Effect of Evolocumab on Coronary Plaque Characteristics

Study Overview
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Brief Summary
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The aim of the study is to assess the effect of evolocumab on coronary plaque morphology using intravascular imaging and gene expression analysis of peripheral blood mononuclear cells (PBMC) in patients with stable CAD on maximally tolerated statin therapy. The study combines multi-modality intravascular imaging approaches and transcriptomic based machine learning algorithms to uncover molecular mechanisms responsible for the beneficial changes in atherosclerotic lesions of patients treated with evolocumab. The primary end-points are the changes from baseline to follow-up in (1) the minimal fibrous cap thickness (FCT) assessed by optical coherence tomography (OCT) and (2) maxLCBI4mm assessed by near-infrared spectroscopy (NIRS) after 26 weeks of evolocumab. The secondary endpoints are the changes in (1) the maximal lipid arc, lipid length, lipid volume index, macrophage accumulation and calcification by OCT; (2) PAV and TAV defined by intravascular ultrasound (IVUS) and (3) Changes in PBMC gene expression.

Detailed Description
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The single center single arm study will be performed in the Cardiac Catheterization laboratory of the Mount Sinai Hospital, New York, NY. After informed consent, patients undergoing clinically indicated elective PCI with a non-obstructive lesion and optimal background statin therapy will be eligible screening. Non-obstructive lesions (30-50% stenosis) identified by angiography in a non-culprit vessel with lipid-rich plaque will be studied. Subjects will receive evolocumab (Repatha) 140 mg subcutaneously every 2 weeks for 26 weeks. Serial NIRS/IVUS and OCT imaging will be performed in the non-obstructive lesions, first during PCI and subsequently after 26 weeks. A total of 25ml of blood will be drawn from the sheath during angiography for transcriptomic profiling of PBMC.

Official Title
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Effect of Evolocumab on Coronary Plaque Characteristics: a Multimodality Imaging Study

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Evolocumab Injections


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Men or women aged 18 years or older at screening who signed written Informed Consent Patients with coronary artery disease undergoing cardiac catheterization and PCI for a target lesion and also have a non-obstructive lesion (30-50% stenosis) identified by angiography Patients who are not candidates for PCI or CABG currently or over the next 12 months, in the opinion of the investigator Patients treated with statins for at least 4 weeks with LDL-C level ≥ 80 mg/dL for low- or moderate -intensity statin use and ≥ 60 mg/dL for high-dose statin. Patients with history of statin intolerance and LDL-C ≥ 100 mg/dL. Angiographic criteria: 30-50% reduction of lumen diameter in addition to the target lesion accessible by the OCT catheter. The target segment should not have a history of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and may not be a bypass graft. OCT criteria: target segment should have a lipid-rich plaque with lipid arc >90° and fibrous cap thickness ≤120 µm. Women of childbearing potential must agree to be on an acceptable method of birth control/contraceptive Exclusion criteria: Patients who have acute myocardial infarction (Q wave or non-Q wave with CK-MB > 5 times above the upper normal (31.5 ng/ml) within 72 hours) Patients who are in cardiogenic shock Patients with left main disease, in-stent restenotic lesions or patients requiring coronary artery bypass graft surgery Patients with elevated CK-MB (>6.3 ng/ml) or Tnl (>0.5 ng/ml) Patients with platelet count < 100,000 cell/mm3 Patients who have co-morbidity which reduces life expectancy to one year Patients who are currently participating in another investigational drug/device study Patients with liver disease Patient with creatinine > 2.0 mg/dL Pregnant women and women of childbearing potential who intend to have children during the duration of the trial Patients having undergone heart transplantation, or those that may undergo heart transplantation during the study period Patients with active autoimmune disease

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: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: The study team will screen patients scheduled for elective PCI, who are receiving statin therapy for at least 4 weeks with acceptable LDL-C levels. Patients with non-obstructive lesion (30-50% stenosis) by angiography and lipid-rich plaque with lipid arc >90° and minimal fibrous cap thickness ≤ 120 µm detected by OCT will comprise the final study population. Serial NIRS/IVUS and OCT imaging will be performed in a non-target lesions, first during PCI and subsequently after 26 weeks.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Evolocumab subcutaneously administered 140 mg every 2 weeks for 26 weeks | Drug: Evolocumab Injections<br>* Administered on day 1 (the day of the first treatment) and through week 26 with a personal injector or prefilled auto injector/pens.<br>* Other names: Repatha;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Minimal Fibrous Cap Thickness (FCT) | Changes in the minimal Minimal Fibrous Cap Thickness (FCT) is assessed by Optical Coherence Tomography (OCT) imaging and measured in microns. FCT describes plaque morphology composition. | Baseline and 26 Weeks | 
| Number of Participants With FCT <65 µm |  | Baseline and 26 Weeks | 
| Number of Participants With Increased Fibrous Cap |  | 26 weeks | 
| Change in maxNIRS4mm | Changes in maximal lipid-core burden index within 4 mm (maxLCBI4mm). LCBI4mm is assessed by NIRS and calculated as the fraction of yellow pixels on a chemogram multiplied by 1000. Each pixel on the chemogram represents a probability of lipid presence in the given region; pixels are color-coded on a red-to-yellow color scale, with the low probability of lipid shown as red and the high probability of lipid shown as yellow. Maximal lipid-core burden index is calculated as a fraction of yellow pixels (representing lipid) obtained from the NIRS chemogram multiplied by 1000. It ranges is from 0 to 1000 and represents the amount of lipid in the investigated segment with 0 corresponding to no lipid and 1000 representing all lipid lesion. | Baseline and 26 Weeks | 
| Number of Participants With Decreased maxLCBI4mm |  | 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Maximal Lipid Arc | Change in Maximal lipid arc assessed by OCT and measured in degrees. | Baseline and 26 Weeks | 
| Change in Lipid Length | Change in Lipid length by OCT, measured in millimeters. | Baseline and 26 weeks | 
| Change in Lipid Volume Index (LVI) | Change in Lipid Volume Length (LVI) calculated as the average lipid arc multiplied by lipid length assessed by OCT. | Baseline and 26 Weeks | 
| Change in Macrophage Accumulation | Change in the prevalence of Macrophage accumulation (maximum and average) by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.) | Baseline and 26 Weeks | 
| Change in Macrophage Volume Index | Change in the Macrophage Volume Index by OCT, a marker of inflammation (expressed as frequency of the presence of macrophages in lesions.) | Baseline and 26 Weeks | 
| Change in Macrophage Length |  | Baseline and 26 Weeks | 
| Change in Calcification Accumulation | Change in Calcification accumulation by OCT expressed as frequency of the presence of calcification in lesions. | Baseline and 26 Weeks | 
| Change in Calcium Length |  | Baseline and 26 Weeks | 
| Change in Percent Atheroma Volume (PAV) | Change in PAV assessed by Intravascular Ultrasound (IVUS). PAV characterizes coronary plaque burden and calculated as the proportion of total vessel wall volume occupied by atherosclerotic plaque. The percent atheroma volume is calculated as the proportion of total vessel wall volume occupied by atherosclerotic plaque - plaque volume divided by vessel volume and multiplied by 100. | Baseline and 26 weeks | 
| Change in Total Atheroma Volume (TAV) | Change in TAV assessed by IVUS. TAV characterizes the total volume of coronary plaque. | Baseline and 26 Weeks | 
| Change in PBMC Gene Expression | Change in PBMC gene expression. Messenger RNA sequencing data will be processed using statistical and bioinformatics analyses. | Baseline and 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Disease, Coronary Plaque, Optical Coherence Tomography, Near-Infrared Spectroscopy, Evolocumab, Statin