The Efficacy of DL-NBP in Patients With Mild Subcortical Ischemic Vascular Dementia

Study Overview
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Brief Summary
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This is a 48-week, double-blind, randomized, placebo-controlled study. Sixty-four patients are randomly assigned to take NBP (600mg per day) or placebo for 48 weeks, with 32 patients in each treatment group. Anti-dementia treatment-naive patients meet the inclusion/exclusion criteria are enrolled. Patients are assigned to NBP will take 200mg tid daily. Patients are visited at baseline, as well as 4, 12, 24, 36, 48weeks after baseline. Safety data is recorded until an additional 30 days after the last treatment (48 weeks). The primary outcomes include cognitive function and activities of daily living (ADL). All subjects are assessed at baseline, 4w, 12w,24w, 36w intermittent visit and 48w endpoint with the Auditory Verbal Learning Test (AVLT), the Brief Visuospatial Memory Test-Revised (BVMT-R), the Symbol Digit Modalities Test (SDMT), the Trail Making Test-A/B (TMT-A/B), the Benton Judgment of Line Orientation (JLO), the verbal fluency test, the Boston Naming Test (BNT), the Controlled Oral Word Association Test (COWAT), the Stroop test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the ADL. The secondary outcomes include the global function and behavioral and psychological symptoms of dementia (BPSD), which are evaluated with the Clinical Dementia Rating (CDR) and the Neuropsychiatric Inventory (NPI), respectively. Independent raters who are blinded to patients' distribution are assigned to assess the participants. The exploratory outcomes are markers of vascular regulation, including circulating endothelial progenitor cells (EPCs), white matter hyperintensities (WMH) on MRI, cerebral blood flow (CBF) measured with transcranial Doppler (TCD) and arterial spin labeling (ASL) MRI, and parameters of carotid duplex ultrasonic (CDU). In addition, apolipoprotein E (APOE) polymorphism and plasma biomarkers are also detected. Safety are assessed at each visit.

Official Title
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The Efficacy of DL-3-n-butylphthalide (DL-NBP) on the Cognitive Function and Vascular Regulation in Patients With Mild Vascular Dementia (VaD) Caused by Subcortical Ischemic Vascular Disease (SIVD)

Conditions
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Subcortical Vascular Dementia, Cerebral Small Vessel Diseases

Intervention / Treatment
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* Drug: NBP
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients meet the criteria of major neurocognitive disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); Patients aged with 50-80 years, years of education no less than 3, an MMSE range of 15 26, an MoCA < 26, an Hamilton Depression Scale (HAMD) < 17; The MRI (one research dedicated machine 3.0 T) features satisfy subcortical small vessel disease, including (1) multiple (>=3) supratentorial subcortical lacunes (3-20 mm in diameter), with/without white matter hyperintensities (WMH) of any degree; (2) moderate to severe WMH (score>= 2 according to the Fazekas rating scale in either periventricular region or deep white matter) with/without lacunes; (3) one or more strategically located subcortical small infarcts in the deep grey matters; Patients or legal representative should sign the informed consent and have a reliable caregiver. Exclusion Criteria: Cognitive impairment caused by other central nervous system diseases, such as AD, dementia with Lewy body, frontal-temporal lobe degeneration, etc; Cognitive impairment due to other conditions, such as severe depression, vitamin B 12 deficiency, abnormal thyroid function, etc; Alcoholism, drug abuse or other conditions influenced the evaluation of cognition; Patients unable to undertake MRI assessment. Patients with a history of other severe disease such as epilepsy, myocardial infarction or heart failure will be excluded; Administration of other investigational drugs, psychotropic drugs, drugs with psychiatric side effects, and oral anticoagulants are not allowed

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double-blind, randomized, placebo controlled study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NBP<br>DL-3-n-butylphthalide (NBP), soft capsule, 200mg Tid, po, for 48 weeks. | Drug: NBP<br>* NBP soft capsules<br>* Other names: DL-3-n-butylphthalide;|
| Placebo Comparator: Placebos<br>Placebo, soft capsule, 200mg Tid, po, for 48 weeks. | Drug: Placebos<br>* Soft capsules manufactured to mimic NBP<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Auditory Verbal Learning Test (AVLT) at endpoint and change from baseline | AVLT is used to evaluate verbal learning and memory ability. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Brief Visuospatial Memory Test-Revised (BVMT-R) at endpoint and change from baseline | BVMT-R is used to evaluate spatial memory ability. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Digital span (DS) at endpoint and change from baseline | DS is used to assess attention. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Symbol Digit Modalities Test (SDMT) at endpoint and change from baseline | SDMT is used to assess information processing speed. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Trail Making Test-A (TMT-A) at endpoint and change from baseline | TMT-A is used to assess information processing speed. Lower score indicates better performance. | 48 weeks post-dose and change from baseline | 
| TMT-B at endpoint and change from baseline | TMT-B is used to assess executive function. Lower score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Stroop test at endpoint and change from baseline | Stroop test is used to assess executive function. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Benton Judgment of Line Orientation (JLO) at endpoint and change from baseline | JLO is used to assess visuospatial function. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Verbal fluency test at endpoint and change from baseline | Verbal fluency test is used to evaluate language function. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Boston Naming Test (BNT) at endpoint and change from baseline | BNT is used to evaluate language function. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Controlled Oral Word Association Test (COWAT) at endpoint and change from baseline | COWAT is used to evaluate language function. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Mini-Mental State Examination (MMSE) at endpoint and change from baseline | MMSE is used to evaluate global cognition. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Montreal Cognitive Assessment (MoCA) at endpoint and change from baseline | MoCA is used to evaluate global cognition. Higher score indicates better performance. | 48 weeks post-dose and change from baseline | 
| Activity of daily living (ADL) at endpoint and change from baseline | ADL is used to evaluate activities of daily living. | 48 weeks post-dose and change from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global function at endpoint and change from baseline | Clinical Dementia Rating (CDR) is used to evaluate global function. | 48 weeks post-dose and change from baseline | 
| Neuropsychiatric Inventory (NPI) at endpoint and change from baseline | NPI is used to evaluate behavioral and psychological symptoms of dementia (BPSD). | 48 weeks post-dose and change from baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DL-3-n-butylphthalide, vascular dementia, cerebral small vessel disease, cognitive function, cerebral blood flow