Effect of Evolocumab on Saphenous Vein Graft Patency Following Coronary Artery Bypass Surgery

Study Overview
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Brief Summary
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The purpose of this study is to determine if evolocumab added to regular statin therapy improves vein graft patency after coronary artery bypass graft (CABG) surgery.

Detailed Description
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Coronary artery bypass graft (CABG) surgery is a procedure in which an artery or vein from the body is grafted to a critically narrowed coronary artery to restore flow of oxygenated blood to the heart. Statins are frequently prescribed after CABG surgery in order to lower LDL cholesterol levels and reduce the chances of coronary artery obstruction recurring. Despite this preventive measure, new vein grafts do end up becoming blocked in a significant proportion of patients. Evolocumab (Repatha®) is a recently approved medication that has been shown to effectively lower LDL cholesterol levels in the blood. NEWTON-CABG is an investigator-initiated multicenter, double-blind, randomized, placebo-controlled, parallel group study of evolocumab [140mg administered subcutaneously (SC) every two weeks (Q2W)] added to statin therapy for 24 months postoperatively in a broad population of patients undergoing CABG surgery. Eligible subjects will be randomized to receive evolocumab or placebo within 21 days of index CABG. Prior to randomization, post-operative patients will be on moderate or high intensity statin therapy (atorvastatin 40-80mg, rosuvastatin 20-40mg or simvastatin 40mg daily unless another statin/dose or non-statin alternative is clinically justified). A CTAngiogram will be conducted at 24 months following CABG. Routine study visits will be done 3, 6, 12, 18 and 24 months post-surgery. This study is supported by Amgen Inc.

Official Title
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A Randomized Trial of Evolocumab on Saphenous Vein Graft Patency Following Coronary Artery Bypass Surgery (NEWTON-CABG)

Conditions
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Coronary Artery Bypass Graft Surgery, Atherosclerosis, Vein Occlusion

Intervention / Treatment
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* Drug: Evolocumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - To be considered eligible for participation in this study, a participant must satisfy each of the following criteria: Age ≥ 18 years Scheduled to undergo coronary artery bypass graft (CABG) surgery (with or without cardiopulmonary bypass (CPB); with or without single valve repair/replacement) CABG procedure included/planned to include at least two saphenous vein grafts CABG procedure occurred within the past 21 days, or is planned within the next 60 days On a moderate to high intensity statin therapy (defined as atorvastatin 40-80mg daily, rosuvastatin 20-40mg or simvastatin 40mg daily) unless a lower dose, or another statin or non-statin therapy is clinically justified Exclusion Criteria - A participant will be ineligible for participation in this study if he or she satisfies any one or more of the following criteria: Patients in whom additional lowering of LDL-C with evolocumab is deemed to be clinically inappropriate Allergy to contrast dye Known severe hepatic impairment (Childs-Pugh, Class C). Known renal disease with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow) Use of cholesterylester transfer protein (CETP) inhibition treatment within 12 months prior to randomization. Current, prior within past year, or known planned use of PCSK9 inhibition treatment Severe cardiovascular or concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 2 years Major active infection, or major hematologic, renal, respiratory, metabolic, gastrointestinal or endocrine dysfunction Women who are pregnant or breastfeeding Women of child bearing potential who are unwilling to use proper family planning or birth control methods to avoid pregnancy. Women are considered post-menopausal and not of childbearing potential after 12 months of natural (spontaneous) amenorrhea or have had a surgical procedure such as hysterectomy which makes pregnancy impossible. Known intolerance or allergy to evolocumab or other PCSK9 inhibitors. Currently taking simvastatin >40mg/day, niacin or bile acid sequestrants Known latex allergy Inability to comply with protocol-required study visits or procedures, including administration of study drug Known history of cancer within the past 5 years (except for carcinoma in-situ of the cervix, stage 1 prostate cancer or adequately treated non-melanoma carcinomas of the skin) Participation in another investigational device or drug study which is likely to affect the primary outcome, within 30 days of planned initiation of study drug NYHA class IV Pacemaker or other implantable device implanted within 30 days prior to screening Additional postoperative exclusion criteria: Received only <2 vein grafts Major peri-operative complications following CABG surgery (e.g. stroke, MI, renal failure requiring dialysis, or postoperative ICU stay > 5 days) prior to randomization

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, double-blind, randomized, placebo-controlled, parallel group study of evolocumab.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Treatment<br>Participants will receive subcutaneous injections of the placebo Q2W (every 2 weeks) | Other: Placebo<br>* Placebo cartridges will contain vehicle only; placebo will be administered via subcutaneous injection.<br>* Other names: Control;|
| Experimental: Evolocumab Treatment<br>Participants will receive subcutaneous injections of 140mg of evolocumab Q2W (every two weeks) | Drug: Evolocumab<br>* REPATHA (evolocumab) is a human immunoglobulin G2 (IgG2) monoclonal antibody that has high affinity binding to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9); it will be administered via subcutaneous injection<br>* Other names: Repatha®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saphenous vein graft disease rate (VGDR) | Saphenous vein graft disease rate (VGDR) is defined as the proportion of vein grafts with significant stenosis or total occlusion (≥50%) on 64-slice (or greater) cardiac CT angiography (CTA) or clinically indicated coronary angiography. | 24 months post CABG | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with at least 1 vein graft totally (100%) occluded. | Proportion of patients who have at least 1 totally (100%) occluded vein graft at 24 months post CABG. | 24 months post CABG | 
| The percentage of vein grafts which are totally (100%) occluded grafts. | Percentage of vein grafts that are totally (100%) occluded at 24 months post CABG. | 24 months post CABG | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Bypass Surgery, CABG, Saphenous Vein Graft, Evolocumab, Repatha