UMIN-CTR Clinical Trial

Public title

A Multicenter, Randomized Controlled Trial of Cilostazol in Patients with Mild Cognitive Impairment

Acronym

COMCID

Scientific Title

A Multicenter, Randomized Controlled Trial of Cilostazol in Patients with Mild Cognitive Impairment

Scientific Title:Acronym

COMCID

Region

Japan

Condition

Mild cognitive impairment (MCI)

Classification by specialty

Neurology

Geriatrics

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

Epidemiological, clinicopathological and animal studies show that vascular disease in various forms contributes to cognitive decline. Increasing age is the strongest risk for dementia irrespective of whether it results from a vascular etiology or neurodegenerative disease processes such as in Alzheimer's disease (AD). AD and vascular cognitive impairment, the two most common causes of dementia, represent two extremes of a spectrum of disorders; however, a number of entities, which possess varying degrees of neurodegenerative and vascular pathologies, occur in between. The pure forms of the disorders are preferred for convenience to label, treat or manage but conditions within the spectrum are the norm rather than the exception as dementia advances. Therefore, combinatorial therapy directed at both vascular and neurodegenerative aspects of dementia is a promising approach for the treatment of dementia in the elderly.
Cilostazol acts as an antiplatelet agent and has other pleiotropic effects based on phosphodiesterase-3-dependent mechanisms. Increasing evidence suggests that cilostazol offers endothelial protection, via pleiotropic effects. Intriguingly, cilostazol has been shown to decrease amyloid beta (Abeta) accumulation and protect Abeta-induced cognitive deficits in an experimental model. In a pilot study of 10 patients with moderate AD (mean MMSE score, 11.9 points) who received donepezil, cilostazol add-on treatment for 5-6 months demonstrated significantly increased MMSE score in comparison to baseline. Moreover, cilostazol was shown to be effective in preventing cognitive decline in patients with AD with cerebrovascular diseases, mild cognitive impairment (MCI), and mild dementia who received donepezil.
These results highlight the need for a comprehensive prospective cohort study to analyze the effect of cilostazol on the preservation of cognitive function in patients with early-stage cognitive impairment, namely MCI.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Explanatory

Developmental phase

Phase II

Primary outcomes

To evaluate the efficacy of Cilostazol with respect to the cognitive function measured by MMSE in patients with MCI (mild cognitive impairment)

Key secondary outcomes

1.To evaluate the efficacy of Cilostazol in preventing conversion from MCI to All-cause Dementia.
2.To evaluate the efficacy of Cilostazol with respect to the cognitive function measured by CDR-SB in patients with MCI.
3.To evaluate the efficacy of Cilostazol with respect to the cognitive function measured by ADAS-Cog 14 in patients with MCI.
4.To evaluate the efficacy of Cilostazol with respect to the cognitive function measured by the Logical Memory subtest of the Wechsler Memory Scale-Revised (WMS-R) in patients with MCI.
5.To evaluate the efficacy of Cilostazol with respect to the activity of daily living measured by Alzheimer's Disease Cooperative Study - Activities of Daily Living in MCI (ADCS-MCI-ADL).
6.To evaluate the efficacy of Cilostazol with respect to the brain atrophy measured by brain MRI in patients with MCI.

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Double blind -all involved are blinded

Control

Placebo

Stratification

NO

Dynamic allocation

YES

Institution consideration

Institution is considered as adjustment factor in dynamic allocation.

Blocking

NO

Concealment

No need to know

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

After the registration, the Site Investigators should start protocol treatment within 28 days including the day of registration.
Protocol treatment defines as follows;

Investigational Treatment:
Cilostazol 50mg B.I.D. p.o. 96 Weeks

Interventions/Control_2

After the registration, the Site Investigators should start protocol treatment within 28 days including the day of registration.
Protocol treatment defines as follows;

Comparative Treatment:
Placebo B.I.D. p.o. 96 Weeks

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

55

years-old

<=

Age-upper limit

84

years-old

>=

Gender

Male and Female

Key inclusion criteria

1) Age between 55-84 (inclusive)

2) Study partner who lives with subject available for all visits

3) Patients with MCI who satisfy the core clinical criteria of NIA/AA for MCI (nearly equivalent to mild neurocognitive disorder in DSM-5) and who also satisfy the following three criteria:
i) Memory complaint by subject or study partner
Type I: Memory complaint by subject that is verified by a study partner
Type II: Otherwise, memory complaint by study partner with the evidence of memory impairment
Note) Memory complaint by subject that is not verified by study partner will be excluded.
ii) Mini-Mental State Examination (MMSE) scores between 22 and 28 (inclusive)
iii) Clinical Dementia Rating (CDR) = 0.5

4) Written informed consent provided for study participation

Key exclusion criteria

1) Parkinson's disease, Huntington's disease, normal pressure hydrocephalus, progressive supranuclear palsy, epilepsy, multiple sclerosis, cerebral infection, or subsequent complication caused by head trauma.
2) Findings of multiple infarction, brain tumor, or subdural hematoma on MRI performed within 48 weeks before provisional registration.
3) Contraindications for MRI such as magnetic body or metal.
4) History of major depression or bipolar disorder within 48 weeks before provisional registration, alcohol or other substance abuse within 96 weeks before provisional registration, other diseases or unstable conditions.
5) Poorly controlled diabetes mellitus (HbA1c>9.0%) within 24 weeks before provisional registration.
6) Cognitive impairment due to deficiency of vitamin B12 or folate.
7) Neurosyphilis.
8) Thyroid function abnormality.
9) Psychoactive drugs within 4 weeks before provisional registration.
10) Oral anticoagulants within 4 weeks before provisional registration.
11) Double antiplatelet therapy (cf. Aspirin, Clopidogrel but not Cilostazol) within 4 weeks before provisional registration.
12) Poorly controlled diabetes mellitus treated with insulin within 4 weeks before provisional registration.
13) Episode of hypoglycemic attack with loss of consciousness within 4 weeks before provisional registration.
14) Anti-dementia drugs within 4 weeks before provisional registration.
15) Participation in any other new drug study for Alzheimer's disease.
16) Current bleeding or bleeding disorders.
17) Congestive heart failure.
18) Coronary artery stenosis.
19) Sustained high blood pressure within 2 weeks before provisional registration.
20) History of drug hypersensitivity to Cilostazol.
21) The subject or the subject's spouse pregnant or breast-feeding at the time of provisional registration.
22) Difficulty in neuropsychological tests due to hearing or visual impairment.
23) Considered by the principal investigator to be ineligible.

Target sample size

200

Name of lead principal investigator

1st name	Masafumi
Middle name
Last name	Ihara

Organization

National Cerebral and Cardiovascular Center

Division name

Division of Neurology

Zip code

564-8565

Address

6-1 Kishibe Shimmachi, Suita, Osaka 564-8565, Japan

TEL

06-6170-1070

Email

ihara@ncvc.go.jp

Name of contact person

1st name	Ryosuke
Middle name
Last name	Kakuta

Organization

National Cerebral and Cardiovascular Center

Division name

Division of Neurology

Zip code

564-8565

Address

6-1 Kishibe Shimmachi, Suita, Osaka 564-8565, Japan

TEL

06-6170-1070

Homepage URL

Email

r_kakuta@ncvc.go.jp

Institute

National Cerebral and Cardiovascular Center

Institute

Department

Personal name

Organization

Otsuka Pharmaceutical Co., Ltd.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

National Cerebral and Cardiovascular Center

Address

6-1 Kishibe Shimmachi, Suita

Tel

06-6170-1070

Email

matsumura.narumi.hp@ncvc.go.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2015

Year

06

Month

15

Day

URL releasing protocol

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651350/

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

166

Results

Results date posted

Results Delayed

Delay expected

Results Delay Reason

Results, submitted to an internatinal journal

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2015

Year

05

Month

25

Day

Date of IRB

2015

Year

04

Month

27

Day

Anticipated trial start date

2015

Year

06

Month

15

Day

Last follow-up date

2020

Year

03

Month

14

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2812524

Registered date

2015

Year

06

Month

01

Day

Last modified on

2023

Year

12

Month

18

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000020389