CES1 Crossover Trial of Clopidogrel and Ticagrelor

NCT ID: NCT03161678

Last Updated: 2024-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 111 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-22
• Study Completion Date: 2022-12-12

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.

Conditions

Myocardial Infarction; Thrombosis; Platelet Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Clopidogrel

Intervention Type: DRUG

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

Ticagrelor

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Clopidogrel

Intervention Type: DRUG

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

Ticagrelor

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Clopidogrel

Intervention Type: DRUG

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

Ticagrelor

Intervention Type: DRUG

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

Interventions

Clopidogrel

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

Intervention Type: DRUG

Ticagrelor

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

Intervention Type: DRUG

Other Intervention Names

Plavix; Brilinta

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Maryland, Baltimore

OTHER

Sponsor Role: lead

Responsible Party

Joshua Lewis

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Joshua P Lewis, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Maryland

Locations

Amish Research Clinic

Lancaster, Pennsylvania, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HP-00074967

Identifier Type: -

Identifier Source: org_study_id