CES1 Crossover Trial of Clopidogrel and Ticagrelor

Phase 4

Completed

Conditions: Myocardial Infarction
Thrombosis
Platelet Dysfunction

Interventions: Drug: Clopidogrel
Drug: Ticagrelor

Registration Number: NCT03161678

Lead Sponsor: University of Maryland, Baltimore

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 111

Inclusion Criteria

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.

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Wild-Type Genotype	Clopidogrel	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.
Carriers of the CES1 G143E Mutation	Ticagrelor	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.
Carriers of the CES1 G143E Mutation	Clopidogrel	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.
Wild-Type Genotype	Ticagrelor	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.
Carriers of CES1 rs7498748 Mutation	Ticagrelor	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.
Carriers of CES1 rs7498748 Mutation	Clopidogrel	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.

Primary Outcome Measures

Name	Time	Method
Change in Maximal Platelet Aggregation in Response to Clopidogrel	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	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.

Secondary Outcome Measures