Cilostazol Augmentation Study in Dementia

• Sponsor: Seoul National University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01409564
• Collaborator: Korea OIAA (Other)
• Enrollment: 46
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the effects of cilostazol augmentation in mild to moderate Alzheimer disease patients with subcortical white matter hyperintensities (WMHI) treated by donepezil.

Dementia is the most disabling disease in the old age. The prevalence of dementia is 5-10% of the elders. AchEIs (donepezil, galantamine, rivastigmine) are used to treat mild to moderate dementia, but these drugs only relate to symptomatic improvement and the response rates are less than 30%.

Cilostazol is a cyclic adenosine monophosphate phosphodiesterase 3 inhibitor (PDE3I) and used as antiplatelet agent in subcortical vascular disease (WMHI). And it upregulates phosphorylation of cyclic adenosine monophosphate-pathway response element binding protein (CREB) which plays a crucial role in memory enhancement and synaptic plasticity related to neurodegeneration prevention.

The investigators will try cilostazol augmentation in dementia patients with WMHI receiving donepezil to see the addictive effects of cilostazol using cognitive tasks and PET imaging.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Dementia	Drug: Cilostazol; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Cilostazol Augmentation Study In Dementia (CASID): A Randomized, Placebo-controlled Pilot Study to Compare the Efficacy Between Donepezil Monotherapy and Cilostazol Augmentation Therapy in Alzheimer's Disease Patients With Subcortical White Matter Hyperintensities
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cilostazol Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.	Drug: Cilostazol; Cilostazol 100mg bid per day will be administered orally and the period is total 24 weeks. The first week is a period for increasing the quantity, and during this period, cilostazol 50mg bid per day will be administered orally.
Placebo Comparator: Placebo Placebo group means dementia patients group receiving donepezil with placebo.	Drug: Placebo; Placebo with similar shape and color to cilostazol 100mg bid per day will be administered orally and the period is total 24 weeks. The first week is a period for increasing the quantity, and during this period, placebo 50mg bid per day will be administered orally.

Outcome Measures

Primary Outcome Measures

1. Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method [Baseline, 24-week]

   Regional cerebral glucose uptake level was measured as the ratio value of FDG uptake of the each unit level to the global mean uptake value.

Secondary Outcome Measures

1. Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) [Baseline, 12-week, 24-week]

   The ADAS-Cog score is measured by the number of questions answered incorrectly, therefore the higher is the worse. Score Scale: 0-75 (min-MAX) Each subcategory scores are summed. Word-recall test (0-10) Commands (0-5) Constructional praxis (0-5) Naming Objects/ Fingers (0-5) Ideational Praxis (0-5) Orientation (0-8) Word Recognition (0-12) Remembering Test Instructions (0-5) Spoken Language Ability (0-5) Word Finding Difficulty (0-5) Comprehension (0-5)

2. Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet) [Baseline, 12-month, 24-month]

   Basic cognitive functions are checked. (0-30) The score is better when higher.

3. Activities of Daily Living (ADCS-ADL) [Baseline, 12-month, 24-month]

   The caregiver answered to the questions given to measure the cognitive function level of the patients in daily living. Lower scores indicate greater severity. 23 questions Score Scale: 0-78 (min-MAX)

4. Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) [Baseline, 12-month, 24-month]

   Measured by professionally trained clinicians. Higher score indicates more severe AD symptoms. Score Scale: 0-18 (min-MAX)

5. Fazekas Scale [Baseline]

   Level of severity of white matter lesions in AD patients who can be legitimately administered with cilostazol. Measured by professionally trained clinicians. The higher score indicates more severe white matter lesion. Max-min: 0-3

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men/women over sixty years old

• Patients with slight and moderate dementia (MMSE score is over 10 under 26.)

• Patients with probable Alzheimer's disease according to the standard of NINCDS-ADRDA

• Patients accompanied with WMHI on Brain MRI (Fazeka's scale 1~3)

Exclusion Criteria:

• Those who do not agree to the test in a written form

• Patients who accompany other diseases except cerebral atrophy or change of subcortical white matter due to Alzheimer's disease on brain MRI

• Patients who should not use Cilostazol (① patients with bleeding tendency ② patients with congestive heart failure ③ patients who have a medical history of hypersensitivity to this medicine or constituent of this medicine ④ those who use anticoagulant and clot buster)

• Patients who suffer from nerve diseases or mental diseases which have influence on cognitive function except Alzheimer's disease (for example, schizophrenia, severe depression, mental retardation and etc.)

• Patients who are suspected to have a personal history of drug addiction or alcoholism within recent 10 years

• Patients who have severe problems in eye sight or hearing so that it is impossible to conduct the test smoothly

• Patients who the researchers think are inappropriate for taking part in the test

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	SMG-SNU Boramae Medical Center	Seoul		Korea, Republic of	156-707

Sponsors and Collaborators

• Seoul National University Hospital
• Korea OIAA

Investigators

• Principal Investigator: Jung-Seok Choi, MD, PhD, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jung-Seok Choi, Assistant Professor, Seoul National University Hospital
• ClinicalTrials.gov Identifier: NCT01409564
• Other Study ID Numbers: 06-2009-145
• First Posted: Aug 4, 2011
• Last Update Posted: May 13, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Jung-Seok Choi, Assistant Professor, Seoul National University Hospital: Alzheimer's dementia; Cilostazol
• Additional relevant MeSH terms: Dementia; Alzheimer Disease; Cilostazol

Study Results

Participant Flow

Recruitment Details	46 Subjects were enrolled in the single center of Seoul National University Boramae Hospital. The diagnosis of probable AD was made according to the criteria of NINCDS-ADRDA (MMSE score 10 ~ 26). Enrollment has started in July 2010 to end in March 2012.

Arm/Group Title	Cilostazol	Placebo
Arm/Group Description	Cilostazol group includes dementia patients receiving donepezil with cilostazol augmentation. All the randomly assigned AD patients in cilostazol group received 10 mg of Donepezil along with 200 mg of cilostazol per a day, doubly blinded. All the medications were orally administered. For the initial two weeks, patients only received 100 mg of cilstazol per a day to minimize the instabilities. Afterwards, for 22 weeks, patients received 200 mg of cilostazol.	Placebo group includes dementia patients receiving donepezil with placebo. All the patients were randomly assigned as placebo group and received 10 mg of Donepezil along with the same dose of sugar pill as normal cilostazol. All the clinical assessments and medications were doubly blinded. All the medications were orally administered.
Period Title: Overall Study
STARTED	23	23
COMPLETED	18	18
NOT COMPLETED	5	5

Baseline Characteristics

Arm/Group Title	Cilostazol	Placebo	Total
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.	Placebo group means dementia patients group receiving donepezil with placebo.	Total of all reporting groups
Overall Participants	18	18	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	18 100%	18 100%	36 100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	79.00 (6.26)	78.05 (6.09)	78.53 (6.11)
Sex: Female, Male (Count of Participants)
Female	13 72.2%	15 83.3%	28 77.8%
Male	5 27.8%	3 16.7%	8 22.2%
Region of Enrollment (participants) [Number]
Korea, Republic of	18 100%	18 100%	36 100%

Outcome Measures

1. Primary Outcome

Title	Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method
Description	Regional cerebral glucose uptake level was measured as the ratio value of FDG uptake of the each unit level to the global mean uptake value.
Time Frame	Baseline, 24-week

Outcome Measure Data

Analysis Population Description

Number of patients with increased whole brain glucose uptake level. In the real analysis, however, a voxel-based image analysis results were used; therefore, data which can be entered here is not much meaningful.

Arm/Group Title	Cilostazol, Baseline	Cilostazol, 24-week	Placebo, Baseline	Placebo, 24-week
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation at the baseline.	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation after 24 weeks.	Placebo group means dementia patients group receiving donepezil with placebo at the baseline.	Placebo group means dementia patients group receiving donepezil with placebo after 24 weeks.
Measure Participants	18	18	18	18
Left Parietal Lobe	81.70 (9.51)	80.40 (8.27)	84.60 (7.47)	81.33 (6.82)
Right Parietal Lobe	80.03 (10.26)	79.00 (9.55)	85.29 (8.62)	81.91 (8.37)
Left Inferior Frontal Gyrus	85.74 (7.03)	86.82 (6.06)	85.97 (5.72)	83.12 (5.81)
Right Inferior Frontal Gyrus	72.11 (6.48)	71.39 (4.82)	74.02 (6.38)	71.44 (5.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week, Placebo, Baseline, Placebo, 24-week
	Comments	Repeated-measures analysis of variance (ANOVA) was used to test group*time interaction effect in glucose uptake of Left Parietal Lobe in two groups on two data points (baseline, 24-week).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Repeated ANOVA
	Comments	Uncorrected, Repeated ANOVA

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week, Placebo, Baseline, Placebo, 24-week
	Comments	Repeated-measures analysis of variance (ANOVA) was used to test group*time interaction effect in glucose uptake of Right Parietal Lobe in two groups on two data points (baseline, 24-week).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Repeated ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week, Placebo, Baseline, Placebo, 24-week
	Comments	Repeated-measures analysis of variance (ANOVA) was used to test group*time interaction effect in glucose uptake of Left Inferior Frontal Gyrus in two groups on two data points (baseline, 24-week).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Repeated ANOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week, Placebo, Baseline, Placebo, 24-week
	Comments	Repeated-measures analysis of variance (ANOVA) was used to test group*time interaction effect in glucose uptake of Right Inferior Frontal Gyrus in two groups on two data points (baseline, 24-week).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Repeated ANOVA
	Comments

2. Secondary Outcome

Title	Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)
Description	The ADAS-Cog score is measured by the number of questions answered incorrectly, therefore the higher is the worse. Score Scale: 0-75 (min-MAX) Each subcategory scores are summed. Word-recall test (0-10) Commands (0-5) Constructional praxis (0-5) Naming Objects/ Fingers (0-5) Ideational Praxis (0-5) Orientation (0-8) Word Recognition (0-12) Remembering Test Instructions (0-5) Spoken Language Ability (0-5) Word Finding Difficulty (0-5) Comprehension (0-5)
Time Frame	Baseline, 12-week, 24-week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cilostazol	Placebo
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.	Placebo group means dementia patients group receiving donepezil with placebo.
Measure Participants	18	18
Baseline	29.28 (8.79)	27.78 (7.89)
12-week	26.33 (6.75)	24.83 (7.67)
24-week	25.78 (8.19)	24.78 (7.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week
	Comments	Repeated ANOVA, tested for group*time interaction effect of ADAS-Cog scores on three data points (Baseline, 12-week, 24-week)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Repeated ANOVA
	Comments

3. Secondary Outcome

Title	Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet)
Description	Basic cognitive functions are checked. (0-30) The score is better when higher.
Time Frame	Baseline, 12-month, 24-month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cilostazol	Placebo
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.	Placebo group means dementia patients group receiving donepezil with placebo.
Measure Participants	18	18
Baseline	15.11 (3.61)	15.44 (3.96)
12-week	16.67 (4.04)	15.83 (4.84)
24-week	15.39 (3.94)	16.22 (4.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week
	Comments	Repeated ANOVA, tested for group*time interaction effect of MMSE scores on three data points (Baseline, 12-week, 24-week)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Repeated ANOVA
	Comments

4. Secondary Outcome

Title	Activities of Daily Living (ADCS-ADL)
Description	The caregiver answered to the questions given to measure the cognitive function level of the patients in daily living. Lower scores indicate greater severity. 23 questions Score Scale: 0-78 (min-MAX)
Time Frame	Baseline, 12-month, 24-month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cilostazol	Placebo
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.	Placebo group means dementia patients group receiving donepezil with placebo.
Measure Participants	18	18
Baseline	50.17 (11.61)	53.56 (14.86)
12-week	48.00 (13.14)	49.33 (17.38)
24-week	46.33 (15.88)	51.17 (16.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week
	Comments	Repeated ANOVA, tested for group*time interaction effect of ADCS-ADL scores on three data points (Baseline, 12-week, 24-week)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments
	Method	Repeated ANOVA
	Comments

5. Secondary Outcome

Title	Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB)
Description	Measured by professionally trained clinicians. Higher score indicates more severe AD symptoms. Score Scale: 0-18 (min-MAX)
Time Frame	Baseline, 12-month, 24-month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cilostazol	Placebo
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.	Placebo group means dementia patients group receiving donepezil with placebo.
Measure Participants	18	18
Baseline	5.11 (2.30)	4.72 (1.56)
12-week	5.42 (2.05)	5.28 (2.18)
24-week	5.44 (2.49)	5.33 (2.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week
	Comments	Repeated ANOVA, tested for group*time interaction effect of Summed CDR scores on three data points (Baseline, 12-week, 24-week)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Fazekas Scale
Description	Level of severity of white matter lesions in AD patients who can be legitimately administered with cilostazol. Measured by professionally trained clinicians. The higher score indicates more severe white matter lesion. Max-min: 0-3
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cilostazol	Placebo
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.	Placebo group means dementia patients group receiving donepezil with placebo.
Measure Participants	18	18
Number of Patients Scored 1	13 72.2%	11 61.1%
Number of Patients Scored 2	3 16.7%	5 27.8%
Number of Patients Scored 3	2 11.1%	2 11.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cilostazol, Baseline, Cilostazol, 24-week
	Comments	Distribution of Fazekas scale in two groups according to Chi-square test results.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Arm/Group Title	Cilostazol		Placebo
Arm/Group Description	Cilostazol group means dementia patients group receiving donepezil with cilostazol augmentation.		Placebo group means dementia patients group receiving donepezil with placebo.
All Cause Mortality
	Cilostazol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cilostazol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Cilostazol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/18 (22.2%)		3/18 (16.7%)
Gastrointestinal disorders
GI discomfort	1/18 (5.6%)	1	0/18 (0%)	0
General disorders
Nausea, Dizziness	1/18 (5.6%)	1	0/18 (0%)	0
Diarrhea	1/18 (5.6%)	1	0/18 (0%)	0
Vomiting	0/18 (0%)	0	1/18 (5.6%)	1
Headache	0/18 (0%)	0	1/18 (5.6%)	1
Psychiatric disorders
Depression	0/18 (0%)	0	1/18 (5.6%)	1
Vascular disorders
Hypertension	1/18 (5.6%)	1	0/18 (0%)	0

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.