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Background and Purpose: Cerebral small vessel disease (CSVD) is the most common cause of vascular dementia and a major contributor to mixed dementia. CSVD is characterized by progressive cerebral white matter changes (WMC) due to chronic low perfusion and loss of autoregulation. In addition to its antiplatelet effect, cilostazol exerts a vasodilating effect and improves endothelial function. This study aims to compare the effects of cilostazol and aspirin on changes in WMC volume in CSVD. Methods: The comparison study of Cilostazol and aspirin on cHAnges in volume of cerebral smaLL vEssel disease white matter chaNGEs (CHALLENGE) is a double blind, randomized trial involving 19 hospitals across South Korea. Patients with moderate or severe WMC and ≥ 1 lacunar infarction detected on brain magnetic resonance imaging (MRI) are eligible; the projected sample size is 254. Participants are randomly assigned to a cilostazol or aspirin group at a 1:1 ratio. Cilostazol slow release 200 mg or aspirin 100 mg are taken once daily for 2 years. The primary outcome measure is the change in WMC volume on MRI from baseline to 104 weeks. Secondary imaging outcomes include changes in the number of lacunes and cerebral microbleeds, fractional anisotropy and mean diffusivity on diffusion tensor imaging, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability. Conclusions: CHALLENGE will provide evidence to support the selection of long-term antiplatelet therapy in CSVD. Trial Registration: ClinicalTrials.gov Identifier: NCT01932203

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