Trial Outcomes & Findings for Pharmacodynamic Study of Cilostazol in Healthy Volunteers (NCT NCT02554721)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

77 participants

Primary outcome timeframe

Baseline, Visit 5 (Day 22-29)

Results posted on

2021-10-13

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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).	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).	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).	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).	Not Assigned Two participants who received cilostazol in Period A were not assigned to a group.
Overall Study STARTED	20	19	19	17	2
Overall Study COMPLETED	19	19	19	17	0
Overall Study NOT COMPLETED	1	0	0	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	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).	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).	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).	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).	Not Assigned Two participants who received cilostazol in Period A were not assigned to a group.
Overall Study Adverse Event	1	0	0	0	1
Overall Study Noncompliance	0	0	0	0	1

Baseline Characteristics

Pharmacodynamic Study of Cilostazol in Healthy Volunteers

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1 (CYP2C19 EM) n=20 Participants 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).	Group 2 (CYP2C19 EM) n=19 Participants 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).	Group 3 (CYP2C19 IM) n=19 Participants 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).	Group 4 CYP2C19 PM) n=17 Participants 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).	Not Assigned n=2 Participants Two participants who received cilostazol in Period A were not assigned to a group.	Total n=77 Participants Total of all reporting groups
Age, Continuous	25.8 years STANDARD_DEVIATION 4.3 • n=5 Participants	28.3 years STANDARD_DEVIATION 6.5 • n=7 Participants	25.9 years STANDARD_DEVIATION 4.6 • n=5 Participants	24.2 years STANDARD_DEVIATION 4.0 • n=4 Participants	26.5 years STANDARD_DEVIATION 4.9 • n=21 Participants	26.1 years STANDARD_DEVIATION 5.0 • n=10 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	19 Participants n=7 Participants	19 Participants n=5 Participants	17 Participants n=4 Participants	2 Participants n=21 Participants	77 Participants n=10 Participants
Race/Ethnicity, Customized White	20 Participants n=5 Participants	19 Participants n=7 Participants	19 Participants n=5 Participants	17 Participants n=4 Participants	2 Participants n=21 Participants	77 Participants n=10 Participants
Region of Enrollment Germany	20 Participants n=5 Participants	19 Participants n=7 Participants	19 Participants n=5 Participants	17 Participants n=4 Participants	2 Participants n=21 Participants	77 Participants n=10 Participants

PRIMARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	Acetylsalicylic Acid - Cilostazol n=15 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).	Clopidogrel - Cilostazol n=51 Participants 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).
Ex-vivo Inhibition Of Platelet Aggregation (IPA) 5 µM ADP	0.82 ratio Interval 0.5 to 1.37	1.21 ratio Interval 1.09 to 1.35
Ex-vivo Inhibition Of Platelet Aggregation (IPA) 500 mg/L AA	1.03 ratio Interval 1.01 to 1.05	4.42 ratio Interval 3.42 to 5.73

SECONDARY outcome

Timeframe: 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)

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.