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

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ClinicalTrials.gov Identifier: NCT03207945
Recruitment Status : Recruiting
First Posted : July 5, 2017
Last Update Posted : October 9, 2019
Sponsor:
Collaborator:
Massachusetts General Hospital
Information provided by (Responsible Party):
Priscilla Hsue, MD, University of California, San Francisco

Brief 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.


Condition or disease Intervention/treatment Phase
Dyslipidemias Cardiovascular Diseases HIV Infections Drug: Alirocumab Other: Placebo Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effect of PCSK9 Inhibition on Cardiovascular Risk in Treated HIV Infection (EPIC-HIV Study)
Actual Study Start Date : April 30, 2018
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : November 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Alirocumab

Arm Intervention/treatment
Experimental: Alirocumab
Patients randomized into the alirocumab arm will start off with 75 mg alirocumab administered every two weeks for two doses and will be upwardly titrated to 150 mg alirocumab if subjects demonstrate LDL ≥ 50 mg/dL at week 4. Subjects demonstrating LDL-C <50mg/dl will remain on the same 75mg dose throughout the trial.
Drug: Alirocumab
Alirocumab (Sar236553/REG 727) is a fully humanized monoclonal antibody against the proprotein convertase subtilisin kexin type 9 (PCSK9) enzyme responsible for the degradation of the low-density lipoprotein receptor (LDLR), and is developed by Regeneron Pharmaceuticals/Sanofi.
Other Name: Sar236553/REG727

Placebo Comparator: Placebo
Patients randomized into the placebo arm will receive 75 mg or 150 mg or placebo administered once every two weeks throughout the trial
Other: Placebo
Placebo




Primary Outcome Measures :
  1. 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

  2. FDG PET/CT Endpoint [ Time Frame: Baseline Week 24, and 52 ]
    Percent change from baseline in fasting TC, HDL-C, triglycerides, non HDL-C, ApoB, ApoA-I at week 24, and 52

  3. FDG PET/CT Endpoint [ Time Frame: Baseline, Week 24, and 52 ]
    Percent change from baseline in fasting oxidized LDL, Lp(a), LpPLA2, sCD14 and T-Cell activation at week 24, and 52

  4. FDG PET/CT Endpoint [ Time Frame: Baseline and Week 52 ]
    Correlation of lipid and immune activation parameters to arterial inflammation


Secondary Outcome Measures :
  1. Flow mediated vasodilation of the brachial artery (FMD) endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
    Change in FMD from baseline to follow-up at weeks 24, and 52

  2. Flow mediated vasodilation of the brachial artery (FMD) endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
    Correlation of FMD changes to lipid parameters

  3. Flow mediated vasodilation of the brachial artery (FMD) endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
    Correlation of FMD changes to immune parameters

  4. Flow mediated vasodilation of the brachial artery (FMD) endpoint [ Time Frame: Baseline Week 24 and Week 52 ]
    Microvascular changes from baseline to weeks 24, and 52

  5. Flow mediated vasodilation of the brachial artery (FMD) endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
    Correlation of microvascular changes to lipid parameters

  6. Flow mediated vasodilation of the brachial artery (FMD) endpoint [ Time Frame: Baseline, Week 24 and Week 52 ]
    Correlation of microvascular changes to immune parameters


Other Outcome Measures:
  1. Coronary CTA Endpoint [ Time Frame: Baseline and Week 52 ]
    Change in non-calcified plaque from baseline to follow-up study at 52 weeks

  2. Coronary CTA Endpoint [ Time Frame: Baseline and Week 52 ]
    Change in high-risk plaque from baseline to follow-up study at 52 weeks.

  3. Coronary CTA Endpoint [ Time Frame: Baseline and Week 52 ]
    Incidence of new lesions from baseline to follow-up study at 52 weeks

  4. Coronary CTA Endpoint [ Time Frame: Baseline and Week 52 ]
    Correlations between change in lipid and change in volume of non-calcified coronary plaque

  5. Coronary CTA Endpoint [ Time Frame: Baseline and Week 52 ]
    Correlations between change in lipid and change in high-risk coronary plaque

  6. Coronary CTA Endpoint [ Time Frame: Baseline and Week 52 ]
    Correlations between change in immune parameters and change in volume of non-calcified coronary plaque b.change in high-risk coronary plaque

  7. Coronary CTA Endpoint [ Time Frame: Baseline and Week 52 ]
    Correlations between change in immune parameters and change in high-risk coronary plaque



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03207945


Contacts
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Contact: Kelvin Moore 628-206-5145 kelvin.moorejr@ucsf.edu
Contact: Sohee Park 628-206-5801 rebecca.park2@ucsf.edu

Locations
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United States, California
San Francisco General Hospital Recruiting
San Francisco, California, United States, 94110
Contact: Danny Li    415-206-5801    danny.li@ucsf.edu   
Contact: Brendan Neilan    415-206-8037    Brendan.Neilan@ucsf.edu   
Principal Investigator: Priscilla Hsue, MD         
Sponsors and Collaborators
University of California, San Francisco
Massachusetts General Hospital
Investigators
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Principal Investigator: Priscilla Hsue, MD University of California, San Francisco

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Responsible Party: Priscilla Hsue, MD, Professor of Medicine, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03207945     History of Changes
Other Study ID Numbers: 17-22800
First Posted: July 5, 2017    Key Record Dates
Last Update Posted: October 9, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infection
Communicable Diseases
HIV Infections
Acquired Immunodeficiency Syndrome
Dyslipidemias
Cardiovascular Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Lipid Metabolism Disorders
Metabolic Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs