Clopidogrel and Response Variability Investigation Study 2 (CLOVIS2)

This study has been completed.
Sponsor:
Collaborator:
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT00822666
First received: January 13, 2009
Last updated: December 10, 2012
Last verified: January 2009

January 13, 2009
December 10, 2012
October 2008
December 2009   (final data collection date for primary outcome measure)
Inhibition of residual platelet activity 6 hours after a loading dose of clopidogrel [ Time Frame: 6 hours ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00822666 on ClinicalTrials.gov Archive Site
  • Maximum platelet aggregation instead of IRPA [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • RPA with 5µM and 50 µM of ADP [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • 3. Measure of clopidogrel and its active metabolites (carboxylated and thiol) at different time points following the loading dose (H0, H1, H2 ,H6) with respect to the presence of the genetic variant CYP2C19*2 [ Time Frame: H0, H1, H2, H6 ] [ Designated as safety issue: No ]
  • Relationship between active metabolites concentration and IRPA [ Time Frame: during the study ] [ Designated as safety issue: No ]
  • Relationship between active metabolites and dose of clopidogrel [ Time Frame: during the study ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Clopidogrel and Response Variability Investigation Study 2
Effect of the Genetic Variant 2C19*2 on Clopidogrel Biological Response in Patients With Premature Coronary Artery Disease

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.

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)

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Coronary Artery Disease
Drug: clopidogrel
comparison of two loading strategies of clopidogrel (300mg vs 900mg) in the two genetic profiles
Other Name: clopidogrel
  • Active Comparator: 1
    patients homozygous for the 2C19*1 genetic variant
    Intervention: Drug: clopidogrel
  • Experimental: 2
    carriers of the 2C19*2 genetic variant (homozygous or heterozygous)
    Intervention: Drug: clopidogrel

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
109
December 2009
December 2009   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Age > 18
  • Male gender
  • Included in the AFIJI registry
  • No high bleeding risk profile
  • No recent history of acute coronary syndrome (< 3 months)
  • Written informed consent obtained
  • Genotype CYP2C19 : *1/*1, *1/*2 ou *2/*2
  • Genotype P2Y12 : H1/H1 ou H1/H2

Exclusion Criteria:

  • Female gender
  • Patient with a contraindication to clopidogrel
  • Patient who has received a loading dose of clopidogrel in the past 7 days
  • Patient treated with ticlopidine or GP2B/3A receptor antagonist prior to loading
  • Non compliance
  • Génotype P2Y12 : H2/H2.
  • Patient treated with drugs interacting with platelet aggregation (NSAID, persantine, serotonin inhibitors )
  • Patient treated with drugs interacting 2C19
  • Not affiliated to the national health insurance
  • Patient participating to another randomized study
Male
18 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
France
 
NCT00822666
P070117
No
Assistance Publique - Hôpitaux de Paris
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
Principal Investigator: Jean-Philippe Collet, MD Assistance Publique - Hôpitaux de Paris
Assistance Publique - Hôpitaux de Paris
January 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP