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Impact of Evolocumab on the Effects of Clopidogrel in Patients With High On-Treatment Platelet Reactivity

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ClinicalTrials.gov Identifier: NCT03096288
Recruitment Status : Recruiting
First Posted : March 30, 2017
Last Update Posted : March 19, 2019
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
University of Florida

Brief Summary:

Clopidogrel is the most widely used P2Y12 receptor inhibitor and is the only agent of this class currently recommended in patients with stable coronary artery disease (CAD) undergoing PCI, and for the treatment of stroke or PAD. Pharmacodynamic (PD) studies have shown that approximately 30-40% of patients experience high on-treatment platelet reactivity (HPR) while receiving clopidogrel treatment. Importantly HPR status has been strongly associated with an increased risk of ischemic events. Multiple approaches have been advocated to reduce HPR rates. In a previous study treatment with high-dose atorvastatin in addition to double-dose clopidogrel reduced platelet reactivity significantly more than double-dose clopidogrel alone in statin-naïve patients with stable CAD and HPR. To date, the exact biological mechanisms involved in the statin modulation of platelet function are not fully understood, although likely attributed to both its lipid-lowering and non-lipid-related effects.

Evolocumab is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). The use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced the incidence of cardiovascular events. Whether the reduction in cardiovascular events is simply due to LDL reduction or might be related to other mechanisms is currently subject of investigation. Although LDL reduction with statin therapies has been associated with reduction in platelet reactivity, to date the effects on platelet aggregation of adjunctive lipid lowering with evolocumab has not been explored.

The aim of the present study is to investigate the effects of evolocumab in addition to statin therapy on HPR rates and platelet reactivity in patients with atherosclerotic cardiovascular disease (ASCVD) and HPR while on clopidogrel treatment.


Condition or disease Intervention/treatment Phase
Atherosclerotic Cardiovascular Disease Drug: Evolocumab Other: Placebo Phase 4

Detailed Description:

Clopidogrel is the most widely used P2Y12 receptor inhibitor and is the only agent of this class currently recommended in patients with stable coronary artery disease (CAD) undergoing PCI, and for the treatment of stroke or PAD. Although the efficacy of DAPT with aspirin and clopidogrel has been consistently shown in different clinical settings, rates of ischemic recurrences remain elevated despite this treatment regimen, especially in high risk patients. This has been in part attributed to the high interindividual variability in responses to clopidogrel. Pharmacodynamic (PD) studies have shown that approximately 30-40% of patients experience high on-treatment platelet reactivity (HPR) while receiving clopidogrel treatment. Importantly HPR status has been strongly associated with an increased risk of ischemic events, in particular stent thrombosis, in patients with ACS and following PCI. This underscores the need for strategies aimed to reduce HPR rates in patients treated with clopidogrel. Multiple approaches have been advocated to reduce HPR rates. The pleiotropic effects associated with lipid lowering therapies, in particular statins, have been subject to extensive research. In a previous study treatment with high-dose atorvastatin in addition to double-dose clopidogrel reduced platelet reactivity significantly more than double-dose clopidogrel alone in statin-naïve patients with stable CAD and HPR. To date, the exact biological mechanisms involved in the statin modulation of platelet function are not fully understood, although likely attributed to both its lipid-lowering and non-lipid-related effects.

Evolocumab is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously (s.c.) at a dosage of 140 mg every 2 weeks or 420 mg once monthly. In clinical trials evolocumab was more effective than placebo and/or ezetimibe in reducing LDL cholesterol, including when added to statin therapy. The use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced the incidence of cardiovascular events. Whether the reduction in cardiovascular events is simply due to LDL reduction or might be related to other mechanisms is currently subject of investigation. Although LDL reduction with statin therapies has been associated with reduction in platelet reactivity, to date the effects on platelet aggregation of adjunctive lipid lowering with evolocumab has not been explored.

The aim of the present study is to investigate the effects of evolocumab in addition to statin therapy on HPR rates and platelet reactivity in patients with atherosclerotic cardiovascular disease (ASCVD) and HPR while on clopidogrel treatment.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind, placebo-controlled
Primary Purpose: Treatment
Official Title: Impact of the PCSK9 Inhibitor Evolocumab on the Pharmacodynamic Effects of Clopidogrel in Patients With Atherosclerotic Cardiovascular Disease and High On-Treatment Platelet Reactivity
Actual Study Start Date : September 18, 2017
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Atherosclerosis

Arm Intervention/treatment
Experimental: Evolocumab
Evolocumab (Repatha) 420 mg s.c. single injection
Drug: Evolocumab
Patients will be randomly assigned to receive a single dose of either evolocumab 420 mg s.c. or placebo (0.9% sodium chloride s.c. injection).
Other Name: Repatha

Placebo Comparator: Placebo
0.9% sodium chloride s.c. single injection
Other: Placebo
Patients will be randomly assigned to receive a single dose of either evolocumab 420 mg s.c. or placebo (0.9% sodium chloride s.c. injection).




Primary Outcome Measures :
  1. HPR rate by VerifyNow [ Time Frame: 30 days ]
    The primary end point of our study is the comparison of HPR rate measured by VerifyNow PRU (PRU>208) between evolocumab and placebo at 30 days after randomization.


Secondary Outcome Measures :
  1. HPR rate by light transmittance aggregometry (LTA) [ Time Frame: 30 days ]
    The secondary end point of our study is the comparison of HPR rate measured by LTA using ADP as agonist between evolocumab and placebo at 30 days after randomization.



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:

  1. Patients with atherosclerotic cardiovascular disease (ASCVD), defined as prior ACS, history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or PAD presumed to be of atherosclerotic origin.
  2. On therapy with clopidogrel (75mg od), with or without low-dose aspirin (81mg od), as per standard-of-care for at least 30 days.
  3. HPR, defined as P2Y12 reaction units (PRU) > 208 by VerifyNow P2Y12.
  4. Fasting LDL-cholesterol ≥70 mg/dL or a non-high-density lipoprotein cholesterol (HDL-C) of ≥100 mg/dL after ≥2 weeks of optimized stable lipid-lowering therapy with maximally tolerated dose of statin, which would ideally include a high-intensity statin, but must be at least moderate intensity statin (i.e. atorvastatin 20 mg or equivalent, with or without ezetimibe. Maximal tolerated dose will be defined based on patient clinical history (no statin re-challenge will be performed).
  5. Age ≥ 18 years old.

Exclusion criteria:

  1. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban).
  2. On treatment with any antiplatelet agent other than aspirin and clopidogrel in the past 14 days.
  3. Use of PCSK9 inhibitors in the past 90 days
  4. Creatinine clearance <30 mL/minute.
  5. Known severe hepatic impairment.
  6. History of a serious hypersensitivity reaction to evolocumab
  7. Hemodynamic instability
  8. Pregnant and breastfeeding women [women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study].

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): NCT03096288


Contacts
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Contact: Dominick Angiolillo, MD, PhD +1-904-244-3378 dominick.angiolillo@jax.ufl.edu
Contact: Andrea Goosen, MPH, CCRP +1-904-244-5617 Andrea.Goosen@jax.ufl.edu

Locations
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United States, Florida
University of Florida Recruiting
Jacksonville, Florida, United States, 32209
Contact: Dominick J Angiolillo, MD, PhD       dominick.angiolillo@jax.ufl.edu   
Principal Investigator: Dominick J Angiolillo, MD, PhD         
Sponsors and Collaborators
University of Florida
Amgen
Investigators
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Principal Investigator: Dominick Angiolillo, MD, PhD University of Florida College of Medicine-Jacksonville

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03096288     History of Changes
Other Study ID Numbers: IIS AMG001
First Posted: March 30, 2017    Key Record Dates
Last Update Posted: March 19, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Platelet Aggregation Inhibitors
Cardiovascular Diseases
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Clopidogrel
Evolocumab
Antibodies, Monoclonal
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Immunologic Factors