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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]).
Study to evaluate the bioequivalence of orally administered European source clopidogrel tablets and US and Japanese source clopidogrel tablets.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| European clopidogrel tablets, 75 mg | Experimental | Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet (Zyllt, KRKA - test) |
|
| Japanese clopidogrel tablets, 75 mg | Active Comparator | 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 | Active Comparator | Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clopidogrel | Drug | 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) |
| 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 |
| 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 |
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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
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| Name | Affiliation | Role |
|---|---|---|
| Rainard Fuhr, Dr. med. | PAREXEL International GmbH, Berlin | Principal Investigator |
| Glenn Carlson, MD | AstraZeneca, Wilmington, US | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Berlin | Germany |
84 participants recruited; 144 screened, 60 excluded (59 did not meet inclusion criteria and 1 refused participation)
Participants recruited at PAREXEL Early Phase Clinical Unit Berlin, Germany between August 2014 and September 2014.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| FG002 | 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 |
| FG003 | 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 |
| FG004 | 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 |
| FG005 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Period |
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| First Washout Period |
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| Second Period |
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| Second Washout Period |
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| Third Period |
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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.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*h/mL | 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 |
|
From screening until follow-up, i.e. up to 7 weeks after the first dose.
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
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | European Clopidogrel Tablets, 75 mg | Treatment A: a single oral dose of clopidogrel 75 mg film-coated tablet Eu(Zyllt, KRKA - test) |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA version 17.0. | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Brilinta Global Clinical Leader | AstraZeneca | +46 31 776 1000 | ClinicalTrialTransparency@astrazeneca.com |
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| ID | Term |
|---|---|
| D000077144 | Clopidogrel |
| ID | Term |
|---|---|
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
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|
| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
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| COMPLETED |
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| NOT COMPLETED |
|
| BG001 | 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 |
| BG002 | 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 |
| BG003 | 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 |
| BG004 | 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 |
| BG005 | 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 |
| BG006 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| BMI (Body Mass Index) | Mean | Standard Deviation | kg/m^2 |
|
| OG001 | 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) |
| OG002 | US Clopidogrel Tablets, 75 mg | Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference) |
|
|
|
| Primary | 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. | 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) | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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 | 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. | 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) | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | 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 |
|
|
|
|
| 0 |
| 81 |
| 19 |
| 81 |
| EG001 | 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) | 0 | 80 | 18 | 80 |
| EG002 | US Clopidogrel Tablets, 75 mg | Treatment C: a single oral dose of clopidogrel 75 mg film-coated tablet (Plavix®, Sanofi-Aventis, reference) | 0 | 82 | 22 | 82 |
| EG003 | Total Number of Participants | total number of subjects exposed to any treatment | 0 | 83 | 38 | 83 |
| Dizziness | Nervous system disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Catheter Site Pain | General disorders | MedDRA version 17.0. | Non-systematic Assessment | includes Administration Site Conditions |
|
| Catheter Site Inflammation | General disorders | MedDRA version 17.0. | Non-systematic Assessment | includes Administration site Conditions |
|
| Fatigue | General disorders | MedDRA version 17.0. | Non-systematic Assessment | includes Administrations Site Conditions |
|
| Nasopharyngitis | Infections and infestations | MedDRA version 17.0. | Non-systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA version 17.0. | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Dysphonia | Respiratory, thoracic and mediastinal disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | MedDRA version 17.0. | Non-systematic Assessment |
|
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.
| D009930 |
| Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| Geometric mean ratio | 105.79 | 2-Sided | 90 | 95.22 | 117.53 | Geometric mean ratio is calculated as A/C, where A= European clopidogrel and C=US clopidogrel | Yes | Non-Inferiority or Equivalence | 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. |
| Geometric mean ratio | 92.03 | 2-Sided | 90 | 84.91 | 99.75 | Geometric mean ratio is calculated as A/C, where A= European clopidogrel and C=US clopidogrel | Yes | Non-Inferiority or Equivalence | 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 |