Clopidogrel Pharmacogenetics (PGX) Bench to Bedside

Study Overview
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Brief Summary
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Clopidogrel (also known as Plavix) is used commonly in patients to prevent heart attacks and conditions caused by blood clots. Although clopidogrel works in many individuals, some people do not respond as well to this drug. The variation in treatment response may be linked to genetics. This study will examine the effects of clopidogrel in a population in which sequencing for certain genes has been performed in order to determine the role that genes play in the response to various clopidogrel maintenance doses.

Detailed Description
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Clopidogrel is a prodrug with high inter-individual response variability. Clopidogrel is converted to an active drug in part through an enzyme encoded by the gene named CYP2C19. Individuals with genetically-impaired CYP2C19 metabolism have lower capacity to convert the prodrug to its active form. Consequently, these individuals have lower blood levels of the activated form of clopidogrel, diminished antiplatelet responses, and higher rates of cardiovascular events and stent thrombosis. Increasing doses of clopidogrel in such patients represents a possible approach to managing the gene-drug interaction. The purpose of this study is to evaluate whether increasing the dose of clopidogrel increases antiplatelet responses and active metabolite exposure in individuals with genetically reduced CYP2C19 metabolism relative to those with normal CYP2C19 metabolism. The primary objective is to assess changes in clopidogrel response and exposure at three clopidogrel dose levels and with coadministration of omeprazole.

Official Title
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Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application

Conditions
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Metabolism of Clopidogrel

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Omeprazole/Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Amish men or women between 20 and 70 years of age who participated in PAPI Exclusion Criteria: Severe hypertension (bp > 160/95 mm Hg) Co-existing malignancy Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 2 times normal Creatinine >2.0 Hct < 32 or Hct > 50 Thyroid Stimulating Hormone (TSH) < 0.40 or >5.50 History of bleeding disorder or gastrointestinal bleeding History of unstable angina, myocardial infarction (MI), angioplasty, coronary artery bypass surgery History of atrial fibrillation, stroke or transient ischemic attacks or deep vein thrombosis Type 2 diabetes Thrombocytosis (platelet count > 500,000) or thrombocytopenia (platelet count < 150,000) Surgery within six months Clopidogrel allergy Pregnant women Currently breast feeding Omeprazole allergy Prospective participants taking medications that would affect the outcome(s) to be measured and who cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation, or who are taking vitamins and/or other supplements and who are unwilling to discontinue their use for at least 1 week prior to study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clopidogrel in poor metabolizers<br>Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 poor metabolizers (PM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, Pharmacogenetics of Anti-platelet Intervention (PAPI) Study (NCT 00799396). Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days. | Drug: Clopidogrel<br>* Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days.<br>* Other names: Plavix;|
| Experimental: Clopidogrel in intermediate metabolizers<br>Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 intermediate metabolizers (IM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, Pharmacogenetics of Anti-platelet Intervention (PAPI) Study (NCT 00799396). Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days. | Drug: Clopidogrel<br>* Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days.<br>* Other names: Plavix;|
| Experimental: Clopidogrel in extensive metabolizers<br>Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 extensive metabolizers (EM) to clopidogrel 75 mg from participants who previously received 75 mg clopidogrel as part of another NIH sponsored clinical trial entitled, Pharmacogenetics of Anti-platelet Intervention (PAPI) Study (NCT 00799396). Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days. | Drug: Clopidogrel<br>* Over a 6 week period participants will be given: 75 mg of clopidogrel for 8 days, at least 1 week washout, 150 mg of clopidogrel for eight days, at least 1 week washout, 300 mg of clopidogrel for eight days.<br>* Other names: Plavix;|
| Experimental: Omeprazole/Clopidogrel in PM<br>PM participants who have completed Arm 1 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. | Drug: Omeprazole/Clopidogrel<br>* After a washout of at least 1 week, participants will have the option to participate in a final intervention in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.<br>* Other names: Plavix;|
| Experimental: Omeprazole/Clopidogrel in IM<br>IM participants who have completed Arm 2 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. | Drug: Omeprazole/Clopidogrel<br>* After a washout of at least 1 week, participants will have the option to participate in a final intervention in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.<br>* Other names: Plavix;|
| Experimental: Omeprazole/Clopidogrel in EM<br>EM participants who have completed Arm 3 will have the option to participate. After a washout of at least one week, these participants will given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days. | Drug: Omeprazole/Clopidogrel<br>* After a washout of at least 1 week, participants will have the option to participate in a final intervention in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.<br>* Other names: Plavix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Platelet Aggregation Following Therapy With Clopidogrel | Adenosine diphosphate (ADP) mediated platelet aggregation measured 4 hours post-dose of clopidogrel on Day 1. | Day 1, 4 hours post clopidogrel dose | 
| Change in Platelet Aggregation Following Therapy With Clopidogrel | ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose | 4 hours post Day 8 dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole | The change in maximum platelet aggregation in response to ADP 4-hours post dose on day 8 of therapy with clopidogrel and omeprazole will be compared to the baseline measure of platelet aggregation at day 1 prior to drug therapy | Baseline, Day 8 | 
| Level of Active Clopidogrel Metabolite | The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the Day One dose is administered for pharmacokinetic analysis. The analysis will measure the Area Under the Curve. | Baseline, 0.25, 0.5, 1, 2, and 4 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clopidogrel, Pharmacogenetics, Platelets, Healthy Subjects