Butylphthalide for Cognitive Impairment in Elderly Patients With Focal Epilepsy

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.

• Trail Making Test Part A (TMT-A) Completion Time Changes [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Trail Making Test Part B (TMT-B) Completion Time Changes [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Digit Span Forward Test Score Changes [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Digit Span Backward Test Score Changes [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Rey Auditory Verbal Learning Test (RAVLT) Immediate Recall Score Changes [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Rey Auditory Verbal Learning Test (RAVLT) Delayed Recall Score Changes [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Average Monthly Seizure Frequency Percentage Change [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48]
• Proportion of Participants with ≥50% Reduction in Seizure Frequency [Срок оценки: Baseline and 48 weeks]
• Activities of Daily Living (ADL) Scale Score Changes [Срок оценки: Baseline, 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Quality of Life in Epilepsy Inventory-31-Patient weighted (QOLIE-31-P) Score Changes [Срок оценки: 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) [Срок оценки: 12 weeks, 24 weeks, 36 weeks, and 48 weeks]
• Number of Participants with Serious Adverse Events [Срок оценки: 12 weeks, 24 weeks, 36 weeks, and 48 weeks]