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Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-function: a Validation Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03489863
Recruitment Status : Completed
First Posted : April 6, 2018
Last Update Posted : March 25, 2019
Sponsor:
Collaborator:
Scott R MacKenzie Foundation
Information provided by (Responsible Party):
University of Florida

Brief Summary:

Polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme has been consistently shown to modulate clopidogrel response. Accordingly, the Food and Drug Administration (FDA) has issued a warning on the potential for reduced efficacy of clopidogrel among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest considering alternative antiplatelet therapies for these individuals.

The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by CYP2C19 genetic polymorphisms. However, to date there are no head-to-head PD comparisons between these agents among patients with different CYP2C19 genetic polymorphisms, which is currently under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 2014-12, NCT 02065479). In order to rule out play of chance findings, pharmacogenetic investigations require external validation cohorts to support the study findings. Therefore, the present randomized study is designed to serve as an external validation cohort conducted in patients with established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 LOF allele carriers.


Condition or disease Intervention/treatment Phase
Coronary Artery Disease Drug: Prasugrel Drug: Ticagrelor Phase 4

Detailed Description:

Therapeutic inhibition of platelet activation is essential for the management of ischemic cardiovascular disease. The use of platelet adenosine diphosphate (ADP) P2Y12 receptor antagonists (clopidogrel, prasugrel, and ticagrelor) in addition to aspirin are associated with a decrease in cardiovascular events in high-risk coronary artery disease (CAD) patients. Clopidogrel is the most broadly utilized P2Y12 receptor antagonist. However, among clopidogrel treated patients, there is broad variability in antiplatelet drug response which is known carry prognostic implications. Polymorphisms of the cytochrome P450 (CYP) 2C19 enzyme has been consistently shown to modulate clopidogrel response. Accordingly, the Food and Drug Administration (FDA) has issued a warning on the potential for reduced efficacy of clopidogrel among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest considering alternative antiplatelet therapies for these individuals.

The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by CYP2C19 genetic polymorphisms. However, to date there are no head-to-head PD comparisons between these agents among patients with different CYP2C19 genetic polymorphisms which is currently under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 2014-12, NCT 02065479). In order to rule out play of chance findings, pharmacogenetic investigations require external validation cohorts to support the study findings. Therefore, the present randomized study is designed to serve as an external validation cohort conducted in patients with established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of prasugrel versus ticagrelor among CYP2C19 LOF allele carriers.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-function Genotype: a Validation Study in Patients With Stable Coronary Artery Disease
Actual Study Start Date : May 30, 2018
Actual Primary Completion Date : March 20, 2019
Actual Study Completion Date : March 20, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Prasugrel
Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose).
Drug: Prasugrel
Maintenance dose will be maintained for 10±3 days.
Other Name: Effient

Active Comparator: Ticagrelor
Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose).
Drug: Ticagrelor
Maintenance dose will be maintained for 10±3 days.
Other Name: Brilinta




Primary Outcome Measures :
  1. P2Y12 Reaction Unit (PRU) [ Time Frame: at 24 hours ]
    Platelet reactivity measured by VerifyNow and reported as PRU


Secondary Outcome Measures :
  1. P2Y12 Reaction Unit (PRU) [ Time Frame: at 10 days ]
    Platelet reactivity measured by VerifyNow and reported as PRU



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Patients with CAD [defined as the presence of at least a 50% stenosis in a major epicardial vessel or major branch, or any prior coronary revascularization (PCI or coronary bypass graft surgery)] on treatment with either aspirin (81mg/day) or aspirin and clopidogrel (75m/day) for at least 30 days as per standard of care
  • Participated in UFJ 2016-14 study with genetic buccal swab test and have at least one CYP 2C19 LOF allele (CYP2C19*2 and CYP2C19*3)
  • Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.

Exclusion criteria:

  • Known allergies to prasugrel or ticagrelor
  • Weight <60kg
  • Considered at high risk for bleeding
  • Currently active bleeding
  • History of ischemic or hemorrhagic stroke or transient ischemic attack, or intracranial hemorrhage
  • Known severe hepatic dysfunction
  • On treatment with oral anticoagulant therapy (Vitamin K antagonists, dabigatran, apixaban, rivaroxaban)
  • Platelet count <80x106/mL
  • Hemoglobin <10 g/dL.
  • Creatinine Clearance <30 mL/minute
  • Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection.
  • Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with ticagrelor): CYP3A Inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin ) and CYP3A Inducers (rifampin, phenytoin, carbamazepine, and phenobarbital)
  • Pregnant or breastfeeding females

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): NCT03489863


Locations
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United States, Florida
University of Florida
Jacksonville, Florida, United States, 32209
Sponsors and Collaborators
University of Florida
Scott R MacKenzie Foundation
Investigators
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Principal Investigator: Dominick J Angiolillo, MD,PhD University of Florida

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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03489863    
Other Study ID Numbers: IRB201703338 -A
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: March 25, 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
Keywords provided by University of Florida:
clopidogrel
prasugrel
ticagrelor
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Ticagrelor
Prasugrel Hydrochloride
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs