CES1 Carriers in the PAPI Study

Sponsor

University of Maryland, Baltimore (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT03188705

Collaborator

(none)

Enrollment

Location

Arm

44.6

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Diseases Coronary Disease Coronary Artery Disease Cardiovascular Diseases Myocardial Ischemia Artery Occlusion Aspirin Sensitivity Clopidogrel, Poor Metabolism of Platelet Dysfunction Platelet Thrombus	Drug: Clopidogrel Drug: Aspirin	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

The investigators will enroll 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.The investigators will enroll 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.

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Enrichment of CES1 Carriers in the Pharmacogenomics Anti-Platelet Intervention Study

Actual Study Start Date :

Oct 14, 2019

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Overall Cohort Participants will receive clopidogrel treatment alone (300 mg loading dose followed by 75 mg/d for 6 days), followed by clopidogrel (75 mg) plus aspirin (324 mg) treatment on day 8.	Drug: Clopidogrel Participants will receive 300 mg of clopidogrel on the first day, then 75 mg per day for the next 6 days. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Other Names: Plavix Drug: Aspirin Participants will receive a single dose of 324 mg aspirin on the last day of clopidogrel administration.

Arm

Intervention/Treatment

Experimental: Overall Cohort

Participants will receive clopidogrel treatment alone (300 mg loading dose followed by 75 mg/d for 6 days), followed by clopidogrel (75 mg) plus aspirin (324 mg) treatment on day 8.

Drug: Clopidogrel

Participants will receive 300 mg of clopidogrel on the first day, then 75 mg per day for the next 6 days. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Other Names:

Plavix

Drug: Aspirin

Participants will receive a single dose of 324 mg aspirin on the last day of clopidogrel administration.

Outcome Measures

Primary Outcome Measures

Changes in Platelet Function in Response to Clopidogrel [Measured at baseline and after 8 days of clopidogrel treatment]
Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation
Changes in Platelet Function in Response to Clopidogrel Plus Aspirin [Measured at baseline and after 8 days clopidogrel administration plus 1 day of aspirin treatment]
Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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