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CES1 Crossover Trial of Clopidogrel and Ticagrelor

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ClinicalTrials.gov Identifier: NCT03161678
Recruitment Status : Recruiting
First Posted : May 22, 2017
Last Update Posted : February 1, 2019
Sponsor:
Information provided by (Responsible Party):
Joshua Lewis, University of Maryland

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.


Condition or disease Intervention/treatment Phase
Myocardial Infarction Thrombosis Platelet Dysfunction Drug: Clopidogrel Drug: Ticagrelor Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
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.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Impact of Genetic Variation in CES1 on Antiplatelet Therapy
Actual Study Start Date : August 22, 2017
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Wild-Type Genotype
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.
Drug: Clopidogrel
Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Other Name: Plavix

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

Experimental: Carriers of the CES1 G143E Mutation
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.
Drug: Clopidogrel
Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Other Name: Plavix

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

Experimental: Carriers of CES1 Functional Mutation
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.
Drug: Clopidogrel
Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Other Name: Plavix

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




Primary Outcome Measures :
  1. CES1 genotype-dependent effect of clopidogrel or ticagrelor on inhibition of platelet aggregation [ Time Frame: 8 days of exposure to either clopidogrel or ticagrelor ]
    One of our primary endpoints will be to determine within each drug group if CES1 genotype is associated with inhibition of platelet aggregation (IPA)

  2. Impact of alternative drug choice on CES1 genotype-dependent maximal platelet aggregation [ Time Frame: 8 days of independent exposure to both clopidogrel and ticagrelor ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03161678


Contacts
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Contact: Joshua P Lewis, PhD 410-706-5087 jlewis2@som.umaryland.edu
Contact: Elizabeth A Streeten, MD 410-706-1627 estreete@som.umaryland.edu

Locations
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United States, Pennsylvania
Amish Research Clinic Recruiting
Lancaster, Pennsylvania, United States, 17602
Contact: Joshua P Lewis, PhD    410-706-5087    jlewis2@som.umaryland.edu   
Contact: Susan Shaub, R.N.    717-392-4985    sshaub@som.umaryland.edu   
Sponsors and Collaborators
University of Maryland
Investigators
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Principal Investigator: Joshua P Lewis, PhD University of Maryland

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Responsible Party: Joshua Lewis, Assistant Professor of Medicine, University of Maryland
ClinicalTrials.gov Identifier: NCT03161678     History of Changes
Other Study ID Numbers: HP-00074967
First Posted: May 22, 2017    Key Record Dates
Last Update Posted: February 1, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Joshua Lewis, University of Maryland:
Pharmacogenetics
Carboxylesterase 1 (CES1)
Antiplatelet therapy

Additional relevant MeSH terms:
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Myocardial Infarction
Myocardial Ischemia
Infarction
Thrombosis
Ischemia
Pathologic Processes
Necrosis
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Embolism and Thrombosis
Clopidogrel
Ticagrelor
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs