Clinical trial NCT03188705: CES1 Carriers in the PAPI Study
Official title: Enrichment of CES1 Carriers in the Pharmacogenomics Anti-Platelet Intervention Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Diseases
Coronary Disease
Coronary Artery Disease
Cardiovascular Diseases
Myocardial Ischemia
Artery Occlusion
Aspirin Sensitivity
Clopidogrel, Poor Metabolism of
Platelet Dysfunction
Platelet Thrombus
Keywords: pharmacogenetics
carboxylesterase
Personalized Medicine
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
First posted: 2017-06-15
Enrollment: 6
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The investigators will enroll up to 50 healthy Amish participants who have been identified through existing whole genome and exome sequencing along with bioinformatic approaches that have genetic variants that are predicted to significantly impact CES1 expression or catalytic function. Enrolled participants will undergo a two-stage intervention with clopidogrel (300 mg loading dose then 75 mg per day for the next 6 days), followed by clopidogrel (75 mg) plus aspirin 324 mg for 1 day. Platelet aggregation studies and other measures of platelet function will be performed before and after each intervention. In combination with previously collected data as part of the PAPI Study, the investigators will then characterize the impact of genetic variation in CES1 on clopidogrel and dual antiplatelet therapy response through single- and multi-variant association modeling.
Primary purpose: BASIC_SCIENCE

Brief summary: This study builds, in part, upon preliminary results generated as part of the Pharmacogenomics Anti-Platelet Intervention (PAPI) Study (NCT00799396). The purpose of this investigation is to assess the impact of genetic variation in the carboxylesterase 1 (CES1) on response to clopidogrel as well as dual antiplatelet therapy (i.e. clopidogrel and aspirin), as assessed by ex vivo platelet aggregometry, in healthy Amish individuals. The investigators hypothesize that participants who carry alleles that modify the activity or expression of CES1 will have altered response to clopidogrel as well as dual antiplatelet therapy.


Eligibility criteria: Inclusion Criteria:

* Age 20 years or older
* Of Old Order Amish descent

Exclusion Criteria:

* Currently pregnant or less than 6 months have passed since delivery
* Currently breast feeding
* Has a history of a bleeding disorder or major spontaneous bleed, such as peptic ulcer, epistasis, or intracranial bleed
* Has severe hypertension, defined by a blood pressure above 160/95 mm Hg
* Takes medications that would affect the outcome(s) to be measured and cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation
* Is taking vitamins or other supplements and is unwilling to discontinue use for at least 1 week prior to study
* Has a coexisting malignancy
* Has a creatinine level greater than 2.0 mg/dl, aspartate transaminase (AST) or alanine transaminase (ALT) greater than two times the upper limit of normal, hematocrit less than 32%, or a thyroid-stimulating hormone (TSH) less than 0.4 or greater than 5.5 mIU/L
* Has a bleeding disorder or history of gastrointestinal bleeding or other major bleeding episode
* Is currently taking aspirin, clopidogrel, or anti-coagulants, such as warfarin, heparin, or GPIIb/IIIa antagonists, and have conditions that might place the participant at increased risk from withdrawal of these medications 14 days prior to protocol initiation
* History of unstable angina, heart attack, angioplasty (including stent placement), coronary artery bypass surgery, atrial fibrillation, stroke or transient ischemic attacks, diabetes, or deep vein thrombosis or other thrombosis
* Has polycythemia, or thrombocytosis, defined by a platelet count greater than 500,000
* Has thrombocytopenia, defined by a platelet count less than 75,000
* Has had surgery within the last 6 months
* Has an aspirin or clopidogrel allergy

Primary outcomes:
measure: Changes in Platelet Function in Response to Clopidogrel
timeFrame: Measured at baseline and after 8 days of clopidogrel treatment
measure: Changes in Platelet Function in Response to Clopidogrel Plus Aspirin
timeFrame: Measured at baseline and after 8 days clopidogrel administration plus 1 day of aspirin treatment
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: