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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-002633-38 | EudraCT Number |
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The primary objective of this study is to investigate the effects of Cilostazol, Acetylsalycylic acid and Clopidogrel alone as well as combinations of Cilostazol/Acetylsalicylic acid and Cilostazol/ Clopidogrel on ex-vivo Platelet Function (PF) testing.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1 (CYP2C19 Wild Type) | Experimental | Trial period A: Cilostazol 100 mg twice daily for 1 week (Days 1-7) Trial period B: Wash out period (Days 8-14) Trial period C: Acetylsalicylic acid 100 mg once daily for 1 week (Days 15-21) Trial period D: Cilostazol 100 mg twice daily and Acetylsalicylic acid 100mg once daily for 1 week (Days 22-28) |
|
| Group 2 (CYP2C19 Wild Type) | Experimental | Trial period A: Cilostazol 100 mg twice daily for 1 week (Days 1-7) Trial period B: Wash out period (Days 8-14) Trial period C: Clopidogrel 75 mg once daily for 1 week (Days 15-21) Trial period D: Cilostazol 100 mg twice daily and Clopidogrel 75 mg once daily for 1 week (Days 22-28) |
|
| Group 3 (CYP2C19 heterozygous (*1/*2) ) | Experimental | Trial period A: Cilostazol 100 mg twice daily for 1 week (Days 1-7) Trial period B: Wash out period (Days 8-14) Trial period C: Clopidogrel 75 mg once daily for 1 week (Days 15-21) Trial period D: Cilostazol 100 mg twice daily and Clopidogrel 75 mg once daily for 1 week (Days 22-28) |
|
| Group 4 (CYP2C19 homozygous (*2/*2)) | Experimental | Trial period A: Cilostazol 100 mg twice daily for 1 week (Days 1-7) Trial period B: Wash out period (Days 8-14) Trial period C: Clopidogrel 75 mg once daily for 1 week (Days 15-21) Trial period D: Cilostazol 100 mg twice daily and Clopidogrel 75 mg once daily for 1 week (Days 22-28) |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cilostazol | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ex-vivo Inhibition Of Platelet Aggregation (IPA) | The effect of ASA in combination with cilostazol and clopidogrel in combination with cilostazol on IPA was determined ex vivo in citrated platelet rich plasma (PRP) after stimulation of aggregation by low-level adenosine diphosphate (ADP) (5 micromolar [uM]) and arachidonic acid (AA) (500 milligrams/liter [mg/L]). Light transmission aggregometry (LTA) was used to measure residual aggregation (the percentage of aggregation 5 minutes after the addition of ADP or AA). Results are reported as the 95% confidence intervals for the reported geometric mean ratios (GMRs) ([cilostazol+reference (ASA or clopidogrel)]/reference) for IPA. | Baseline, Visit 5 (Day 22-29) |
| Measure | Description | Time Frame |
|---|---|---|
| Effects On Skin Bleeding Time (BT) | The effect of ASA in combination with cilostazol and clopidogrel in combination with cilostazol on skin BT (minutes) was determined with the Ivy method, utilizing standardized bleeding with the Surgicutt device. Results include the 95% confidence intervals for the reported GMRs ([cilostazol+reference]/reference) for skin BT. | Visit 5 (Day 22-29) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Osamu Sato | Otsuka Pharmaceutical Co., Ltd. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bad Krozingen | Germany |
A total of 77 healthy adult male participants were enrolled. Following administration of cilostazol in Period A and wash-out in Period B, participants were stratified according to CYP2C19 genotype and assigned to Groups 1-4 for further treatment in Periods C and D. Two participants who received cilostazol in Period A were not assigned to a group.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group 1 (CYP2C19 EM) | Participants received cilostazol 100 milligrams (mg) twice daily (BID) for 7 consecutive days from Day 1 to Day 7 (Period A). A 7-day wash-out period (Period B) allowed a return to baseline in relation to platelet function (PF) and skin bleeding time (BT) from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with normal, extensive metabolic (EM) activity (CYP2C19 EM) received ASA 100 mg once daily (QD) for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to ASA 100 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| FG001 | Group 2 (CYP2C19 EM) | Participants received cilostazol 100 mg BID for 7 consecutive days from Day 1 to Day 7 (Period A). A 7- day wash-out period (Period B) allowed a return to baseline in relation to PF and skin BT from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with normal EM activity (CYP2C19 EM) received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| FG002 | Group 3 (CYP2C19 IM) | Participants received cilostazol 100 mg BID for 7 consecutive days from Day 1 to Day 7 (Period A). A 7- day wash-out period (Period B) allowed a return to baseline in relation to PF and skin BT from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with intermediate metabolic (IM) activity (CYP2C19 IM) received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| FG003 | Group 4 CYP2C19 PM) | Participants received cilostazol 100 mg BID for 7 consecutive days from Day 1 to Day 7 (Period A). A 7- day wash-out period (Period B) allowed a return to baseline in relation to PF and skin BT from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with poor metabolic (PM) activity (CYP2C19 PM) received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| FG004 | Not Assigned | Two participants who received cilostazol in Period A were not assigned to a group. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety Analysis Set: All subjects who received at least 1 dose of trial medication
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| ID | Title | Description |
|---|---|---|
| BG000 | Group 1 (CYP2C19 EM) | Participants received cilostazol 100 milligrams (mg) twice daily (BID) for 7 consecutive days from Day 1 to Day 7 (Period A). A 7-day wash-out period (Period B) allowed a return to baseline in relation to platelet function (PF) and skin bleeding time (BT) from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with normal, extensive metabolic (EM) activity (CYP2C19 EM) received ASA 100 mg once daily (QD) for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to ASA 100 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| 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 | Ex-vivo Inhibition Of Platelet Aggregation (IPA) | The effect of ASA in combination with cilostazol and clopidogrel in combination with cilostazol on IPA was determined ex vivo in citrated platelet rich plasma (PRP) after stimulation of aggregation by low-level adenosine diphosphate (ADP) (5 micromolar [uM]) and arachidonic acid (AA) (500 milligrams/liter [mg/L]). Light transmission aggregometry (LTA) was used to measure residual aggregation (the percentage of aggregation 5 minutes after the addition of ADP or AA). Results are reported as the 95% confidence intervals for the reported geometric mean ratios (GMRs) ([cilostazol+reference (ASA or clopidogrel)]/reference) for IPA. | Full Analysis Set: All subjects who completed both periods of treatment with reference medication alone (Period C) and treatment with reference medication and cilostazol (Period D) | Posted | Geometric Mean | 95% Confidence Interval | ratio | Baseline, Visit 5 (Day 22-29) |
|
Treatment-emergent adverse events were collected from Day 1 to Day 29
Subjects receiving at least 1 dose of study medication were included in the safety analysis.
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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 | Cilostazol | All 77 enrolled participants received cilostazol 100 milligrams (mg) twice daily (BID) for 7 consecutive days from Day 1 to Day 7. A 7-day wash-out period (Period B) allowed a return to baseline in relation to platelet function (PF) and skin bleeding time (BT) from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). After returning to baseline, all participants were stratified and randomized to the following 4 treatment groups in a 1:1:1:1 ratio for treatment in Periods C and D: Group 1, normal, extensive metabolizer (EM); Group 2, EM; Group 3, intermediate metabolizer (IM); Group 4, poor metabolizer (PM). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Palpitations | Cardiac disorders | MedDRA Ver. 20.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director of Clinical Trials | Otsuka Pharmaceutical Co., LTD. | +81-3-6361-7366 | CL_OPCJ_RDA_Team@otsuka.jp |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 7, 2018 | Aug 5, 2021 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 9, 2018 | Aug 5, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000077407 | Cilostazol |
| D001241 | Aspirin |
| D000077144 | Clopidogrel |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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|
| Acetylsalicylic acid | Drug |
|
| Clopidogrel | Drug |
|
| Noncompliance |
|
| BG001 | Group 2 (CYP2C19 EM) | Participants received cilostazol 100 mg BID for 7 consecutive days from Day 1 to Day 7 (Period A). A 7- day wash-out period (Period B) allowed a return to baseline in relation to PF and skin BT from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with normal EM activity (CYP2C19 EM) received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| BG002 | Group 3 (CYP2C19 IM) | Participants received cilostazol 100 mg BID for 7 consecutive days from Day 1 to Day 7 (Period A). A 7- day wash-out period (Period B) allowed a return to baseline in relation to PF and skin BT from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with intermediate metabolic (IM) activity (CYP2C19 IM) received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| BG003 | Group 4 CYP2C19 PM) | Participants received cilostazol 100 mg BID for 7 consecutive days from Day 1 to Day 7 (Period A). A 7- day wash-out period (Period B) allowed a return to baseline in relation to PF and skin BT from Day 8 to Day 14. Participants who failed to return to baseline with respect to PF and skin BT were retested within a further week (Day 15 to Day 21). Participants with poor metabolic (PM) activity (CYP2C19 PM) received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21 or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit 7 days after last administration of cilostazol (from Day 1 to Day 7) (Period C). In the following week, participants received cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| BG004 | Not Assigned | Two participants who received cilostazol in Period A were not assigned to a group. |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
Participants with normal CYP2C19 activity (EM) (Group 1) who received ASA 100 mg QD for 7 consecutive days from Day 15 to Day 21 (Period C) went on to receive cilostazol 100 mg BID as an add-on therapy to ASA 100 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
| OG001 | Clopidogrel - Cilostazol | Participants with EM, IM, and PM CYP2C19 activity (Groups 2-4, respectively) who received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21 (Period C) went on to receive cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35 (Period D). |
|
|
| Secondary | Effects On Skin Bleeding Time (BT) | The effect of ASA in combination with cilostazol and clopidogrel in combination with cilostazol on skin BT (minutes) was determined with the Ivy method, utilizing standardized bleeding with the Surgicutt device. Results include the 95% confidence intervals for the reported GMRs ([cilostazol+reference]/reference) for skin BT. | Full Analysis Set: All subjects who completed both periods of treatment with reference medication alone (Period C) and treatment with reference medication and cilostazol (Period D) | Posted | Geometric Mean | 95% Confidence Interval | ratio | Visit 5 (Day 22-29) |
|
|
|
| 0 |
| 77 |
| 0 |
| 77 |
| 62 |
| 77 |
| EG001 | Acetylsalicylic Acid | Participants with extensive CYP2C19 activity (EM) received ASA 100 mg QD for 7 consecutive days from Day 15 to Day 21, or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit at 7 days after last administration of cilostazol (from Day 1 to Day 7). | 0 | 20 | 0 | 20 | 3 | 20 |
| EG002 | Clopidogrel | Participants with EM, IM, and PM CYP2C19 activity received clopidogrel 75 mg QD for 7 consecutive days from Day 15 to Day 21, or Day 22 to Day 28 for participants who failed to return to baseline with respect to PF testing and skin BT at the scheduled visit at 7 days after last administration of cilostazol (from Day 1 to Day 7). | 0 | 55 | 0 | 55 | 3 | 55 |
| EG003 | Acetylsalicylic Acid - Cilostazol | Participants with extensive CYP2C19 activity (EM) received cilostazol 100 mg BID as an add-on therapy to ASA 100 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35. | 0 | 20 | 0 | 20 | 10 | 20 |
| EG004 | Clopidogrel - Cilostazol | Participants with EM, IM, and PM CYP2C19 activity received cilostazol 100 mg BID as an add-on therapy to clopidogrel 75 mg QD for 7 consecutive days from Day 22 to Day 28 or Day 29 to Day 35. | 0 | 55 | 0 | 55 | 41 | 55 |
| Headache | Nervous system disorders | MedDRA Ver. 20.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA Ver. 20.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA Ver. 20.0 | Systematic Assessment |
|
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| D011804 |
| Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D011725 | Pyridines |