Butylphthalide for Cognitive Impairment in Elderly Patients With Focal Epilepsy

Safety and Efficacy of Butylphthalide Soft Capsules for Cognitive Impairment Comorbid With Focal Epilepsy in Elderly Patients: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

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.

Inclusion Criteria:

• Age 60-85 years (inclusive)
• Diagnosed with focal epilepsy according to ILAE 2025 latest classification standards, with disease duration ≥2 years
• Currently receiving stable anti-seizure medication (ASM) treatment for ≥3 months, with good seizure control (monthly seizure frequency ≤4 times in the past 3 months)
• Cognitive impairment: Montreal Cognitive Assessment (MoCA) score 18-25 points (inclusive)
• Basic Chinese language comprehension and expression ability, able to cooperate with neuropsychological testing
• Voluntary participation and signed informed consent

Exclusion Criteria:

• Diagnosed with various types of dementia (including Alzheimer's disease, vascular dementia, etc.)
• Clear history of stroke with corresponding lesions on neuroimaging, or severe white matter lesions on brain MRI
• Other neurological diseases that may cause cognitive impairment (traumatic brain injury, encephalitis, hydrocephalus, etc.)
• Systemic diseases that may cause cognitive impairment (severe cardiac, hepatic, renal dysfunction, endocrine diseases, etc.)
• Current severe depression or other psychiatric diseases affecting cognitive assessment
• History of alcohol dependence, drug abuse, or other substance use affecting cognitive function
• Allergy to butylphthalide or its excipients
• Participation in other drug clinical trials within 30 days
• Other conditions deemed inappropriate for participation by investigators