CES1 Crossover Trial of Clopidogrel and Ticagrelor

NCT03161678 | Completed Phase 4 Results FDA Drug

• 1 other identifier: HP-00074967
• Study Type: interventional
• Target: 111
• Locations: 1 country
• Sites: 1

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.

Conditions

Myocardial Infarction; Thrombosis; Platelet Dysfunction

Keywords

Pharmacogenetics; Carboxylesterase 1 (CES1); Antiplatelet therapy

Outcome Measures

Primary Outcomes (2)

• Change in Maximal Platelet Aggregation in Response to Clopidogrel

  Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of clopidogrel \[75mg/d\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after clopidogrel administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-clopidogrel visits.

  8 days of exposure to clopidogrel (change from baseline at day 8 reported)

• Change in Maximal Platelet Aggregation in Response to Ticagrelor

  Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of ticagrelor \[90 mg twice daily\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after ticagrelor administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-ticagrelor visits.

  8 days of independent exposure to ticagrelor (change from baseline at day 8 reported)

Study Arms (3)

Wild-Type Genotype

ACTIVE COMPARATOR

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; Drug: Ticagrelor

Carriers of the CES1 G143E Mutation

EXPERIMENTAL

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; Drug: Ticagrelor

Carriers of CES1 rs7498748 Mutation

EXPERIMENTAL

Research subjects who carry a CES1 rs7498748 minor allele 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; Drug: Ticagrelor

Interventions

Clopidogrel DRUG

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

Also known as: Plavix

Carriers of CES1 rs7498748 Mutation; Carriers of the CES1 G143E Mutation; Wild-Type Genotype

Ticagrelor DRUG

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

Also known as: Brilinta

Carriers of CES1 rs7498748 Mutation; Carriers of the CES1 G143E Mutation; Wild-Type Genotype

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Of Amish descent
• Age 18 to 75 years
• Participant in the Phamacogenomics of Anti-Platelet Intervention (PAPI-1) Study or other Amish Research Center study, or a family member of an Amish Research Center study participant.

You may not qualify if:

• Clopidogrel or ticagrelor allergy
• Platelet count \< 100,000 mm3 or \> 500,000 mm3
• Hematocrit (Hct) \< 32% or \> 50%
• Blood pressure \> 160/95 mm Hg
• Co-existing malignancy
• Creatinine \> 2.0 mg/dl
• Aspartate transaminase (AST) or alanine transaminase (ALT) \> 2 times the upper limit of normal
• Thyroid-stimulating hormone (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 atrioventricular 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

Sponsors & Collaborators

• University of Maryland, Baltimore: lead

Study Sites (1)

Amish Research Clinic

Lancaster, Pennsylvania, 17602, United States

Location

MeSH Terms

Conditions

Myocardial Infarction; Thrombosis

Interventions

Clopidogrel; Ticagrelor

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Embolism and Thrombosis

Intervention Hierarchy (Ancestors)

Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Adenosine; Purine Nucleosides; Purines; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Joshua P. Lewis, PhD
• Organization: University of Maryland, School of Medicine

jlewis2@som.umaryland.edu

410-706-5087

Study Officials

• Joshua P Lewis, PhD

  University of Maryland

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: 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.

Study Record Dates

• First Submitted: May 18, 2017
• First Posted: May 22, 2017
• Study Start: August 22, 2017
• Primary Completion: December 12, 2022
• Study Completion: December 12, 2022
• Last Updated: May 6, 2024
• Results First Posted: May 6, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share

Locations

US (1)