CES1 Crossover Trial of Clopidogrel and Ticagrelor

Myocardial Infarction Clinical Trial

Official title:

Impact of Genetic Variation in CES1 on Antiplatelet Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03161678
• Other study ID #: HP-00074967
• Status: Completed
• Phase: Phase 4
• Start date: August 22, 2017
• Est. completion date: December 12, 2022

Study information

• Verified date: May 2024
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 111
• Est. completion date: December 12, 2022
• Est. primary completion date: December 12, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• Platelet Dysfunction
• Thrombosis

Intervention

Drug:
• Clopidogrel
Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
• Ticagrelor
Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Locations

Country	Name	City	State
United States	Amish Research Clinic	Lancaster	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)