CES1 Carriers in the PAPI Study

Study Overview
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Brief Summary
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This study builds, in part, upon preliminary results generated as part of the Pharmacogenomics Anti-Platelet Intervention (PAPI) Study (NCT00799396). The purpose of this investigation is to assess the impact of genetic variation in the carboxylesterase 1 (CES1) on response to clopidogrel as well as dual antiplatelet therapy (i.e. clopidogrel and aspirin), as assessed by ex vivo platelet aggregometry, in healthy Amish individuals. The investigators hypothesize that participants who carry alleles that modify the activity or expression of CES1 will have altered response to clopidogrel as well as dual antiplatelet therapy.

Official Title
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Enrichment of CES1 Carriers in the Pharmacogenomics Anti-Platelet Intervention Study

Conditions
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Heart Diseases, Coronary Disease, Coronary Artery Disease, Cardiovascular Diseases, Myocardial Ischemia, Artery Occlusion, Aspirin Sensitivity, Clopidogrel, Poor Metabolism of, Platelet Dysfunction, Platelet Thrombus

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 20 years or older Of Old Order Amish descent Exclusion Criteria: Currently pregnant or less than 6 months have passed since delivery Currently breast feeding Has a history of a bleeding disorder or major spontaneous bleed, such as peptic ulcer, epistasis, or intracranial bleed Has severe hypertension, defined by a blood pressure above 160/95 mm Hg Takes medications that would affect the outcome(s) to be measured and cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation Is taking vitamins or other supplements and is unwilling to discontinue use for at least 1 week prior to study Has a coexisting malignancy Has a creatinine level greater than 2.0 mg/dl, aspartate transaminase (AST) or alanine transaminase (ALT) greater than two times the upper limit of normal, hematocrit less than 32%, or a thyroid-stimulating hormone (TSH) less than 0.4 or greater than 5.5 mIU/L Has a bleeding disorder or history of gastrointestinal bleeding or other major bleeding episode Is currently taking aspirin, clopidogrel, or anti-coagulants, such as warfarin, heparin, or GPIIb/IIIa antagonists, and have conditions that might place the participant at increased risk from withdrawal of these medications 14 days prior to protocol initiation History of unstable angina, heart attack, angioplasty (including stent placement), coronary artery bypass surgery, atrial fibrillation, stroke or transient ischemic attacks, diabetes, or deep vein thrombosis or other thrombosis Has polycythemia, or thrombocytosis, defined by a platelet count greater than 500,000 Has thrombocytopenia, defined by a platelet count less than 75,000 Has had surgery within the last 6 months Has an aspirin or clopidogrel allergy

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: The investigators will enroll up to 50 healthy Amish participants who have been identified through existing whole genome and exome sequencing along with bioinformatic approaches that have genetic variants that are predicted to significantly impact CES1 expression or catalytic function. Enrolled participants will undergo a two-stage intervention with clopidogrel (300 mg loading dose then 75 mg per day for the next 6 days), followed by clopidogrel (75 mg) plus aspirin 324 mg for 1 day. Platelet aggregation studies and other measures of platelet function will be performed before and after each intervention. In combination with previously collected data as part of the PAPI Study, the investigators will then characterize the impact of genetic variation in CES1 on clopidogrel and dual antiplatelet therapy response through single- and multi-variant association modeling.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Overall Cohort<br>Participants will receive clopidogrel treatment alone (300 mg loading dose followed by 75 mg/d for 6 days), followed by clopidogrel (75 mg) plus aspirin (324 mg) treatment on day 8. | Drug: Clopidogrel<br>* Participants will receive 300 mg of clopidogrel on the first day, then 75 mg per day for the next 6 days. Measures of pharmacodynamics will be assessed pre- and post-drug administration.<br>* Other names: Plavix;Drug: Aspirin<br>* Participants will receive a single dose of 324 mg aspirin on the last day of clopidogrel administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Platelet Function in Response to Clopidogrel | Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel administration but before aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change. | Measured at baseline and after 8 days of clopidogrel treatment | 
| Changes in Platelet Function in Response to Clopidogrel Plus Aspirin | Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel and aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change. | Measured at baseline and after 8 days clopidogrel administration plus 1 day of aspirin treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacogenetics, carboxylesterase, Personalized Medicine