CES1 Crossover Trial of Clopidogrel and Ticagrelor

Sponsor

University of Maryland, Baltimore (Other)

Overall Status

Recruiting

CT.gov ID

NCT03161678

Collaborator

(none)

Enrollment

Location

Arms

70.3

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myocardial Infarction Thrombosis Platelet Dysfunction	Drug: Clopidogrel Drug: Ticagrelor	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention 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.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)

Primary Purpose:

Basic Science

Official Title:

Impact of Genetic Variation in CES1 on Antiplatelet Therapy

Actual Study Start Date :

Aug 22, 2017

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Clopidogrel Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Other Names: Plavix Drug: Ticagrelor Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Other Names: Brilinta
Experimental: 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.	Drug: Clopidogrel Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Other Names: Plavix Drug: Ticagrelor Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Other Names: Brilinta
Experimental: Carriers of CES1 Functional Mutation 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 Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Other Names: Plavix Drug: Ticagrelor Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Other Names: Brilinta

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Clopidogrel

Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Other Names:

Plavix

Drug: Ticagrelor

Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Other Names:

Brilinta

Experimental: 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.

Drug: Clopidogrel

Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Other Names:

Plavix

Drug: Ticagrelor

Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Other Names:

Brilinta

Experimental: Carriers of CES1 Functional Mutation

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

Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Other Names:

Plavix

Drug: Ticagrelor

Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Other Names:

Brilinta

Outcome Measures

Primary Outcome Measures

CES1 genotype-dependent effect of clopidogrel or ticagrelor on inhibition of platelet aggregation [8 days of exposure to either clopidogrel or ticagrelor]
One of our primary endpoints will be to determine within each drug group if CES1 genotype is associated with inhibition of platelet aggregation (IPA)
Impact of alternative drug choice on CES1 genotype-dependent maximal platelet aggregation [8 days of independent exposure to both clopidogrel and ticagrelor]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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