Clopidogrel bioequivalence study in healthy subjects

Study identifier:D5130C00131

ClinicalTrials.gov identifier:NCT02185534

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

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.

Medical condition

Bioequivalence, AUC, Cmax, Pharmacokinetics

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Clopidogrel

Sex

All

Actual Enrollment

144

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 01 Aug 2014

Primary Completion Date: 01 Oct 2014

Study Completion Date: 01 Oct 2014

Study design

Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science

Verification:

Verified 01 May 2016 by AstraZeneca

Collaborators

Inclusion and exclusion criteria

Inclusion Criteria

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.

Location

Research Site

Berlin, Germany

Arms	Assigned Interventions
Experimental: European clopidogrel tablets, 75 mg Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet (Zyllt, KRKA - test)	Drug: Clopidogrel 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) Other Name: Zyllt Other Name: Plavix
Active Comparator: Japanese clopidogrel tablets, 75 mg Treatment B: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Brystol-Myer Squibb,Sanofi-Aventis, reference)	Drug: Clopidogrel 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) Other Name: Zyllt Other Name: Plavix
Active Comparator: US clopidogrel tablets, 75 mg Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference)	Drug: Clopidogrel 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) Other Name: Zyllt Other Name: Plavix

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants recruited at PAREXEL Early Phase Clinical Unit Berlin, Germany between August 2014 and September 2014.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
84 participants recruited; 144 screened, 60 excluded (59 did not meet inclusion criteria and 1 refused participation)

Reporting Groups

	Description
First European, then Japanese, then US clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 3
First European, then US, then Japanese clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi-Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 3
First Japanese, then European, then US clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi-Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 3
First Japanese, then US, then European clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi-Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 3
First US, then European, then Japanese clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 1, a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 3
First US, then Japanese, then European clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 3

Participant Flow for 5 periods

Period 1: First Period

	First European, then Japanese, then US clopidogrel	First European, then US, then Japanese clopidogrel	First Japanese, then European, then US clopidogrel	First Japanese, then US, then European clopidogrel	First US, then European, then Japanese clopidogrel	First US, then Japanese, then European clopidogrel
STARTED	14	14	14	14	14	14
COMPLETED	14	14	14	13	14	14
NOT COMPLETED	0	0	0	1	0	0
Withdrawal by Subject	0	0	0	1	0	0

Period 2: First Washout Period

	First European, then Japanese, then US clopidogrel	First European, then US, then Japanese clopidogrel	First Japanese, then European, then US clopidogrel	First Japanese, then US, then European clopidogrel	First US, then European, then Japanese clopidogrel	First US, then Japanese, then European clopidogrel
STARTED	14	14	14	13	14	14
COMPLETED	13	14	14	13	13	13
NOT COMPLETED	1	0	0	0	1	1
Withdrawal by Subject	1	0	0	0	1	0
Protocol Violation	0	0	0	0	0	1

Period 3: Second Period

	First European, then Japanese, then US clopidogrel	First European, then US, then Japanese clopidogrel	First Japanese, then European, then US clopidogrel	First Japanese, then US, then European clopidogrel	First US, then European, then Japanese clopidogrel	First US, then Japanese, then European clopidogrel
STARTED	13	14	14	13	13	13
COMPLETED	13	14	14	13	13	13
NOT COMPLETED	0	0	0	0	0	0

Period 4: Second Washout Period

	First European, then Japanese, then US clopidogrel	First European, then US, then Japanese clopidogrel	First Japanese, then European, then US clopidogrel	First Japanese, then US, then European clopidogrel	First US, then European, then Japanese clopidogrel	First US, then Japanese, then European clopidogrel
STARTED	13	14	14	13	13	13
COMPLETED	13	14	14	13	13	13
NOT COMPLETED	0	0	0	0	0	0

Period 5: Third Period

	First European, then Japanese, then US clopidogrel	First European, then US, then Japanese clopidogrel	First Japanese, then European, then US clopidogrel	First Japanese, then US, then European clopidogrel	First US, then European, then Japanese clopidogrel	First US, then Japanese, then European clopidogrel
STARTED	13	14	14	13	13	13
COMPLETED	13	14	14	13	13	13
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

The overall number of baseline participants is 84, as it comprised all randomized subjects, although one subject withdrew consent prior to the first dose. Thus the safety population includes 83 subjects only.

Reporting Groups

	Description
First European, then Japanese, then US clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 3
First European, then US, then Japanese clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi-Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 3
First Japanese, then European, then US clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi-Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 3
First Japanese, then US, then European clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi-Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 3
First US, then European, then Japanese clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 1, a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 3
First US, then Japanese, then European clopidogrel	A single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Sanofi- Aventis, reference) in Period 1; a single oral dose of clopidogrel 75 mg filmcoated tablet (Plavix®, Brystol-Myer Squibb, Sanofi- Aventis, reference) in Period 2; a single oral dose of clopidogrel 75 mg filmcoated tablet (Zyllt, KRKA - test) in Period 3

Baseline Measures

	First European, then Japanese, then US clopidogrel	First European, then US, then Japanese clopidogrel	First Japanese, then European, then US clopidogrel	First Japanese, then US, then European clopidogrel	First US, then European, then Japanese clopidogrel	First US, then Japanese, then European clopidogrel	Total
Number of Participants [units: Participants]	14	14	14	14	14	14	84
Age Continuous [units: years] Mean ± Standard Deviation	33 ± 9	37 ± 11	36 ± 10	35 ± 8	34 ± 9	36 ± 11	35 ± 9
Gender, Male/Female [units: participants]
Female	7	7	8	7	4	4	37
Male	7	7	6	7	10	10	47
Race/Ethnicity, Customized [units: participants]
Black or African American	1	0	0	0	0	0	1
White	13	14	13	14	12	13	79
Other	0	0	1	0	2	1	4
Race/Ethnicity, Customized [units: participants]
Hispanic or Latino	0	0	0	0	2	1	3
Not Hispanic or Latino	14	14	14	14	12	13	81
BMI (Body Mass Index) [units: kg/m^2] Mean ± Standard Deviation	23.7 ± 3.1	24.7 ± 3.5	23.4 ± 2.9	24.1 ± 2.7	23.0 ± 3.1	23.9 ± 3.1	23.8 ± 3.0

Outcome Measures

1. Primary Outcome Measure: Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero extrapolated to infinity (AUC(0-inf)) [ Time Frame: 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 ]

Measure Type	Primary
Measure Name	Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero extrapolated to infinity (AUC(0-inf))
Measure Description	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.
Time Frame	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
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacokinetic population consisted of 79 subjects, i.e. all subjects in the safety population for whom AUC(0-last) and Cmax could be calculated for clopidogrel for the test treatment (European) and at least one of the reference treatments (Japanese, US). AUC(0-inf) could not be reliably calculated for many of these subjects.

Reporting Groups

	Description
European clopidogrel tablets, 75 mg	Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet Eu(Zyllt, KRKA - test)
Japanese clopidogrel tablets, 75 mg	Treatment B: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Brystol-Myer Squibb,Sanofi- Aventis, reference)
US clopidogrel tablets, 75 mg	Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference)

Measured Values

	European clopidogrel tablets, 75 mg	Japanese clopidogrel tablets, 75 mg	US clopidogrel tablets, 75 mg
Number of Participants Analyzed [units:participants]	41	45	38
Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero extrapolated to infinity (AUC(0-inf)) [units: ng*h/mL] Geometric Mean (Geometric Coefficient of Variation)	1.05 (139.0%)	0.992 (117.9%)	1.09 (106.9%)

Statistical Analysis 1 for Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero extrapolated to infinity (AUC(0-inf))

Groups^[1]	European clopidogrel tablets, 75 mg, Japanese clopidogrel tablets, 75 mg
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	104.43
90% Confidence Interval	( 92.27 to 118.19 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The analysis was conducted using an analysis of variance (ANOVA) including fixed effects for treatment, sequence, period and subject within sequence. All pharmacokinetic parameters were log-transformed prior to analysis. Bioequivalence was concluded, when the 90% confidence interval (CI) for the geometric LS mean ratios were fully contained within the predefined equivalence limits of 0.80 to 1.25
[5]	Other relevant estimation information:
	Geometric mean ratio is calculated as A/B, where A= European clopidogrel and B=Japanese clopidogrel

Statistical Analysis 2 for Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero extrapolated to infinity (AUC(0-inf))

Groups^[1]	European clopidogrel tablets, 75 mg, US clopidogrel tablets, 75 mg
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	97.19
90% Confidence Interval	( 81.12 to 116.45 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The analysis was conducted using an analysis of variance (ANOVA) including fixed effects for treatment, sequence, period and subject within sequence. All pharmacokinetic parameters were log-transformed prior to analysis. Bioequivalence was concluded, when the 90% confidence interval (CI) for the geometric LS mean ratios were fully contained within the predefined equivalence limits of 0.80 to 1.25
[2]	Additional details about a non-inferiority or equivalence analysis:
	Geometric mean ratio is calculated as A/C, where A= European clopidogrel and C=US clopidogrel
[5]	Other relevant estimation information:
	Geometric mean ratio is calculated as A/C, where A= European clopidogrel and C=US clopidogrel

2. Primary Outcome Measure: Pharmacokinetics of clopidogrel by assessment of observed maximum plasma concentration (Cmax) [ Time Frame: 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 ]

Measure Type	Primary
Measure Name	Pharmacokinetics of clopidogrel by assessment of observed maximum plasma concentration (Cmax)
Measure Description	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.
Time Frame	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
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacokinetic population consisted of 79 subjects, i.e. all subjects in the safety population for whom AUC(0-last) and Cmax could be calculated for clopidogrel for the test treatment (European) and at least one of the reference treatments (Japanese, US)

Reporting Groups

	Description
European clopidogrel tablets, 75 mg	Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet Eu(Zyllt, KRKA - test)
Japanese clopidogrel tablets, 75 mg	Treatment B: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Brystol-Myer Squibb,Sanofi- Aventis, reference)
US clopidogrel tablets, 75 mg	Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference)

Measured Values

	European clopidogrel tablets, 75 mg	Japanese clopidogrel tablets, 75 mg	US clopidogrel tablets, 75 mg
Number of Participants Analyzed [units:participants]	79	79	79
Pharmacokinetics of clopidogrel by assessment of observed maximum plasma concentration (Cmax) [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	0.551 (122.6%)	0.511 (150.6%)	0.521 (122.4%)

Statistical Analysis 1 for Pharmacokinetics of clopidogrel by assessment of observed maximum plasma concentration (Cmax)

Groups^[1]	European clopidogrel tablets, 75 mg, Japanese clopidogrel tablets, 75 mg
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	108.06
90% Confidence Interval	( 95.46 to 122.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The analysis was conducted using an analysis of variance (ANOVA) including fixed effects for treatment, sequence, period and subject within sequence. All pharmacokinetic parameters were log-transformed prior to analysis. Bioequivalence was concluded, when the 90% confidence interval (CI) for the geometric LS mean ratios were fully contained within the predefined equivalence limits of 0.80 to 1.25.
[5]	Other relevant estimation information:
	Geometric mean ratio is calculated as A/B, where A= European clopidogrel and B=Japanese clopidogrel

Statistical Analysis 2 for Pharmacokinetics of clopidogrel by assessment of observed maximum plasma concentration (Cmax)

Groups^[1]	European clopidogrel tablets, 75 mg, US clopidogrel tablets, 75 mg
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	105.79
90% Confidence Interval	( 95.22 to 117.53 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The analysis was conducted using an analysis of variance (ANOVA) including fixed effects for treatment, sequence, period and subject within sequence. All pharmacokinetic parameters were log-transformed prior to analysis. Bioequivalence was concluded, when the 90% confidence interval (CI) for the geometric LS mean ratios were fully contained within the predefined equivalence limits of 0.80 to 1.25.
[5]	Other relevant estimation information:
	Geometric mean ratio is calculated as A/C, where A= European clopidogrel and C=US clopidogrel

3. Secondary Outcome Measure: Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero to the time of last quantifiable concentration (AUC(0-last)) [ Time Frame: 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 ]

Measure Type	Secondary
Measure Name	Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero to the time of last quantifiable concentration (AUC(0-last))
Measure Description	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.
Time Frame	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
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The pharmacokinetic population consisted of 79 subjects, i.e. all subjects in the safety population for whom AUC(0-last) and Cmax could be calculated for clopidogrel for the test treatment (European) and at least one of the reference treatments (Japanese, US)

Reporting Groups

	Description
European clopidogrel tablets, 75 mg	Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet Eu(Zyllt, KRKA - test)
Japanese clopidogrel tablets, 75 mg	Treatment B: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Brystol-Myer Squibb,Sanofi- Aventis, reference)
US clopidogrel tablets, 75 mg	Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference)

Measured Values

	European clopidogrel tablets, 75 mg	Japanese clopidogrel tablets, 75 mg	US clopidogrel tablets, 75 mg
Number of Participants Analyzed [units:participants]	79	79	79
Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero to the time of last quantifiable concentration (AUC(0-last)) [units: h*ng/mL] Geometric Mean (Geometric Coefficient of Variation)	0.705 (114.8%)	0.751 (116.5%)	0.767 (107.1%)

Statistical Analysis 1 for Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero to the time of last quantifiable concentration (AUC(0-last))

Groups^[1]	European clopidogrel tablets, 75 mg, Japanese clopidogrel tablets, 75 mg
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	93.94
90% Confidence Interval	( 87.12 to 101.29 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The analysis was conducted using an analysis of variance (ANOVA) including fixed effects for treatment, sequence, period and subject within sequence. All pharmacokinetic parameters were log-transformed prior to analysis. Bioequivalence was concluded, when the 90% confidence interval (CI) for the geometric LS mean ratios were fully contained within the predefined equivalence limits of 0.80 to 1.25.
[5]	Other relevant estimation information:
	Geometric mean ratio is calculated as A/B, where A= European clopidogrel and B=Japanese clopidogrel

Statistical Analysis 2 for Pharmacokinetics of clopidogrel by assessment of area under the curve from time zero to the time of last quantifiable concentration (AUC(0-last))

Groups^[1]	European clopidogrel tablets, 75 mg, US clopidogrel tablets, 75 mg
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	92.03
90% Confidence Interval	( 84.91 to 99.75 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	The analysis was conducted using an analysis of variance (ANOVA) including fixed effects for treatment, sequence, period and subject within sequence. All pharmacokinetic parameters were log-transformed prior to analysis. Bioequivalence was concluded, when the 90% confidence interval (CI) for the geometric LS mean ratios were fully contained within the predefined equivalence limits of 0.80 to 1.25
[5]	Other relevant estimation information:
	Geometric mean ratio is calculated as A/C, where A= European clopidogrel and C=US clopidogrel

Serious Adverse Events

Time Frame	From screening until follow-up, i.e. up to 7 weeks after the first dose.
Additional Description	Adverse events (AEs) were assigned to the treatment after which they occurred: Treatment A: AEs starting at the time of /after dosing of European clopidogrel tablets Treatment B: AEs starting at the time of / after dosing of Japanese clopidogrel tablets Treatment C: AEs starting at the time of / after dosing of US clopidogrel tablets

Reporting Groups

	Description
European clopidogrel tablets, 75 mg	Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet Eu(Zyllt, KRKA - test)
Japanese clopidogrel tablets, 75 mg	Treatment B: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Brystol-Myer Squibb,Sanofi- Aventis, reference)
US clopidogrel tablets, 75 mg	Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference)
Total number of participants	total number of subjects exposed to any treatment

Serious Adverse Events

	European clopidogrel tablets, 75 mg	Japanese clopidogrel tablets, 75 mg	US clopidogrel tablets, 75 mg	Total number of participants
Total, serious adverse events
# participants affected / at risk	0/81 (0.00%)	0/80 (0.00%)	0/82 (0.00%)	0/83 (0.00%)

Other Adverse Events

Time Frame	From screening until follow-up, i.e. up to 7 weeks after the first dose.
Additional Description	Adverse events (AEs) were assigned to the treatment after which they occurred: Treatment A: AEs starting at the time of /after dosing of European clopidogrel tablets Treatment B: AEs starting at the time of / after dosing of Japanese clopidogrel tablets Treatment C: AEs starting at the time of / after dosing of US clopidogrel tablets

Frequency Threshold

Threshold above which other adverse events are reported	1%

Reporting Groups

	Description
European clopidogrel tablets, 75 mg	Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet Eu(Zyllt, KRKA - test)
Japanese clopidogrel tablets, 75 mg	Treatment B: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Brystol-Myer Squibb,Sanofi- Aventis, reference)
US clopidogrel tablets, 75 mg	Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference)
Total number of participants	total number of subjects exposed to any treatment

Other Adverse Events

European clopidogrel tablets, 75 mg

Japanese clopidogrel tablets, 75 mg

US clopidogrel tablets, 75 mg

Total number of participants

Total, other (not including serious) adverse events

# participants affected / at risk

19/81 (23.46%)

18/80 (22.50%)

22/82 (26.83%)

38/83 (45.78%)

Nervous system disorders

Headache¹

# participants affected / at risk

16/81 (19.75%)

15/80 (18.75%)

16/82 (19.51%)

29/83 (34.94%)

# events

Nervous system disorders

Dizziness¹

# participants affected / at risk

0/81 (0.00%)

1/80 (1.25%)

3/82 (3.66%)

4/83 (4.82%)

# events

Nervous system disorders

Presyncope¹

# participants affected / at risk

0/81 (0.00%)

1/80 (1.25%)

0/82 (0.00%)

1/83 (1.20%)

# events

Gastrointestinal disorders

Abdominal Pain¹

# participants affected / at risk

1/81 (1.23%)

1/80 (1.25%)

1/82 (1.22%)

3/83 (3.61%)

# events

Gastrointestinal disorders

Diarrhoea¹

# participants affected / at risk

0/81 (0.00%)

1/80 (1.25%)

2/82 (2.44%)

3/83 (3.61%)

# events

Gastrointestinal disorders

Nausea¹

# participants affected / at risk

0/81 (0.00%)

0/80 (0.00%)

2/82 (2.44%)

2/83 (2.41%)

# events

Gastrointestinal disorders

Vomiting¹

# participants affected / at risk

0/81 (0.00%)

0/80 (0.00%)

1/82 (1.22%)

1/83 (1.20%)

# events

General disorders

Catheter Site Pain¹
includes Administration Site Conditions

# participants affected / at risk

0/81 (0.00%)

2/80 (2.50%)

0/82 (0.00%)

2/83 (2.41%)

# events

General disorders

Catheter Site Inflammation¹
includes Administration site Conditions

# participants affected / at risk

0/81 (0.00%)

0/80 (0.00%)

1/82 (1.22%)

1/83 (1.20%)

# events

General disorders

Fatigue¹
includes Administrations Site Conditions

# participants affected / at risk

1/81 (1.23%)

0/80 (0.00%)

0/82 (0.00%)

1/83 (1.20%)

# events

Infections and infestations

Nasopharyngitis¹

# participants affected / at risk

0/81 (0.00%)

0/80 (0.00%)

2/82 (2.44%)

2/83 (2.41%)

# events

Injury, poisoning and procedural complications

Contusion¹

# participants affected / at risk

1/81 (1.23%)

0/80 (0.00%)

1/82 (1.22%)

2/83 (2.41%)

# events

Respiratory, thoracic and mediastinal disorders

Cough¹

# participants affected / at risk

1/81 (1.23%)

0/80 (0.00%)

0/82 (0.00%)

1/83 (1.20%)

# events

Respiratory, thoracic and mediastinal disorders

Dysphonia¹

# participants affected / at risk

0/81 (0.00%)

0/80 (0.00%)

1/82 (1.22%)

1/83 (1.20%)

# events

Ear and labyrinth disorders

Tinnitus¹

# participants affected / at risk

0/81 (0.00%)

0/80 (0.00%)

1/82 (1.22%)

1/83 (1.20%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA version 17.0.

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: If a publication (e.g., in a scientific journal) based on the results of this study is envisaged, approval from AstraZeneca will be obtained and a draft manuscript will be submitted to AstraZeneca for scrutiny and comment. The choice of conduit will be mutually agreed on by the Principal Investigator and AstraZeneca.