title: The effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease: A multicentre, randomized, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Vascular cognitive impairment without dementia is very common among the aged and tends to progress to dementia, but there have been no proper large-scale intervention trials dedicated to it. Vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease (hereinafter, subcortical Vascular cognitive impairment without dementia) represents a relatively homogeneous disease process and is a suitable target for therapeutic trials investigating Vascular cognitive impairment without dementia. Preclinical trials showed that dl-3-n-butylphthalide (NBP) is effective for cognitive impairment of vascular origin.
  
  
  METHODS
  In this randomized, double-blind, placebo-controlled trial, we enrolled patients aged 50-70 years who had a diagnosis of subcortical Vascular cognitive impairment without dementia at 15 academic medical centers in China. Inclusion criteria included a clinical dementia rating ≥0.5 on at least one domain and global score ≤0.5; a mini-mental state examination score ≥20 (primary school) or ≥24 (junior school or above); and brain magnetic resonance imaging consistent with subcortical ischemic small vessel disease. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer-generated randomization protocol. All patients and study personnel were masked to treatment assignment. Primary outcome measures were the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention-to-treat (ITT) population and the per protocol population.
  
  
  RESULTS
  This study enrolled 281 patients. NBP showed greater effects than placebo on ADAS-cog (NBP change -2.46 vs. placebo -1.39; P = .03; ITT) and CIBIC-plus (80 [57.1%] vs. 59 [42.1%] patients improved; P = .01; ITT). NBP-related AE were uncommon and primarily consisted of mild gastrointestinal symptoms.
  
  
  CONCLUSIONS
  Over the 6-month treatment period, NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety.
authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China; Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, China. Electronic address: jjp@ccmu.edu.cn.
authors.forename: Jianping
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authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
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authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
authors.forename: Junhua
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authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
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authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
authors.forename: Xiumei
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authors.lastname: Zuo
authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
authors.forename: Haiqing
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authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
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authors.affiliation: Department of Neurology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, China.
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authors.affiliation: Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
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authors.affiliation: Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
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authors.affiliation: Department of Neurology, The First Teaching Hospital of Jilin University, Changchun, Jilin, China.
authors.forename: Jiang
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authors.affiliation: Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Kai
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authors.lastname: Wang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou, China.
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authors.lastname: Chu
authors.affiliation: Department of Neurology, Beijing Hospital, Beijing, China.
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authors.affiliation: Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China.
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authors.affiliation: Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Hongzhi
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authors.lastname: Guo
authors.affiliation: Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
authors.forename: Xiaoyuan
authors.initials: X
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authors.affiliation: Department of Neurology, Northern Jiangsu People's Hospital of Yangzhou University, Yangzhou, Jiangsu, China.
authors.forename: Yingzhu
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authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Wanli
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authors.lastname: Dong
authors.affiliation: Department of Neurology, Anshan Changda Hospital, Anshan, Liaoning, China.
authors.forename: Xiujie
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, Liaoning, China.
authors.forename: Boyan
authors.initials: B
authors.lastname: Fang
authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
authors.forename: Mao
authors.initials: M
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authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
authors.forename: Qian
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authors.affiliation: Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China.
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mesh_terms: D000368:Aged; D001572:Benzofurans / Q000627:therapeutic use*; D059345:Cerebral Small Vessel Diseases / Q000150:complications*; D002681:China; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009483:Neuropsychological Tests
chemical_list: D001572:Benzofurans; D018696:Neuroprotective Agents; C027125:3-n-butylphthalide
keywords: Cerebral small vessel disease; DL-3-n-Butylphthalide; Multicentre study; Randomized controlled trial; Vascular cognitive impairment without dementia