Cholesterol and Inflammation Lowering Via Bempedoic Acid, an ACL-inhibiting Regimen in HIV Trial (CLEAR HIV Trial)

• ClinicalTrials.gov Identifier: NCT05488431
• Recruitment Status: Not yet recruiting
• First Posted: August 4, 2022
• Last Update Posted: January 9, 2023
• Sponsor: Priscilla Hsue, MD
• Collaborators: University of California, Los Angeles; University of Utah; Massachusetts General Hospital
• Information provided by (Responsible Party): Priscilla Hsue, MD, University of California, San Francisco

Tracking Information

• First Submitted Date: July 25, 2022
• First Posted Date: August 4, 2022
• Last Update Posted Date: January 9, 2023
• Estimated Study Start Date: February 1, 2023
• Estimated Primary Completion Date: February 1, 2028 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 2, 2022)

FDG PET/CT Endpoint [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 2, 2022)

• Total Cholesterol Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in total cholesterol will be assessed from baseline to week 24 and week 52.
• HDL Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in HDL will be assessed from baseline to week 24 and week 52.
• LDL Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in LDL will be assessed from baseline to week 24 and week 52.
• Triglycerides Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in triglycerides will be assessed from baseline to week 24 and week 52.
• Apolipoprotein B Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in apolipoprotein B will be assessed from baseline to week 24 and week 52.
• Hb A1c Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in HbA1c from baseline to week 24 and week 52.
• Fasting glucose Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in fasting glucose measurements from baseline to week 24 and week 52.
• Insulin Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in insulin measurements from baseline to week 24 and week 52.
• homeostatic Model Assessment for Insulin Resistance (HOMA-IR) Endpoints [ Time Frame: Baseline, Week 24 and Week 52 ]
  The change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), a calculation based on insulin and glucose, will also be assessed from baseline to week 24 and 52. The equation simplifies to [HOMA-IR = fasting insulin *fasting glucose /22.5] where fasting plasma insulin is measured in (µIU/mL) and fasting plasma glucose is measured in (mmol/L). Values below 1.0 are generally considered optimal.
• Adipose Volume Endpoint [ Time Frame: Baseline and Week 52 ]
  Change in adipose tissue volumes will be assessed by FDG PET/CT (as measured in primary outcome) from baseline to week 52.
• hsCRP Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in hsCRP from baseline to follow-up at weeks 24 and 52.
• IL-1B Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in IL-1B from baseline to follow-up at weeks 24 and 52.
• IL-18 Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in IL-18 from baseline to follow-up at weeks 24 and 52.
• SAA Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in SAA from baseline to follow-up at weeks 24 and 52.
• Lp-PLA2 Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in Lp-PLA2 from baseline to follow-up at weeks 24 and 52.
• sCD163 Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in sCD163 from baseline to follow-up at weeks 24 and 52.
• IL-6 Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in IL-6 from baseline to follow-up at weeks 24 and 52.
• D-Dimer Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in D-Dimer from baseline to follow-up at weeks 24 and 52.
• Fibrinogen Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in fibrinogen from baseline to follow-up at weeks 24 and 52.
• T-cell Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in T-cell marker from baseline to follow up at weeks 24 and 52.
• B-cell Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in B-cell marker from baseline to follow up at weeks 24 and 52.
• Monocyte activation Endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
  Change in monocyte activation marker from baseline to follow up at weeks 24 and 52.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: August 3, 2022)

• Coronary CTA Non-calcified Plaque Endpoint [ Time Frame: Baseline and Week 52 ]
  Change in non-calcified plaque as measured by Coronary CTA from baseline to follow-up study at 52 weeks
• Coronary CTA High-risk Plaque Endpoint [ Time Frame: Baseline and Week 52 ]
  Change in high-risk plaque as measured by Coronary CTA from baseline to follow-up study at 52 weeks.
• Coronary CTA Coronary Plaque Incidence Endpoint [ Time Frame: Baseline and Week 52 ]
  Incidence of new coronary lesions as measured by Coronary CTA from baseline to follow-up study at 52 weeks

Original Other Pre-specified Outcome Measures (submitted: August 2, 2022)

• Non-calcified Plaque Endpoint [ Time Frame: Baseline and Week 52 ]
  Change in non-calcified plaque from baseline to follow-up study at 52 weeks
• High-risk Plaque Endpoint [ Time Frame: Baseline and Week 52 ]
  Change in high-risk plaque from baseline to follow-up study at 52 weeks.
• Coronary Plaque Incidence Endpoint [ Time Frame: Baseline and Week 52 ]
  Incidence of new coronary lesions from baseline to follow-up study at 52 weeks

Descriptive Information

• Brief Title: 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)
• 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, UCLA, and University of Utah; 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, UCLA, and Univ. of Utah. 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).
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Dyslipidemias
• Cardiovascular Diseases
• HIV Infections
• Atherosclerosis

Intervention

• Drug: Bempedoic acid
  Bempedoic Acid is an oral first-in-class small molecular adenosine triphosphate (ATP)-citrate lyase (ACL) inhibitor which lowers LDL-C by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Inhibition of ACL by bempedoyl-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of LDL receptors and concomitant suppression of hepatic fatty acid biosynthesis. BA has been studied in >4300 individuals and is currently being studied in >14,000 individuals in CLEAR Outcomes (NCT02993406).
  Other Name: BA
• Other: Placebo
  Placebo

Study Arms

• Experimental: Bempedoic acid (BA)
  Patients randomized into the BA arm will receive 180 mg BA administered orally once daily without food for 52 weeks.
  Intervention: Drug: Bempedoic acid
• Placebo Comparator: Placebo
  Patients randomized into the placebo arm will receive 180 mg placebo administered orally once daily without food for 52 weeks.
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: August 2, 2022): 121
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 1, 2028
• Estimated Primary Completion Date: February 1, 2028 (Final data collection date for primary outcome measure)

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 ≥ 100 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Victor M Arechiga, BA; 206-5432 ext 628; victor.arechiga@ucsf.edu

Contact: Shreya Swaminathan, BS; 206-5801 ext 628; shreya.swaminathan@ucsf.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05488431
• Other Study ID Numbers: 1.0
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Priscilla Hsue, MD, University of California, San Francisco
• Original Responsible Party: Same as current
• Current Study Sponsor: Priscilla Hsue, MD
• Original Study Sponsor: Same as current

Collaborators

• University of California, Los Angeles
• University of Utah
• Massachusetts General Hospital

Investigators

• Principal Investigator: Priscilla Hsue, MD; University of California, San Francisco

• PRS Account: University of California, San Francisco
• Verification Date: January 2023