Clinical trial NCT01341600: Clopidogrel Pharmacogenetics (PGX) Bench to Bedside
Official title: Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Metabolism of Clopidogrel
Keywords: Clopidogrel
Pharmacogenetics
Platelets
Healthy Subjects
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: Food and Drug Administration (FDA)
name: National Cancer Institute (NCI)
name: National Institute of General Medical Sciences (NIGMS)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2011-04-25
Enrollment: 18
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Platelet Aggregation Following Therapy With Clopidogrel
timeFrame: Day 1, 4 hours post clopidogrel dose
measure: Change in Platelet Aggregation Following Therapy With Clopidogrel
timeFrame: 4 hours post Day 8 dose
Secondary outcomes:
measure: Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole
timeFrame: Baseline, Day 8
measure: Level of Active Clopidogrel Metabolite
timeFrame: Baseline, 0.25, 0.5, 1, 2, and 4 hours
Other outcomes:
Locations:
city: Lancaster
country: United States
facility: Amish Research Clinic
state: Pennsylvania
Study officials:
affiliation: University of Maryland, Baltimore
name: Richard B Horenstein, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.