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| Name | Class |
|---|---|
| Taizhou Hospital | OTHER |
| Lishui Country People's Hospital | OTHER |
| Affiliated Yueqing Hospital of Wenzhou Medical University | OTHER |
| The Third Affiliated Hospital of Wenzhou Medical University |
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This is a multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of butylphthalide soft capsules for treating cognitive impairment in elderly patients with focal epilepsy.
Study Population: 220 elderly patients (60-85 years) with focal epilepsy and mild to moderate cognitive impairment (Montreal Cognitive Assessment score 18-25).
Intervention: Participants will be randomly assigned 1:1 to receive either butylphthalide soft capsules (0.2g three times daily) or matching placebo for 48 weeks, while continuing their stable anti-seizure medication regimen.
Primary Outcome: Change in Montreal Cognitive Assessment (MoCA) total score from baseline to 48 weeks.
Secondary Outcomes: Changes in neuropsychological tests (Trail Making Test, Digit Span, Rey Auditory Verbal Learning Test), seizure control measures, functional status (Activities of Daily Living, Quality of Life in Epilepsy), and exploratory neurobiological markers.
This study addresses an important unmet medical need, as current epilepsy treatments focus primarily on seizure control but lack effective interventions for epilepsy-associated cognitive impairment. Butylphthalide, a neuroprotective agent approved for acute ischemic stroke in China, has shown promise in other cognitive disorders and may benefit this patient population through its multiple neuroprotective mechanisms.
Background and Rationale:
Epilepsy affects approximately 9 million people in China, with focal epilepsy comprising 60-70% of adult cases. Cognitive impairment occurs in 40-60% of elderly patients with focal epilepsy, significantly impacting quality of life and daily functioning. Current anti-seizure medications effectively control seizures in ~70% of patients but provide limited benefit for cognitive symptoms, and some may even worsen cognitive function.
Butylphthalide (DL-3-n-butylphthalide) is a multi-target neuroprotective compound originally derived from celery seeds, approved in China for acute ischemic stroke treatment. Its mechanisms include improving cerebral microcirculation, protecting mitochondrial function, reducing oxidative stress, anti-inflammatory effects, and anti-apoptotic properties. Previous studies have demonstrated efficacy in vascular cognitive impairment and mild cognitive impairment, but its effects in epilepsy-associated cognitive dysfunction remain unexplored.
Study Design:
This investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial will enroll 220 participants across 5 centers in China. The study represents off-label use of butylphthalide for cognitive impairment comorbid with epilepsy.
Participants will undergo comprehensive cognitive assessment including MoCA, Trail Making Tests A/B, Digit Span (forward/backward), Rey Auditory Verbal Learning Test, Activities of Daily Living scale, and Quality of Life in Epilepsy inventory. Exploratory endpoints include functional near-infrared spectroscopy, electroencephalography parameters, and serum biomarkers (BDNF, NGF, NSE, S100β, inflammatory markers).
The 48-week treatment period reflects the chronic nature of cognitive impairment and allows adequate time to detect clinically meaningful changes. Safety monitoring includes regular laboratory assessments, vital signs, and adverse event reporting. A 24-hour emergency contact system ensures participant safety.
Statistical Considerations:
Sample size calculation is based on a minimal clinically important difference of 2.5 points on the MoCA scale, with 80% power and 20% dropout rate. Primary analysis uses ANCOVA comparing 48-week MoCA change scores between groups, adjusting for baseline values and study center. Mixed-effects models will analyze repeated measures for secondary endpoints.
This study may provide evidence for a novel therapeutic approach to epilepsy-associated cognitive impairment, potentially expanding treatment options for this underserved patient population.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Butylphthalide Group | Experimental | Participants receive butylphthalide soft capsules 0.2g (two 0.1g capsules) orally three times daily before meals for 48 weeks, while continuing their stable anti-seizure medication regimen. |
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| Placebo Group | Placebo Comparator | Participants receive matching placebo capsules orally three times daily before meals for 48 weeks, while continuing their stable anti-seizure medication regimen. Placebo capsules are identical in appearance, weight, and odor to butylphthalide capsules. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Butylphthalide | Drug | Butylphthalide soft capsules (0.1g per capsule) manufactured by CSPC NBP Pharmaceutical Co., Ltd. Participants take 2 capsules (0.2g total) orally three times daily, 15-30 minutes before meals, for 48 weeks. This represents off-label use for cognitive impairment comorbid with epilepsy, as the drug is currently approved in China only for acute ischemic stroke treatment. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Montreal Cognitive Assessment (MoCA) Total Score from Baseline to 48 Weeks | The Montreal Cognitive Assessment (MoCA) is a validated cognitive screening tool that evaluates multiple cognitive domains including visuospatial/executive function, naming, memory, attention, language, abstraction, delayed recall, and orientation. The total score ranges from 0 to 30 points, with higher scores indicating better cognitive function. The primary outcome is the change in MoCA total score from baseline to 48 weeks, calculated as: (MoCA score at 48 weeks) - (MoCA score at baseline). A positive change indicates cognitive improvement, while a negative change indicates cognitive decline. | Baseline and 48 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Trail Making Test Part A (TMT-A) Completion Time Changes | Trail Making Test Part A (TMT-A) assesses visual scanning speed and psychomotor speed. Participants connect numbered circles in ascending order (1-2-3-4-5...-25). Completion time is measured in seconds, with typical ranges from 15-300 seconds depending on age and education. Lower completion times indicate better performance. The outcome is calculated as: (TMT-A time at assessment point) - (TMT-A time at baseline). A negative change indicates improvement. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Huiqin Xu, MD | Contact | +86-13858806368 | xuhuiqin@wmu.edu.cn | |
| Jiahe Lin, PhD | Contact | +86-13587572321 | linjiahe@wmu.edu.cn |
| Name | Affiliation | Role |
|---|---|---|
| Huiqin Xu, MD | Department of Neurology, First Affiliated Hospital of Wenzhou Medical University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| First Affiliated Hospital of Wenzhou Medical University | Recruiting | Wenzhou | Zhejiang | 325000 | China |
The data sharing plan is currently under consideration and will be determined in consultation with all participating centers, institutional review boards, and relevant regulatory authorities. Factors being evaluated include compliance with Chinese data protection regulations, patient consent provisions, and journal publication policies. A final decision on individual participant data sharing will be made prior to study completion and updated in this registration record.
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| ID | Term |
|---|---|
| D004828 | Epilepsies, Partial |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D004827 | Epilepsy |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| C027125 | 3-n-butylphthalide |
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| OTHER |
Participants will be randomly assigned in a 1:1 ratio to receive either butylphthalide soft capsules or matching placebo for 48 weeks. Both groups will continue their stable anti-seizure medication regimen throughout the study period.
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Double-blind design where participants, care providers, investigators, and outcomes assessors are masked to treatment assignment. Emergency unblinding procedures are available when medically necessary.
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| Placebo | Drug | Matching placebo capsules identical in appearance, weight, and odor to butylphthalide soft capsules, manufactured by the same company following GMP standards. Participants take 2 capsules orally three times daily, 15-30 minutes before meals, for 48 weeks. Placebo contains starch and appropriate excipients. |
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| Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Trail Making Test Part B (TMT-B) Completion Time Changes | Trail Making Test Part B (TMT-B) assesses executive function including cognitive flexibility and attention switching. Participants alternate between numbers and letters (1-A-2-B-3-C...). Completion time is measured in seconds, with typical ranges from 30-600 seconds depending on age and education. Lower completion times indicate better performance. The outcome is calculated as: (TMT-B time at assessment point) - (TMT-B time at baseline). A negative change indicates improvement. | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Digit Span Forward Test Score Changes | Digit Span Forward Test assesses attention and short-term memory capacity. Participants repeat number sequences in the same order as presented. Scores range from 0 to 9 points, with higher scores indicating better attention and short-term memory performance. The outcome is calculated as: (Digit Span Forward score at assessment point) - (Digit Span Forward score at baseline). A positive change indicates improvement. | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Digit Span Backward Test Score Changes | Digit Span Backward Test assesses working memory and mental manipulation abilities. Participants repeat number sequences in reverse order. Scores range from 0 to 8 points, with higher scores indicating better working memory performance. The outcome is calculated as: (Digit Span Backward score at assessment point) - (Digit Span Backward score at baseline). A positive change indicates improvement. | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Rey Auditory Verbal Learning Test (RAVLT) Immediate Recall Score Changes | Rey Auditory Verbal Learning Test (RAVLT) Immediate Recall assesses verbal learning and immediate memory capacity. Participants recall a 15-word list immediately after the fifth presentation. Scores range from 0 to 15 words correctly recalled, with higher scores indicating better immediate verbal memory performance. The outcome is calculated as: (RAVLT immediate recall score at assessment point) - (RAVLT immediate recall score at baseline). A positive change indicates improvement. | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Rey Auditory Verbal Learning Test (RAVLT) Delayed Recall Score Changes | Rey Auditory Verbal Learning Test (RAVLT) Delayed Recall assesses long-term verbal memory retention. Participants recall the 15-word list after a 30-minute delay. Scores range from 0 to 15 words correctly recalled, with higher scores indicating better long-term verbal memory performance. The outcome is calculated as: (RAVLT delayed recall score at assessment point) - (RAVLT delayed recall score at baseline). A positive change indicates improvement. | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Average Monthly Seizure Frequency Percentage Change | Percentage change in average monthly seizure frequency from baseline to each assessment timepoint. Seizure frequency is recorded daily through seizure diary maintained by patients and caregivers, verified during clinical visits. The outcome is calculated as: [(Average monthly frequency at assessment point) - (Average monthly frequency at baseline)] / (Average monthly frequency at baseline) × 100%. A negative percentage indicates reduction in seizure frequency (improvement). | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 |
| Proportion of Participants with ≥50% Reduction in Seizure Frequency | Percentage of participants achieving at least 50% reduction in average monthly seizure frequency compared to baseline. Response is defined as: (Baseline monthly frequency - Average monthly frequency during weeks 45-48) / Baseline monthly frequency ≥ 50%. Seizure data collected through daily seizure diary and verified by caregivers. | Baseline and 48 weeks |
| Activities of Daily Living (ADL) Scale Score Changes | Activities of Daily Living (ADL) Scale is a 14-item assessment tool that evaluates both basic activities of daily living (BADL) including feeding, bathing, grooming, dressing, bowel control, and bladder control, and instrumental activities of daily living (IADL) including using telephone, shopping, food preparation, housekeeping, laundry, transportation, medication responsibility, and financial management. Each item is scored from 1 to 4 points, with total scores ranging from 14 to 56 points. Higher scores indicate greater functional impairment (worse outcome). The outcome is calculated as: (ADL score at assessment point) - (ADL score at baseline). A negative change indicates functional improvement. | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Quality of Life in Epilepsy Inventory-31-Patient weighted (QOLIE-31-P) Score Changes | Quality of Life in Epilepsy Inventory-31-Patient weighted (QOLIE-31-P) evaluates epilepsy-specific quality of life across 7 domains: seizure worry, overall quality of life, emotional well-being, energy/fatigue, cognitive functioning, medication effects, and social function. Total scores range from 0 to 100 points, with higher scores indicating better quality of life. The outcome is calculated as: (QOLIE-31-P score at assessment point) - (QOLIE-31-P score at baseline). A positive change indicates improvement. | Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Number of Participants with Treatment-Related Adverse Events as Assessed by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) | Safety and tolerability assessed by incidence of treatment-related adverse events classified and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All adverse events will be recorded and their relationship to study drug will be assessed by investigators as unrelated, unlikely, possible, probable, or definite. | 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Number of Participants with Serious Adverse Events | Incidence of serious adverse events (SAEs) defined according to International Conference on Harmonisation (ICH) guidelines as events that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, are congenital anomaly/birth defect, or are medically important events. | 12 weeks, 24 weeks, 36 weeks, and 48 weeks |
| Number of Participants with Clinically Significant Hepatic Function Abnormalities | Incidence of clinically significant hepatic function abnormalities defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2 times the upper limit of normal (ULN), or total bilirubin greater than 1.5 times ULN as measured by standard laboratory methods. | 24 weeks and 48 weeks |
| Number of Participants with Clinically Significant Renal Function Abnormalities | Incidence of clinically significant renal function abnormalities defined as serum creatinine levels greater than 1.5 times the upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) decrease by ≥25% from baseline as measured by standard laboratory methods. | 24 weeks and 48 weeks |
| Number of Participants with Clinically Significant Hematological Abnormalities | Incidence of clinically significant hematological abnormalities including hemoglobin decrease to less than 11 g/dL, white blood cell count less than 3,000/μL or greater than 11,000/μL, or platelet count less than 100,000/μL or greater than 450,000/μL as measured by standard hematology laboratory methods. | 24 weeks and 48 weeks |
| D003072 |
| Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |