Butylphthalide for Long-term Efficacy in Minor Stroke Study

Official title

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Long-Term Efficacy of Butylphthalide in Patients With Minor Acute Ischemic Stroke (BLESS)

Overview

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.

Detailed 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.

Interventions

• Drug Butylphthalide
  Butylphthalide (NBP) is a neuroprotective agent derived from celery seed. It has demonstrated potential benefits in improving microcirculation, reducing oxidative stress, and protecting against neuronal injury in ischemic stroke. This study uses butylphthalide soft capsules (200 mg per dose) administered orally, three times daily for 12 months, to evaluate its long-term efficacy and safety in patients with minor acute ischemic stroke
• Drug Placebo
  Matching placebo soft capsules, identical in appearance to butylphthalide capsules, administered orally at a dose of one capsule (200 mg equivalent) three times daily for 12 months. The placebo contains inactive ingredients without pharmacological effects and is used as a control to assess the efficacy and safety of butylphthalide in patients with minor acute ischemic stroke.

Primary outcome measures

• All cause mortality [Time frame: 12 months]
• Stroke recurrence [Time frame: 12 months]
• Modified Rankin Scale (mRS) Score ≥2 [Time frame: 12 months]
• New MRI-Confirmed Infarcts [Time frame: 12 months]
• Change in Montreal Cognitive Assessment (MoCA) Score from Baseline [Time frame: 12 months]

Secondary outcome measures (11)

• All cause mortality [Time frame: 12 months]
• Stroke Recurrence [Time frame: 12 months]
• Distribution of Modified Rankin Scale (mRS) Scores [Time frame: 12 months]
• New MRI-Confirmed Infarcts [Time frame: 12 months]
• Change in Mini-Mental State Examination (MMSE) Score from Baseline [Time frame: 12 months]
• Change in Montreal Cognitive Assessment (MoCA) Score from Baseline [Time frame: 12 months]
• Change in Instrumental Activities of Daily Living (IADL) Score [Time frame: 12 months]
• Change in White Matter Hyperintensity (WMH) Fazekas Score from Baseline [Time frame: 12 months]
• Change in White Matter Hyperintensity Volume from Baseline [Time frame: 12 months]
• Change in Diffusion Tensor Imaging (DTI) Parameters from Baseline [Time frame: 12 months]
• Modified Rankin Scale (mRS) score ≥2 [Time frame: 12 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Tan Z, Zhao Y, Yang W, He S, Ding Y, Xu A. Efficacy and Safety of Adherence to dl-3-n-Butylphthalide Treatment in Patients With Non-disabling Minor Stroke and TIA-Analysis From a Nationwide, Multicenter Registry. Front Neurol. 2021 Sep 22;12:720664. doi: 10.3389/fneur.2021.720664. eCollection 2021. PMID 34630292
• Amarenco P, Lavallee PC, Monteiro Tavares L, Labreuche J, Albers GW, Abboud H, Anticoli S, Audebert H, Bornstein NM, Caplan LR, Correia M, Donnan GA, Ferro JM, Gongora-Rivera F, Heide W, Hennerici MG, Kelly PJ, Kral M, Lin HF, Molina C, Park JM, Purroy F, Rothwell PM, Segura T, Skoloudik D, Steg PG, Touboul PJ, Uchiyama S, Vicaut E, Wang Y, Wong LKS; TIAregistry.org Investigators. Five-Year Risk o PMID 29766771

Identifiers

NCT: NCT07230587 · BLESS · 2023ZD0504900

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗