Japan's first multicenter investigator-initiated clinical trial of patients with mild cognitive impairment: Results of the COMCID study

This study demonstrated the safety of cilostazol^*1 in patients with MCI,^*2 but did not demonstrate any efficacy in preventing disease progression. However, after administration of cilostazol, the blood concentrations of the albumin and β-amyloid complex (albumin-Aβ complex) increased in the treated patients compared with those receiving placebo.^*3 This finding indicates that cilostazol may promote the clearance of β-amyloid—a waste product that accumulates in the brains of patients with dementia—into the blood. In previous studies, we demonstrated the effect of cilostazol metabolites in improving cognitive function (Saito S, et al. Alzheimers Dement (N Y) 2021). Therefore, in future, we plan to identify a group in which cilostazol is effective (cilostazol-responders), to enable investigation of its anti-dementia effects.

■Background
Currently, more than 5 million dementia patients are in Japan, and the MCI patient total is soon estimated to reach a similar number. A global initiative is presently underway to develop methods to halt the progression of this disease. Previously, a group led by Masafumi Ihara, Director of the NCVC Department of Neurology, discovered through animal experiments that the antiplatelet drug cilostazol promoted the elimination of β-amyloid, which accumulates in the brains of many patients with dementia (Maki T, et al. Ann Clin Trans Neurol 2014). However, whether cilostazol is effective for preventing dementia in humans remains unclear, emphasizing the need for verification.

■Research methods
In May 2015, a research group led by Director Masafumi Ihara began conducting a nationwide, multicenter, investigator-initiated, double-blinded, and randomized trial termed COMCID (cilostazol for the prevention of Conversion from MCI to Dementia) study. In the COMCID study, patients with MCI received either cilostazol or a placebo for 96 weeks.

■Research results
This study demonstrated that cilostazol was safe when administered to patients with MCI; however, it did not prevent progression of MCI to dementia. Nevertheless, the blood concentrations of the albumin and β-amyloid complex (albumin-Aβ complex) in patients receiving cilostazol increased following treatment compared with those receiving placebos. This suggests that cilostazol may have promoted the clearance of β-amyloid from the brain into the blood, consistent with the results of past animal experiments.

■Future outlook and issues
This study did not demonstrate that cilostazol was beneficial for all patients with MCI. Consequently, in future research, we plan to identify a group of patients in which cilostazol is effective (cilostazol-responders) to enable exploration of its anti-dementia effects in specific patients. However, this study did establish an important clinical trial-ready cohort^*4 for future research investigating cognitive dysfunction. Based on clinical trials conducted in Japan, the COMCID cohort has great significance and enables further exploration of the efficacy and safety of anti-dementia drug candidates developed worldwide.

^※An investigator-initiated clinical trial
Before patients are treated with new drugs, their safety and efficacy against the target disease requires confirmation and approval from the Ministry of Health, Labour, and Welfare. Thus, clinical trials confirming the effectiveness and safety of new drugs are needed to obtain authorization. Clinical trials primarily conducted by physicians and researchers, rather than pharmaceutical companies, are referred to as investigator-initiated clinical trials.

^※1Cilostazol
This drug suppresses platelet function in the blood, thereby preventing blood clot formation. Cilostazol also dilates blood vessels and increases cerebral blood flow.

^※2Mild cognitive impairment (MCI)
MCI is a condition characterized by forgetfulness that is not fully considered dementia. Cognitive impairment can be clearly distinguished from normal aging and produces symptoms that are recognized by the person experiencing it as well as those in close contact, including family.

^※3Placebo group
A placebo group receives sham drugs (placebos) lacking active medical ingredients.

^※4Clinical trial-ready cohort
A clinical trial-ready cohort provides a structure allowing immediate clinical trials. Prior to the COMCID research, no multicenter investigator-initiated clinical trials targeting patients with MCI had been initiated in Japan. Multicenter clinical trials require coordination of procedures, including adjustments to ensure that each facility performs the same tests. The completion of a multicenter, joint, and investigator-initiated clinical trial by the National Cerebral and Cardiovascular Center has simplified planning for future clinical trials including MCI patients in Japan.

Efficacy and safety of cilostazol in mild cognitive impairment: a randomized clinical trial.
JAMA Netw Open. 2023;6(12):e2344938. doi:10.1001/jamanetworkopen.2023.44938

Satoshi Saito,^a MD, PhD; Keisuke Suzuki,^b MD, PhD; Ryo Ohtani,^c MD, PhD; Takakuni Maki,^d MD, PhD; Hisatomo Kowa,^e MD, PhD; Hisatsugu Tachibana,^e MD, PhD; Kazuo Washida,^a MD, PhD; Nobuya Kawabata,^f MD, PhD; Toshiki Mizuno,^g MD, PhD; Rie Kanki,^h MD, PhD; Shinji Sudoh,ⁱ MD, PhD; Hiroshi Kitaguchi,^j MD, PhD; Katsuro Shindo,^j MD, PhD; Akihiro Shindo,^k MD, PhD; Nobuyuki Oka,^l MD, PhD; Keiichi Yamamoto,^m MD, PhD; Fumihiko Yasuno,ⁿ MD, PhD; Chikage Kakuta,^a MA; Ryosuke Kakuta,^o BS; Yumi Yamamoto,^p PhD; Yorito Hattori,^a MD, PhD; Yukako Takahashi,^a MD, PhD; Yuriko Nakaoku,^d MD, PhD; Shuichi Tonomura,^d MD; Naoya Oishi,^q MD, PhD; Toshihiko Aso,^r MD, PhD; Akihiko Taguchi,^s MD, PhD; Tatsuo Kagimura,^t PhD; Shinsuke Kojima,^t MD, PhD; Masanori Taketsuna,^t MSc; Hidekazu Tomimoto,^k MD, PhD; Ryosuke Takahashi,^d MD, PhD; Hidenao Fukuyama,^u MD, PhD; Kazuyuki Nagatsuka,^a MD, PhD; Haruko Yamamoto,^o MD, PhD; Masanori Fukushima,^v MD, PhD; Masafumi Ihara,^a* MD, PhD; the COMCID Trial Investigator Group

^aDepartment of Neurology, National Cerebral and Cardiovascular Center
^bInnovation Center for Translational Research, National Center for Geriatrics and Gerontology
^cDepartment of Neurology, National Hospital Organization Kyoto Medical Center
^dDepartment of Neurology, Graduate School of Medicine, Kyoto University
^eDivision of Neurology, Kobe University Hospital
^fDivision of Neurology, Yachiyo Hospital
^gDepartment of Neurology, Kyoto Prefectural University of Medicine
^hDepartment of Neurology, Osaka City General Hospital
ⁱDepartment of Neurology, National Hospital Organization, Utano National Hospital
^jDepartment of Neurology, Kurashiki Central Hospital
^kDepartment of Neurology, Graduate School of Medicine, Mie University
^lDepartment of Neurology, National Hospital Organization Minami Kyoto Hospital
^mInternal Medicine and Neurology, Nara Midori Clinic
ⁿDepartment of Psychiatry, National Center for Geriatrics and Gerontology
^oDepartment of Data Science, National Cerebral and Cardiovascular Center
^pDepartment of Molecular Innovation in Lipidemiology, National Cerebral and Cardiovascular Center
^qDepartment of Psychiatry, Kyoto University Graduate School of Medicine
^rLaboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research
^sDepartment of Regenerative Medicine Research, Institute of Biomedical Research and Innovation
^tTranslational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe
^uResearch and Educational Unit of Leaders for Integrated Medical System, Kyoto University
^vFoundation of Learning Health Society Institute

 

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