EVOLVE: Effect of Evolocumab on Coronary Endothelial Function

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03500302
• Collaborator: American Heart Association (Other)
• Enrollment: 19
• Location: 1
• Arm: 1
• Actual Duration (Months): 18.9
• Patients Per Site Per Month: 1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Human Immunodeficiency Virus; Coronary Artery Disease	Drug: Evolocumab	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention 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.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)
• Primary Purpose: Treatment
• Official Title: Effect of Evolocumab on Coronary Endothelial Function
• Actual Study Start Date: May 4, 2018
• Actual Primary Completion Date: Nov 30, 2019
• Actual Study Completion Date: Nov 30, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Coronary Endothelial Function as Assessed by Percent Coronary Artery Area Change With Isometric Handgrip Exercise [1 week and 6 weeks]

   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

1. LDL Cholesterol Level [At 6 weeks]

   LDL cholesterol level: mg/dL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University	Baltimore	Maryland	United States	21205

Sponsors and Collaborators

• Johns Hopkins University
• American Heart Association

Investigators

• Principal Investigator: Allison Hays, MD, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 25, 2017

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT03500302
• Other Study ID Numbers: IRB00127952
• First Posted: Apr 18, 2018
• Last Update Posted: Jul 24, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Coronary Artery Disease; Evolocumab

Study Results

Participant Flow

Arm/Group Title	Evolocumab
Arm/Group Description	All enrolled patients (people living with HIV) who received evolocumab sq once a month for a total of two doses
Period Title: Overall Study
STARTED	19
COMPLETED	19
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Evolocumab Group
Arm/Group Description	Patients (people living with HIV) who received Evolocumab sq once a month for total of 2 doses
Overall Participants	19
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	19 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52 (9)
Sex: Female, Male (Count of Participants)
Female	4 21.1%
Male	15 78.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	14 73.7%
White	5 26.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	19 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	26 (5)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Patients with HIV receiving Evolocumab sq (2 doses total)
Measure Participants	19
Mean (Standard Deviation) [percent change in coronary artery area]	5.6 (5.5)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evolocumab
Arm/Group Description	Patients with HIV receiving Evolocumab sq (2 doses total)
Measure Participants	19
Mean (Standard Deviation) [mg/dL]	37 (19)

Adverse Events

Time Frame	Up to 10 weeks from start of study.
Arm/Group Title	Evolocumab
Arm/Group Description	All enrolled patients who received evolocumab sq once a month for a total of two doses.
All Cause Mortality
	Evolocumab
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Serious Adverse Events
	Evolocumab
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Other (Not Including Serious) Adverse Events
	Evolocumab
	Affected / at Risk (%)	# Events
Total	0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.