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Trial record 21 of 1053 for:    clopidogrel

Role of CYP2C19 Polymorphism in the Drug Interaction Between Clopidogrel and Omeprazole

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ClinicalTrials.gov Identifier: NCT01094275
Recruitment Status : Completed
First Posted : March 26, 2010
Last Update Posted : January 31, 2018
Sponsor:
Information provided by (Responsible Party):
Neil Kleiman, MD, The Methodist Hospital System

Brief Summary:
Clopidogrel, an inhibitor of ADP induced platelet aggregation and activation, is one of the most commonly used drugs in patients with cardiovascular disease. The specific aim of the proposed study is to determine whether the interaction between proton-pump inhibitors (PPIs) and clopidogrel is dependent on CYP2C19 haplotype.

Condition or disease Intervention/treatment
Coronary Artery Disease Drug: Clopidogrel 75mg, Omeprazole 20mg

Detailed Description:

Clopidogrel, an inhibitor of ADP induced platelet aggregation and activation, is one of the most commonly used drugs in patients with cardiovascular disease; coronary-stenting would not be possible without the robust anti platelet function of this drug. Clopidogrel is a pro-drug that is transformed through a series of hepatic cytochrome p-450 (CYP) enzymes to an active metabolite. One of these CYP enzymes, 2C19 is subject to competitive inhibition by commonly used proton-pump inhibitors (PPIs). PPIs are commonly used for gastro-esophageal protection in patients treated with clopidogrel. Around 63% of 3,799 patients on clopidogrel received a PPI at TMH in 2008.

Recently, a series of publications indicated that clopidogrel active metabolite levels and platelet inhibition are lower in patients receiving PPIs. In addition, a recent survey of >16,690 patients in Medco database indicates that use of PPIs is associated with a 51% increase in the risk of death or myocardial infarction in patients receiving clopidogrel. Recent data have also indicated that patients with loss of function (LOF) haplotypes of the CYP2C19 gene have lower levels of the active metabolite after dosing with clopidogrel. These patients have higher rates of death, myocardial infarction, stent thrombosis and other ischemic complications than do patients with the wild type enzyme. Inadequate responses to clopidogrel therapy have been implicated as an important predictor of adverse clinical events. The reported prevalence of non-responsiveness to clopidogrel among patients with cardiovascular disease is between 4% and 34%, depending on the method and definition used to assess this parameter. Approximately 25% of American population carries a LOF mutation of CYP2C19.

It is unclear whether the concomitant use of omeprazole (PPI) with clopidogrel would result in a decrease in platelet function parameters through the CYP2C19 clopidogrel activation pathway. The specific aim of the proposed study is to determine whether the interaction between PPIs and clopidogrel is dependent on CYP2C19 haplotype. We hypothesize that among subjects with a LOF genotype, the interaction between clopidogrel and PPIs is greater than that in subjects with the wild type genotype7 and is manifest in both platelet function parameters and in conversion of clopidogrel to its active metabolite.

Approximately 75 randomly selected healthy volunteer subjects will be screened with the intent of identifying at least 16 subjects who are heterozygous for a LOF mutation of CYP2C19 (known as *2/rs4244285, *3).

Subjects with the LOF allele will be selected along with age and gender-matched wild type controls and baseline platelet function studies will be performed (n=16 for each group). Subjects in each stratum will then be randomly assigned to receive one week of clopidogrel in combination with omeprazole or clopidogrel alone. Subjects initially assigned to clopidogrel + omeprazole will then take clopidogrel only and subjects initially assigned to clopidogrel only will take both clopidogrel and omeprazole.


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Study Type : Observational [Patient Registry]
Actual Enrollment : 75 participants
Observational Model: Case-Crossover
Time Perspective: Prospective
Target Follow-Up Duration: 6 Months
Official Title: Role of CYP2C19 Polymorphism in the Drug Interaction Between Clopidogrel and Omeprazole
Study Start Date : January 2010
Actual Primary Completion Date : June 30, 2014
Actual Study Completion Date : June 30, 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

Group/Cohort Intervention/treatment
wild / normal type allele of CYP2C gene
clopidogrel 75 mg alone.
Drug: Clopidogrel 75mg, Omeprazole 20mg
Clopidogrel and or Omeprazole as applicable
Other Name: Plavix , Prilosec OTC

wild / normal type allele of CYP2C
clopidogrel 75 mg + omeprazole 20 mg.
Drug: Clopidogrel 75mg, Omeprazole 20mg
Clopidogrel and or Omeprazole as applicable
Other Name: Plavix , Prilosec OTC

Loss of Haplotype CYP2C19
clopidogrel 75mg alone
Drug: Clopidogrel 75mg, Omeprazole 20mg
Clopidogrel and or Omeprazole as applicable
Other Name: Plavix , Prilosec OTC

Loss of function haplotype of CYP2C
clopidogrel 75mg + omerprazole 20mg.
Drug: Clopidogrel 75mg, Omeprazole 20mg
Clopidogrel and or Omeprazole as applicable
Other Name: Plavix , Prilosec OTC




Primary Outcome Measures :
  1. The effect of omeprazole on platelet inhibition by clopidogrel [ Time Frame: 3 weeks ]
    To test whether concomitant administration of omeprazole will decrease the platelet inhibitory properties of clopidogrel in subjects with LOF mutation of CYP2C19 (known as *2 and *3)


Secondary Outcome Measures :
  1. The effect of omeprazole on the conversion of clopidogrel [ Time Frame: 3 weeks ]
    To test whether concomitant administration of omeprazole will decrease the conversion of clopidogrel to its active metabolite in subjects with loss of function (LOF) mutation of CYP2C19 (known as *2 and *3)


Biospecimen Retention:   None Retained
Cheek swabs for DNA, blood samples for drug metabolite estimation and platelet function study.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Healthy subjects aged 18-65.
Criteria

Inclusion Criteria:

  • age 18- 65
  • healthy - not taking any drugs / over the counter drugs regularly.
  • ability and commitment to take the drugs and volunteer for 3 blood draws.

Exclusion Criteria:

  • Taking any scheduled medication known to affect platelet function such as clopidogrel or NSAIDS11, COX2 inhibitors, beta blockers, calcium channel blockers, diuretics, anti-coagulants, older psychotropic agents, and recent ingestion of alcohol and caffeine
  • Known history of heart disease
  • Bleeding disorders
  • Known allergy or contraindications to omeprazole or clopidogrel
  • Pregnant and nursing women will also be excluded.

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): NCT01094275


Locations
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United States, Texas
The Methodist Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Neil Kleiman, MD
Investigators
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Principal Investigator: Neal S Kleiman, MD Methodist DeBakey Heart Center.

Additional Information:

Publications:
Srinivas Nadipalli, Sashidar Guthikonda, Timothy R. DelaO, Ali J. Marian, Federico Monzon, Ping Wang, Neal S. KleimanDOES A LOSS OF FUNCTION POLYMORPHISM OF CYP2C19 MODULATE THE EFFECTS OF CLOPIDOGREL. J Am Coll Cardiol. 2011;57 E1201.

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Responsible Party: Neil Kleiman, MD, Professor of Medicine Weill Cornell Medical College Medical Director Cardiac Catheterization Laboratories, The Methodist Hospital System
ClinicalTrials.gov Identifier: NCT01094275     History of Changes
Other Study ID Numbers: Pro00003846
First Posted: March 26, 2010    Key Record Dates
Last Update Posted: January 31, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Plan to share data to be determined.
Keywords provided by Neil Kleiman, MD, The Methodist Hospital System:
drug resistance
gene polymorphism
Additional relevant MeSH terms:
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Clopidogrel
Coronary Artery Disease
Coronary Disease
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Omeprazole
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
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors