Clopidogrel Pharmacogenetics (PGX) Bench to Bedside

Not Applicable

Completed

Conditions: Metabolism of Clopidogrel

Interventions: Drug: Omeprazole/Clopidogrel
Drug: Clopidogrel

Registration Number: NCT01341600

Lead Sponsor: University of Maryland, Baltimore

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 18

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Omeprazole/Clopidogrel in PM	Omeprazole/Clopidogrel	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.
Omeprazole/Clopidogrel in IM	Omeprazole/Clopidogrel	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.
Omeprazole/Clopidogrel in EM	Omeprazole/Clopidogrel	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.
Clopidogrel in poor metabolizers	Clopidogrel	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.
Clopidogrel in extensive metabolizers	Clopidogrel	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.
Clopidogrel in intermediate metabolizers	Clopidogrel	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.

Primary Outcome Measures

Name	Time	Method
Change in Platelet Aggregation Following Therapy With Clopidogrel	4 hours post Day 8 dose	ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose

Secondary Outcome Measures

Name	Time	Method
Level of Active Clopidogrel Metabolite	Baseline, 0.25, 0.5, 1, 2, and 4 hours	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.
Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole	Baseline, Day 8	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