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Effect of Evolocumab on Coronary Endothelial Function (EVOLVE)

Primary Purpose

Human Immunodeficiency Virus, Coronary Artery Disease

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Evolocumab
Sponsored by
Johns Hopkins University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Human Immunodeficiency Virus

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Johns Hopkins University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Evolocumab

Arm Description

All enrolled patients will receive evolocumab sq once a month for a total of two doses

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

LDL Cholesterol Level
LDL cholesterol level: mg/dL.

Full Information

First Posted
November 27, 2017
Last Updated
July 23, 2020
Sponsor
Johns Hopkins University
Collaborators
American Heart Association
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1. Study Identification

Unique Protocol Identification Number
NCT03500302
Brief Title
Effect of Evolocumab on Coronary Endothelial Function
Acronym
EVOLVE
Official Title
Effect of Evolocumab on Coronary Endothelial Function
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
May 4, 2018 (Actual)
Primary Completion Date
November 30, 2019 (Actual)
Study Completion Date
November 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Johns Hopkins University
Collaborators
American Heart Association

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus, Coronary Artery Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Pilot clinical trial to study HIV+ patients with baseline coronary endothelial dysfunction and assess changes in that function from the baseline measure to 1 and 6 weeks following initiation of therapy with evolocumab so as to test the hypotheses that PCSK9 inhibition with evolocumab improves coronary endothelial function (CEF) measured directly and non-invasively with MRI at 1 week and 6 weeks after initiation of evolocumab.
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Evolocumab
Arm Type
Experimental
Arm Description
All enrolled patients will receive evolocumab sq once a month for a total of two doses
Intervention Type
Drug
Intervention Name(s)
Evolocumab
Other Intervention Name(s)
Repatha
Intervention Description
Evolocumab sq once a month for a total of two doses
Primary Outcome Measure Information:
Title
Coronary Endothelial Function as Assessed by Percent Coronary Artery Area Change With Isometric Handgrip Exercise
Description
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.
Time Frame
1 week and 6 weeks
Secondary Outcome Measure Information:
Title
LDL Cholesterol Level
Description
LDL cholesterol level: mg/dL.
Time Frame
At 6 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Allison Hays, MD
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32674634
Citation
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.
Results Reference
derived

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Effect of Evolocumab on Coronary Endothelial Function

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