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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
  Purpose

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.


Condition Intervention Phase
Coronary Artery Disease
Drug: clopidogrel
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effect of the Genetic Variant 2C19*2 on Clopidogrel Biological Response in Patients With Premature Coronary Artery Disease

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Inhibition of residual platelet activity 6 hours after a loading dose of clopidogrel [ Time Frame: 6 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 109
Study Start Date: October 2008
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
patients homozygous for the 2C19*1 genetic variant
Drug: clopidogrel
comparison of two loading strategies of clopidogrel (300mg vs 900mg) in the two genetic profiles
Other Name: clopidogrel
Experimental: 2
carriers of the 2C19*2 genetic variant (homozygous or heterozygous)
Drug: clopidogrel
comparison of two loading strategies of clopidogrel (300mg vs 900mg) in the two genetic profiles
Other Name: clopidogrel

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)

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00822666

Locations
France
Hopital la Pitié-Salpétrière Institut de cardiologie
Paris, France, 75013
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
Principal Investigator: Jean-Philippe Collet, MD Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided by Assistance Publique - Hôpitaux de Paris

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT00822666     History of Changes
Other Study ID Numbers: P070117
Study First Received: January 13, 2009
Last Updated: December 10, 2012
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Platelet aggregation
Platelet
Thrombosis
Clopidogrel

Additional relevant MeSH terms:
Coronary Artery Disease
Coronary Disease
Myocardial Ischemia
Arterial Occlusive Diseases
Arteriosclerosis
Cardiovascular Diseases
Heart Diseases
Vascular Diseases
Clopidogrel
Ticlopidine
Cardiovascular Agents
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Purinergic Agents
Purinergic Antagonists
Purinergic P2 Receptor Antagonists
Purinergic P2Y Receptor Antagonists
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014