Impact of Genetic Variation in CES1 on Antiplatelet Therapy
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 111
- 试验地点
- 2
- 主要终点
- Change in Maximal Platelet Aggregation in Response to Clopidogrel
研究概览
简要总结
The purpose of this investigation is to evaluate when genetic variation in the carboxylesterase 1 (CES1) gene influences antiplatelet therapy response, as assessed by ex vivo platelet aggregometry, in healthy participants treated with clopidogrel and ticagrelor. We hypothesize that genetic variation in CES1 will significantly impact on-clopidogrel platelet aggregation while having a minimal effect in ticagrelor-treated subjects.
Specific Aim: To conduct a prospective randomized crossover study of clopidogrel and ticagrelor in healthy individuals stratified by CES1 genotype. Participants will be recruited by CES1 genotype into a randomized crossover study of clopidogrel (75 mg daily for 7d) and ticagrelor (90 mg twice daily for 7d) with extensive phenotyping including ex vivo platelet aggregometry performed pre- and post-drug administration in order to assess the interaction of genotype and drug choice on on-treatment platelet function.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Of Amish descent
- •Age 18 to 75 years
- •Participant in the Phamacogenomics of Anti-Platelet Intervention (PAPI-1) Study or other Amish Research Center study, or a family member of an Amish Research Center study participant.
排除标准
- •Clopidogrel or ticagrelor allergy
- •Platelet count < 100,000 mm3 or > 500,000 mm3
- •Hematocrit (Hct) < 32% or > 50%
- •Blood pressure > 160/95 mm Hg
- •Co-existing malignancy
- •Creatinine > 2.0 mg/dl
- •Aspartate transaminase (AST) or alanine transaminase (ALT) > 2 times the upper limit of normal
- •Thyroid-stimulating hormone (TSH) < 0.40 or > 5.50 mU/L
- •Pregnant or breast feeding
- •History of gastrointestinal bleeding, a major life-threatening bleeding event, active pathological bleeding, bleeding diathesis, or coagulopathy
- •History of stroke or transient ischemic attack, deep vein thrombosis, or atrial fibrillation
- •History of myocardial infarction, coronary artery bypass surgery, unstable angina, or angioplasty
- •History of sick sinus syndrome, 2nd or 3rd degree atrioventricular block, or bradycardia-related syncope
- •Type 1 or Type 2 diabetes mellitus
- •Surgery in the past 3 months or planned surgery in the next 3 months
- •Participant cannot willingly and safely discontinue medications that, in the opinion of the study physician would affect the outcomes to be measured for at least 1 week prior to study initiation through completion of the study
- •Participant is unwilling to discontinue taking vitamins and/or supplements that, in the opinion of the study physician would affect the outcomes to be measured for 1 week prior to the study initiation through the the completion of the study
- •Any other condition that would place prospective participants at unacceptable risk or render them unable to meet the requirements of the protocol in the opinion of the site investigator
研究组 & 干预措施
Wild-Type Genotype
Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
干预措施: Clopidogrel (Drug)
Wild-Type Genotype
Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
干预措施: Ticagrelor (Drug)
Carriers of the CES1 G143E Mutation
Research subjects who carry the CES1 G143E allele (rs71647871) will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
干预措施: Clopidogrel (Drug)
Carriers of the CES1 G143E Mutation
Research subjects who carry the CES1 G143E allele (rs71647871) will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
干预措施: Ticagrelor (Drug)
Carriers of CES1 rs7498748 Mutation
Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
干预措施: Clopidogrel (Drug)
Carriers of CES1 rs7498748 Mutation
Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.
干预措施: Ticagrelor (Drug)
结局指标
主要结局
Change in Maximal Platelet Aggregation in Response to Clopidogrel
时间窗: 8 days of exposure to clopidogrel (change from baseline at day 8 reported)
Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of clopidogrel \[75mg/d\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after clopidogrel administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-clopidogrel visits.
Change in Maximal Platelet Aggregation in Response to Ticagrelor
时间窗: 8 days of independent exposure to ticagrelor (change from baseline at day 8 reported)
Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of ticagrelor \[90 mg twice daily\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after ticagrelor administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-ticagrelor visits.
次要结局
未报告次要终点
研究者
Braxton Mitchell
Professor of Medicine
University of Maryland, Baltimore