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Effect of Evolocumab on Saphenous Vein Graft Patency Following Coronary Artery Bypass Surgery (NEWTON-CABG)

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ClinicalTrials.gov Identifier: NCT03900026
Recruitment Status : Recruiting
First Posted : April 2, 2019
Last Update Posted : July 13, 2020
Sponsor:
Collaborator:
Applied Health Research Centre
Information provided by (Responsible Party):
Unity Health Toronto

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Coronary Artery Bypass Graft Surgery Atherosclerosis Vein Occlusion Drug: Evolocumab Other: Placebo Phase 4

Detailed Description:

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 766 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter, double-blind, randomized, placebo-controlled, parallel group study of evolocumab.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Randomized Trial of Evolocumab on Saphenous Vein Graft Patency Following Coronary Artery Bypass Surgery (NEWTON-CABG)
Actual Study Start Date : May 30, 2019
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : December 1, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Evolocumab

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo Treatment
Participants will receive subcutaneous injections of the placebo Q2W (every 2 weeks)
 Other: Placebo
Placebo cartridges will contain vehicle only; placebo will be administered via subcutaneous injection.
Other Name: Control
Experimental: Evolocumab Treatment
Participants will receive subcutaneous injections of 140mg of evolocumab Q2W (every two weeks)
 Drug: Evolocumab
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
Other Name: Repatha®


Outcome Measures
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Primary Outcome Measures :
  1. Saphenous vein graft disease rate (VGDR) [ Time Frame: 24 months post CABG ]
    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.


Secondary Outcome Measures :
  1. The proportion of patients with at least 1 vein graft totally (100%) occluded. [ Time Frame: 24 months post CABG ]
    Proportion of patients who have at least 1 totally (100%) occluded vein graft at 24 months post CABG.

  2. The percentage of vein grafts which are totally (100%) occluded grafts. [ Time Frame: 24 months post CABG ]
    Percentage of vein grafts that are totally (100%) occluded at 24 months post CABG.


Other Outcome Measures:
  1. Composite rate of fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, cardiovascular death, coronary heart disease death, repeat coronary revascularization [ Time Frame: 24 months post CABG ]
    composite rate of occurrence of the above mentioned clinical outcomes at 24 months post CABG.

  2. Rate of fatal and non-fatal myocardial infarction. [ Time Frame: 24 months post CABG ]
    Rate of occurrence of the above mentioned clinical outcome at 24 months post CABG.

  3. Rate of fatal and non-fatal stroke. [ Time Frame: 24 months post CABG ]
    Rate of occurrence of the above mentioned clinical outcome at 24 months post CABG.

  4. Rate of cardiovascular death. [ Time Frame: 24 months post CABG ]
    Rate of occurrence of the above mentioned clinical outcome at 24 months post CABG.

  5. Rate of coronary heart disease death. [ Time Frame: 24 months post CABG ]
    Rate of occurrence of the above mentioned clinical outcome at 24 months post CABG.

  6. Rate of repeat coronary revascularization. [ Time Frame: 24 months post CABG ]
    Rate of occurrence of the above mentioned clinical outcome at 24 months post CABG.

  7. Rate of all-cause mortality. [ Time Frame: 24 months post CABG ]
    Proportion of patients who have died at 24 months post CABG.

  8. Rate of total vein graft patency at 24 months. [ Time Frame: 24 months post CABG ]
    Rate of total vein graft patency defined as 1-VGDR at 24 months post CABG.

  9. Percentage of patients free of vein graft disease at 24 months. [ Time Frame: 24 months post CABG ]
    Percentage of patients who are free of vein graft disease at 24 months defined as having no vein grafts with ≥ 50% stenosis.

  10. Vein graft plaque volume. [ Time Frame: 24 months post CABG ]
    Volume of vein graft plaque at 24 months post CABG.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria - To be considered eligible for participation in this study, a participant must satisfy each of the following criteria:

  1. Age ≥ 18 years
  2. Scheduled to undergo coronary artery bypass graft (CABG) surgery (with or without cardiopulmonary bypass (CPB); with or without single valve repair/replacement)
  3. CABG procedure included/planned to include at least two saphenous vein grafts
  4. CABG procedure occurred within the past 21 days, or is planned within the next 60 days
  5. 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:

  1. Patients in whom additional lowering of LDL-C with evolocumab is deemed to be clinically inappropriate
  2. Allergy to contrast dye
  3. Known severe hepatic impairment (Childs-Pugh, Class C).
  4. Known renal disease with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2
  5. Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow)
  6. Use of cholesterylester transfer protein (CETP) inhibition treatment within 12 months prior to randomization.
  7. Current, prior within past year, or known planned use of PCSK9 inhibition treatment
  8. Severe cardiovascular or concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 2 years
  9. Major active infection, or major hematologic, renal, respiratory, metabolic, gastrointestinal or endocrine dysfunction
  10. Women who are pregnant or breastfeeding
  11. 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.
  12. Known intolerance or allergy to evolocumab or other PCSK9 inhibitors.
  13. Currently taking simvastatin >40mg/day, niacin or bile acid sequestrants
  14. Known latex allergy
  15. Inability to comply with protocol-required study visits or procedures, including administration of study drug
  16. 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)
  17. 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
  18. NYHA class IV
  19. Pacemaker or other implantable device implanted within 30 days prior to screening

Additional postoperative exclusion criteria:

  1. Received only <2 vein grafts
  2. Major peri-operative complications following CABG surgery (e.g. stroke, MI, renal failure requiring dialysis, or postoperative ICU stay > 5 days) prior to randomization
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03900026


Contacts
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Contact: Danusha Nandamalavan 416-864-6060 ext 77038 NandamalavaD@smh.ca

Locations
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United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06511
Contact: Kimberly Kunze    203-737-2150    kim.kunze@yale.edu   
Principal Investigator: Umer Darr         
United States, Florida
Jacksonville Center for Clinical Research Recruiting
Jacksonville, Florida, United States, 32216
Contact: Heather Burns    904-576-0166    heathburns@encoredocs.com   
Principal Investigator: Michael Koren         
United States, Maine
Maine Medical Center Recruiting
Portland, Maine, United States, 04102
Contact: Betsey Gallant       WIGHTA@mmc.org   
Contact    207-662-1489      
Principal Investigator: Robert Kramer         
Canada, Alberta
University of Alberta Recruiting
Edmonton, Alberta, Canada, T6G 2R8
Contact: Maliha Muneer    780-407-8614    muneer@ualberta.ca   
Principal Investigator: Andrew Shaw         
Canada, Ontario
Hamilton Health Sciences Recruiting
Hamilton, Ontario, Canada
Contact: Courtney Mullen    905.521.2100 ext 44342    Courtney.Mullen@phri.ca   
Principal Investigator: Richard Whitlock         
Kingston Health Sciences Centre Recruiting
Kingston, Ontario, Canada, K7L 2V7
Contact: Deborah DuMerton    613-549-6666 ext 3224    Deborah.DuMerton@kingstonhsc.ca   
Principal Investigator: Tarit Saha         
St. Michael's Hospital Recruiting
Toronto, Ontario, Canada, M5B 1W8
Contact: Shira Brodutch    416-864-6060 ext 49419    Shira.Brodutch@unityhealth.to   
Canada, Quebec
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval Recruiting
Québec, Quebec, Canada
Contact: Hugo Tremblay    418-656-8711 ext 3797    hugo.tremblay@criucpq.ulaval.ca   
Principal Investigator: Francois Dagenais         
Canada
Foothills Medical Centre Recruiting
Calgary, Canada
Contact: Karen Maier       Karen.Maier@albertahealthservices.ca   
Principal Investigator: Alex Gregory         
Sponsors and Collaborators
Unity Health Toronto
Applied Health Research Centre
Investigators
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Principal Investigator: David Mazer, MD Unity Health Toronto
Principal Investigator: Subodh Verma, MD Unity Health Toronto
Study Chair: Lawrence Leiter, MD Unity Health Toronto
More Information
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Responsible Party: Unity Health Toronto
ClinicalTrials.gov Identifier: NCT03900026    
Other Study ID Numbers: NEWTON CABG (Cardiolink-007)
First Posted: April 2, 2019    Key Record Dates
Last Update Posted: July 13, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Unity Health Toronto:
Coronary Artery Bypass Surgery
CABG
Saphenous Vein Graft
Evolocumab
Repatha
Additional relevant MeSH terms:
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Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Evolocumab
PCSK9 Inhibitors
Anticholesteremic Agents
 Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Lipid Regulating Agents