Back to results

CES1 Crossover Trial of Clopidogrel and Ticagrelor

Primary Purpose

Myocardial Infarction, Thrombosis, Platelet Dysfunction

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Clopidogrel

Ticagrelor

About this trial

This is an interventional basic science trial for Myocardial Infarction focused on measuring Pharmacogenetics, Carboxylesterase 1 (CES1), Antiplatelet therapy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Of Amish descent
Age 18 to 75 years
Participant in the 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
Hct < 32% or > 50%
Blood pressure > 160/95 mm Hg
Co-existing malignancy
Creatinine > 2.0 mg/dl
AST or ALT > 2 times the upper limit of normal
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 AV 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

Sites / Locations

Amish Research Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Wild-Type Genotype

Carriers of the CES1 G143E Mutation

Carriers of CES1 Functional Mutation

Arm Description

Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.

Research subjects who carry the CES1 G143E allele (rs71647871) will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.

Research subjects who carry a CES1 mutation of potential functional impact (to be determined...studies ongoing) will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.

Outcomes

Primary Outcome Measures

CES1 genotype-dependent effect of clopidogrel or ticagrelor on inhibition of platelet aggregation

One of our primary endpoints will be to determine within each drug group if CES1 genotype is associated with inhibition of platelet aggregation (IPA)

Impact of alternative drug choice on CES1 genotype-dependent maximal platelet aggregation

We will also assess the influence of drug choice (i.e. clopidogrel and ticagrelor) on change in maximal platelet aggregation (ΔMPA) in the context of CES1 genotype

Secondary Outcome Measures

Full Information

NCT ID

NCT03161678

First Posted

May 18, 2017

Last Updated

March 8, 2023

Sponsor

University of Maryland, Baltimore

1. Study Identification

Unique Protocol Identification Number

NCT03161678

Brief Title

CES1 Crossover Trial of Clopidogrel and Ticagrelor

Official Title

Impact of Genetic Variation in CES1 on Antiplatelet Therapy

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Completed

Study Start Date

August 22, 2017 (Actual)

Primary Completion Date

December 12, 2022 (Actual)

Study Completion Date

December 12, 2022 (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.

Yes

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

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

Myocardial Infarction, Thrombosis, Platelet Dysfunction

Keywords

Pharmacogenetics, Carboxylesterase 1 (CES1), Antiplatelet therapy

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

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.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

89 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Wild-Type Genotype

Arm Type

Active Comparator

Arm Description

Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment.

Arm Title

Carriers of the CES1 G143E Mutation

Arm Type

Experimental

Arm Description

Arm Title

Carriers of CES1 Functional Mutation

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Clopidogrel

Other Intervention Name(s)

Plavix

Intervention Description

Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Intervention Type

Drug

Intervention Name(s)

Ticagrelor

Other Intervention Name(s)

Brilinta

Intervention Description

Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.

Primary Outcome Measure Information:

Title

CES1 genotype-dependent effect of clopidogrel or ticagrelor on inhibition of platelet aggregation

Description

One of our primary endpoints will be to determine within each drug group if CES1 genotype is associated with inhibition of platelet aggregation (IPA)

Time Frame

8 days of exposure to either clopidogrel or ticagrelor

Title

Impact of alternative drug choice on CES1 genotype-dependent maximal platelet aggregation

Description

We will also assess the influence of drug choice (i.e. clopidogrel and ticagrelor) on change in maximal platelet aggregation (ΔMPA) in the context of CES1 genotype

Time Frame

8 days of independent exposure to both clopidogrel and ticagrelor

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Of Amish descent Age 18 to 75 years Participant in the 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 Hct < 32% or > 50% Blood pressure > 160/95 mm Hg Co-existing malignancy Creatinine > 2.0 mg/dl AST or ALT > 2 times the upper limit of normal 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 AV 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

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

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 Crossover Trial of Clopidogrel and Ticagrelor

We'll reach out to this number within 24 hrs