Clopidogrel Pharmacogenomics Project

Loss-of-function mutation of the gene encoding the CYP450 2C19 enzyme has emerged as a likely determinant of resistance to clopidogrel therapy. The primary hypothesis of the proposed research is that among patients with confirmed loss-of-function alleles of the CYP2C19 gene, increasing the maintenance clopidogrel dose from 75 to 150 mg will result in significant reduction in the rate of measured clopidogrel resistance defined by multiple measures of platelet function

Study Overview

• Status: Completed
• Conditions: Disease Susceptibility
• Intervention / Treatment: Drug: clopidogrel 75 mg; Drug: Clopidogrel 150 mg

Detailed Description

The first phase of the clinical trial will involve subject recruitment and informed consent for genetic testing. Because the target population is patients with stable coronary artery disease, patients will be recruited from the outpatient setting during clinic visits or at the time of outpatient cardiac catheterization. It is expected that all potential candidates will be initially screened for eligibility by their treating cardiologist. If a patient agrees to undergo formal screening, they will be approached by a member of the research team and receive a written summary of the clinical trial protocol that will be reviewed with the trial personnel. The initial informed consent will allow the patient to undergo genetic testing and baseline VerifyNow assay, and will also give the trial personnel permission to contact the patient by phone if they are found to be eligible for the interventional phase of the trial. The goal for enrollment in the genetic testing portion of this clinical trial is 200 patients.

If the genetic testing results confirm that the patient is a candidate for the interventional study, they will be contacted and asked to make an outpatient appointment to initiate the interventional study protocol. The therapeutic portion of this study will be a randomized, unblinded cross-over comparison of two clopidogrel dosing strategies. It is anticipated that all eligible patients will have continued their previous chronic clopidogrel therapy with standard dosing of 75 mg/day. Because all patients will be receiving chronic clopidogrel at the initiation of the intervention protocol, steady state levels should be present in all patients. Dose dependent inhibition of platelet aggregation can be seen two hours after a single oral dose of clopidogrel. Repeated doses of 75mg daily produce steady state inhibition between day 3 and day 7 of administration.

Patients who agree to participate in the therapeutic protocol, and who meet the eligibility criteria, will be randomized to an initial dosing strategy of 75 or 150 mg daily for a minimum of 30 days. At day 30 (+/- 5 days), patients will return for repeat platelet function testing. In a randomly selected subset of 15 patients, blood will be tested for the active metabolite of clopidogrel. At that time, there will be a crossover with those patients receiving 75 mg qD increased to 150 mg qD and those receiving 150 mg qD decreased to 75 mg qD. At day 60 (+/- 5 days), participants will again return for comprehensive platelet function testing and a second randomly selected group of patients will undergo testing for clopidogrel metabolites. Chronic clopidogrel dosing will be reduced to 75mg in all participants. Please see the attached schedule of events for a summary of the trial schedule.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:• Currently taking clopidogrel 75 mg/day and aspirin (minimum 81 mg/day) with an indication for chronic dual antiplatelet therapy (>90 days)

• No evidence of acute coronary syndrome within 30 days of enrollment, defined by elevation of Troponin I above the upper limit of normal
• Coronary atherosclerosis documented on previous coronary angiogram
• No known contraindications to combination therapy with aspirin and clopidogrel
• Prognosis for survival greater than one year based on physician's assessment
• Able to attend all scheduled visits.
• Access to phone
• Subject is a female with a negative urine or serum pregnancy test or post-menopausal for at least 1 year prior to randomization. Females of childbearing potential must be practicing adequate birth control to be eligible. It is the Investigator's responsibility for determining whether the Subject has adequate birth control for study participation

Exclusion Criteria:• Recent acute coronary syndrome (<30 days)

• Recent hospitalization or physician visit for bleeding disorder(<90 days) or history of chronic blood loss
• Recent blood transfusion (<90 days)
• Any contraindication to aspirin or clopidogrel therapy
• Acute Febrile illness at the time of enrollment
• Subject is pregnant or lactating or planning to become pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 75 mg clopidogrel	Drug: clopidogrel 75 mg; 75 mg once daily; Other Names: Plavix
Active Comparator: 150 mg clopidogrel	Drug: Clopidogrel 150 mg; clopidogrel 150 mg; Other Names: Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clopidogrel Resistance, Defined by P2Y12 Reaction Units (PRU)Value >230	P2Y12 Reaction Units are measured using the VerifyNow P2Y12 assay. Percent of patients with clopidogrel resistance defined by PRU value will be compared among low and high dose clopidogrel groups after 30 days of therapy.	Approximately 90 days

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Investigators: Principal Investigator: Joseph Rossi, MD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: March 30, 2010
• First Submitted That Met QC Criteria: March 31, 2010
• First Posted (Estimate): April 1, 2010

Study Record Updates

• Last Update Posted (Actual): December 12, 2017
• Last Update Submitted That Met QC Criteria: November 14, 2017
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Clopidogrel pharmacogenomics study; Performing genetic study looking at clopidogrel resistance
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel
• Other Study ID Numbers: 09-2104