Effect of Evolocumab on Coronary Endothelial Function (EVOLVE)

The investigators propose a pilot study using (1) MRI to assess coronary artery endothelial function, (2) brachial ultrasound to assess systemic endothelial function, (3) serum markers of inflammation and of endothelial cell function and (4) echocardiographic measures of left ventricular diastolic and systolic properties, before and following initiation of PCSK9 antibody in HIV positive subjects.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Evolocumab

Detailed Description

To evaluate the effect of the PCSK9 inhibitor evolocumab on coronary and systemic endothelial function, systemic biomarkers of endothelial function and of inflammation, and echocardiographic measures of left ventricular diastolic and systolic properties in subjects who are HIV+. Potential participants will be asked to undergo a screening MRI exam. Those who have evidence of coronary endothelial dysfunction on the MRI exam will receive evolocumab 420 mg sq (the dose that is approved for treatment of hypercholesterolemia) following the screening exam and again at one month. Repeat MRI and ultrasound measures of coronary and systemic endothelial function, as well as serum markers of endothelial function and inflammation, and echocardiographic measures of diastolic and systolic left ventricular function will be obtained at one and six weeks following the first administration of evolocumab.

The investigators will test the hypotheses that PCSK9 inhibition improves endothelial function measured non-invasively on MRI and systemic markers of inflammation at one week (+/- 3 days) and six weeks after initiation of the PCSK9 antibody.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants of either gender who are >21 years of age (no upper age limit)
• HIV (Human Immunodeficiency Virus) positive and taking stable Anti-Retroviral Therapy (ART), no change in regimen in last 3 months)
• Undetectable HIV viral load (plasma HIV RNA concentration, RNA=Ribonucleic Adic)
• Abnormal coronary endothelial function on MRI (Magnetic Resonance Imaging) at baseline (<5% change in coronary cross sectional area during isometric handgrip exercise as compared to resting value).
• Lipids at screening visit: Fasting LDL-C >70 mg/dL (LDL-C=Low Density Lipoprotein Cholesterol); fasting TG<500 mg/dL (TG=Triglycerides)
• Permission of treating physician

Exclusion Criteria:

• Patients unable to understand the risks, benefits, and alternatives of participation and give meaningful consent.
• Patients with contraindications to MRI such as implanted metallic objects (pre-existing cardiac pacemakers, cerebral clips),
• History of a recent cardiovascular or cerebrovascular events or procedure (e.g. myocardial infarction, stroke, transient ischemic attack, angioplasty, Coronary artery bypass surgery) during the past 90 days.
• Subjects with prior exposure to evolocumab or another PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitor.
• Pregnant women or breastfeeding women. Women of childbearing potential (even if using oral contraceptive agents) or intention to breastfeed.
• 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 recreational drugs within 6 months prior to screening.
• Renal impairment defined by estimated glomerular filtration rate <45 ml/min.
• Moderate-severe hepatic disease (elevation in hepatic transaminases >3x upper limit of normal, ULN) or direct bilirubin >3.0 X ULN at screening.
• Cluster of differentiation 4 (CD4)<200 cell/mm3
• Congestive heart failure, New York Heart Association functional class III or greater, or left ventricular ejection fraction measured by imaging known to be <30%. (Imaging not required for study inclusion).
• History of allergic or anaphylactic reaction to any therapeutic monoclonal antibody (IgG protein) or molecules made of components of monoclonal antibodies
• Active phase hepatitis. Stable patients with hepatitis B or C infection >3 years before randomization are eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evolocumab; All enrolled patients will receive evolocumab sq once a month for a total of two doses	Drug: Evolocumab; Evolocumab sq once a month for a total of two doses; Other Names: Repatha

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coronary Endothelial Function as Assessed by Percent Coronary Artery Area Change With Isometric Handgrip Exercise	Coronary endothelial function will be assessed by the percent change in cross sectional coronary artery area (measured on MRI) from rest to isometric handgrip stress exercise at week 1 and week 6. The percent change from week 1 to week 6 is presented below.	1 week and 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDL Cholesterol Level	LDL cholesterol level: mg/dL.	At 6 weeks

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Allison Hays, MD, Johns Hopkins University

Publications and helpful links

General Publications

• Leucker TM, Gerstenblith G, Schar M, Brown TT, Jones SR, Afework Y, Weiss RG, Hays AG. Evolocumab, a PCSK9-Monoclonal Antibody, Rapidly Reverses Coronary Artery Endothelial Dysfunction in People Living With HIV and People With Dyslipidemia. J Am Heart Assoc. 2020 Jul 21;9(14):e016263. doi: 10.1161/JAHA.120.016263. Epub 2020 Jul 17.

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2018
• Primary Completion (Actual): November 30, 2019
• Study Completion (Actual): November 30, 2019

Study Registration Dates

• First Submitted: November 27, 2017
• First Submitted That Met QC Criteria: April 12, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): July 24, 2020
• Last Update Submitted That Met QC Criteria: July 23, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Slow Virus Diseases; HIV Infections; Coronary Artery Disease; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: IRB00127952

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes