Clinical trial NCT01123824: Pharmacodynamic and Pharmacokinetic Study of 2 Different Dose Regimen of Clopidogrel in CYP2C19 Genotyped Healthy Subjects
Official title: A Randomized, Double-blind, Double-dummy, Two Period, Two Treatment Cross-over Pharmacodynamic and Pharmacokinetic Study of Clopidogrel Given as 5-day Repeated Oral Doses (300 mg Loading Dose Followed by 75 mg/Day and 600 mg Loading Dose Followed by 150 mg/Day) in 4 Different Groups of CYP2C19 Genotyped Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: healthy subjects
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2010-05-14
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Primary Objective:

* Investigate the possible role of the CYP2C19 genotype in Adenosine diphosphate (ADP)-induced platelet aggregation after administration of a standard dose regimen of clopidogrel (300 mg loading dose followed by 75 mg/day for 4 days) in healthy male and female subjects

Secondary Objectives:

* Assess the pharmacodynamic activity of a higher dose regimen of clopidogrel (600 mg loading dose followed by 150 mg/day for 4 days)
* Compare the pharmacokinetic profiles of clopidogrel active metabolite between the selected groups of genotyped subjects and the 2 dose regimen

Detailed description: The total study duration per subject is 10-12 weeks broken down as follows:

* Screening: 2 to 40 days before the first dosing
* Period 1: 7 days including 5 days treatment
* Washout: At least 14 days after the last dosing
* Period 2: 7 days including 5 days treatment
* End of study: 7 to 10 days after the last dosing

Eligibility criteria: Inclusion criteria:

Healthy subject in good health, as determined by a medical history, physical examination including vital signs and clinical laboratory tests:

* with a body weight between 45 kg and 95 kg if male, between 40 kg and 85 kg if female, and with a Body Mass Index (BMI) between 18 and 30 kg/m²
* classified into one of the 4 groups of metabolizers according to his/her CYP2C19 genotype:

  * Ultrarapid Metabolizers (UMs, CYP2C19\*1/\*17 and CYP2C19\*17/\*17)
  * homozygous Extensive Metabolizers (homoEMs, CYP2C19\*1/\*1)
  * heterozygous Extensive Metabolizers (heteroEMs, CYP2C19\*1/\*2 and CYP2C19\*1/\*3)
  * Poor Metabolizers (PMs, CYP2C19\*2/\*2 and CYP2C19\*2/\*3)

Exclusion criteria:

* Evidence of inherited disorder of coagulation/hemostasis functions
* Subject smoking more than 10 cigarettes or equivalent per day
* Unability to abstain from intake of any drug affecting hemostasis throughout the whole study duration

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Maximum platelet aggregation intensity (MAI) induced by Adenosine diphosphate (ADP) 5 µM after 5 days treatment
timeFrame: Day 5 of each period
Secondary outcomes:
measure: Maximum platelet aggregation intensity (MAI) induced by ADP 20 µM after 5 days treatment
timeFrame: Day 5 of each period
measure: Platelet reactivity index -Vasodilator-stimulated phosphoprotein test (PRI-VASP) after 5 days treatment
timeFrame: Day 5 of each period
measure: Clopidogrel active metabolite pharmacokinetic parameters (Cmax, tmax, AUC0-24, AUClast) after 5 days treatment
timeFrame: Up to 24 hours postdose on Day 5 for each period
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Sanofi-Aventis Administrative Office
Study officials:
affiliation: Sanofi
name: International Clinical Development Study Director
role: STUDY_CHAIR
References:
citation: Simon T, Bhatt DL, Bergougnan L, Farenc C, Pearson K, Perrin L, Vicaut E, Lacreta F, Hurbin F, Dubar M. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clin Pharmacol Ther. 2011 Aug;90(2):287-95. doi: 10.1038/clpt.2011.127. Epub 2011 Jun 29.