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

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)

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.

Study Overview

• Status: Unknown
• Conditions: Cerebral Small Vessel Diseases; Subcortical Vascular Dementia
• Intervention / Treatment: Drug: NBP; Drug: Placebos

• Study Type: Interventional
• Enrollment (Anticipated): 64
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300052
      • Recruiting
      • Tianjin Medicial University General Hospital
      • Contact: Nan Zhang, MD, PhD; Phone Number: 8622 60119688; Email: nkzhangnan@163.com
      • Principal Investigator: Nan Zhang, MD, PhD
      • Sub-Investigator: Mengya Xing, MD, PhD
      • Sub-Investigator: Meng Liu, MD
      • Sub-Investigator: Xiaojiao Liu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients meet the criteria of major neurocognitive disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5);
2. 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;
3. 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;
4. Patients or legal representative should sign the informed consent and have a reliable caregiver.

Exclusion Criteria:

1. Cognitive impairment caused by other central nervous system diseases, such as AD, dementia with Lewy body, frontal-temporal lobe degeneration, etc;
2. Cognitive impairment due to other conditions, such as severe depression, vitamin B 12 deficiency, abnormal thyroid function, etc;
3. Alcoholism, drug abuse or other conditions influenced the evaluation of cognition;
4. Patients unable to undertake MRI assessment.
5. Patients with a history of other severe disease such as epilepsy, myocardial infarction or heart failure will be excluded;
6. Administration of other investigational drugs, psychotropic drugs, drugs with psychiatric side effects, and oral anticoagulants are not allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hamilton Depression Scale (HAMD) at endpoint and change from baseline	HAMD is used to evaluate depressive symptoms.	48 weeks post-dose and change from baseline
Geriatric Depression Scale (GDS) at endpoint and change from baseline	GDS is used to evaluate depressive symptoms.	48 weeks post-dose and change from baseline
Regulation of endothelial progenitor cell at endpoint and change from baseline	Circulating endothelial progenitor cell (EPC) is detected with flow cytometry.	48 weeks post-dose and change from baseline
Transcranial Doppler (TCD) at endpoint and change from baseline	TCD is used to measure cerebral blood flow.	48 weeks post-dose and change from baseline
Carotid duplex ultrasonic (CDU) at endpoint and change from baseline	CDU is used to evaluate cerebral blood flow and arteriosclerosis.	48 weeks post-dose and change from baseline
Arterial spin labeling (ASL) MRI at endpoint and change from baseline	Arterial spin labeling (ASL) is used to measure cerebral blood flow.	48 weeks post-dose and change from baseline
White matter hyperintensities (WMH) at endpoint and change from baseline	The extent and volume of WMH are analyzed on MRI.	48 weeks post-dose and change from baseline

Collaborators and Investigators

• Sponsor: Tianjin Medical University General Hospital
• Investigators: Principal Investigator: Nan Zhang, MD, PhD, Tianjin Medical University General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2017
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): January 31, 2020

Study Registration Dates

• First Submitted: March 27, 2019
• First Submitted That Met QC Criteria: April 3, 2019
• First Posted (Actual): April 8, 2019

Study Record Updates

• Last Update Posted (Actual): April 8, 2019
• Last Update Submitted That Met QC Criteria: April 3, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: cognitive function; cerebral small vessel disease; cerebral blood flow; vascular dementia; DL-3-n-butylphthalide
• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Intracranial Arterial Diseases; Intracranial Arteriosclerosis; Leukoencephalopathies; Dementia; Dementia, Vascular; Cerebral Small Vessel Diseases; Physiological Effects of Drugs; Platelet Aggregation Inhibitors; Neuroprotective Agents; Protective Agents; 3-n-butylphthalide
• Other Study ID Numbers: TianjinMUGH001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be available
• IPD Sharing Time Frame: Data will be available within 6 months of study completion.
• IPD Sharing Access Criteria: Data access requests will be reviewed by an external Independent Review Panel. Requestors will be required to sign a Data Access Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No