Effect of PCSK9 Inhibition on Cardiovascular Risk in Treated HIV Infection (EPIC-HIV Study)

• Status: Recruiting
• Trial end date: 2021-11-01
• Target enrollment: 0
• Participant gender: All

Summary

Atherosclerosis in the setting of HIV infection is distinct and includes increased vascular inflammation, worsened endothelial function, and a predominance of non-calcified plaque. These outcomes can be assessed using specialized noninvasive imaging which strongly predict future CV events in the general population.

PCSK9 has emerged as an important pharmacologic target for cholesterol lowering in the general population and recent studies among individuals without HIV have shown that PCSK9 inhibitor therapy is safely tolerated and significantly reduces major CV events in the general population.

The investigators will perform a clinical trial of PCSK9 inhibition in the setting of HIV infection. This will be a randomized, placebo-controlled study to evaluate the effects of PCSK9 inhibition on vascular inflammation, endothelial function, and non-calcified plaque using a PCSK9 inhibitor called alirocumab. This study will recruit 140 treated individuals with HIV who are aged 40 and older, with known CVD or risk factors for CVD and who have evidence of vascular inflammation at baseline.

The primary and secondary objective of this study is to determine whether PCSK9 inhibition can improve arterial inflammation as assessed by FDG-PET/CT and endothelial function as assessed by flow mediated vasodilation. The investigators will correlate changes in arterial inflammation and endothelial function with lipids and markers of inflammation and immune activation.

The tertiary objective is to perform a pilot evaluation of the impact of PCSK9 inhibition on non-calcified plaque as measured by coronary CT angiography. Non-calcified plaque measurements will be correlated with changes in lipid parameters and markers of inflammation and immune activation.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of California, San Francisco
• Collaborator: Massachusetts General Hospital
• Treatments: Antibodies, Monoclonal

Criteria

Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.

2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

3. Males and females equal or greater than 40 years of age.

4. Documented HIV infection.

5. HIV-1 RNA level below 200 copies/mL for at least 12 weeks prior to study entry

6. CD4 T Cells ≥200 cells/mm3 at screening

7. Continuous ART for at least 12 weeks with no change in regimen prior to study entry.

8. Moderate or high CVD risk defined as: documented CVD as assessed by meeting at least 1 of 3 criteria below:

1. Coronary artery disease (CAD)

2. Cerebrovascular disease

3. Peripheral arterial disease

OR any one of the following CVD risk factors:

1. Controlled type II diabetes mellitus (HbA1C ≤ 8.0%)

2. Family history: a first degree relative who had a heart attack, stroke, or documented CVD as defined in the previous section that occurred: a. When they were age 55 years or younger for males (father, uncle, or brother) b. When they were age 60 years or younger for females (mother, aunt, or sister)

3. Current smoking

4. Hypertension

5. Dyslipidemia

6. A hsCRP ≥ 2mg/L at screening.

9. Lipids at screening visit:

• Fasting LDL-C ≥ 70 mg/dL (1.81 mmol/L);

• Fasting TG ≤ 600 mg/dL (6.78 mmol/L).

10. If subjects meet ACC/AHA criteria for statin therapy and are not currently on a statin, subjects must be taking a stable dose of statin for at least 4 weeks, unless they are statin intolerant, refuse to take a statin, or have a medical condition (e.g. chronic hepatitis) where a statin is contraindicated.

Exclusion Criteria:

1. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Regeneron employees.

2. Participation in other studies involving small molecule investigational drug(s).

3. Subjects who are unable to receive injections, as either a self-injection, or administered by another person.

4. Subjects requiring daily insulin therapy

5. Intended modification of ART in the next 52 weeks

6. History of a cardiovascular or cerebrovascular event or procedure (e.g., myocardial infarction, stroke, transient ischemic attack, angioplasty) during the past 90 days.

7. Congestive heart failure, New York Heart Association functional class IV, or left ventricular ejection fraction measured by imaging known to be <25%. (Imaging not required for study inclusion).

8. Poorly controlled hypertension

9. Any history of hemorrhagic stroke or lacunar infarct.

10. Current untreated hypothyroidism or thyroid stimulating hormone (TSH)

11. Current history of alcoholism or drug addiction according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria within 12 months prior to screening. Use of any illicit drug confirmed by urine toxicology test at screening that would in the opinion of the investigator interfere with study procedures or results.

12. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer resolved by excision, or cervical carcinoma in situ).

13. Any disease or condition that might compromise the hematological, renal, hepatic, pulmonary, endocrine, central nervous, immune, or gastrointestinal systems.

14. Undergoing apheresis or have a planned start of apheresis.

15. Initiation of or change in non-lipid lowering prescription drugs, herbal medicine or supplements (including foods with added plant sterols and stanols) within 6 weeks of screening with the exception of initiation or change in multivitamins used for general health purposes. Short-term use of medications to treat acute conditions, and vaccines are allowed (e.g., antibiotics or allergy medication).

16. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibodies (e.g., Enbrel® which contains the Fc portion of an antibody or Lucentis® which is a Fab).

17. Any abnormal hematology values, clinical chemistries, or ECGs at screening judged by the Investigator as clinically significant, which could impact on subject safety, were the potential subject to be included in the study, or interfere with the interpretation of study results.

18. Active phase hepatitis. Stable patients with hepatitis B or C infection >2 years before randomization are eligible.

19. Aspartate transaminase (AST) or alanine transaminase (ALT) > 5 X ULN at screening.

20. Direct bilirubin > 4 X ULN at screening.

22. GFR < 60 mL/min/1.73m2 at screening or undergoing dialysis.

23. Changes in lipid-lowering or antihypertensive medication within 90 days prior to study entry or expected need to modify these medications during study

24. Female subject who has either (1) not used at least 1 highly effective method of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 105 days after the end of treatment, unless the subject is sterilized or postmenopausal.

• Highly effective methods of birth control include not having intercourse or using birth control methods that work at least 99% of the time when used correctly and include: birth control pills, shots, implants or patches, intrauterine devices (IUDs), tubal ligation/occlusion, sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide

• Achieved post-menopausal status is defined as 12 months of spontaneous and continuous amenorrhea in a female

• 55 years old or 12 months of spontaneous and continuous amenorrhea with a follicle-stimulating hormone (FSH) level > 40 IU/L (or according to the definition of "postmenopausal range" for the laboratory involved in a female <50 years old unless the subject has undergone bilateral oophorectomy.

25. Pregnant females; breastfeeding females.

26. Additional exclusion criteria for the FDG-PET/CT imaging (patients with these exclusions may participate in the rest of the trial):

a. Significant radiation exposure during the year prior to randomization. Significant exposure is defined as i) more than 2 PCI procedures, ii) more than 2 myocardial perfusion studies, or iii) more than 2 CT angiograms.

b. Any history of radiation therapy.

c. Current insulin use

26. Additional exclusion criteria for CTA imaging:

1. Significant radiation exposure during the year prior to randomization. Significant exposure is defined as i) more than 2 PCI procedures, ii) more than 2 myocardial perfusion studies, or iii) more than 2 CT angiograms (as with FDG-PET/CT).

2. Any history of radiation therapy (as with FDG-PET/CT).

3. Any contraindication to beta-blocker (atenolol and metoprolol) or nitroglycerin use, because these drugs are given as part of the standard cardiac CT protocol.

4. Significant renal dysfunction (defined as an eGFR < 60 mL/min/1.73m2).

5. Body weight > 300 pounds (136 Kg), because of the CT scanner table limitations.

6. Allergy to iodine-containing contrast media.

7. Any history of CABG.