Clinical trial NCT03161678: CES1 Crossover Trial of Clopidogrel and Ticagrelor
Official title: Impact of Genetic Variation in CES1 on Antiplatelet Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Myocardial Infarction
Thrombosis
Platelet Dysfunction
Keywords: Pharmacogenetics
Carboxylesterase 1 (CES1)
Antiplatelet therapy
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
First posted: 2017-05-22
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: Change in Maximal Platelet Aggregation in Response to Clopidogrel
timeFrame: 8 days of exposure to clopidogrel (change from baseline at day 8 reported)
measure: Change in Maximal Platelet Aggregation in Response to Ticagrelor
timeFrame: 8 days of independent exposure to ticagrelor (change from baseline at day 8 reported)
Secondary outcomes:
Other outcomes:
Locations:
city: Lancaster
country: United States
facility: Amish Research Clinic
state: Pennsylvania
Study officials:
affiliation: University of Maryland
name: Joshua P Lewis, PhD
role: PRINCIPAL_INVESTIGATOR
References: