Clinical trial NCT05488431: Cholesterol and Inflammation Lowering Via Bempedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial)
Official title: Cholesterol and Inflammation Lowering Via Bempedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Dyslipidemias
Cardiovascular Diseases
HIV Infections
Atherosclerosis
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: University of California, Los Angeles
name: Massachusetts General Hospital
First posted: 2022-08-04
Enrollment: 121
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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).

Eligibility criteria: Inclusion Criteria:

* 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 ≥ 70 mg/dL
* Documented cardiovascular disease as defined by: 1. Prior myocardial infarction, 2. Prior cerebrovascular disease, 3. Prior peripheral arterial disease, 4. History of percutaneous coronary intervention, 5. History of coronary artery bypass graft OR 6. 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.

Exclusion Criteria:

* 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

Primary outcomes:
measure: FDG PET/CT Endpoint
timeFrame: Baseline and Week 52
Secondary outcomes:
measure: Total Cholesterol Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: HDL Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: LDL Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Triglycerides Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Apolipoprotein B Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Hb A1c Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Fasting glucose Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Insulin Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Endpoints
timeFrame: Baseline, Week 24 and Week 52
measure: Adipose Volume Endpoint
timeFrame: Baseline and Week 52
measure: hsCRP Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: IL-1B Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: IL-18 Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: SAA Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Lp-PLA2 Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: sCD163 Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: IL-6 Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: D-Dimer Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Fibrinogen Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: T-cell Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: B-cell Endpoint
timeFrame: Baseline, Week 24 and Week 52
measure: Monocyte activation Endpoint
timeFrame: Baseline, Week 24 and Week 52
Other outcomes:
measure: Coronary CTA Non-calcified Plaque Endpoint
timeFrame: Baseline and Week 52
measure: Coronary CTA High-risk Plaque Endpoint
timeFrame: Baseline and Week 52
measure: Coronary CTA Coronary Plaque Incidence Endpoint
timeFrame: Baseline and Week 52
Locations:
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
Study officials:
affiliation: University of California, San Francisco
name: Priscilla Hsue, MD
role: PRINCIPAL_INVESTIGATOR
References: