55.5 years STANDARD_DEVIATION 12.38 | 56.7 years STANDARD_DEVIATION 12.44 | 56.5 years STANDARD_DEVIATION 12.23 | 47.7 years STANDARD_DEVIATION 5.69 | 54.7 years STANDARD_DEVIATION 0.58 | 40 years STANDARD_DEVIATION 13.75 | 64 years STANDARD_DEVIATION 0 | 51 years STANDARD_DEVIATION 14.76 | 59.2 years STANDARD_DEVIATION 10.26 | 53.4 years STANDARD_DEVIATION 15.4 | 54.6 years STANDARD_DEVIATION 5.55 |
| Ethnicity (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Hispanic or Latino | 26 Participants | 7 Participants | 12 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Not Hispanic or Latino | 140 Participants | 31 Participants | 62 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 11 Participants | 11 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) Hispanic or Latino | 21 Participants | 7 Participants | 10 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) Not Hispanic or Latino | 116 Participants | 26 Participants | 53 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 9 Participants | 6 Participants | 9 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Asian | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Black or African American | 31 Participants | 9 Participants | 17 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) White | 130 Participants | 28 Participants | 54 Participants | 4 Participants | 3 Participants | 1 Participants | 2 Participants | 12 Participants | 9 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) Black or African American | 23 Participants | 5 Participants | 14 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Part 2: Open-label extension period (Week 16 and onwards) White | 111 Participants | 28 Participants | 47 Participants | 3 Participants | 3 Participants | 0 Participants | 1 Participants | 9 Participants | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Female | 124 Participants | 27 Participants | 54 Participants | 3 Participants | 2 Participants | 4 Participants | 1 Participants | 11 Participants | 8 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Part 1: 16-week double-blind, randomized, placebo-controlled treatment period (Day 1 to Week 16) Male | 42 Participants | 11 Participants | 20 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Part 2: Open-label extension period (Week 16 and onwards) Female | 106 Participants | 24 Participants | 47 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 9 Participants | 4 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Part 2: Open-label extension period (Week 16 and onwards) Male | 31 Participants | 9 Participants | 16 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 12 | 0 / 11 | 0 / 12 | 0 / 2 | 0 / 4 | 0 / 3 | 0 / 4 | 1 / 74 | 0 / 38 | 0 / 5 | 0 / 11 | 0 / 6 | 0 / 9 | 0 / 1 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 63 | 0 / 33 |
| other Total, other adverse events | 5 / 6 | 11 / 12 | 10 / 11 | 12 / 12 | 2 / 2 | 4 / 4 | 3 / 3 | 4 / 4 | 64 / 74 | 33 / 38 | 5 / 5 | 11 / 11 | 6 / 6 | 8 / 9 | 1 / 1 | 2 / 3 | 3 / 3 | 3 / 3 | 50 / 63 | 30 / 33 |
| serious Total, serious adverse events | 0 / 6 | 1 / 12 | 0 / 11 | 2 / 12 | 0 / 2 | 0 / 4 | 0 / 3 | 1 / 4 | 7 / 74 | 2 / 38 | 2 / 5 | 5 / 11 | 3 / 6 | 6 / 9 | 0 / 1 | 1 / 3 | 2 / 3 | 1 / 3 | 9 / 63 | 9 / 33 |
Outcome results
Primary
Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo
Overall treatment effect in exercise capacity, as measured by the total distance walked in 6 minutes (6MWD) mean change from baseline though Week 16. A lower 6MWD reflects greater severity thus, a positive change from baseline suggests an improvement.
Time frame: Baseline through Week 16
Population: mITT population included all randomized patients receiving at least 28 doses of study treatment, did not undergo heart or lung transplantation during the treatment period, and performed at least one-post baseline 6MWD assessment. Only Part 1 patients are included since the primary outcome is the change from baseline in 6MWD through Week 16. Primary outcome assessed for subgroups of participants with PAH from Cohorts 1, 2 and 3 of the study and participants with PH, Cohort 4 of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Dose-Ranging Bardoxolone Methyl 2.5 mg/Part 2: Open-Label | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 32.5 meters | Standard Deviation 29.14 |
| Part 1: Dose-Ranging Bardoxolone Methyl 5 mg/Part 2: Open-Label | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 24 meters | Standard Deviation 30.08 |
| Part 1: Dose-Ranging Bardoxolone Methyl 10 mg/Part 2: Open-Label | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 3.4 meters | Standard Deviation 31.28 |
| Part 1: Dose-Ranging Bardoxolone Methyl 20 mg/Part 2: Open-Label | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | -3.2 meters | Standard Deviation 39.53 |
| Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone Methyl 2.5 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 20.3 meters | Standard Deviation 13.08 |
| Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone Methyl 5 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 24.6 meters | Standard Deviation 59.4 |
| Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 23.8 meters | Standard Deviation 34.54 |
| Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone Methyl 20 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | -21.8 meters | Standard Deviation 4.17 |
| Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 13.9 meters | Standard Deviation 41.15 |
| Part 1: Dose Titration: Bardoxolone Methyl 10 mg/Part 2: Bardoxolone Methyl 10 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PH | 7.6 meters | Standard Deviation 32.01 |
| Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PAH | 19.4 meters | Standard Deviation 21.06 |
| Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone Methyl 10 mg | Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo | Change from Baseline though Week 16 for participants with PH | 10.8 meters | Standard Deviation 32.01 |
Comparison: Overall treatment effect in participants with PAH. Mean overall treatment effect across all visits for change from baseline in 6MWD was estimated and compared with placebo through 16 weeks of treatment using mixed-model repeated measures (MMRM), with treatment group, visit, and the interaction between treatment and visit as fixed factors. A compound symmetry covariance matrix was assumed. Data from Wks 4, 8, 12, and 16 used in the model with the change from baseline at Wk16 as primary endpoint.p-value: 0.813395% CI: [-16.22, 12.74]Mixed Models Analysis
Comparison: Overall treatment effect in participants with PH. Mean overall treatment effect across all visits for change from baseline in 6MWD was estimated \& compared with placebo through 16 wks of treatment using mixed-model repeated measures (MMRM), with treatment group, visit, and the interaction between treatment \& visit as fixed factors. Compound symmetry covariance matrix was assumed. Data from Wks 4, 8, 12, and 16 were used in the model with the change from baseline at Wk 16 as the primary endpointp-value: 0.75995% CI: [-23.54, 17.2]Mixed Models Analysis