Clopidogrel PGX Bench to Bedside (PGXB2B)

This study has been completed.
Sponsor:
Collaborators:
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
Alan Shuldiner, University of Maryland
ClinicalTrials.gov Identifier:
NCT01341600
First received: April 22, 2011
Last updated: September 28, 2012
Last verified: September 2012
  Purpose

Clopidogrel (also known as Plavix) is used commonly in patients to prevent heart attacks and conditions caused by blood clots. Although clopidogrel works in many individuals, some people do not respond as well to this drug. The variation in treatment response may be linked to genetics. This study will examine the effects of clopidogrel in a population whose genes are well known in order to determine the role that genes play in the response to various clopidogrel maintenance doses.


Condition Intervention
Metabolism of Clopidogrel
Drug: Clopidogrel, Omeprazole

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application

Resource links provided by NLM:


Further study details as provided by University of Maryland:

Primary Outcome Measures:
  • Change in platelet aggregation following therapy with Clopidogrel [ Time Frame: Baseline, Day 1, Day 8 ] [ Designated as safety issue: Yes ]
    platelet aggregation will be measured at baseline and at 4-hours post-dose of clopidogrel on day 1 and at 4-hours post-dose of clopidogrel on day 8. The primary endpoint of this study will be the change in maximal platelet aggregation 4-hours post-dose (MPA4; units are a percentage) on day 8 of each study period compared to baseline.


Secondary Outcome Measures:
  • Change in platelet aggregation following therapy with Clopidogrel and Omeprazole [ Time Frame: Baseline, Day 8 ] [ Designated as safety issue: Yes ]
    The change in maximum platelet aggregation in response to ADP 4-hours post dose on day 8 of therapy with clopidogrel and omeprazole will be compared to the baseline measure of platelet aggregation at day 1 prior to drug therapy

  • Level of active clopidogrel metabolite [ Time Frame: Baseline, 4 hours ] [ Designated as safety issue: Yes ]
    The level of the active clopidogrel metabolite will be measured at at 0.25, 0.5, 1, 2, and 4 hours after the dose is administered for pharmacokinetic analysis


Enrollment: 18
Study Start Date: July 2010
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: poor metabolizers
Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 poor metabolizers to clopidogrel 75 mg from participants who previously received clopidogrel as part of another NIH sponsored clinical trial entitled, "Pharmacogenetics of Anti-platelet Intervention" (PAPI) Study.
Drug: Clopidogrel, Omeprazole

Over a 6 week period participants will be given:

75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.

Other Names:
  • Plavix
  • Prilosec OTC
Experimental: intermediate metabolizers
Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 intermediate metabolizers to clopidogrel 75 mg in PAPI
Drug: Clopidogrel, Omeprazole

Over a 6 week period participants will be given:

75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.

Other Names:
  • Plavix
  • Prilosec OTC
Experimental: extensive metabolizers
Healthy subjects who have been genotyped for CYP2C19*2 and received clopidogrel as part of a prior study (PAPI) will be recruited. We will select 6 extensive metabolizers to clopidogrel 75 mg in PAPI
Drug: Clopidogrel, Omeprazole

Over a 6 week period participants will be given:

75mg of clopidogrel for 8 days, at least 1 week washout, 150mg of clopidogrel for eight days, at least 1 week washout, 300mg of clopidogrel for eight days. Participants will have the option to participate in a final week in which they will be given 75 mg of clopidogrel together with 20 mg of omeprazole daily for eight days.

Other Names:
  • Plavix
  • Prilosec OTC

Detailed Description:

Clopidogrel is a prodrug with high inter-individual response variability. Clopidogrel is converted to an active drug through an enzyme encoded by the gene named CYP2C19. Individuals with genetically-impaired CYP2C19 metabolism have lower capacity to convert the prodrug to its active form. Consequently, these individuals have lower blood levels of the activated form of clopidogrel, diminished antiplatelet responses, and higher rates of cardiovascular events and stent thrombosis. Increasing doses of clopidogrel in such patients represents a possible approach to managing the gene-drug interaction.

The purpose of this study is to evaluate whether increasing the dose of clopidogrel increases antiplatelet responses and active metabolite exposure in individuals with genetically reduced CYP2C19 metabolism relative to those with normal CYP2C19 metabolism.

The primary objective is to assess changes in clopidogrel response and exposure at three clopidogrel dose levels and with coadministration of omeprazole.

  Eligibility

Ages Eligible for Study:   20 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Amish men or women between 20 and 70 years of age who participated in PAPI

Exclusion Criteria:

  • Severe hypertension (bp > 160/95 mm Hg)
  • Co-existing malignancy
  • AST or ALT > 2 times normal
  • Creatinine >2.0
  • Hct < 32 or Hct > 50
  • TSH < 0.40 or >5.50
  • History of bleeding disorder or gastrointestinal bleeding
  • History of unstable angina, MI, angioplasty, coronary artery bypass surgery
  • History of atrial fibrillation, stroke or transient ischemic attacks or deep vein thrombosis
  • Type 2 diabetes
  • Thrombocytosis (platelet count > 500,000) or thrombocytopenia (platelet count < 150,000)
  • Surgery within six months
  • Clopidogrel allergy
  • Pregnant women
  • Currently breast feeding
  • Omeprazole allergy
  • Prospective participants taking medications that would affect the outcome(s) to be measured and who cannot willingly and safely, in the opinion of the treating physician and study physician, discontinue these medications for 1 week prior to protocol initiation, or who are taking vitamins and/or other supplements and who are unwilling to discontinue their use for at least 1 week prior to study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01341600

Locations
United States, Pennsylvania
Amish Research Clinic
Lancaster, Pennsylvania, United States, 17601
Sponsors and Collaborators
University of Maryland
Food and Drug Administration (FDA)
Investigators
Principal Investigator: Richard B Horenstein, M.D. University of Maryland
  More Information

Publications:
Responsible Party: Alan Shuldiner, Professor of Medicine, University of Maryland
ClinicalTrials.gov Identifier: NCT01341600     History of Changes
Other Study ID Numbers: HP-00044487, 3U01GM074518-05S1
Study First Received: April 22, 2011
Last Updated: September 28, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by University of Maryland:
Clopidogrel
Pharmacogenetics
Platelets
Healthy Subjects

Additional relevant MeSH terms:
Omeprazole
Clopidogrel
Ticlopidine
Anti-Ulcer Agents
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Proton Pump Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Hematologic Agents
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Fibrinolytic Agents
Fibrin Modulating Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on August 01, 2014