CHALLENGE.

Study name	Efficacy study of cilostazol and aspirin on cerebral small vessel disease (Challenge)
Methods	Multicentre, randomised, double‐blind study
Participants	Inclusion criteria Aged 50–85 years Can walk to the hospital (walking frame or stick is permissible). Cerebral small vessel disease is observed on brain MRI: presence of ≥ 1 lacunar infarction and moderate or severe confluent leukoaraiosis (defined as grade 2 or 3 on a modified Fazekas scale): periventricular WMCs with cap or rims > 5 mm and deep subcortical WMCs > 10 mm in maximum diameter Written informed consent Exclusion criteria Any contraindication of antiplatelets Any person with cardioembolic source Carotid bruit or large cerebral artery stenosis > 50% Cortical infarction or subcortical infarction > 1.5 cm Bleeding tendency Chronic liver disease (AST or ALT > 100 IU/L) Chronic renal disease (creatinine > 3.0 mg/dL) Active gastrointestinal ulcer People with any severe or unstable medical disease that may prevent them from completing study requirements (i.e. unstable or severe asthma) Anaemia (haemoglobin < 10 g/dL) or thrombocytopenia Cardiac pacemaker or contraindication to MRI Pregnancy or breastfeeding Drug or alcohol addiction Any other white matter disease (i.e. multiple sclerosis, sarcoidosis or brain irradiation, etc.) or brain tumour Parkinson's disease, Alzheimer's disease or any other neurodegenerative disease Any hearing or visual impairment that can disturb the efficient evaluation of the patient Recent cerebral infarction with 3 months
Interventions	Aspirin 100 mg once daily for 104 weeks  Cilostazol 200 mg once daily for 104 weeks
Outcomes	Primary outcome Volume of WMCs on brain MRI on week 104 vs baseline Secondary outcomes Mean diffusivity and fraction anisotropy on diffusion tensor imaging Number of lacunes Number of micro‐bleeds Brain volume and cortical thickness MMSE Neuro‐cognitive test (Seoul Verbal Learning Test, Boston Naming test‐short form, complex figure copy, animal fluency, phonemic fluency, Stroop test, Digit‐symbol test, Trail Making Test) Clinical Dementia Rating scale Sum of Boxes King's Health Questionnaire Geriatric Depression Scale – Short Form Caregiver‐Administered Neuropsychiatric Inventory Bayer Activities of Daily Living Barthel Index Pyramidal and Extrapyramidal Scale Timed Up and Go test Adverse events 'Other' outcomes All ischaemic stroke events (cerebral infarction and TIA) – all vascular events (including ischaemic stroke, TIA, myocardial infarction, angina pectoris, cerebral venous thrombosis, pulmonary embolism, symptomatic deep vein thrombosis, symptomatic peripheral artery occlusion, other vascular occlusion and any revascularisation procedure
Starting date	2013
Contact information	Principal Investigator: Seong Hye Choi, Inha University Hospital
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