Butylphthalide for Long-term Efficacy in Minor Stroke Study

• Background and Rationale Minor acute ischemic stroke accounts for a significant proportion of all ischemic strokes and is associated with a substantial risk of recurrent stroke and cognitive impairment. Despite advances in secondary stroke prevention, effective long-term treatments targeting both functional recovery and neuroprotection remain limited. Butylphthalide, a compound originally derived from celery seed, has demonstrated neuroprotective, anti-inflammatory, and microcirculatory-enhancing effects in preclinical and clinical studies. Previous trials have suggested its potential benefits in improving neurological function and preventing stroke progression.

The BLESS Trial (Butylphthalide for Long-term Efficacy in Minor Stroke Study) is designed to evaluate the long-term efficacy and safety of butylphthalide in patients with minor acute ischemic stroke, focusing on its impact on functional outcomes, cognitive performance, and neuroimaging markers.

• Study Design and Methods

This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll approximately 1200 participants across 50 sites in China. Participants will be randomized in a 1:1 ratio to receive: Butylphthalide soft capsules (200 mg, three times daily) for 12 months, or Matching placebo for 12 months.

Participants will undergo regular follow-ups with comprehensive assessments of clinical, cognitive, and imaging parameters.

• Primary Outcome Measure

A hierarchical composite endpoint assessed at 12 months using the Win Ratio method, prioritizing the following outcomes:

• All-cause mortality

②Stroke recurrence

③Modified Rankin Scale (mRS) score ≥2

④New MRI-confirmed infarcts

⑤Change in Montreal Cognitive Assessment (MoCA) score from baseline

4.Secondary Outcome Measures

• All-cause mortality

• Recurrent stroke

• Modified Rankin Scale (mRS) score ≥2

• MRI-confirmed new infarcts

• Composite endpoint of ① + ② + ③

• Composite endpoint of ① + ② + ③ + ④

• Distribution of mRS scores ⑧ Change in MMSE score from baseline

• Change in MoCA score from baseline

• IADL score ⑪ Change in total Fazekas score of white matter hyperintensities from baseline ⑫ Change in white matter hyperintensity volume from baseline

⑬ Change in DTI parameters from baseline

• Statistical Analysis The Win Ratio method will be used for primary endpoint analysis, prioritizing mortality and severe disability outcomes. Secondary outcomes will be analyzed using Cox proportional hazards models, mixed-effects models, and logistic regression as appropriate. A significance level of P < 0.05 will be considered statistically significant.

6.Study Significance This study aims to determine whether butylphthalide can improve long-term functional and cognitive outcomes in minor stroke patients and provide a novel neuroprotective strategy for secondary stroke prevention. If successful, the findings could influence clinical guidelines for stroke management.

1.Inclusion Criteria:

• Age between 40 and 80 years old.
• NIHSS score 0-5 at the time of stroke diagnosis, with MRI-confirmed acute ischemic infarct.
• Time from stroke onset to enrollment ≤ 2 weeks.
• Pre-stroke mRS score ≤ 1.
• No prior diagnosis of cognitive impairment or dementia.
• Informed consent must be voluntarily signed by the patient or their legal representative.

Exclusion criteria

• Based on the TOAST classification, consider cardioembolic stroke, stroke of other determined etiology, or stroke of undetermined etiology.
• Intracranial hemorrhagic diseases on imaging: hemorrhagic stroke, epidural hematoma, subarachnoid hemorrhage, etc. (If hemorrhagic transformation is present, eligibility is at investigator's discretion.)
• Carotid artery stenosis > 50% requiring surgical intervention.
• Systemic diseases causing cognitive impairment (e.g., endocrine diseases, vitamin deficiency, systemic autoimmune diseases).
• Neurological disorders causing cognitive impairment, such as CNS infections, Creutzfeldt-Jakob disease, primary Parkinson's disease, traumatic brain injury, epilepsy, brain tumors.
• Pre-stroke diagnosis of severe psychiatric disorders, including but not limited to depression, non-vascular cognitive impairment, or dementia (e.g., Alzheimer's disease, Parkinson's disease dementia, Lewy body dementia, frontotemporal dementia, drug or alcohol-induced cognitive impairment).
• Severe hemiplegia and aphasia that significantly affect cognitive assessment.
• Use of cognitive-enhancing drugs within 4 weeks before screening, including cholinesterase inhibitors (donepezil, rivastigmine, galantamine), NMDA receptor antagonists (memantine), sodium oligomannate (GV-971), or monoclonal antibodies (lecanemab, donanemab, aducanumab).
• Severe liver disease (e.g., acute hepatitis, active chronic hepatitis, cirrhosis) or ALT/AST > 2× ULN.
• Severe kidney disease or renal impairment (serum creatinine > 1.5× ULN).
• Coagulation disorders or thrombocytopenia (platelet count < 100 × 10⁹/L).
• Severe systemic diseases with an expected survival < 1 year.
• Contraindications for MRI or inability to complete MRI scan.
• Allergy to butylphthalide.
• Pregnancy, lactation, or planned pregnancy.
• Participation in another clinical trial within 30 days before randomization.
• Deemed unsuitable for the study by the investigator.