This study is a multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of Edaravone Dexborneol Sublingual Tablets in patients with acute ischemic stroke due to small vessel disease (TASTE-SVD). The study will enroll approximately 600 participants aged 30 to 80 years who have experienced a recent small subcortical infarct (RSSI) confirmed by MRI. Participants will be randomized in a 1:1 ratio into either the Edaravone Dexborneol Sublingual Tablets group or the placebo group, with a 24-week treatment period followed by a 28-week follow-up. The primary endpoint is a hierarchical composite endpoint at week 24, including all-cause mortality, modified Rankin Scale (mRS) score ≥2, recurrent stroke, changes in MoCA score, and changes in VaDAS-Cog score. Secondary endpoints include additional functional and cognitive assessments at 24 and 52 weeks, as well as MRI markers of white matter hyperintensities, new infarctions, microbleeds, and brain atrophy. Safety assessments will include adverse events (AEs), treatment-related adverse events (TRAEs), and serious adverse events (SAEs). The study aims to determine whether Edaravone Dexborneol Sublingual Tablets improve functional outcomes and cognitive performance in patients with small vessel disease-related stroke.
This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of Edaravone Dexborneol Sublingual Tablets in patients with acute ischemic stroke due to small vessel disease (TASTE-SVD). 1. Background and Rationale Cerebral small vessel disease (CSVD) is a major contributor to stroke, cognitive decline, and disability. Currently, there are no approved targeted therapies specifically addressing the pathophysiology of CSVD-related ischemic stroke. Edaravone Dexborneol, a novel free radical scavenger and anti-inflammatory agent, has shown neuroprotective effects in preclinical models and clinical trials for ischemic stroke. The TASTE-SL trial demonstrated that Edaravone Dexborneol improved functional outcomes at 90 days in acute ischemic stroke patients. 2. Study Design and Methods A total of 600 participants will be recruited across 50 clinical sites in China. Participants must be 30-80 years old and have an MRI-confirmed recent small subcortical infarct (RSSI). Eligible participants will be randomized 1:1 into: * Treatment group: Edaravone Dexborneol Sublingual Tablets (Edaravone 30 mg + Dexborneol 6 mg), twice daily for 24 weeks. * Control group: Placebo, twice daily for 24 weeks. Following the 24-week treatment period, participants will enter a 28-week follow-up phase, making the total study duration 52 weeks per participant. 3. Primary and Secondary Endpoints Primary endpoint (Week 24): A hierarchical composite endpoint including: 1. All-cause mortality 2. Modified Rankin Scale (mRS) score ≥2 3. Recurrent stroke 4. Change in MoCA score from baseline 5. Change in VaDAS-Cog score from baseline Secondary endpoints include (Week 24 \& 52): * Cognitive and functional assessments (MoCA, MMSE, IADL, HAMD, TMT-A/B) * MRI markers of disease progression (e.g., white matter hyperintensities, infarct burden, microbleeds, brain atrophy) * Safety outcomes, including adverse events (AEs), treatment-related AEs (TRAEs), and serious AEs (SAEs). 4\. Statistical Analysis The primary analysis will use the Win Ratio method to compare hierarchical composite endpoints between treatment groups. Secondary endpoints will be analyzed using Cochran-Mantel-Haenszel tests (for categorical outcomes) and Mixed-Effect Models for Repeated Measures (MMRM) (for continuous outcomes). 5\. Significance This study aims to determine whether Edaravone Dexborneol Sublingual Tablets can improve functional outcomes, prevent cognitive decline, and reduce stroke recurrence in CSVD-related ischemic stroke. If successful, the findings may support a new treatment approach for this high-risk population.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
600
One tablet of Edaravone Dexborneol Sublingual Tablet (containing 30mg Edaravone and 6mg Dexborneol) to be taken sublingually, twice daily.
One placebo tablet, to be taken sublingually, twice daily
Peking Union Medical College Hospital
Beijing, China
RECRUITINGHierarchical Composite Endpoint
This composite outcome consists of five hierarchical endpoints at 24 weeks, analyzed using the Win Ratio method: 1. All-Cause Mortality 2. Modified Rankin Scale (mRS) Score ≥2 3. Stroke Recurrence 4. Change in Montreal Cognitive Assessment (MoCA) Score from Baseline 5. Change in Vascular Dementia Assessment Scale-Cognitive Subscale (VaDAS-Cog) Score from Baseline The Win Ratio approach will be used to analyze these outcomes in order of priority.
Time frame: 24 weeks
All-Cause Mortality
The number of participants who experience all-cause mortality at 24 weeks. All-cause mortality includes death from any reason, such as cardiovascular, neurological, or other systemic causes. This measure is used to assess the overall survival impact of the intervention.
Time frame: 24weeks
Modified Rankin Scale (mRS) Score ≥2
The proportion of participants with a modified Rankin Scale (mRS) score ≥2 at 24 weeks. The mRS is a widely used functional outcome measure that assesses the degree of disability or dependence in daily activities following a stroke. The scale ranges from 0 (no symptoms) to 6 (death), with scores of 2 or higher indicating functional dependence. A higher proportion of participants with mRS ≥2 suggests a worse functional outcome.
Time frame: 24 weeks
Stroke Recurrence
The number of participants who experience a recurrent stroke within 24 weeks of treatment. Recurrent stroke is defined as a new ischemic or hemorrhagic stroke occurring after the initial qualifying event, confirmed by neurological symptoms lasting ≥24 hours and neuroimaging evidence (MRI or CT). This measure assesses the effectiveness of the intervention in preventing subsequent strokes
Time frame: 24 weeks
Change in Montreal Cognitive Assessment (MoCA) Score from Baseline
The change in Montreal Cognitive Assessment (MoCA) scores from baseline to 24 weeks of treatment. The MoCA is a cognitive screening tool that assesses multiple domains, including attention, concentration, executive function, memory, language, visuospatial skills, abstract thinking, calculation, and orientation. Scores range from 0 to 30, with higher scores indicating better cognitive function. A greater positive change from baseline represents an improvement in cognitive function.
Time frame: 24 weeks
Change in Vascular Dementia Assessment Scale-Cognitive Subscale (VaDAS-Cog) Score from Baseline
The change in Vascular Dementia Assessment Scale-Cognitive Subscale (VaDAS-Cog) score from baseline to 24 weeks of treatment. The VaDAS-Cog is a neuropsychological assessment tool specifically designed to evaluate cognitive impairments associated with vascular dementia. VaDAS-Cog was created by adding five subtests to the ADAS-Cog that reflect attention and executive functions. The total score ranges from 0 to 70, with lower scores indicating lesser severity.
Time frame: 24 weeks
All cause mortality
The number of participants who experience all-cause mortality at 24 weeks. All-cause mortality includes death from any reason, such as cardiovascular, neurological, or other systemic causes. This measure is used to assess the overall survival impact of the intervention.
Time frame: 24 weeks
Modified Rankin Scale (mRS) Score ≥2
The proportion of participants with a modified Rankin Scale (mRS) score ≥2 at 24 weeks. The mRS is a widely used functional outcome measure that assesses the degree of disability or dependence in daily activities following a stroke. The scale ranges from 0 (no symptoms) to 6 (death), with scores of 2 or higher indicating functional dependence. A higher proportion of participants with mRS ≥2 suggests a worse functional outcome.
Time frame: 24 weeks
Stroke recurrence
The number of participants who experience a recurrent stroke within 24 weeks of treatment. Recurrent stroke is defined as a new ischemic or hemorrhagic stroke occurring after the initial qualifying event, confirmed by neurological symptoms lasting ≥24 hours and neuroimaging evidence (MRI or CT). This measure assesses the effectiveness of the intervention in preventing subsequent strokes
Time frame: 24 weeks
Post-stroke cognitive impairment
Number of participants with post-stroke cognitive impairment, defined as a MOCA score \< 22
Time frame: 24 weeks
Cognitive function (MMSE)
Changes in Mini-Mental State Examination (MMSE) score from baseline. MMSE includes the assessment of 11 cognitive functions, which encompass orientation, registration of information, attention/calculation abilities, recall, naming, repetition, comprehension (both verbal and written), writing, and visuospatial construction skills. The MMSE scale ranges from 0 to 30 points, with higher scores indicating a better outcome.
Time frame: 24 weeks
Cognitive function (MoCA)
The change in Montreal Cognitive Assessment (MoCA) scores from baseline to 24 weeks of treatment. The MoCA is a cognitive screening tool that assesses multiple domains, including attention, concentration, executive function, memory, language, visuospatial skills, abstract thinking, calculation, and orientation. Scores range from 0 to 30, with higher scores indicating better cognitive function. A greater positive change from baseline represents an improvement in cognitive function.
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Time frame: 24 weeks
Cognitive function (VaDAS-Cog)
Changes in Vascular Dementia Assessment Scale-Cognitive (VaDAS-Cog) score from baseline. The VaDAS-Cog is a neuropsychological assessment tool specifically designed to evaluate cognitive impairments associated with vascular dementia. VaDAS-Cog was created by adding five subtests to the ADAS-Cog that reflect attention and executive functions. The total score ranges from 0 to 70, with lower scores indicating lesser severity.
Time frame: 24 weeks
Depression (HAMD)
Changes in Hamilton Depression Rating Scale (HAMD) score from baseline. The HAMD is a widely used clinical tool for assessing the severity of depression. It consists of multiple items that evaluate various aspects of depressive symptoms, including mood, guilt, suicidal ideation, work and interest, among others. It is scored on a scale from 0 to 52, with higher scores indicating more severe symptoms.
Time frame: 24 weeks
Activity of Daily Living
Changes in Instrumental Activities of Daily Living (IADL) score from baseline.IADL are activities that support daily life and are oriented toward interacting with your environment. Common IADLs include: Care of others; Care of pets; Child rearing; Communication management; Driving and community mobility; Financial management; Health management and maintenance; Home establishment and management; Meal preparation and clean up; Religious and spiritual activities and expressions; Safety procedure and emergency responses; Shopping. It is scored on a scale from 0 to 31, with higher scores indicating more severe symptoms.
Time frame: 24 weeks
Adverse events
Adverse events, confirmed by the Clinical Event Committee.
Time frame: 24 weeks
Serious adverse events
Serious adverse events, confirmed by the Clinical Event Committee.
Time frame: 24 weeks
Liver function impairment
Number of participants with Alanine Aminotransferase level \>2.0×upper limit of the normal
Time frame: 24 weeks
Renal function impairment
Number of participants with serum creatinine \>1.5×upper limit of the normal.
Time frame: 24 weeks
Composite endpoint
Composite endpoint comprising all-cause mortality, mRS ≥2, and stroke recurrence.
Time frame: 24 weeks
Change in White Matter Hyperintensity Fazekas Score from Baseline
The change in White Matter Hyperintensity (WMH) Fazekas Score from baseline to 52 weeks. The Fazekas scale is a validated measure of small vessel disease burden, ranging from 0 (no WMH) to 6 (severe WMH involvement). An increase in Fazekas score suggests disease progression, while a decrease or stabilization may indicate treatment efficacy.
Time frame: 52 weeks
Number of New MRI-Confirmed Infarcts
The number of new infarcts confirmed by MRI at 52 weeks, compared to baseline. New infarcts are defined as newly developed ischemic lesions identified on diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) sequences. A higher number of new infarcts indicates increased disease progression.
Time frame: 52 weeks
Change in Number of Microbleeds from Baseline
The change in the number of microbleeds on MRI from baseline to 52 weeks, assessed using susceptibility-weighted imaging (SWI) or T2-weighted gradient-echo imaging\*. Microbleeds are markers of cerebral small vessel disease and increased burden may indicate worsening vascular pathology.
Time frame: 52 weeks
Change in White Matter Hyperintensity Volume from Baseline
The change in White Matter Hyperintensity (WMH) volume from baseline to 52 weeks, assessed using quantitative MRI analysis. This measure is to evaluate the impact of treatment on the progression of small vessel disease. A decrease in WMH volume suggests treatment efficacy.
Time frame: 52 weeks
Change in Brain Atrophy Index from Baseline
The change in Brain Atrophy Index from baseline to 52 weeks, measured using MRI volumetric analysis. Brain atrophy is associated with cognitive decline and small vessel disease progression. A higher atrophy index suggests neurodegeneration, while stabilization or a slower rate of change may indicate treatment benefit
Time frame: 52 weeks
All cause mortality
The number of participants who experience all-cause mortality at 24 weeks. All-cause mortality includes death from any reason, such as cardiovascular, neurological, or other systemic causes. This measure is used to assess the overall survival impact of the intervention.
Time frame: 52weeks
Modified Rankin Scale (mRS) Score ≥2
The proportion of participants with a modified Rankin Scale (mRS) score ≥2 at 24 weeks. The mRS is a widely used functional outcome measure that assesses the degree of disability or dependence in daily activities following a stroke. The scale ranges from 0 (no symptoms) to 6 (death), with scores of 2 or higher indicating functional dependence. A higher proportion of participants with mRS ≥2 suggests a worse functional outcome.
Time frame: 52weeks
Stroke recurrence
The number of participants who experience a recurrent stroke within 24 weeks of treatment. Recurrent stroke is defined as a new ischemic or hemorrhagic stroke occurring after the initial qualifying event, confirmed by neurological symptoms lasting ≥24 hours and neuroimaging evidence (MRI or CT). This measure assesses the effectiveness of the intervention in preventing subsequent strokes
Time frame: 52 weeks
Post-stroke cognitive impairment
Number of participants with post-stroke cognitive impairment, defined as a MOCA score \< 22
Time frame: 52weeks
Cognitive function (MMSE)
Changes in Mini-Mental State Examination (MMSE) score from baseline. MMSE includes the assessment of 11 cognitive functions, which encompass orientation, registration of information, attention/calculation abilities, recall, naming, repetition, comprehension (both verbal and written), writing, and visuospatial construction skills. The MMSE scale ranges from 0 to 30 points, with higher scores indicating a better outcome.
Time frame: 52weeks
Cognitive function (MoCA)
The change in Montreal Cognitive Assessment (MoCA) scores from baseline to 24 weeks of treatment. The MoCA is a cognitive screening tool that assesses multiple domains, including attention, concentration, executive function, memory, language, visuospatial skills, abstract thinking, calculation, and orientation. Scores range from 0 to 30, with higher scores indicating better cognitive function. A greater positive change from baseline represents an improvement in cognitive function.
Time frame: 52weeks
Cognitive function (VaDAS-Cog)
Changes in Vascular Dementia Assessment Scale-Cognitive (VaDAS-Cog) score from baseline. The VaDAS-Cog is a neuropsychological assessment tool specifically designed to evaluate cognitive impairments associated with vascular dementia. VaDAS-Cog was created by adding five subtests to the ADAS-Cog that reflect attention and executive functions. The total score ranges from 0 to 70, with lower scores indicating lesser severity.
Time frame: 52weeks
Depression (HAMD)
Changes in Hamilton Depression Rating Scale (HAMD) score from baseline. The HAMD is a widely used clinical tool for assessing the severity of depression. It consists of multiple items that evaluate various aspects of depressive symptoms, including mood, guilt, suicidal ideation, work and interest, among others. It is scored on a scale from 0 to 52, with higher scores indicating more severe symptoms.
Time frame: 52weeks
Activity of Daily Living
Changes in Instrumental Activities of Daily Living (IADL) score from baseline.IADL are activities that support daily life and are oriented toward interacting with your environment. Common IADLs include: Care of others; Care of pets; Child rearing; Communication management; Driving and community mobility; Financial management; Health management and maintenance; Home establishment and management; Meal preparation and clean up; Religious and spiritual activities and expressions; Safety procedure and emergency responses; Shopping. It is scored on a scale from 0 to 31, with higher scores indicating more severe symptoms
Time frame: 52weeks
Adverse events
Adverse events, confirmed by the Clinical Event Committee.
Time frame: 52weeks
Serious adverse events
Serious adverse events, confirmed by the Clinical Event Committee.
Time frame: 52weeks
Liver function impairment
Number of participants with Alanine Aminotransferase level \>2.0×upper limit of the normal
Time frame: 52weeks
Renal function impairment
Number of participants with serum creatinine \>1.5×upper limit of the normal.
Time frame: 52weeks
Composite endpoint
Composite endpoint comprising all-cause mortality, mRS ≥2, and stroke recurrence.
Time frame: 52weeks