Clopidogrel Pharmacogenetics (PGX) Bench to Bedside

NCT ID: NCT01341600

Last Updated: 2024-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-07-31
• Study Completion Date: 2011-05-31

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.

Conditions

Metabolism of Clopidogrel

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Clopidogrel in poor metabolizers

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.

Group Type: EXPERIMENTAL

Clopidogrel

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Clopidogrel

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Clopidogrel

Intervention Type: DRUG

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.

Omeprazole/Clopidogrel in PM

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.

Group Type: EXPERIMENTAL

Omeprazole/Clopidogrel

Intervention Type: DRUG

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.

Omeprazole/Clopidogrel in IM

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.

Group Type: EXPERIMENTAL

Omeprazole/Clopidogrel

Intervention Type: DRUG

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.

Omeprazole/Clopidogrel in EM

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.

Group Type: EXPERIMENTAL

Omeprazole/Clopidogrel

Intervention Type: DRUG

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.

Interventions

Clopidogrel

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.

Intervention Type: DRUG

Omeprazole/Clopidogrel

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.

Intervention Type: DRUG

Other Intervention Names

Plavix; Prilosec; Plavix

Eligibility Criteria

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

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Food and Drug Administration (FDA)

FED

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Maryland, Baltimore

OTHER

Sponsor Role: lead

Responsible Party

Alan Shuldiner

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard B Horenstein, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Maryland, Baltimore

Locations

Amish Research Clinic

Lancaster, Pennsylvania, United States

Countries

United States

References

Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849-57. doi: 10.1001/jama.2009.1232.

Reference Type: BACKGROUND

PMID: 19706858 (View on PubMed)

Jiang XL, Samant S, Lewis JP, Horenstein RB, Shuldiner AR, Yerges-Armstrong LM, Peletier LA, Lesko LJ, Schmidt S. Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults. Eur J Pharm Sci. 2016 Jan 20;82:64-78. doi: 10.1016/j.ejps.2015.10.024. Epub 2015 Oct 30.

Reference Type: BACKGROUND

PMID: 26524713 (View on PubMed)

Horenstein RB, Madabushi R, Zineh I, Yerges-Armstrong LM, Peer CJ, Schuck RN, Figg WD, Shuldiner AR, Pacanowski MA. Effectiveness of clopidogrel dose escalation to normalize active metabolite exposure and antiplatelet effects in CYP2C19 poor metabolizers. J Clin Pharmacol. 2014 Aug;54(8):865-73. doi: 10.1002/jcph.293. Epub 2014 Apr 7.

Reference Type: BACKGROUND

PMID: 24710841 (View on PubMed)

Other Identifiers

U01GM074518

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01HL105198

Identifier Type: NIH

Identifier Source: secondary_id

View Link

128475

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

ZICSC006536

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ZICSC006537

Identifier Type: NIH

Identifier Source: secondary_id

View Link

HP-00044487

Identifier Type: -

Identifier Source: org_study_id