Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Change in Platelet Aggregation Following Therapy With Clopidogrel
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Amish men or women between 20 and 70 years of age who participated in PAPI
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Clopidogrel (Drug)
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.
干预措施: Clopidogrel (Drug)
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.
干预措施: Clopidogrel (Drug)
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.
干预措施: Omeprazole/Clopidogrel (Drug)
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.
干预措施: Omeprazole/Clopidogrel (Drug)
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.
干预措施: Omeprazole/Clopidogrel (Drug)
结局指标
主要结局
Change in Platelet Aggregation Following Therapy With Clopidogrel
时间窗: 4 hours post Day 8 dose
ADP mediated platelet aggregation measured 4 hours post Day 8 clopidogrel dose
次要结局
- Level of Active Clopidogrel Metabolite(Baseline, 0.25, 0.5, 1, 2, and 4 hours)
- Change in Platelet Aggregation Following Therapy With Clopidogrel and Omeprazole(Baseline, Day 8)
研究者
Alan Shuldiner
Professor of Medicine
University of Maryland, Baltimore