A Dose-Ranging Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Pulmonary Hypertension
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Biogen
- 入组人数
- 166
- 试验地点
- 32
- 主要终点
- Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent;
- •BMI > 18.5 kg/m²
- •Symptomatic pulmonary hypertension WHO class II and III;
- •WHO Group I, III, or V PH according to the following criteria:
- •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
- •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
- •If WHO Group V PH then patient must be diagnosed with sarcoidosis;
- •Had a diagnostic right heart catheterization performed and documented within 36 months prior to Day 1 that confirmed a diagnosis of PH
- •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;
- •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;
排除标准
- •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;
- •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;
- •Stopped receiving any PH chronic therapy within 60 days prior to Day 1;
- •Requirement for receipt of intravenous inotropes within 30 days prior to Day 1;
- •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;
- •Has systolic BP < 90 mm Hg during Screening after a period of rest;
- •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%;
- •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:
- •Congenital or acquired valvular disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension;
- •Pericardial constriction;
- •Restrictive or congestive cardiomyopathy;
- •Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 60 days of Day 1;
- •Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or anginal chest pain);
- •Acutely decompensated heart failure within 30 days prior to Day 1, as per Investigator assessment;
- •History of atrial septostomy within 180 days prior to Day 1;
- •History of obstructive sleep apnea that is untreated;
- •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);
- •Serum aminotransferase (ALT or AST) levels > the upper limit of normal (ULN) at Screening;
- •For patients with HIV-associated PAH, any of the following:
- •Concomitant active opportunistic infections within 180 days prior to Screening;
- •Detectable viral load within 90 days prior to Screening;
- •Cluster designation (CD+) T-cell count < 200 mm3 within 90 days prior to Screening;
- •Changes in antiretroviral regimen within 90 days prior to Screening;
- •Using inhaled pentamidine
研究组 & 干预措施
Part 1 Dose-Ranging Bardoxolone methyl 2.5 mg/Part 2: Open-Label
Participants received bardoxolone methyl 2.5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Bardoxolone methyl 5 mg/Part 2: Open-Label
Participants received bardoxolone methyl 5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Bardoxolone methyl 10 mg/Part 2: Open-Label
Participants received bardoxolone methyl 10 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Bardoxolone methyl 20 mg/Part 2: Open-Label
Participants received bardoxolone methyl 20 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone methyl 2.5 mg
Participants received bardoxolone methyl 2.5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Placebo 2.5 mg/Part 2: Bardoxolone methyl 2.5 mg
Participants received bardoxolone methyl 2.5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Placebo (Drug)
Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone methyl 5 mg
Participants received bardoxolone methyl 5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Placebo 5 mg/Part 2: Bardoxolone methyl 5 mg
Participants received bardoxolone methyl 5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Placebo (Drug)
Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg
Participants received bardoxolone methyl 10 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg
Participants received bardoxolone methyl 10 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Placebo (Drug)
Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone methyl 20 mg
Participants received bardoxolone methyl 20 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose-Ranging Placebo 20 mg/Part 2: Bardoxolone methyl 20 mg
Participants received bardoxolone methyl 20 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards)
干预措施: Placebo (Drug)
Part 1: Dose Titration: Bardoxolone methyl 10 mg/Part 2: Bardoxolone methyl 10 mg
Participants in Part 1 started with bardoxolone methyl 5 mg once-daily from Day 1 and escalated to bardoxolone methyl 10 mg once-daily starting at Week 4 thru Week 16. Participants who continued to Part 2 continued to receive the same bardoxolone methyl dose once-daily in Part 2 (Week 16 and onwards)
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg
Participants in Part 1 received Placebo once-daily from Day 1 thru Week 16. Participants who continued to Part 2 initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from week 20 onwards
干预措施: Bardoxolone methyl (Drug)
Part 1: Dose Titration: Placebo 10 mg/Part 2: Bardoxolone methyl 10 mg
Participants in Part 1 received Placebo once-daily from Day 1 thru Week 16. Participants who continued to Part 2 initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from week 20 onwards
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline Though Week 16 in 6-Minute Walk Distance (6MWD) for Bardoxolone Methyl Compared to Placebo
时间窗: 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.
次要结局
未报告次要终点