Cholesterol and Inflammation Lowering Via Bempedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 121
- 试验地点
- 3
- 主要终点
- FDG PET/CT Endpoint
研究概览
简要总结
This is a randomized placebo-controlled study in treated and suppressed HIV-infected individuals aged ≥40 years with either known CVD or 1 CVD risk factor to study the effect of Bempedoic acid (BA) on safety, arterial inflammation as assessed by FDG-PET/CT, lipids, inflammation, immune activation, cardiometabolic indices, and non-calcified plaque (NCP) in the coronary arteries (assessed by coronary CT angiography, CCTA). This trial will be enrolled at UCSF and UCLA. Collaborators at Massachusetts General Hospital (MGH) will serve as the core facility for imaging.
详细描述
Persons living with HIV infection (PLWH) have a 2-fold higher risk of myocardial infarction and are twice as likely to develop cardiovascular disease accounting for a significant global burden of disease. While the mechanism underlying this excess risk remains poorly understood, studies demonstrate that atherosclerosis in the setting of HIV is distinct and characterized by heightened arterial inflammation as assessed by FDG-PET/CT. HIV and antiretroviral medication can worsen cardiometabolic parameters. Thus a therapeutic strategy that can lower lipids, inflammation, and improve glycemic parameters may be even more advantageous in HIV. Bempedoic acid (BA, an inhibitor of ATP citrate lyase), is safely tolerated, significantly lowers LDL-C and inflammatory markers (on top of statin therapy), and is FDA approved for individuals with heterozygous familial hypercholesterolemia or with established ASCVD who require additional LDL-C lowering. Additionally, BA has a protective effect on glycemic parameters and may reduce adiposity. Given the key role of lipids and inflammation in atherosclerosis in HIV, the purpose of this proof-of-concept mechanistic trial is to evaluate the impact of BA on the biology of HIV-associated atherosclerosis. This is a randomized placebo controlled study of effectively treated PLWH aged 40 years and older with either known CVD or 1 CVD risk factor to study the effect of BA on arterial inflammation (assessed by FDG-PET/CT), lipid levels, biomarkers of inflammatory/immune activation, cardiometabolic indices, and non-calcified plaque in the coronary arteries (assessed by CCTA). This multicenter trial will include PLWH enrolled at UCSF and UCLA. Long term collaborators at MGH will serve as the core facility for the imaging end-points. There are three specific aims for the: Cholesterol and inflammation Lowering via BEmpedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial): Aim 1: To determine whether BA can safely reduce arterial inflammation including carotid plaque as assessed by FDG-PET/CT; Aim 2: To determine whether BA improves cardiometabolic measures (lipid, inflammatory, glycemic and adipose parameters) among PLWH. Exploratory objectives will be to assess BA's effect (vs. placebo) on glycemic as well as adipose tissue measures (HbA1c, HOMA IR, and adipose tissue volumes); Aim 3: To evaluate the impact of BA on non-calcified coronary plaque volume as measured by coronary CT angiography (CCTA).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented HIV infection
- •On continuous antiretroviral therapy and virologically suppressed HIV infection for ≥12 weeks prior to study entry
- •CD4 T-cell count ≥ 200 cells/mm3
- •Male or female between the ages ≥ 40 years of age
- •LDL-C ≥ 50 mg/dL
- •Documented cardiovascular disease as defined by:
- •Prior myocardial infarction,
- •Prior cerebrovascular disease,
- •Prior peripheral arterial disease,
- •History of percutaneous coronary intervention,
- •History of coronary artery bypass graft OR
- •Angiographic evidence of >50% stenosis in at least one coronary artery] OR 1 CVD risk factor (T2DM, current smoking, hypertension, dyslipidemia, hsCRP≥2mg/L, family history)
- •TBR of >1.6 of the MDS of the carotid/aorta at baseline. This baseline arterial TBR cutoff excludes the rare individual that lacks appreciable arterial inflammation. It is notable that while 5-10% of uninfected individuals will have lower TBRs, it is rare that an HIV infected individual will fall below this range.
- •Female subjects must either be of non-childbearing potential (defined as post-menopausal or amenorrhea > 12 months) or agree to use two forms of contraception (one hormonal and one barrier) throughout the study and for at least one month following study completion and have a negative pregnancy test at screening and prior to the first dose of drug.
- •Males must use at least one method of contraception throughout the study.
排除标准
- •Pregnant/nursing women (as there is no data on bempedoic acid in this setting)
- •Diabetes requiring insulin (as insulin treatment alters the uptake of 18FDG)
- •Uncontrolled HTN as defined by baseline blood pressure reading of ≥160 mmHg systolic OR ≥100 mmHg diastolic (exclusion criteria in other studies with BA)
- •AST/ALT or alkaline phosphatase >2x ULN
- •Triglycerides >500 mg/dL at screening
- •Cancer within the last 5 years with exception of squamous cell carcinoma and basal cell carcinoma
- •Individuals on simvastatin >20mg or pravastatin >40mg. All other dosages and statins will be permitted with close monitoring for myopathies including assessment of CK levels
- •Nephrotic syndrome or eGFR <30 mL/min/1.73m2
- •Cytopenias which include 1) WBC <3.5 x103/uL 2) Platelet <120 x103/uL 3) ANC <1.5 x103/uL, and absolute lymphocytes <0.8 x 103/uL
- •Anemia as fined by Hgb <10 g/dL
- •Acute systemic infection within 30 days
研究组 & 干预措施
Bempedoic acid (BA)
Patients randomized into the BA arm will receive 180 mg BA administered orally once daily without food for 52 weeks.
干预措施: Bempedoic acid (Drug)
Placebo
Patients randomized into the placebo arm will receive 180 mg placebo administered orally once daily without food for 52 weeks.
干预措施: Placebo (Other)
结局指标
主要结局
FDG PET/CT Endpoint
时间窗: Baseline and Week 52
Change in Target-to-background ratio from baseline to follow-up study at 52 weeks. The main arterial endpoint is the most diseased segment of the index vessel. These findings will be correlated to measurements in the secondary endpoint.
次要结局
- Hb A1c Endpoint(Baseline, Week 24 and Week 52)
- Fasting glucose Endpoint(Baseline, Week 24 and Week 52)
- IL-18 Endpoint(Baseline, Week 24 and Week 52)
- sCD163 Endpoint(Baseline, Week 24 and Week 52)
- IL-6 Endpoint(Baseline, Week 24 and Week 52)
- Fibrinogen Endpoint(Baseline, Week 24 and Week 52)
- B-cell Endpoint(Baseline, Week 24 and Week 52)
- Lp-PLA2 Endpoint(Baseline, Week 24 and Week 52)
- Total Cholesterol Endpoint(Baseline, Week 24 and Week 52)
- hsCRP Endpoint(Baseline, Week 24 and Week 52)
- homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Endpoints(Baseline, Week 24 and Week 52)
- SAA Endpoint(Baseline, Week 24 and Week 52)
- D-Dimer Endpoint(Baseline, Week 24 and Week 52)
- HDL Endpoint(Baseline, Week 24 and Week 52)
- LDL Endpoint(Baseline, Week 24 and Week 52)
- Triglycerides Endpoint(Baseline, Week 24 and Week 52)
- Apolipoprotein B Endpoint(Baseline, Week 24 and Week 52)
- Insulin Endpoint(Baseline, Week 24 and Week 52)
- Adipose Volume Endpoint(Baseline and Week 52)
- IL-1B Endpoint(Baseline, Week 24 and Week 52)
- T-cell Endpoint(Baseline, Week 24 and Week 52)
- Monocyte activation Endpoint(Baseline, Week 24 and Week 52)
研究者
Priscilla Hsue, MD
Dr. Priscilla Hsue
University of California, San Francisco