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

Coronary Artery Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03489863
• Other study ID #: IRB201703338 -A
• Status: Completed
• Phase: Phase 4
• Start date: May 30, 2018
• Est. completion date: March 20, 2019

Study information

• Verified date: August 2020
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: March 20, 2019
• Est. primary completion date: March 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia

Intervention

Drug:
• Prasugrel
Maintenance dose will be maintained for 10±3 days.
• Ticagrelor
Maintenance dose will be maintained for 10±3 days.

Locations

Country	Name	City	State
United States	University of Florida	Jacksonville	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Scott R MacKenzie Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	P2Y12 Reaction Unit (PRU)	Platelet reactivity measured by VerifyNow and reported as PRU	at 24 hours post loading dose