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Clopidogrel Preventive Effect Based on CYP2C19 Genotype in Ischemic Stroke

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ClinicalTrials.gov Identifier: NCT04072705
Recruitment Status : Not yet recruiting
First Posted : August 28, 2019
Last Update Posted : August 28, 2019
Sponsor:
Collaborator:
SAMJIN PHARM
Information provided by (Responsible Party):
KyungYul Lee, Gangnam Severance Hospital

Brief Summary:
The hypothesis of this study is that "the poor metabolizer or intermediate metabolizer of the cytochrome P450 2C19 genotype in patients with acute ischemic stroke is associated with increased risk of composite cardiovascular events (recurrent stroke, myocardial infarction, cardiovascular death) compared to those who of extensive metabolizer of the cytochrome P450 2C19 genotype".

Condition or disease Intervention/treatment
Acute Ischemic Stroke Drug: General principles of care and judgement of researcher

Detailed Description:

Clopidogrel, one of the antiplatelet agents used for secondary prevention in patients with ischemic stroke and coronary artery disease, has been shown to have a superior antiplatelet effect compared to aspirin, and is therefore being administered to many patients with stroke and coronary artery disease. Clopidogrel inhibits platelet-derived ADP receptor, P2Y12, in the liver to produce an anti-platelet effect. It has been suggested that clopidogrel resistance could be occurred from drug-drug interaction via the same pharmacological metabolic pathway. Previous studies reported that the genotypes of Cytochrome P450 2C19, which is involved in the metabolism of clopidogrel in the liver, lead to differences in drug response and recurrence rates of cardiovascular disease. The risk of recurrence of ischemic stroke was reported to be about 4 times higher in patients with a poor metabolizer or intermediate metabolizer genotype of the Cytochrome P450 2C19 genotype compared to the extensive metabolizer genotype. This genotypes of Cytochrome P450 2C19 were also different according to race.

The researches about cytochrome P450 2C19 genotype and clopidogrel resistance have been conducted mainly in patients with coronary artery disease and are not known in stroke patients. Few studies have examined whether the resistance of clopidogrel according to the genotype of cytochrome P450 2C19 in stroke patients is related to the occurrence and/or recurrence of cardiovascular disease. The hypothesis of this study is that "the poor metabolizer or intermediate metabolizer of the cytochrome P450 2C19 genotype in patients with acute ischemic stroke is associated with increased risk of cardiovascular disease and mortality compared to those who of extensive metabolizer of the cytochrome P450 2C19 genotype".


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Study Type : Observational
Estimated Enrollment : 2927 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Multicenter Prospective observationaL Study to evAluate the effecT of Clopidogrel on the prEvention of Major vascuLar Events According to the gEnotype of Cytochrome P450 2C19 in Ischemic Stroke paTients; PLATELET Study
Estimated Study Start Date : August 20, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
1. Poor and intermediate metabolizer group
Poor and intermediate metabolizer group: acute ischemic stroke patients with poor and intermediate metabolizer genotype of cytochrome P450 2C19 for clopidogrel.
Drug: General principles of care and judgement of researcher
Because our study will be performed by observational design, there will be no intervention for our study. Because it is a registry-based study, overall decision making for medications will be performed according to the general principles of care and judgement of researcher.

2. Extensive metabolizer group
Extensive metabolizer group: acute ischemic stroke patients with Extensive metabolizer genotype of cytochrome P450 2C19 for clopidogrel.
Drug: General principles of care and judgement of researcher
Because our study will be performed by observational design, there will be no intervention for our study. Because it is a registry-based study, overall decision making for medications will be performed according to the general principles of care and judgement of researcher.




Primary Outcome Measures :
  1. composite cardiovascular events [ Time Frame: up to 6 months ]
    Occurrence of composite cardiovascular events (recurrent stroke, myocardial infarction, cardiovascular death)


Secondary Outcome Measures :
  1. cardiovascular events [ Time Frame: up to 6 months ]
    Occurrence of ischemic stroke

  2. cardiovascular events [ Time Frame: up to 6 months ]
    Occurrence of transient ischemic attack

  3. cardiovascular events [ Time Frame: up to 6 months ]
    Revascularization of cerebral, coronary, peripheral artery or aorta

  4. cardiovascular events [ Time Frame: up to 6 months ]
    Occurrence of myocardial infarction

  5. early neurological worsening [ Time Frame: up to 7 days ]
    increased National Institutes of Health Stroke Scale within 7 day after admission)

  6. Prognosis [ Time Frame: 3 months ]
    ratio of modified Rankin scale (0 - 2) at 3 months


Other Outcome Measures:
  1. Incidence of major adverse events [ Time Frame: Tile frame: participants will be followed at 0, 1, 3, 6 months ]

    Occurrence of major bleeding (fatal bleeding, symptomatic cerebral hemorrhage, ocular hemorrhage, bleeding which needs absolute bed rest or hospitalization or transfusion (more than 2 pack of whole blood or RBC).

    Occurrence of all-causes mortality



Biospecimen Retention:   Samples With DNA
Cytochrome P450 2C19 genotype


Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with acute ischemic stroke who received clopidogrel 75 mg to 300 mg (in the case of loading dose) within 24 hours of symptom onset and who underwent Cytochrome P450 2C19 genotyping test
Criteria

Inclusion Criteria:

  1. Ischemic stroke confirmed by brain CT or MRI
  2. Patient who received clopidogrel within 72 hours after onset of ischemic stroke
  3. Adults over 19 years
  4. Patients who agreed to participate in this study within 7 days after ischemic stroke
  5. Patients who underwent Cytochrome P450 2C19 genotype test.

Exclusion Criteria:

  1. Patients who currently take anticoagulation or is expected to take anticoagulation with 6 months from the screening date
  2. Patients who need other antiplatelet drugs except aspirin and clopidogrel
  3. Patients who were taking clopidogrel prior to ischemic stroke
  4. Patients scheduled for coronary artery stenting, coronary artery bypass surgery, carotid endarterectomy, carotid and cerebral artery stenting
  5. Patients with severe comorbidities or active cancer with an estimated life expectancy of less than two years
  6. Patients who participated in other drug clinical trials within the past 30 days
  7. Patients with high risk source of potential cardiac source of embolism in TOAST classification
  8. Patients who are expected to unable to participate or continue the study

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): NCT04072705


Contacts
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Contact: KyungYul Lee 82-2-2019-4632 ext 3325 kylee@yuhs.ac

Sponsors and Collaborators
Gangnam Severance Hospital
SAMJIN PHARM
Investigators
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Principal Investigator: KyungYul Lee Gangnam Severance Hospital

Publications:

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Responsible Party: KyungYul Lee, KyungYul Lee, Professor, Gangnam Severance Hospital
ClinicalTrials.gov Identifier: NCT04072705     History of Changes
Other Study ID Numbers: 3-2019-0195
First Posted: August 28, 2019    Key Record Dates
Last Update Posted: August 28, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by KyungYul Lee, Gangnam Severance Hospital:
Pharmacogenetics
Cytochrome P450 2C19
Clopidogrel
Stroke
Additional relevant MeSH terms:
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Stroke
Cerebral Infarction
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Clopidogrel
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