CiloMecT: Pharmacodynamic Study of Cilostazol in Healthy Volunteers

• Sponsor: Otsuka Pharmaceutical Co., Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02554721
• Collaborator: (none)
• Enrollment: 77
• Location: 1
• Arms: 4
• Actual Duration (Months): 31.9
• Patients Per Site Per Month: 2.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Cilostazol; Drug: Acetylsalicylic acid; Drug: Clopidogrel	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 77 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effect of Cilostazol as an add-on Treatment to a Single Antiplatelet Agent (Acetylsalicylic Acid or Clopidogrel) on Platelet Function Testing and Bleeding Time in Healthy Volunteers
• Actual Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Mar 30, 2018
• Actual Study Completion Date: Mar 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 (CYP2C19 Wild Type) 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)	Drug: Cilostazol; Drug: Acetylsalicylic acid
Experimental: Group 2 (CYP2C19 Wild Type) 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)	Drug: Cilostazol; Drug: Clopidogrel
Experimental: Group 3 (CYP2C19 heterozygous (*1/*2) ) 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)	Drug: Cilostazol; Drug: Clopidogrel
Experimental: Group 4 (CYP2C19 homozygous (*2/*2)) 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)	Drug: Cilostazol; Drug: Clopidogrel

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Male
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Bad Krozingen		Germany

Sponsors and Collaborators

• Otsuka Pharmaceutical Co., Ltd.

Investigators

• Study Director: Osamu Sato, Otsuka Pharmaceutical Co., Ltd.

Study Documents (Full-Text)

• Study Protocol - Mar 7, 2018
• Statistical Analysis Plan - May 9, 2018

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Co., Ltd.
• ClinicalTrials.gov Identifier: NCT02554721
• Other Study ID Numbers: 21-13-102; 2013-002633-38
• First Posted: Sep 18, 2015
• Last Update Posted: Oct 13, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by Otsuka Pharmaceutical Co., Ltd.: Healthy Volunteers
• Additional relevant MeSH terms: Aspirin; Cilostazol; Clopidogrel

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Group 1 (CYP2C19 EM)	Group 2 (CYP2C19 EM)	Group 3 (CYP2C19 IM)	Group 4 CYP2C19 PM)	Not Assigned
Arm/Group Description	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).	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).	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).	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).	Two participants who received cilostazol in Period A were not assigned to a group.
Period Title: Overall Study
STARTED	20	19	19	17	2
COMPLETED	19	19	19	17	0
NOT COMPLETED	1	0	0	0	2

Baseline Characteristics

Arm/Group Title	Group 1 (CYP2C19 EM)	Group 2 (CYP2C19 EM)	Group 3 (CYP2C19 IM)	Group 4 CYP2C19 PM)	Not Assigned	Total
Arm/Group Description	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).	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).	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).	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).	Two participants who received cilostazol in Period A were not assigned to a group.	Total of all reporting groups
Overall Participants	20	19	19	17	2	77
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.8 (4.3)	28.3 (6.5)	25.9 (4.6)	24.2 (4.0)	26.5 (4.9)	26.1 (5.0)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	20 100%	19 100%	19 100%	17 100%	2 100%	77 100%
Race/Ethnicity, Customized (Count of Participants)
White	20 100%	19 100%	19 100%	17 100%	2 100%	77 100%
Region of Enrollment (Count of Participants)
Germany	20 100%	19 100%	19 100%	17 100%	2 100%	77 100%

Outcome Measures

1. Primary Outcome

Title	Ex-vivo Inhibition Of Platelet Aggregation (IPA)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Acetylsalicylic Acid - Cilostazol	Clopidogrel - Cilostazol
Arm/Group Description	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).	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).
Measure Participants	15	51
5 µM ADP	0.82	1.21
500 mg/L AA	1.03	4.42

2. Secondary Outcome

Title	Effects On Skin Bleeding Time (BT)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Acetylsalicylic Acid - Cilostazol	Clopidogrel - Cilostazol
Arm/Group Description	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).	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).
Measure Participants	17	51
Geometric Mean (95% Confidence Interval) [ratio]	1.31	1.27

Adverse Events

Time Frame	Treatment-emergent adverse events were collected from Day 1 to Day 29
Adverse Event Reporting Description	Subjects receiving at least 1 dose of study medication were included in the safety analysis.
Arm/Group Title	Cilostazol		Acetylsalicylic Acid		Clopidogrel		Acetylsalicylic Acid - Cilostazol		Clopidogrel - Cilostazol
Arm/Group Description	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).		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).		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).		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.		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.
All Cause Mortality
	Cilostazol		Acetylsalicylic Acid		Clopidogrel		Acetylsalicylic Acid - Cilostazol		Clopidogrel - Cilostazol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/77 (0%)		0/20 (0%)		0/55 (0%)		0/20 (0%)		0/55 (0%)
Serious Adverse Events
	Cilostazol		Acetylsalicylic Acid		Clopidogrel		Acetylsalicylic Acid - Cilostazol		Clopidogrel - Cilostazol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/77 (0%)		0/20 (0%)		0/55 (0%)		0/20 (0%)		0/55 (0%)
Other (Not Including Serious) Adverse Events
	Cilostazol		Acetylsalicylic Acid		Clopidogrel		Acetylsalicylic Acid - Cilostazol		Clopidogrel - Cilostazol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/77 (80.5%)		3/20 (15%)		3/55 (5.5%)		10/20 (50%)		41/55 (74.5%)
Cardiac disorders
Palpitations	5/77 (6.5%)		0/20 (0%)		0/55 (0%)		2/20 (10%)		3/55 (5.5%)
Gastrointestinal disorders
Abdominal pain	0/77 (0%)		2/20 (10%)		0/55 (0%)		0/20 (0%)		0/55 (0%)
Infections and infestations
Nasopharyngitis	2/77 (2.6%)		0/20 (0%)		1/55 (1.8%)		0/20 (0%)		3/55 (5.5%)
Nervous system disorders
Headache	60/77 (77.9%)		1/20 (5%)		2/55 (3.6%)		10/20 (50%)		38/55 (69.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.