Butylphthalide for Long-term Efficacy in Minor Stroke Study (BLESS)

Chinese Academy of Medical Sciences & Peking Union Medical College

Status and phase: Not yet enrolling; Phase 3

Conditions: Ischemic Stroke; Minor Stroke

Treatments: Drug: Butylphthalide; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT07230587

BLESS

2023ZD0504900 (Other Grant/Funding Number)

Details and patient eligibility

About

This study is a multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the long-term efficacy and safety of butylphthalide in patients with minor acute ischemic stroke (BLESS Trial).

A total of 1200 participants aged 40 to 80 years with a minor acute ischemic stroke confirmed by MRI will be enrolled. Participants will be randomly assigned in a 1:1 ratio to receive butylphthalide or placebo for 12 months.

The primary outcome is a hierarchical composite endpoint assessed at 12 months, including:

1. All-cause mortality
2. Stroke recurrence
3. Modified Rankin Scale (mRS) score ≥2
4. New MRI-confirmed infarcts
5. Change in Montreal Cognitive Assessment (MoCA) score from baseline

Secondary outcomes include additional functional, cognitive, and imaging-based assessments at 12 months.

This study aims to determine whether butylphthalide can improve long-term functional and cognitive outcomes in patients with minor ischemic stroke, contributing to better secondary stroke prevention strategies.

Full description

1. 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.

2. 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.

3. 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

                  5. 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.

Enrollment: 1,200 estimated patients

Sex: All

Ages: 40 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

1.Inclusion Criteria:

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

Exclusion Criteria:

1. Based on the TOAST classification, consider cardioembolic stroke, stroke of other determined etiology, or stroke of undetermined etiology.
2. Intracranial hemorrhagic diseases on imaging: hemorrhagic stroke, epidural hematoma, subarachnoid hemorrhage, etc. (If hemorrhagic transformation is present, eligibility is at investigator's discretion.)
3. Carotid artery stenosis > 50% requiring surgical intervention.
4. Systemic diseases causing cognitive impairment (e.g., endocrine diseases, vitamin deficiency, systemic autoimmune diseases).
5. Neurological disorders causing cognitive impairment, such as CNS infections, Creutzfeldt-Jakob disease, primary Parkinson's disease, traumatic brain injury, epilepsy, brain tumors.
6. 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).
7. Severe hemiplegia and aphasia that significantly affect cognitive assessment.
8. 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).
9. Severe liver disease (e.g., acute hepatitis, active chronic hepatitis, cirrhosis) or ALT/AST > 2× ULN.
10. Severe kidney disease or renal impairment (serum creatinine > 1.5× ULN).
11. Coagulation disorders or thrombocytopenia (platelet count < 100 × 10⁹/L).
12. Severe systemic diseases with an expected survival < 1 year.
13. Contraindications for MRI or inability to complete MRI scan.
14. Allergy to butylphthalide.
15. Pregnancy, lactation, or planned pregnancy.
16. Participation in another clinical trial within 30 days before randomization.
17. Deemed unsuitable for the study by the investigator.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

1,200 participants in 2 patient groups, including a placebo group

Butylphthalide

Experimental group

Description:

Butylphthalide 200 mg (oral soft capsules), three times daily for 12 months

Treatment:

Drug: Butylphthalide

Placebo

Placebo Comparator group

Description:

Placebo (matching oral soft capsules), three times daily for 12 months.

Treatment:

Drug: Placebo