Evolocumab in Acute Coronary Syndrome

Study Overview
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Brief Summary
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Vascular and myocardial inflammation are significantly increased in Acute Coronary Syndrome (ACS) patients, are closely correlated to LDL-C levels, and are associated with these adverse consequences in the post-ACS patient population. Serum proprotein convertase subtilisin/kerin type 9 (PCSK9) levels are also increased in ACS, may raise LDL-C, and the investigators' pre-clinical studies indicate that PCSK9 is also a potent inducer of vascular inflammation. The addition of the PCSK9 antibody evolocumab, currently approved to lower LDL-C in certain patient populations, to current medical therapies would appear to be of particular benefit in an important subset of ACS patients, those with non-ST elevation myocardial infarction (NSTEMI) by markedly reducing LDL-C, stabilizing vulnerable plaque, and limiting inflammation-associated myocardial cell loss and resultant dysfunction.

Detailed Description
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In a placebo-controlled, randomized double blind trial, the addition of evolocumab to standard care in NSTEMI patients (1) decreases LDL-C during hospitalization and at 30 days, (2) decreases vascular/plaque and myocardial inflammation as assessed by Positron Emission Tomography (PET) scanning at 30 days, and improves (3) serum markers of endothelial function at hospital discharge and at 30 days, and (4) echocardiographic assessment of left ventricular function at 30 days and six months. This is the first PCSK9 inhibitor trial which examines these outcomes in the ACS patient population. It will provide valuable data on the extent and time course of LDL-C reduction as well as the impact of inhibition on inflammatory markers and on imaging assessment of vascular and myocardial inflammation, all of which may significantly impact important clinical outcomes in this high risk patient cohort.

Official Title
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Evolocumab in Acute Coronary Syndrome: A Double-Blind Randomized Placebo Controlled Study

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Evolocumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non ST segment elevation myocardial infarction Troponin I >/ 5.0 ng/dL Permission of attending physician Exclusion Criteria: ST elevation myocardial infarction Patients requiring invasive hemodynamic support Scheduled for cardiac surgery Current or prior treatment with a PCSK9 antibody Current participation in an intervention clinical trial Female of childbearing potential who has not used acceptable method(s) of birth control for at least one month prior to screening Contraindication to statin therapy Subject likely not able to complete protocol related visits or procedures Latex allergy History of hypersensitivity to any monoclonal antibody

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 90 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, placebo controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab<br>420 mg evolocumab administered subcutaneously using an autoinjector/pen in NSTEMI patients within 24 hours, or one day, of admission. | Drug: Evolocumab<br>* 420 mg evolocumab administered subcutaneously using an autoinjector/pen in NSTEMI patients within 24 hours, or one day, of admission.<br>* Other names: Repatha;|
| Placebo Comparator: Placebo<br>Placebo administered subcutaneously using an autoinjector/pen in NSTEMI patients within 24 hours, or one day, of admission. | Drug: Placebo<br>* Placebo administered subcutaneously using an autoinjector/pen in NSTEMI patients within 24 hours, or one day, of admission.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LDL-Cholesterol | The mean percent change from baseline in LDL-C comparing placebo and evolocumab groups at 30 days | 30 days | 
| PET Imaging for inflammation | Change from baseline in target to background ratio Fluorodeoxyglucose (FDG) PET scans in the myocardium, aorta and / or carotid artery between the two treatment groups. | 30 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular volume as assessed by echocardiography | Evaluation of left ventricular volume (ml) by echocardiography | Baseline, day 30 and 6 months | 
| Change in ejection fraction as assessed by echocardiography | Evaluation of ejection fraction (%) by echocardiography | Baseline, day 30 and 6 months | 
| Change in plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels (ng/ml) | Change from baseline in PCSK9 serum levels | Baseline, day 30 and 6 months | 
| Change in plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) | Change from baseline in plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) (pg/ml) | Baseline, day 30 and 6 months | 
| PET-FDG assessed vascular inflammation | Target artery to background ratio endpoint [standardized uptake value] for carotid artery or aorta | Baseline and day 30 | 
| Change in New York Heart Association (NYHA) Class | Assess NYHA class I-IV | Baseline, day 30 and 6 months | 
| Change in high sensitivity C-reactive protein (hs-CRP) serum levels | Change from baseline in hs-CRP serum levels (mg/L) | Baseline, day 30 and 6 months | 
| Change in tumor necrosis factor (TNF)-alpha serum levels | Change from baseline in TNF-alpha serum levels (pg/mL) | Baseline, day 30 and 6 months | 
| Change in plasma levels of Interleukin 1 | Change from baseline in serum levels of Interleukin 1 (pg/mL) | Baseline, day 30 and 6 months | 
| Change in serum levels of Interleukin 6 | Change in baseline in serum levels of Interleukin 6 (pg/mL) | Baseline, day 30 and 6 months | 
| Change in serum levels of Interleukin 10 | Change in baseline in serum levels of Interleukin 10 (pg/mL) | Baseline, day 30 and 6 months | 
| Change in Canadian Angina Class | Assess Canadian Angina Classification, I-IV | Baseline, 30 days, 6 months |