Effect of Butyphthalide on Cognitive Level Change After Cerebral Vascular Event-a Randomized Control Trial (Be-CLEVER) (Be-CLEVER)

Post-stroke cognitive impairment (PSCI) refers to a clinical syndrome characterized by cognitive impairment that occurs after a stroke event and persists for at least 24 weeks. Due to the early recovery of conditions such as delirium and transient cognitive impairment after stroke, the diagnosis of PSCI often requires cognitive assessment at 12 to 24 weeks post-stroke to determine the severity of cognitive impairment. It can be classified according to the severity of cognitive impairment as post-stroke cognitive impairment no dementia (PSCIND) and post-stroke dementia (PSD). Recent large international cohort studies have reported an incidence rate of PSCI ranging from 24% to 53.4%, and patients with PSCI have a significantly higher mortality rate compared to those without cognitive impairment. Guidelines such as American Heart Association/American Society of Anesthesiologists (AHA/ASA) and the Chinese "Expert Consensus on the Management of Post-Stroke Cognitive Impairment" propose integrating cognitive impairment and stroke intervention strategies. Early comprehensive intervention and treatment for high-risk individuals after stroke, aiming to delay or prevent the progression from PSCIND to PSD, are the primary goals in the current treatment of PSCI. However, there is currently a lack of large randomized controlled trials (RCTs) for PSCI, and research is still needed to determine whether cognitive-enhancing drugs can reduce the risk of PSCI occurrence and improve outcomes and prognosis for PSCI patients. A randomized, double-blind, multicenter clinical study involving 281 non-dementia vascular cognitive impairment (VCI) patients showed that the overall cognitive scores of patients treated with donepezil for 24 weeks significantly improved compared to the placebo group.

The aim of this study is to evaluate the effectiveness of donepezil in the treatment of post-stroke cognitive impairment. It will be a multicenter, randomized, double-blind, placebo-controlled trial with a 48-week treatment duration. The study will observe the difference in PSCI incidence rate between the donepezil treatment group and the conventional stroke treatment group at 24 weeks and evaluate the improvement in post-stroke cognitive impairment after 6 months of donepezil treatment compared to conventional treatment.

This study will be conducted in two stages: the first stage (0-24 weeks) aims to assess whether donepezil can reduce the risk of PSCI occurrence and will be a multicenter, randomized, double-blind, placebo-controlled study. The second stage (24-48 weeks) aims to evaluate whether donepezil can improve the prognosis of PSCI patients and will also be a multicenter, randomized, double-blind, placebo-controlled study.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Post-stroke Cognitive Impairment (PSCI)
• Intervention / Treatment: Drug: dl-3-butylphthalide; Drug: dl-3-butylphthalide placebo

• Study Type: Interventional
• Enrollment (Estimated): 3200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Qiang Dong; Phone Number: +8602152887145; Email: dong_qiang@fudan.edu.cn

Study Locations

• China
  • Liaoning
    • Dandong, Liaoning, China
      • Recruiting
      • Donggang Center Hospitol
      • Contact: Lili wang; Phone Number: 15842554006
      • Sub-Investigator: Jing Li

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

First stage:

• Acute ischemic stroke (AIS) symptom onset within 14 days Signs and symptoms consistent with the diagnosis of an acute ischemic stroke by CT/MRI.
• Age >= 60 years，
• Baseline NIHSS 3-18.
• Patient can complete questionnaire survey, physical examination, cranial MRI and other medical examinations
• Patient/legally authorized representative has signed the Informed Consent Form

Second stage:

• Patient with stage I diagnosis of PSCI.
• Patient can complete questionnaire survey, physical examination, cranial MRI and other medical examinations.
• Patient/legally authorized representative has signed the Informed Consent Form

Exclusion Criteria:

First stage:

• Patients who had been diagnosed with dementia prior to stroke
• Other related factors affecting cognitive function: central nervous system infection, neurodegenerative diseases, trauma, poisoning, intracranial space occupying lesions, metabolic diseases, etc.
• Other serious central nervous system diseases: Parkinson's disease, epilepsy, multiple sclerosis, motor neurone disease, immune-related encephalomyelopathy, etc.
• Serious mental illness: anxiety disorder, depression, delirium, schizophrenia, bipolar disorder, mental retardation, which is diagnosed or controlled by medication.
• Uncorrectable visual and hearing impairments and inability to complete neuropsychological tests
• Severe liver and kidney dysfunction
• The presence of a malignant tumor or other serious/life-threatening disease that could cause the subject's death within 12 months.
• Current known alcohol or illicit drug abuse or dependence
• Patients undergoing thrombectomy, thrombolysis, carotid endarterectomy, or other surgical procedures during the acute infarction.
• Using cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, or Sodium oligomannate (GV-971).
• Allergic to any component of butylphthalein
• Pregnancy or lactation, have the possibility of becoming pregnant, and who plan to become pregnant
• Participants in other interventional clinical trials
• MRI contraindications (e.g., claustrophobia, hypersensitivity to contrast media, etc.)

Second stage:

• During the first phase of follow-up, participants' compliance was poor, with study medication compliance less than 80% or greater than 120%; Follow-up was less than 24 weeks or did not complete the follow-up within the follow-up window..
• Recurrent stroke in the first stage

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: dl-3-butylphthalide; Routine treatment and dl-3-butylphthalide	Drug: dl-3-butylphthalide; First stage： Routine stroke treatment: hypoglycemic, antihypertensive, antiplatelet, anticoagulant and other conventional cerebrovascular disease treatment drugs. Placebo group: routine stroke treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: routine stroke treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Second stage： 14d washout period after first stage. Routine PSCI treatment: 5-10 mg Donepezil, qd. Placebo group: Routine PSCI treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: Routine PSCI treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks.; Other Names: DL-3-n-butylphthalide (NBP); Drug: dl-3-butylphthalide placebo; First stage： Routine stroke treatment: hypoglycemic, antihypertensive, antiplatelet, anticoagulant and other conventional cerebrovascular disease treatment drugs. Placebo group: routine stroke treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: routine stroke treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Second stage： 14d washout period after first stage. Routine PSCI treatment: 5-10 mg Donepezil, qd. Placebo group: Routine PSCI treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: Routine PSCI treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks.; Other Names: NBP placebo
Placebo Comparator: dl-3-butylphthalide Placebo; Routine treatment and dl-3-butylphthalide Placebo	Drug: dl-3-butylphthalide; First stage： Routine stroke treatment: hypoglycemic, antihypertensive, antiplatelet, anticoagulant and other conventional cerebrovascular disease treatment drugs. Placebo group: routine stroke treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: routine stroke treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Second stage： 14d washout period after first stage. Routine PSCI treatment: 5-10 mg Donepezil, qd. Placebo group: Routine PSCI treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: Routine PSCI treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks.; Other Names: DL-3-n-butylphthalide (NBP); Drug: dl-3-butylphthalide placebo; First stage： Routine stroke treatment: hypoglycemic, antihypertensive, antiplatelet, anticoagulant and other conventional cerebrovascular disease treatment drugs. Placebo group: routine stroke treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: routine stroke treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Second stage： 14d washout period after first stage. Routine PSCI treatment: 5-10 mg Donepezil, qd. Placebo group: Routine PSCI treatment + oral Butylphthalide Placebo Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks. Butylphthalide group: Routine PSCI treatment + oral Butylphthalide Soft Capsules, 2 capsules/time, tid, an empty stomach for 24 weeks.; Other Names: NBP placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSCI incidence	Compared with routine stroke treatment, the difference of the PSCI incidence at 24 weeks with butylphthalide treatment.	24 weeks (first stage)
vadas-cog score	Compared with routine treatment, improvement of vadas-cog scores at 24 weeks with butylphthalide treatment	6 months (Second stage)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of infarct volume by cranial magnetic resonance imaging (MRI) at 24 weeks after treatment with butylphthalein compared with routine stroke treatment.	Changes of infarct volume by cranial magnetic resonance imaging (MRI) at 24 weeks after treatment with butylphthalein compared with routine stroke treatment.	24 weeks (first stage)
Changes of infarct location by cranial magnetic resonance imaging (MRI) at 24 weeks after treatment with butylphthalein compared with routine stroke treatment.	Changes of infarct location by cranial magnetic resonance imaging (MRI) at 24 weeks after treatment with butylphthalein compared with routine stroke treatment.	24 weeks (first stage)
Changes of Montreal Cognitive Assessment (MoCA) at 24 weeks compared with baseline	Changes of Montreal Cognitive Assessment (MoCA) at 24 weeks compared with baseline	24 weeks (first stage)
Changes of Mini-Mental State Examination (MMSE) at 24 weeks compared with baseline	Changes of Mini-Mental State Examination (MMSE) at 24 weeks compared with baseline	24 weeks (first stage)
Changes of Neuropsychiatric Inventory Questionnaire (NPI-Q) at 24 weeks compared with baseline	Changes of Neuropsychiatric Inventory Questionnaire (NPI-Q) at 24 weeks compared with baseline	24 weeks (first stage)
Changes of Hamilton Anxiety Scale (HAMA) at 24 weeks compared with baseline	Changes of Hamilton Anxiety Scale (HAMA) at 24 weeks compared with baseline	24 weeks (first stage)
Changes of Hamilton Depression Scale (HAMD) at 24 weeks compared with baseline	Changes of Hamilton Depression Scale (HAMD) at 24 weeks compared with baseline	24 weeks (first stage)
Changes of 23-item version of Alzheimer's Disease Cooperative Study- activities of daily living scale (ADCS-ADL23) for activities of daily living at 24 weeks compared with baseline	Changes of 23-item version of Alzheimer's Disease Cooperative Study- activities of daily living scale (ADCS-ADL23) for activities of daily living at 24 weeks compared with baseline	24 weeks (first stage)
Changes of Clinical Dementia Rating (CDR) at 24 weeks compared with baseline	Changes of Clinical Dementia Rating (CDR) at 24 weeks compared with baseline	24 weeks (first stage)
stroke recurrence	Difference in stroke recurrence rate of butylphthalein treatment compared with routine stroke treatment at 24 weeks	24 weeks (first stage)
Changes of modified Rankin Scale score (mRS) at 24 weeks compared with baseline.	The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The mRS is a range from 0-6. 0=No symptoms, 1=No significant disability. Able to carry out all usual activities, despite some symptoms. 2=Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3=Moderate disability. Requires some help, but able to walk unassisted. 4=Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5=Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6=Dead	24 weeks (first stage)
Changes of Montreal Cognitive Assessment (MoCA) at 48 weeks compared with baseline	Changes of Montreal Cognitive Assessment (MoCA) at 48 weeks compared with baseline	48 weeks (second stage)
Changes of Mini-Mental State Examination (MMSE) at 48 weeks compared with baseline	Changes of Mini-Mental State Examination (MMSE) at 48 weeks compared with baseline	48 weeks (second stage)
Changes cognitive domain level by Symbol Digit Modalities Test at 48 weeks compared with baselinel	Changes cognitive domain level by Symbol Digit Modalities Test at 48 weeks compared with baseline	48 weeks (second stage)
Changes cognitive domain level by Trail Making Test at 48 weeks compared with baseline.	Changes cognitive domain level by Trail Making Test at 48 weeks compared with baseline.	48 weeks (second stage)
Changes of Neuropsychiatric Inventory Questionnaire (NPI-Q) at 48 weeks compared with baseline	Changes of Neuropsychiatric Inventory Questionnaire (NPI-Q) at 48 weeks compared with baseline	48 weeks (second stage)
Changes of Hamilton Anxiety Scale (HAMA) at 48 weeks compared with baseline	Changes of Hamilton Anxiety Scale (HAMA) at 48 weeks compared with baseline	48 weeks (second stage)
Changes of Hamilton Depression Scale (HAMD) at 48 weeks compared with baseline	Changes of Hamilton Depression Scale (HAMD) at 48 weeks compared with baseline	48 weeks (second stage)
Changes of Clinical Dementia Rating (CDR) at 48 weeks compared with baseline	Changes of Clinical Dementia Rating (CDR) at 48 weeks compared with baseline	48 weeks (second stage)
Changes of 23-item version of Alzheimer's Disease Cooperative Study- activities of daily living scale (ADCS-ADL23) for activities of daily living at 48 weeks compared with baseline	Changes of 23-item version of Alzheimer's Disease Cooperative Study- activities of daily living scale (ADCS-ADL23) for activities of daily living at 48 weeks compared with baseline	48 weeks (second stage)
stroke recurrence	Difference in stroke recurrence rate of butylphthalein treatment compared with routine stroke treatment at 48 weeks	48 weeks (second stage)
Changes of mRS at 48 weeks compared with baseline.	The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The mRS is a range from 0-6. 0=No symptoms, 1=No significant disability. Able to carry out all usual activities, despite some symptoms. 2=Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3=Moderate disability. Requires some help, but able to walk unassisted. 4=Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5=Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6=Dead	48 weeks (second stage)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events [Safety]	Incidence of Treatment-Emergent Adverse Events [Safety]	12 weeks, 24 weeks, 36 weeks and 48 weeks
Dropout rates and reasons [Safety]	Dropout rates and reasons [Safety]	12 weeks, 24 weeks, 36 weeks and 48 weekss

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: July 6, 2023
• First Submitted That Met QC Criteria: July 27, 2023
• First Posted (Actual): August 4, 2023

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: stroke; Butylphthalide; PSCI
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Physiological Effects of Drugs; Platelet Aggregation Inhibitors; Neuroprotective Agents; Protective Agents; 3-n-butylphthalide
• Other Study ID Numbers: Be-CLEVER

Drug and device information, study documents

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