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 Introduction 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. Discussion 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.