Effect of Evolocumab on Coronary Artery Plaque Volume and Composition by CCTA and Microcalcification by F18-NaF PET

Study Overview
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Brief Summary
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This study will quantify changes in coronary plaque volumes and plaque composition in patients treated with evolocumab. Previous intravascular ultrasound studies have shown that treatment with a lipid-lowering PCSK9 enzyme inhibitor, such as evolocumab, to be associated with a reduction of the fatty deposits that cause plaque in the arteries, however, it is not known how evolocumab affects specific coronary plaque types and plaque inflammation. Investigators will use quantitative assessment of non-invasive coronary computed tomography angiography (CCTA) and positron emission tomography (PET)imaging to evaluate functional changes in plaque burden, plaque composition and vascular inflammation before and after treatment with evolocumab. Investigators propose to show that patients treated with evolocumab in combination with statins demonstrate a greater reduction of coronary non-calcified plaque volume, thereby reducing the number of future cardiac events.

Detailed Description
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To evaluate the effect of evolocumab, patients who are taking Evolocumab plus another cholesterol-lowering medication (e.g statins), will undergo diagnostic testing including non-invasive coronary CT angiographic (CCTA) scans and positron emission tomography (PET) scans. The CCTA and PET scans will be done before and after being treated with evolocumab. At the initial visit, standard imaging eligibility screening will take place, as well as blood sampling to test cholesterol levels and presence of proteins (biomarkers) associated with heart disease. A CCTA will be done (if not done for clinical purposes within the past 90 days) and a PET scan with administration of 18F-NaF injection will take place. Patients will receive the first injection of evolocumab and will be taught how to self-inject once or twice a month for 18 months. After the initial visit, patients will self-inject evolocumab at approximately 6, 12 and 18 months in front of a medical professional for site monitoring and re-training. Labs will be drawn to assess blood components related to heart disease. Follow-up phone calls will be made at approximately 1,3, 9, 15 months and approximately 3-7 days after their final on-site visit (18 months) to monitor safety and drug adherence. The final visit (18 months after the initial visit) will involve another PET scan, CCTA and blood collection for biomarker testing.

Official Title
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Effect of Evolocumab on Coronary Artery Plaque Volume and Composition by Coronary CTA (CCTA) and Microcalcification by F18-NaF PET: A Phase 3 Study

Conditions
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Cardiovascular Disease, Hyperlipidemia

Intervention / Treatment
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* Drug: Evolocumab
* Diagnostic Test: 18F-NaF PET
* Diagnostic Test: CCTA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence by CCTA of noncalcified coronary artery plaque (>440 mm3) and thoracic aorta atherosclerosis On-label indications for evolocumab treatment which includes the following criteria: Those who have established cardiovascular disease defined as acute coronary syndrome, history of myocardial infarction, stable angina or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin. Exclusion Criteria: Creatinine > 1.5 mg/dL prior to imaging History of allergy to iodine contrast agents Allergy to evolocumab or any other ingredients contained in study drug Pregnancy Women who are breastfeeding Active atrial fibrillation History of coronary artery bypass graft Inability to lie flat Inability or unwilling to give informed consent Major illness or life expectancy <1 year Planned coronary revascularization or major non-cardiac surgery in the next 12 months Previously or currently on evolocumab

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Early development, single-arm, prospective, open-label study of evolocumab injection in patients with calcified plaque in the coronary artery detected by CCTA. Fifty-five (55) evaluable subjects will be enrolled in the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab, F18-NaF PET, CCTA<br>Evolocumab self-administration for 18 months. Baseline (pre-treatment) and follow-up 18F-NaF PET and CCTA (possible beta-blocker and nitroglycerin, if medically safe). | Drug: Evolocumab<br>* Evolocumab: In patients without homozygous familial hypercholesterolemia (FH), evolocumab will be self-injected as follows: 140mg every 2 weeks or 420mg once a month subcutaneously. Patients with homozygous FH will be instructed to administer 420mg subcutaneously once a month by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector.<br>* Other names: PCSK9 inhibitor;Diagnostic Test: 18F-NaF PET<br>* 18F-NaF PET: Baseline (pre-treatment) and follow-up dual cardiac and respiratory-gated PET- imaging of the thoracic aorta. Dose of 250 MBq 18F-NaF intravenously.<br>* Other names: sodium fluoride PET;Diagnostic Test: CCTA<br>* CCTA: Baseline (pre-treatment) and follow-up CCTA. Bolus injection of 80-100 ml contrast (Omnipaque or Visipaque). Possible beta blocker(metoprolol)administered to achieve a target heart ≤70 beats/min (bpm) and/or 0.4 or 0.8 mg of sublingual nitroglycerin administered, if medical safe.<br>* Other names: Coronary computed tomography angiography;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in noncalcified coronary artery plaque volume (NCPV) | Compare NCPV in mm3 measured on cardiac CT images as analyzed by quantitative software between the two assessments | baseline (pre-treatment) and 18 months after of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plaque composition (fibrous, fibrofatty, fatty, and calcified) | Compare percentages of type of plaque (fibrous, fibrofatty, fatty, and calcified) within the total plaque burden on cardiac CT images as detected by quantitative software between the two assessments | baseline (pre-treatment) and 18 months after of treatment |