Clopidogrel Bioequivalence Study in Healthy Subjects

Study Overview
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Brief Summary
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This study will be an open-label, randomised, three-way crossover study in healthy male and female subjects, performed at a single centre. The objective of the study is to assess the bioequivalence between one test formulation (Clopidogrel 75 mg tablet (commercial blister from KRKA) and two reference formulations (Clopidogrel 75 mg tablet [Plavix, sourced in US and Japan]).

Detailed Description
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Study to evaluate the bioequivalence of orally administered European source clopidogrel tablets and US and Japanese source clopidogrel tablets.

Official Title
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An Open-label, Randomised, Three-way Crossover Study in Healthy Subjects to Assess the Bioequivalence of European Source Generic Clopidogrel Tablets and US and Japanese Source Branded Clopidogrel (Plavix®) Tablets.

Conditions
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Bioequivalence, AUC, Cmax, Pharmacokinetics

Intervention / Treatment
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* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture. Females must have a negative pregnancy test at screening and on each admission to the clinical unit, must not be lactating and • if of non child-bearing potential, confirmed at screening by fulfilling one of the following criteria: Post-menopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. • if of child-bearing potential and are sexually active must use, with their partner, 2 approved methods of highly effective contraception from the time of IMP administration until 3 months after the last dose of IMP. Have a body mass index between 18,5 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive. Be able to understand, read and speak the German language. Exclusion criteria History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the potential subject at risk because of participation in the study, or influence the results or the potential subject's ability to participate in the study. Current smokers or those who have smoked or used nicotine products within the previous 3 months. History of haemophilia, von Willebrand's disease, lupus anticoagulant, or other diseases/syndromes that can either alter or increase the propensity for bleeding. A personal history of vascular abnormalities including aneurysms; a personal history of severe haemorrhage, haematemesis, melena, haemoptysis, severe epistaxis, severe thrombocytopenia, intracranial haemorrhage; or rectal bleeding within 1 year prior to screening; or history suggestive of peptic ulcer disease; or at the discretion of the Investigator. Use of aspirin, ibuprofen, NSAIDS, or any other drug known to increase the propensity for bleeding for 2 weeks before randomisation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: European clopidogrel tablets, 75 mg<br>Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet (Zyllt, KRKA - test) | Drug: Clopidogrel<br>* European clopidogrel tablets, 75 mg (test) versus Japanese clopidogrel tablets, 75 mg (reference); European clopidogrel tablets, 75 mg (test) versus US clopidogrel tablets, 75 mg (reference)<br>* Other names: Plavix;|
| Active Comparator: Japanese clopidogrel tablets, 75 mg<br>Treatment B: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Brystol-Myer Squibb,Sanofi-Aventis, reference) | Drug: Clopidogrel<br>* European clopidogrel tablets, 75 mg (test) versus Japanese clopidogrel tablets, 75 mg (reference); European clopidogrel tablets, 75 mg (test) versus US clopidogrel tablets, 75 mg (reference)<br>* Other names: Plavix;|
| Active Comparator: US clopidogrel tablets, 75 mg<br>Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference) | Drug: Clopidogrel<br>* European clopidogrel tablets, 75 mg (test) versus Japanese clopidogrel tablets, 75 mg (reference); European clopidogrel tablets, 75 mg (test) versus US clopidogrel tablets, 75 mg (reference)<br>* Other names: Plavix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero Extrapolated to Infinity (AUC(0-inf)) | Comparison of the pharmacokinetic profile in terms of plasma concentration-time curve from time zero extrapolated to infinity, AUC(0-inf), of clopidogrel sourced in Europe and Japan. | 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose | 
| Pharmacokinetics of Clopidogrel by Assessment of Observed Maximum Plasma Concentration (Cmax) | Comparison of the pharmacokinetic profile in terms of observed maximum plasma concentration, taken directly from the individual concentration-time curve, Cmax, of clopidogrel sourced in Europe and the US. | 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Clopidogrel by Assessment of Area Under the Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC(0-last)) | Comparison of the pharmacokinetic profile in terms of the area under the plasma concentration-curve from time zero to the time of last quantifiable clopidogrel or SR26334 concentration, AUC(0-last), of clopidogrel sourced in Europe and the US. | 0 hours (pre-dose), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24 and 36 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clopidogrel, Zyllt, Plavix, Phase I, Healthy Subjects, Pharmacokinetics, Bioequivalence