CES1 Crossover Trial of Clopidogrel and Ticagrelor

Impact of Genetic Variation in CES1 on Antiplatelet Therapy

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.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Thrombosis; Platelet Dysfunction
• Intervention / Treatment: Drug: Clopidogrel; Drug: Ticagrelor

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17602
      • Amish Research Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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 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.	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Maximal Platelet Aggregation in Response to Clopidogrel	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.	8 days of exposure to clopidogrel (change from baseline at day 8 reported)
Change in Maximal Platelet Aggregation in Response to Ticagrelor	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.	8 days of independent exposure to ticagrelor (change from baseline at day 8 reported)

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Joshua P Lewis, PhD, University of Maryland

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2017
• Primary Completion (Actual): December 12, 2022
• Study Completion (Actual): December 12, 2022

Study Registration Dates

• First Submitted: May 18, 2017
• First Submitted That Met QC Criteria: May 18, 2017
• First Posted (Actual): May 22, 2017

Study Record Updates

• Last Update Posted (Actual): May 6, 2024
• Last Update Submitted That Met QC Criteria: May 3, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Pharmacogenetics; Antiplatelet therapy; Carboxylesterase 1 (CES1)
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Myocardial Infarction; Infarction; Thrombosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel
• Other Study ID Numbers: HP-00074967

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: It is possible that deidentified data will be deposited into large public databases as per NIH data sharing policies (e.g. database of Genotypes and Phenotypes [dbGAP], Pharmacogenomics Knowledgebase [PharmGKB]). Data to be shared would include, but not limited to, anthropometric data, study outcome data, and relevant covariate data used in statistical models of association. It is anticipated that data would be available after the completion of the trial. The data will be obtained from the participants and the study-related research procedures.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes