CES1 Crossover Trial of Clopidogrel and Ticagrelor

Study Overview
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Brief Summary
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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.

Official Title
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Impact of Genetic Variation in CES1 on Antiplatelet Therapy

Conditions
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Myocardial Infarction, Thrombosis, Platelet Dysfunction

Intervention / Treatment
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* Drug: Clopidogrel
* Drug: Ticagrelor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Of Amish descent Age 18 to 75 years Participant in the PAPI-1 Study or other Amish Research Center study, or a family member of an Amish Research Center study participant. Exclusion Criteria: Clopidogrel or ticagrelor allergy Platelet count < 100,000 mm3 or > 500,000 mm3 Hct < 32% or > 50% Blood pressure > 160/95 mm Hg Co-existing malignancy Creatinine > 2.0 mg/dl AST or ALT > 2 times the upper limit of normal 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 AV 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Ninety healthy Amish subjects (30 CES1 G143E allele carriers, 30 carriers of a risk variant to be determined, and 30 age/sex-matched controls) will be enrolled. We will prospectively evaluate the effect of CES1 genotype on clopidogrel and ticagrelor response, as assessed by agonist-stimulated platelet aggregation, through the completion of a randomized crossover study of clopidogrel (75 mg per day for 7 d) and ticagrelor (90 mg twice daily for 7 d) in 90 healthy Amish individuals stratified by CES1 genotype as described above, with at least a 14-day washout period between drug interventions.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Wild-Type Genotype<br>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. | Drug: Clopidogrel<br>* Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.<br>* Other names: Plavix;Drug: Ticagrelor<br>* Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.<br>* Other names: Brilinta;|
| Experimental: Carriers of the CES1 G143E Mutation<br>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. | Drug: Clopidogrel<br>* Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.<br>* Other names: Plavix;Drug: Ticagrelor<br>* Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.<br>* Other names: Brilinta;|
| Experimental: Carriers of CES1 Functional Mutation<br>Research subjects who carry a CES1 mutation of potential functional impact (to be determined...studies ongoing) 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. | Drug: Clopidogrel<br>* Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.<br>* Other names: Plavix;Drug: Ticagrelor<br>* Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.<br>* Other names: Brilinta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CES1 genotype-dependent effect of clopidogrel or ticagrelor on inhibition of platelet aggregation | One of our primary endpoints will be to determine within each drug group if CES1 genotype is associated with inhibition of platelet aggregation (IPA) | 8 days of exposure to either clopidogrel or ticagrelor | 
| Impact of alternative drug choice on CES1 genotype-dependent maximal platelet aggregation | We will also assess the influence of drug choice (i.e. clopidogrel and ticagrelor) on change in maximal platelet aggregation (ΔMPA) in the context of CES1 genotype | 8 days of independent exposure to both clopidogrel and ticagrelor | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiplatelet therapy, Pharmacogenetics, Carboxylesterase 1 (CES1)