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

Importance: Recent evidence indicates the efficacy of ß-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote ß-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.

Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase-II Trial: AdrenoMedullin for Ischemic Stroke Study.

OBJECTIVES: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke. MATERIALS AND METHODS: The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24 h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). In the second cohort, patients will be assigned to the investigation treatment B (56 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). RESULTS: Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups. CONCLUSIONS: AM is expected to be a safe and effective treatment for ischemic stroke.

A multicenter, randomized, placebo-controlled trial for cilostazol in patients with mild cognitive impairment: The COMCID study protocol.

INTRODUCTION: There are currently no effective treatments preventing conversion from mild cognitive impairment (MCI) to Alzheimer's disease. Cilostazol is a selective type-3 phosphodiesterase inhibitor that ameliorates accumulation of amyloid-ß and has prevented cognitive decline in rodent models. Furthermore, cilostazol is known to suppress platelet aggregation, protect vascular endothelia, dilate vessels, and increase cerebral blood flow. Beneficial effects have also been shown in observational cohort studies, demonstrating the need for a prospective clinical trial. METHODS: The Cilostazol for prevention of COnversion from MCI to Dementia (COMCID) study is a double-blind, randomized phase II study of patients with MCI. Participants will receive cilostazol or placebo for 96 weeks. The primary objective is to evaluate whether cilostazol slows down cognitive decline measured by the Mini-Mental State Examination. Secondary objectives are assessing time to conversion from MCI to dementia and assessing incremental changes in several psychological assessment scales. DISCUSSION: The COMCID trial will identify the therapeutic potential of cilostazol. This trial, which is based on a drug repositioning strategy, may aid the development of a neurovascular treatment for neurocognitive disorders.