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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cilostazol 50mg B.I.D. | Experimental | 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 |
|
| Placebo B.I.D. | Placebo Comparator | 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cilostazol | Drug |
| ||
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Change from baseline in Mini Mental State Examination (MMSE) | 96 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Conversion from MCI to All-cause Dementia | Dementia is diagnosed clinically when the patient meets core clinical criteria for dementia with reference to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. | up to 96 weeks |
| Cognitive Decline on Clinical dementia rating-sum of boxes (CDR-SB) |
| Measure | Description | Time Frame |
|---|---|---|
| Cognitive Decline on Free and Cued Selective Reminding Test (FCSRT) | baseline, 48 weeks, and 96 weeks | |
| Cognitive Decline on Trail making test (TMT) | baseline, 48 weeks, and 96 weeks |
Inclusion Criteria:
Age between 55-84 (inclusive)
Study partner who sufficiently knows the daily life of the patient
Patients with MCI who satisfy the core clinical criteria of National Institute for Aging-Alzheimer Association for MCI (nearly equivalent to mild neurocognitive disorder in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) 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
Written informed consent provided for study participation
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Cerebral and Cardiovascular Center | Suita | Osaka | 564-8565 | Japan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38048134 | Derived | Saito S, Suzuki K, Ohtani R, Maki T, Kowa H, Tachibana H, Washida K, Kawabata N, Mizuno T, Kanki R, Sudoh S, Kitaguchi H, Shindo K, Shindo A, Oka N, Yamamoto K, Yasuno F, Kakuta C, Kakuta R, Yamamoto Y, Hattori Y, Takahashi Y, Nakaoku Y, Tonomura S, Oishi N, Aso T, Taguchi A, Kagimura T, Kojima S, Taketsuna M, Tomimoto H, Takahashi R, Fukuyama H, Nagatsuka K, Yamamoto H, Fukushima M, Ihara M; COMCID Trial Investigator Group. Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial. JAMA Netw Open. 2023 Dec 1;6(12):e2344938. doi: 10.1001/jamanetworkopen.2023.44938. |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D000077407 | Cilostazol |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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|
| baseline, 48 weeks, and 96 weeks |
| Cognitive Decline on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) 14 | baseline, 48 weeks, and 96 weeks |
| Cognitive Decline on Logical Memory subtest of the Wechsler Memory Scale-Revised (WMS-R) | baseline, 48 weeks, and 96 weeks |
| Functional Decline on Alzheimer's disease Cooperative Study scale for activities of daily living in MCI (ADCS-MCI-ADL) | baseline, 48 weeks, and 96 weeks |
| Hippocampal volume | Magnetization prepared rapid acquisition with gradient echo is used to assess hippocampal volume. | baseline and 96 weeks |
| D011804 |
| Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |