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.
There is an urgent need for effective therapeutic strategies for acute ischemic cerebral small vessel disease (CSVD). Isosorbide mononitrate and butylphthalide may exert protective effects; however, large-scale randomized controlled trials are required to confirm their efficacy and safety and to guide clinical practice. In this study, patients presenting with a clinical lacunar syndrome within 7 days of onset will be randomly assigned, in a 1:1:1:1 ratio, to one of four groups in addition to routine care: (1) isosorbide mononitrate plus butylphthalide, (2) isosorbide mononitrate plus butylphthalide placebo, (3) isosorbide mononitrate placebo plus butylphthalide, or (4) isosorbide mononitrate placebo plus butylphthalide placebo. The treatment period will last 6 months, with a total follow-up of 1 year, including assessments at 7 days, 1 month, 3 months, 6 months, and 1 year. The primary efficacy outcome is post-stroke disability at 6 months. The primary safety outcome is moderate or more severe headache within 6 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
3,156
Days 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).
Days 1-7: Butylphthalide injection, 25 mg twice daily by intravenous infusion. Days 8-6 months: Butylphthalide soft capsules, 200 mg three times daily orally.
Days 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).
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.
Time frame: 6 months
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.
Time frame: 6 months
Proportion of participants with post-stroke disability at 1 year
The difinition of post-stroke disability is the same as the primary outcome measure.
Time frame: 1 year
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.
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Days 1-7: Butylphthalide injection placebo, twice daily by intravenous infusion. Days 8-6 months: Butylphthalide soft capsule placebo, 2 capsules three times daily orally.
Time frame: 6 months and 1 year
Incidence of recurrent stroke within 6 months and 1 year
Time frame: 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.
Time frame: 6 months and 1 year
National Institutes of Health Stroke Scale (NIHSS) scores at 7 days, 6 months, and 1 year (including changes from baseline)
The National Institutes of Health Stroke Scale (NIHSS) is a standardized tool used to objectively measure the severity of a stroke by quantifying a patient's neurological deficits. Its primary purposes are to evaluate the acuity of a stroke, guide treatment decisions, and predict patient outcomes. The scale's total score ranges from 0 to 42, with higher scores representing more severe neurological impairment.
Time frame: baseline, 7 days, 6 months, and 1 year
Incidence of hypotension within 6 months
Hypotension is defined as a systolic blood pressure (SBP) of less than 100 mmHg or a 30% decrease from baseline.
Time frame: 6 months
Incidence of syncope within 6 months
Syncope is a transient loss of consciousness caused by transient global cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous, complete recovery. The diagnosis requires the following conditions to be met: 1. A transient loss of consciousness with a rapid onset (from a few seconds to 1 minute); 2. A short duration (from a few seconds to a few minutes); 3. Spontaneous and complete recovery; 4. Absence of focal neurological signs; 5. Exclusion of head trauma and epileptic seizures.
Time frame: 6 months
Incidence of liver function impairment within 6 months
Liver function impairment may be diagnosed if at least one of the following criteria is met: 1. Serum AST or ALT \> 5 × the upper limit of normal (ULN), or ALP \> 2 × ULN (or from an abnormal baseline value); 2. Serum total bilirubin (TBil) \> 2.5 mg/dL (42.75 μmol/L) accompanied by any elevation in serum AST, ALT, or ALP levels.
Time frame: 6 months
Incidence of any bleeding within 6 months
Bleeding events are evaluated using the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) classification and categorized as severe, moderate, or mild.
Time frame: 6 months
Incidence of symptomatic intracranial hemorrhage within 6 months
According to the Heidelberg Bleeding Classification established at the 12th Thrombolytic Therapy in Acute Ischemic Stroke workshop in Germany in 2015, symptomatic intracerebral hemorrhage (sICH) is defined as meeting all of the following conditions: 1. Any form of intracranial hemorrhage (including types 1a, 1b, 1c, 2, 3a, 3b, 3c, and 3d of the Heidelberg classification) that is detected by imaging (head CT or MRI) and confirmed by a radiologist; 2. The patient experiences clinical deterioration, defined as: an increase in the NIHSS score of ≥ 4 points from the last score prior to deterioration, OR an increase of ≥ 2 points on any single item of the NIHSS, OR an outcome leading to tracheal intubation, decompressive craniectomy, ventricular drainage, or other major medical/surgical intervention; 3. The clinical deterioration cannot be explained by any cause other than the intracranial hemorrhage.
Time frame: 6 months