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CES1 Carriers in the PAPI Study

Primary Purpose

Heart Diseases, Coronary Disease, Coronary Artery Disease

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Clopidogrel

Aspirin

About this trial

This is an interventional basic science trial for Heart Diseases focused on measuring pharmacogenetics, carboxylesterase, Personalized Medicine

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Amish Research Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Overall Cohort

Arm Description

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.

Outcomes

Primary Outcome Measures

Changes in Platelet Function in Response to Clopidogrel

Baseline minus post clopidogrel/pre-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel administration but before aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change.

Changes in Platelet Function in Response to Clopidogrel Plus Aspirin

Baseline minus post clopidogrel/post-aspirin platelet rich plasma (PRP) maximum aggregation in response to ADP (20 ug/ml) or collagen (5 ug/ml). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline (recorded as a percentage) minus the maximum platelet aggregation value obtained after clopidogrel and aspirin administration (also recorded as percentage). Thus, values recorded below represent a percentage change.

Secondary Outcome Measures

Full Information

NCT ID

NCT03188705

First Posted

June 14, 2017

Last Updated

May 23, 2023

Sponsor

University of Maryland, Baltimore

1. Study Identification

Unique Protocol Identification Number

NCT03188705

Brief Title

CES1 Carriers in the PAPI Study

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Completed

Study Start Date

October 14, 2019 (Actual)

Primary Completion Date

January 17, 2020 (Actual)

Study Completion Date

January 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Maryland, Baltimore

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Single Group Assignment

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.

Masking

None (Open Label)

Allocation

N/A

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Overall Cohort

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Clopidogrel

Other Intervention Name(s)

Plavix

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Aspirin

Intervention Description

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

Primary Outcome Measure Information:

Title

Changes in Platelet Function in Response to Clopidogrel

Description

Time Frame

Measured at baseline and after 8 days of clopidogrel treatment

Title

Changes in Platelet Function in Response to Clopidogrel Plus Aspirin

Description

Time Frame

Measured at baseline and after 8 days clopidogrel administration plus 1 day of aspirin treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joshua P Lewis, PhD

Organizational Affiliation

University of Maryland

Official's Role

Principal Investigator

Facility Information:

Facility Name

Amish Research Clinic

City

Lancaster

State/Province

Pennsylvania

ZIP/Postal Code

17602

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Yes It is possible that deidentified data will be deposited into large public databases as per NIH data sharing policies (e.g. dbGAP, 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.

Learn more about this trial

CES1 Carriers in the PAPI Study

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