Clopidogrel and Response Variability Investigation Study 2
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Study type: Interventional
Phase: Phase 3

Summary: 
      To evaluate the role of the genetic variant 2C19*2 on the pharmacodynamic response as
      assessed by optical aggregometry and on the pharmacokinetic response as assessed by measuring
      active metabolites following an oral administration of a loading dose of 300/900mg of
      clopidogrel in patients with established coronary artery disease.
    

Detailed description: 
      Rationale : Clopidogrel is a specific and irreversible of the P2Y12 platelet receptor leading
      to an inhibition of platelet aggregation. Clopidogrel is a prodrug that must be converted
      into an active metabolite that selectively and irreversibly binds to the P2Y12 platelet
      membrane receptor. As a consequence, a loading dose of 300 mg is necessary in percutaneous
      coronary intervention and in acute coronary syndrome, situations which require a rapid
      inhibition of platelet aggregation due to the high thrombotic risk.

      High platelet reactivity on clopidogrel may be due to various reasons including polymorphism
      in the gene encoding the cytochrome P-450 2C19 enzyme (CYP2C19) which has been shown to
      contribute to the variability of platelet response to clopidogrel. CYP2C19 is a key enzyme in
      this activation process and our group was the first to describe an association between the
      presence of the loss of function CYP2C19 681G>A polymorphism (also called *2) with lower
      clopidogrel responsiveness in healthy subjects.

      Poor responsiveness to clopidogrel has become a major concern given acute recurrent events
      following stent placement.

      Objective : To evaluate the role of the genetic variant 2C19*2 on the pharmacodynamic
      response as assessed by optical aggregometry and on the pharmacokinetic response as assessed
      by measuring active metabolites following an oral administration of a loading dose of
      300/900mg of clopidogrel in patients with established coronary artery disease.

      Target population :Patients of less than 45 years of age and who survived a MI and enrolled
      in the AFIJI multicenter registry (Appraisal of risk Factors in young Ischemic patients
      Justifying aggressive Intervention).

      Primary end-point :Comparison of inhibition of the intensity of residual platelet aggregation
      (IRPA) measured 6 minutes after induction by 20 μmol/L following 300mg or 900 mg of
      clopidogrel with respect to the presence of the genetic variant CYP2C19*2

        1. Maximum platelet aggregation instead of IRPA

        2. RPA with 5µM and 50 µM of ADP

        3. Measure of clopidogrel and its active metabolites (carboxylated and thiol) at different
           time points following the loading dose (H0, H1, H2 et H6) with respect to the presence
           of the genetic variant CYP2C19*2

        4. Relationship between active metabolites concentration and IRPA

        5. Relationship between active metabolites and dose of clopidogrel

        6. Comparison of 300mg vs 900mg on IRPA in the whole population irrespective of the genetic
           variant

      Statistical analysis :Comparison of IRPA with respect to the presence of the genetic variant
      2C19*2 by anova Area under the curve of the production of active metabolites with respect to
      the presence of the genetic variant 2C19*2 Agenda :November 2008 (inclusion of first patient)
      to december 2009 (analysis of the data)
    

Intervention name(s): clopidogrel
Intervention type(s): Drug
Intervention description(s): comparison of two loading strategies of clopidogrel (300mg vs 900mg) in the two genetic profiles
Intervention MeSH terms: Clopidogrel
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Platelet aggregation; Platelet; Thrombosis; Clopidogrel