Efficacy and Safety of Cilostazol in Mild Cognitive Impairment
Authors: Saito Satoshi , Suzuki Keisuke , Ohtani Ryo , Maki Takakuni , Kowa Hisatomo , Tachibana Hisatsugu , Washida Kazuo , Kawabata Nobuya , Mizuno Toshiki , Kanki Rie , Sudoh Shinji , Kitaguchi Hiroshi , Shindo Katsuro , Shindo Akihiro , Oka Nobuyuki , Yamamoto Keiichi , Yasuno Fumihiko , Kakuta Chikage , Kakuta Ryosuke , Yamamoto Yumi , Hattori Yorito , Takahashi Yukako , Nakaoku Yuriko , Tonomura Shuichi , Oishi Naoya , Aso Toshihiko , Taguchi Akihiko , Kagimura Tatsuo , Kojima Shinsuke , Taketsuna Masanori , Tomimoto Hidekazu , Takahashi Ryosuke , Fukuyama Hidenao , Nagatsuka Kazuyuki , Yamamoto Haruko , Fukushima Masanori , Ihara Masafumi ,   COMCID Trial Investigator Group, Tsuji Masahiro , Ouchi Atsushi , Yamauchi Miho 
Published: December 2023

Importance

Recent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage.

Objective

To determine the safety and efficacy of cilostazol in mild cognitive impairment.

Design, Setting, and Participants

The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020.

Interventions

The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks.

Main Outcomes and Measures

The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events.

Results

The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were –0.1 (0.3) at the 24-week visit, –0.8 (0.3) at 48 weeks, –1.2 (0.4) at 72 weeks, and –1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were –0.6 (0.3) at 24 weeks, –1.0 (0.3) at 48 weeks, –1.1 (0.4) at 72 weeks, and –1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically.

Conclusions and Relevance

In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials.

Trial Registration

ClinicalTrials.gov Identifier: NCT02491268