Healthy
Conditions
Keywords
Healthy Volunteers
Brief summary
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.
Interventions
DRUGCilostazol
DRUGAcetylsalicylic acid
DRUGClopidogrel
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Caucasian male subjects * Able to read, to write and to fully understand German language * Provision of written informed consent before screening and baseline * BMI between 19.0 and 30.0 kg/m2, inclusive and body weight between 50.0 and 100.0 kg, inclusive * Good general health as determined by the investigator by medical history, physical examination, vital signs, electrocardiogram, baseline and safety lab
Exclusion criteria
* Personal or family history of bleeding disorders, or reasonable suspicion of vascular malformations, including aneurysms * Known predisposition to bleeding (e.g. active peptic ulceration, recent (within 6 month) haemorrhagic stroke, proliferative diabetic retinopathy, poorly controlled hypertension) * Use of antibiotics within thirty (30) days prior to screening and until baseline visit * Clinically significant abnormalities in medical history, physical examination, vital signs, electrocardiogram, baseline and safety lab * Supine pulse rate \> 100 beats/min or \<50 beats/min * Systolic blood pressure \<100 or \>140 mmHg * Diastolic blood pressure \<50 or \>90 mmHg * Concomitant use of any other medication including over-the-counter preparations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ex-vivo Inhibition Of Platelet Aggregation (IPA) | Baseline, Visit 5 (Day 22-29) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effects On Skin Bleeding Time (BT) | Visit 5 (Day 22-29) | 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. |
Countries
Germany
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 20 |
| 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). | 19 |
| 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). | 19 |
| 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). | 17 |
| Not Assigned Two participants who received cilostazol in Period A were not assigned to a group. | 2 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Noncompliance | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Group 1 (CYP2C19 EM) | Group 2 (CYP2C19 EM) | Group 3 (CYP2C19 IM) | Group 4 CYP2C19 PM) | Not Assigned | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 25.8 years STANDARD_DEVIATION 4.3 | 28.3 years STANDARD_DEVIATION 6.5 | 25.9 years STANDARD_DEVIATION 4.6 | 24.2 years STANDARD_DEVIATION 4 | 26.5 years STANDARD_DEVIATION 4.9 | 26.1 years STANDARD_DEVIATION 5 |
| Race/Ethnicity, Customized White | 20 Participants | 19 Participants | 19 Participants | 17 Participants | 2 Participants | 77 Participants |
| Region of Enrollment Germany | 20 Participants | 19 Participants | 19 Participants | 17 Participants | 2 Participants | 77 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 20 Participants | 19 Participants | 19 Participants | 17 Participants | 2 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 20 | 0 / 55 | 0 / 20 | 0 / 55 |
| other Total, other adverse events | 62 / 77 | 3 / 20 | 3 / 55 | 10 / 20 | 41 / 55 |
| serious Total, serious adverse events | 0 / 77 | 0 / 20 | 0 / 55 | 0 / 20 | 0 / 55 |
Outcome results
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.
Time frame: Baseline, Visit 5 (Day 22-29)
Population: 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)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Acetylsalicylic Acid - Cilostazol | Ex-vivo Inhibition Of Platelet Aggregation (IPA) | 5 µM ADP | 0.82 ratio |
| Acetylsalicylic Acid - Cilostazol | Ex-vivo Inhibition Of Platelet Aggregation (IPA) | 500 mg/L AA | 1.03 ratio |
| Clopidogrel - Cilostazol | Ex-vivo Inhibition Of Platelet Aggregation (IPA) | 5 µM ADP | 1.21 ratio |
| Clopidogrel - Cilostazol | Ex-vivo Inhibition Of Platelet Aggregation (IPA) | 500 mg/L AA | 4.42 ratio |
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.
Time frame: Visit 5 (Day 22-29)
Population: 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)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Acetylsalicylic Acid - Cilostazol | Effects On Skin Bleeding Time (BT) | 1.31 ratio |
| Clopidogrel - Cilostazol | Effects On Skin Bleeding Time (BT) | 1.27 ratio |