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

Study Overview
=================
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.

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.

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

Conditions
-----------------
Coronary Artery Disease

Intervention / Treatment
-----------------
* Drug: Prasugrel
* Drug: Ticagrelor


Participation Criteria
=================
Eligibility 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prasugrel<br>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<br>* Maintenance dose will be maintained for 10±3 days.<br>* Other names: Effient;|
| Active Comparator: Ticagrelor<br>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<br>* Maintenance dose will be maintained for 10±3 days.<br>* Other names: Brilinta;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P2Y12 Reaction Unit (PRU) | Platelet reactivity measured by VerifyNow and reported as PRU | at 24 hours post loading dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
clopidogrel, prasugrel, ticagrelor