DL-3-n-butylphthalide Delays Cognitive Decline in Patients With Mild to Moderate Alzheimer's Disease Already Receiving Donepezil: A Multicenter, Prospective Cohort Study

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Background：Vascular factors and mitochondria dysfunction contributeto thepathogenesis of Alzheimer’s Disease (AD).DL-3-n-butylphthalide (NBP)has an effect in protecting mitochondria and improving microcirculation. We investigated the effect of NBP in patients with mild-moderate AD already receiving donepezil.Methods: It was a prospective cohort study. 92 mild-moderate AD patients were classified into the donepezil alone group (n=43) or the donepezil combined NBP group (n=49) for 48 weeks. The primary outcome was change of Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) from baseline after treatment 48 weeks. All patients were also evaluated with clinician’s interview-based impression of change plus caregiver input (CIBIC-plus), Alzheimer's disease cooperative study-activities of daily living (ADCS-ADL) and neuropsychiatric inventory (NPI) every 12 weeks. All patients were monitored for adverse events (AEs). The efficacy was analyzed using logistic regression analysis.Results:The univariate analysis showed that age wasolder in donepezil alone group(P=0.005), prevalence of hypertension was higher in donepezil alone group(P=0.026).The ADAS-cog score change from baseline in thedonepezil alone group was significant than that in the donepezil combined NBP group at 48 weeks(1.82±5.20 vs -0.38±4.46, P=0.048). The multivariate logistic regression analysis showed that between the 2 groups, there were significant differencesin changes on the ADAS-cog(OR=0.879,95% CI:[0.785,0.984],P=0.026),MMSE(OR=1.270,95% CI:[1.036,1.557],P=0.021), and ADCS-ADL(OR=1.067,95% CI:[1.002,1.136],P=0.042) but no significant differences for changes on the NPI(OR=0.955,95% CI:[0.901，1.013],P=0.125)and CIBIC-plus (OR=0.356,95% CI:[0.093,1.364],P=0.132). The occurrence of AEs was similar in the 2 groups.Conclusions:Over the 48-week treatment period, donepezil combined NBP group had slower cognitive decline and better activities of daily living in patients with mild to moderate AD. These indicated that the multi-target therapeutic effect of NBP may be a new choice for AD treatment.Trial registration:Clinical trial registration URL:https://clinicaltrials.gov/ct2/show/NCT02711683?term=NCT02711683&draw=2&rank=1ClinicalTrials.gov Identifier: NCT02711683. Date of registration: March 14,2016.