Evaluation of the Biological Response to Clopidogrel in Patients With Ischemic Stroke (AAPIX)

Study Description

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Ischemic stroke (AIC) is the leading cause of non-traumatic disability in adults, the second leading cause of dementia and the third leading cause of death in France.

Clopidogrel is one of the recommended first line in the secondary prevention of AIC non cardioembolic origin. However recurrences occur in approximately 9% of patients receiving clopidogrel. Some studies in patients with coronary artery disease have made the connection between these treatment failures and non-biological response to clopidogrel. This non-biological response is found for approximately 30% to 50% of patients. Several mechanisms may explain this non-response. The most accepted mechanism is pharmacokinetic. Indeed, clopidogrel is a prodrug that requires intestinal absorption by P-glycoprotein (PGP) and a transformation by hepatic cytochrome into active metabolites. The genetic polymorphism of proteins involved in these two steps explain the low plasma concentration of active metabolites and thus the low efficacy of clopidogrel in some patients.

A new pharmacodynamic hypothesis suggests the involvement of platelet alpha 2-adrenergic receptors. The activation of these receptors potentiates signaling pathway P2Y12 receptor (channel inhibited by clopidogrel) and helps reduce platelet aggregation inhibiting response to clopidogrel.

Condition or disease	Intervention/treatment
Brain Ischemia; Ischemic Attack	Drug: Clopidogrel

Detailed Description:

Interest in the biological response to clopidogrel in the AIC is innovative because few data are available in this area. In addition to testing a new pharmacodynamic hypothesis, we also wish to study and compare other measures of platelet function methods in order to be able to use commonly in treatment decisions.

Study Design

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Observational
Actual Enrollment :	91 participants
Observational Model:	Case-Only
Time Perspective:	Prospective
Official Title:	Evaluation of the Biological Response to Clopidogrel in Patients With Ischemic Stroke : Role of Platelet alpha2-adrenergic Receptors
Study Start Date :	September 2013
Actual Primary Completion Date :	December 2015
Actual Study Completion Date :	December 2015

Groups and Cohorts

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Group/Cohort	Intervention/treatment
AVC; Patients with non-cardioembolic AIC requiring initiation of treatment with clopidogrel as usual indications	Drug: Clopidogrel; 75 mg milligrams per days of PLAVIX; Other Name: PLAVIX(R)

Outcome Measures

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. adrenergic component of the platelet response [ Time Frame: 5 days after taking clopidogrel ]
   adrenergic component of the platelet response is estimated by the difference between the maximum percentage of platelet aggregation by light transmission aggregometry (LTA) with the addition of ADP(adenosine diphosphate) + ADP versus selective agonist (epinephrine)

Secondary Outcome Measures :

1. VASP-CMF [ Time Frame: After 5 days taking clopidogrel ]
   Platelet reactivity index (PRI) by VASP CMF (flow cytometry) method
2. ELISA VASP [ Time Frame: After 5 days taking clopidogrel ]
   Platelet reactivity index (PRI-ELISA) using ELISA VASP
3. active metabolite of clopidogrel [ Time Frame: After 5 days taking clopidogrel ]
   Rate of residual plasma active metabolite of clopidogrel (R-130964)
4. Genotyping of MDR-1 and P450 2C19 [ Time Frame: After 5 days taking clopidogrel ]
   Genotyping of MDR-1 and P450 2C19

Biospecimen Retention:   Samples With DNA

Blood DNA

Eligibility Criteria

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Patients with non-cardioembolic AIC requiring initiation of treatment with clopidogrel as usual indications

Criteria

Inclusion Criteria:

• Consent signed
• Patients with non-cardioembolic AIC requiring initiation of treatment with clopidogrel as usual indications
• normal standard biological tests

Exclusion Criteria:

• Need to continue aspirin therapy
• Patients with a recurrence of clopidogrel AIC
• Patient already tacking clopidogrel
• Drugs interfering with the adrenergic system alpha blockers, alpha 2 receptor agonists (alpha-methyldopa) and alpha2 receptor inhibitors (Mianserin, Mirtazapine, yohimbine)
• Contra indication of clopidogrel and / or any of its excipients

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

France
CHU de Saint-Etienne
Saint-etienne, France, 42000

Sponsors and Collaborators

Centre Hospitalier Universitaire de Saint Etienne

Groupe de Recherche sur la Thrombose

Investigators

Principal Investigator:	Jerome VARVAT, MD	CHU de Saint-Etienne

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Centre Hospitalier Universitaire de Saint Etienne
ClinicalTrials.gov Identifier:	NCT01955642 History of Changes
Other Study ID Numbers:	1208094; 2013-000313-20 ( EudraCT Number )
First Posted:	October 7, 2013
Last Update Posted:	December 31, 2015
Last Verified:	December 2015

Keywords provided by Centre Hospitalier Universitaire de Saint Etienne:

Clopidogrel; Brain Ischemia; Ischemic attack; Biological response to clopidogrel

Additional relevant MeSH terms:

Ischemia; Brain Ischemia; Pathologic Processes; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Clopidogrel; Ticlopidine; 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; Fibrinolytic Agents; Fibrin Modulating Agents; Cytochrome P-450 CYP2C19 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors