Clopidogrel Pharmacogenetics (PGX) Bench to Bedside (PGXB2B)

University of Maryland Baltimore (UMB)

Status: Completed

Conditions: Metabolism of Clopidogrel

Treatments: Drug: Omeprazole/Clopidogrel; Drug: Clopidogrel

Study type: Interventional

Funder types: Other; Other U.S. Federal agency; NIH

Identifiers

NCT01341600

ZICSC006537 (U.S. NIH Grant/Contract)

U01HL105198 (U.S. NIH Grant/Contract)

128475 (Other Grant/Funding Number)

HP-00044487

ZICSC006536 (U.S. NIH Grant/Contract)

U01GM074518 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 18 patients

Sex: All

Ages: 20 to 70 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

---

18 participants in 6 patient groups

Clopidogrel in poor metabolizers

Experimental group

Description:

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.

Treatment:

Drug: Clopidogrel

Clopidogrel in intermediate metabolizers

Experimental group

Description:

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.

Treatment:

Drug: Clopidogrel

Clopidogrel in extensive metabolizers

Experimental group

Description:

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.

Treatment:

Drug: Clopidogrel

Omeprazole/Clopidogrel in PM

Experimental group

Description:

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.

Treatment:

Drug: Omeprazole/Clopidogrel

Omeprazole/Clopidogrel in IM

Experimental group

Description:

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.

Treatment:

Drug: Omeprazole/Clopidogrel

Omeprazole/Clopidogrel in EM

Experimental group

Description:

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.

Treatment:

Drug: Omeprazole/Clopidogrel