Cilostazol Augmentation Study in Dementia

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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Dementia
• Intervention / Treatment: Drug: Cilostazol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 156-707
    • SMG-SNU Boramae Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 58 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regionally Averaged Cerebral Glucose Uptake Changes Measured by FDG PET Uptake With Voxel-based Method	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.	Baseline, 24-week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)	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)	Baseline, 12-week, 24-week
Mini-Mental State Examination (MMSE) in the Korean Version of the CERAD Assessment Packet)	Basic cognitive functions are checked. (0-30) The score is better when higher.	Baseline, 12-month, 24-month
Activities of Daily Living (ADCS-ADL)	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)	Baseline, 12-month, 24-month
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB)	Measured by professionally trained clinicians. Higher score indicates more severe AD symptoms. Score Scale: 0-18 (min-MAX)	Baseline, 12-month, 24-month
Fazekas Scale	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	Baseline

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: Korea OIAA
• Investigators: Principal Investigator: Jung-Seok Choi, MD, PhD, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea

Publications and helpful links

General Publications

• Lee JY, Lee H, Yoo HB, Choi JS, Jung HY, Yoon EJ, Kim H, Jung YH, Lee HY, Kim YK. Efficacy of Cilostazol Administration in Alzheimer's Disease Patients with White Matter Lesions: A Positron-Emission Tomography Study. Neurotherapeutics. 2019 Apr;16(2):394-403. doi: 10.1007/s13311-018-00708-x.

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: August 3, 2011
• First Submitted That Met QC Criteria: August 3, 2011
• First Posted (Estimate): August 4, 2011

Study Record Updates

• Last Update Posted (Estimate): May 13, 2014
• Last Update Submitted That Met QC Criteria: April 14, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Cilostazol; Alzheimer's dementia
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Dementia; Alzheimer Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Neuroprotective Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Cilostazol
• Other Study ID Numbers: 06-2009-145