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Clinical Trial
. 2023 Dec 1;6(12):e2344938.
doi: 10.1001/jamanetworkopen.2023.44938.

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial

Satoshi Saito  1 , Keisuke Suzuki  2 , Ryo Ohtani  3 , Takakuni Maki  4 , Hisatomo Kowa  5 , Hisatsugu Tachibana  5 , Kazuo Washida  1 , Nobuya Kawabata  6 , Toshiki Mizuno  7 , Rie Kanki  8 , Shinji Sudoh  9 , Hiroshi Kitaguchi  10 , Katsuro Shindo  10 , Akihiro Shindo  11 , Nobuyuki Oka  12 , Keiichi Yamamoto  13 , Fumihiko Yasuno  14 , Chikage Kakuta  1 , Ryosuke Kakuta  15 , Yumi Yamamoto  16 , Yorito Hattori  1 , Yukako Takahashi  1 , Yuriko Nakaoku  4 , Shuichi Tonomura  4 , Naoya Oishi  17 , Toshihiko Aso  18 , Akihiko Taguchi  19 , Tatsuo Kagimura  20 , Shinsuke Kojima  20 , Masanori Taketsuna  20 , Hidekazu Tomimoto  11 , Ryosuke Takahashi  4 , Hidenao Fukuyama  21 , Kazuyuki Nagatsuka  1 , Haruko Yamamoto  15 , Masanori Fukushima  22 , Masafumi Ihara  1 ; COMCID Trial Investigator Group
Collaborators, Affiliations
Clinical Trial

Efficacy and Safety of Cilostazol in Mild Cognitive Impairment: A Randomized Clinical Trial

Satoshi Saito et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Saito reported receiving grants from Otsuka Pharmaceutical Co, Ltd during the conduct of the study and having a patent for cilostazol. Dr Maki reported having a patent for cilostazol. Dr Kawabata reported receiving grants from Otsuka Pharmaceutical Co, Ltd during the conduct of the study. Dr K. Shindo reported receiving grants from Otsuka Pharmaceutical Co, Ltd during the conduct of the study and having a patent for cilostazol issued by the Kurashiki Central Hospital. Mr R. Kakuta reported receiving grants and funding, provision of the investigational drug, and an audit from Otsuka Pharmaceutical Co, Ltd during the conduct of the study. Prof R. Takahashi reported receiving grants from Sumitomo Pharma and Eisai Pharma and receiving personal fees from Eisai Pharma, Ono Pharma, and Takeda Pharma outside the submitted work. Dr Ihara reported receiving grants from Otsuka Pharmaceutical Co, Ltd during the conduct of the study; receiving grants and personal fees from Otsuka Pharmaceutical Co, Ltd outside the submitted work; and having patents for cilostazol. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Patients who received cilostazol or placebo at least once comprised the full analysis set (N = 159). CDR indicates Clinical Dementia Rating; CONSORT, Consolidated Standards of Reporting Trials; MMSE, Mini-Mental State Examination.
Figure 2.
Figure 2.. Effects of Cilostazol on Cognitive Decline
A, A mixed-effects model with repeated measures was applied by considering treatments, time points, sex, and interaction of treatments and time points as fixed effects; patients as a random effect; and baseline scores as a covariate. Error bars represent SEs. B, A Kaplan-Meier plot shows the cumulative incidence of conversion to all-cause dementia (hazard ratio [cilostazol vs placebo], 1.12; 95% CI, 0.60-2.09; P = .71). The log-rank test was performed. MMSE indicates Mini-Mental State Examination.
Figure 3.
Figure 3.. Effects of Cilostazol on Biomarkers
A, Error bars represent SEs. B, The blue and orange lines represent the regression lines between the baseline Aβ-albumin complex levels and the changes in the level of Aβ-albumin complex in the placebo and cilostzol group, respectively. C, The hippocampal volume after the protocol treatment was measured at the 96-week visit (n = 35 in the placebo group; n = 30 in the cilostazol group) or early termination (n = 9 in the placebo group; n = 14 in the cilostazol group). Error bars represent SEs.
See this image and copyright information in PMC

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