The goal of this multicenter, double-blind, 2×2 factorial randomized controlled trial is to evaluate the efficacy and safety of isosorbide mononitrate, butylphthalide, and their combination in reducing disability in patients with acute lacunar stroke.
Age ≥ 30 years;
Clinical lacunar syndrome within 7 days;
a relevant (in time and location) acute lacunar infarct;
if no relevant lesion, symptom duration >24 hours, with no other suspected stroke etiologies (such as cerebral hemorrhage, cortical infarction, seizures, etc.)
Ischemic stroke of large artery atherosclerosis, cardioembolism, or other etiologies (TOAST classification);
Diagnosed or suspected hereditary CSVD;
Intracerebral hemorrhage within the past 3 months including parenchymal, intraventricular, subarachnoid hemorrhage, subdural/epidural hematoma;
Neurodegenerative diseases or systemic diseases that may lead to cognitive impairment, such as Alzheimer's disease, mixed dementia, Parkinson's disease, systemic autoimmune diseases, hepatic encephalopathy, or uremic encephalopathy.
Factorial
Isosorbide Mononitrate
DrugDays 1-7: Isosorbide mononitrate injection, 20 mg once daily by intravenous infusion. Days 8-6 months: Isosorbide mononitrate sustained-release tablets, 40 mg once daily orally (dose reduced to 20 mg once daily during the final week).
Butylphthalide
DrugDays 1-7: Butylphthalide injection, 25 mg twice daily by intravenous infusion. Days 8-6 months: Butylphthalide soft capsules, 200 mg three times daily orally.
Isosorbide Mononitrate Placebo
DrugDays 1-7: Isosorbide mononitrate injection placebo, once daily by intravenous infusion. Days 8-6 months: Isosorbide mononitrate sustained-release tablet placebo, once daily orally (dose reduced to half a tablet once daily during the final week).
Butylphthalide Placebo
DrugDays 1-7: Butylphthalide injection placebo, twice daily by intravenous infusion. Days 8-6 months: Butylphthalide soft capsule placebo, 2 capsules three times daily orally.
Proportion of participants with post-stroke disability at 6 months
A composite endpoint defined as the occurrence of any of the following: modified Rankin Scale (mRS) score ≥ 3, major adverse cardiovascular events (MACE), cognitive impairment, or all-cause mortality. The mRS measures post-stroke functional outcome on a scale from 0 (no symptoms) to 6 (death). MACE includes non-fatal stroke, non-fatal myocardial infarction (MI), and vascular death.The assessment of cognitive function involves three stages: a cognitive screening test, supplementary cognitive testing, and adjudication by an expert panel. The Beijing version of the Montreal Cognitive Assessment (MoCA) is used as the cognitive screening scale. Scores on the MoCA range from 0 to 30, with lower scores indicating greater cognitive impairment.The supplementary cognitive assessment includes the evaluation of several domains: executive function, attention and processing speed, language, and memory, as well as activities of daily living.
Incidence of moderate or more severe headache within 6 months
Headache severity is assessed using the Numerical Rating Scale (NRS), where: 0 indicates no pain; 1 represents a mild headache (including feelings of head pressure or throbbing that are not considered painful); a score of 4 or higher (≥4) represents a headache of at least moderate intensity; and 10 represents the worst headache imaginable to the subject.
Proportion of participants with post-stroke disability at 1 year
The difinition of post-stroke disability is the same as the primary outcome measure.
Proportion of participants with the modified Rankin Scale (mRS) score ≥ 3 at 6 months and 1 year
The modified Rankin Scale (mRS) is used to measure the degree of disability and dependence after a stroke. The scale ranges from 0 to 6. A score of 0 represents no symptoms, 1 represents no significant disability, 2 represents slight disability, 3 represents moderate disability, 4 represents moderately severe disability, 5 represents severe disability, and 6 represents death.
Incidence of recurrent stroke within 6 months and 1 year
Proportion of participants with dementia at 6 months and 1 year
Dementia (all of the following criteria must be met): A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:1.Concern from the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function. 2.A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment. B. The cognitive deficits interfere with independence in everyday activities (i.e., at a minimum, requiring assistance with complex instrumental activities of daily living, such as paying bills or managing medications). C. The cognitive deficits do not occur exclusively in the context of a delirium. D. The cognitive deficits are not better explained by another mental disorder.
≥ 80% of patients taking ≥ 50% of the trial dose up to 6 months
Concentration of blood biomarkers predictive of drug efficacy at 6 months and 1 year
Changes in the levels of neuroinflammation indicators, thormbotic inflammation indicators and novel blood-based biomarkers \[e.g. phosphodiesterase 3A(PDE3A), transgelin 2(TAGLN2), integrin subunit alpha M(ITGAM), protein phosphatase, Mg2+/Mn2+ dependent 1D(PPM1D)\] associated with the prognosis of CSVD compared with baseline levels at 6 months and 1 year.
Changes in white matter integrity at 6 months and 1 year
Assessed using Diffusion Tensor Imaging (DTI) with fiber tractography to evaluate the structural integrity of white matter fibre tract.
Changes in functional connectivity networks at 6 months and 1 year
Assessed using resting-state functional MRI (rs-fMRI) to measure the temporal correlation and connectivity between brain regions within a specific network.
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Beijing Tiantan Hospital
Lead sponsor
Shenzhen Second People's Hospital
Collaborator
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