This study is a single-center, prospective, single-arm, self-controlled clinical trial designed to assess the safety and efficacy of edaravone dexborneol sublingual tablets for blood-brain barrier (BBB) dysfunction in patients with CADASIL. The study will enroll approximately 60 participants aged 18 to 80 years with genetically confirmed CADASIL. Participants will be followed for a total duration of 12 months, including two consecutive phases. * Phase 1 is a 6-month natural history observation period, during which participants do not receive the study drug and continue their routine standard care for CADASIL. * Phase 2 is a 6-month drug intervention period, in which participants will receive edaravone dexborneol sublingual tablets to investigate the effect on the BBB water exchange rate (kw), measured by diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI, and to assess potential benefits on stroke risk reduction, cognitive function, and gait performance. The primary endpoint is the change in kw measured by DP-pCASL. Secondary endpoints include the incidence of clinical stroke events; changes in neuropsychological performance, MRI-based CSVD biomarkers, gait and motor assessments, functional disability and activities-of-daily-living scales, and peripheral blood biomarkers. Safety assessments will include adverse events (AEs) and serious adverse events (SAEs).
This study is a single-center, prospective, single-arm, self-controlled clinical trial evaluating the safety and efficacy of edaravone dexborneol sublingual tablets for blood-brain barrier (BBB) dysfunction in CADASIL patients. 1. Background and Rationale CADASIL is the most common monogenic form of cerebral small vessel disease (CSVD), caused by pathogenic mutations in the NOTCH3 gene. BBB dysfunction is increasingly recognized as one of the core pathophysiological mechanisms in CADASIL, contributing to white matter injury, progressive cognitive decline, and recurrent stroke, and represents a potential therapeutic target. 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 90-day functional outcomes in patients with acute ischemic stroke. Based on these findings, this study is designed to systematically assess the efficacy and safety of edaravone dexborneol sublingual tablets in ameliorating BBB dysfunction in patients with CADASIL, and to investigate their potential benefits in reducing stroke risk and improving cognitive function. 2. Study Design and Methods A total of 60 participants aged 18 to 80 years with genetically confirmed CADASIL will be recruited. The primary endpoint is the change in the BBB water-exchange rate (kw), measured by diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI. The trial consists of two sequential phases: during the first 6 months (natural disease observation period), participants do not receive the study drug and continue their routine standard care for CADASIL, allowing for the characterization of intra-individual natural variability of kw. During the subsequent 6 months (treatment period), all participants will receive edaravone dexborneol sublingual tablets in addition to their routine standard care, and treatment-related changes in kw will be evaluated. All participants will undergo multimodal MRI scanning at baseline, month 6, and month 12, along with comprehensive assessments including cognitive testing, clinical scales, and peripheral blood biomarkers. 3. Significance This study is expected to fill a significant gap in pharmacological intervention research for CADASIL and provide clinical evidence supporting the potential extension of edaravone dexborneol to genetically mediated small vessel disease.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
One tablet (containing edaravone 30 mg and dexborneol 6 mg) is taken sublingually twice daily for the 6-month treatment period.
Huashan Hospital, Fudan University
Shanghai, China
Change in whole-brain blood-brain barrier water exchange rate (kw) measured by DP-pCASL MRI
The blood-brain barrier (BBB) water exchange rate (kw), an imaging marker of BBB function, is quantified on whole-brain diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI at baseline, month 6, and month 12. All participants are untreated during the first 6 months (observation period) and receive edaravone dexborneol sublingual tablets during the subsequent 6 months (treatment period). The change in kw during the observation period (baseline to Month 6) is compared with the change during the treatment period (Month 6 to Month 12) to distinguish the natural trajectory of BBB dysfunction from a potential treatment effect.
Time frame: Baseline, Month 6, and Month 12
Clinical Stroke Events
Number and proportion of participants experiencing any stroke event, including ischemic stroke and hemorrhagic stroke, recorded throughout the study.
Time frame: 12 months
Change in Montreal Cognitive Assessment (MoCA) Score
The Montreal Cognitive Assessment (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.
Time frame: Baseline, Month 6, and Month 12
Change in Auditory Verbal Learning Test (AVLT) Score
Verbal episodic memory is assessed using the Huashan version of the Auditory Verbal Learning Test (AVLT-H). The test uses a list of 12 words from three semantic categories (4 words per category). The examiner reads the list aloud and the participant recalls the words immediately; this is repeated for three consecutive trials. The immediate recall score is the sum of correctly recalled words across the three trials, ranging from 0 to 36, with higher scores indicating better memory function.
Time frame: Baseline, Month 6, and Month 12
Change in Boston Naming Test Score
The Boston Naming Test (BNT) is a widely used neuropsychological assessment that measures confrontation naming-the ability to retrieve and produce the correct name for a visually presented object. Boston Naming Test includes 30 items and evaluates language through measuring the total of correct responses. The minimum score is 0, and the maximum score is 30. Higher score indicates better language.
Time frame: Baseline, Month 6, and Month 12
Change in Stroop Color-Word Test completion time
Inhibitory function and executive control are assessed using the Stroop Color-Word Test. In the color-word interference condition, participants name the ink color of color words while inhibiting the automatic tendency to read the word. The outcome is the completion time in seconds; shorter times indicate better executive function.
Time frame: Baseline, Month 6, and Month 12
Change in Stroop Color-Word Test number of correct responses
Inhibitory function and executive control are assessed using the Stroop Color-Word Test. In the color-word interference condition, participants name the ink color of color words while inhibiting the automatic tendency to read the word. The outcome is the number of correct responses, ranging from 0 to 50, with higher scores indicating better executive function.
Time frame: Baseline, Month 6, and Month 12
Change in Symbol Digit Modalities Test (SDMT) Score
The total number of correct symbol-digit pairings completed within 90 seconds (common score range: 0-105), where a higher score indicates better processing speed, sustained attention, and visual scanning.
Time frame: Baseline, Month 6, and Month 12
Change in Trail Making Test (TMT) Score
The Trail Making Test (TMT) is a widely used neuropsychological test that measures processing speed, visual attention, sequencing, mental flexibility, and executive function. The score is the time it takes to complete the task. Lower times are better, while longer times indicate greater impairment.
Time frame: Baseline, Month 6, and Month 12
Change in Digit Span Test (DST) Score
Digit Span Test (DST) consists of forward and backward subtests, that respectively assess attention and executive function through measuring the number of correct digit sequences. The minimum score is 0 , and the maximum scores are respectively 10 and 9 for forward and backward subtests. The total score is the sum of the forward and backward subtests, ranging from 0 to 19, with higher scores indicating better attention and working memory.
Time frame: Baseline, Month 6, and Month 12
Change in Hamilton Anxiety Rating Scale (HAMA) score
The Hamilton Anxiety Rating Scale (HAMA) is a clinician-administered scale used to assess the severity of anxiety symptoms. The total score ranges from 0 to 56, with higher scores indicating more severe anxiety symptoms.
Time frame: Baseline, Month 6, and Month 12
Change in Hamilton Depression Rating Scale (HAMD) score
The Hamilton Depression Rating Scale (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: Baseline, Month 6, and Month 12
Change in number of lacunes
The change in the number of lacunes on brain MRI, assessed using T1-weighted, T2-weighted, and FLAIR sequences. Lacunes are markers of cerebral small vessel disease; an increased number may indicate progression of vascular pathology.
Time frame: Baseline, Month 6, and Month 12
Change in Number of Microbleeds
The change in the number of cerebral microbleeds on brain MRI, assessed using susceptibility-weighted imaging (SWI) or T2\*-weighted gradient-echo imaging. Cerebral microbleeds are markers of cerebral small vessel disease; an increased burden may indicate worsening vascular pathology.
Time frame: Baseline, Month 6, and Month 12
Change in White Matter Hyperintensity Volume
The change in white matter hyperintensity (WMH) volume, assessed using quantitative MRI analysis and reported in milliliters (mL). This measure evaluates the impact of treatment on the progression of cerebral small vessel disease. A smaller increase or a decrease in WMH volume suggests a treatment benefit.
Time frame: Baseline, Month 6, and Month 12
Change in perivascular space (PVS) score
The change in the burden of enlarged perivascular spaces on brain MRI, rated on a validated visual rating scale (0 to 4) in the basal ganglia and centrum semiovale. Enlarged perivascular spaces are markers of cerebral small vessel disease; a higher score may indicate worsening vascular pathology.
Time frame: Baseline, Month 6, and Month 12
Change in total brain volume
The change in total brain volume on brain MRI, assessed using quantitative volumetric analysis of 3D T1-weighted images and reported in milliliters (mL). Loss of brain volume reflects atrophy associated with cerebral small vessel disease; a greater reduction in brain volume may indicate disease progression.
Time frame: Baseline, Month 6, and Month 12
Change in fractional anisotropy (FA)
The change in fractional anisotropy (FA) derived from diffusion tensor imaging (DTI), an index of white matter microstructural integrity. A decrease in FA reflects loss of white matter integrity and may indicate progression of cerebral small vessel disease.
Time frame: Baseline, Month 6, and Month 12
Change in mean diffusivity (MD)
The change in mean diffusivity (MD) derived from diffusion tensor imaging (DTI). An increase in MD reflects loss of white matter microstructural integrity and may indicate progression of cerebral small vessel disease.
Time frame: Baseline, Month 6, and Month 12
Change in peak width of skeletonized mean diffusivity (PSMD)
The change in peak width of skeletonized mean diffusivity (PSMD) derived from diffusion tensor imaging (DTI), a fully automated marker of cerebral small vessel disease. An increase in PSMD may indicate worsening white matter damage and disease progression.
Time frame: Baseline, Month 6, and Month 12
Change in Tinetti Balance and Gait Assessment score
Assessed using the Tinetti Balance and Gait Evaluation. The scale consists of a balance section (9 items, max 16 points) and a gait section (7 items, max 12 points). Total scores range from 0 to 28, with higher scores indicating better balance and gait, and lower fall risk.
Time frame: Baseline, Month 6, and Month 12
Changes in Short Physical Performance Battery (SPPB) score
Changes in Short Physical Performance Battery (SPPB) score (range 0-12, with higher score indicating better physical performance).
Time frame: Baseline, Month 6, and Month 12
Change in modified Rankin Scale (mRS) score
The change in modified Rankin Scale (mRS) score. The mRS is a widely used functional outcome measure that assesses the degree of disability or dependence in daily activities. The scale ranges from 0 (no symptoms) to 6 (death), with higher scores indicating greater disability. An increase in mRS score suggests a worsening of functional status.
Time frame: Baseline, Month 6, and Month 12
Change in Instrumental Activities of Daily Living (IADL) scale score
The change in Lawton-Brody Instrumental Activities of Daily Living (IADL) scale score. IADLs are activities that support daily life and involve interacting with one's environment, such as managing finances, medication and health, shopping, meal preparation, housekeeping, laundry, communication, and community mobility. The scale is scored from 0 to 8, with higher scores indicating greater functional independence.
Time frame: Baseline, Month 6, and Month 12
Change in serum neurofilament light chain (NfL)
The change in serum neurofilament light chain (NfL) concentration. NfL is a biomarker of neuroaxonal injury; higher levels may indicate greater neuronal damage.
Time frame: Baseline, Month 6, and Month 12
Change in serum high-sensitivity C-reactive protein (hs-CRP)
The change in serum high-sensitivity C-reactive protein (hs-CRP) concentration. hs-CRP is a marker of systemic inflammation; higher levels may indicate a greater inflammatory burden.
Time frame: Baseline, Month 6, and Month 12
Change in serum interleukin-6 (IL-6)
The change in serum interleukin-6 (IL-6) concentration. IL-6 is a pro-inflammatory cytokine; higher levels may indicate a greater inflammatory burden.
Time frame: Baseline, Month 6, and Month 12
Change in serum interleukin-8 (IL-8)
The change in serum interleukin-8 (IL-8) concentration. IL-8 is a pro-inflammatory chemokine; higher levels may indicate a greater inflammatory burden.
Time frame: Baseline, Month 6, and Month 12
Change in serum interleukin-10 (IL-10)
The change in serum interleukin-10 (IL-10) concentration. IL-10 is an anti-inflammatory cytokine; higher levels reflect an anti-inflammatory response.
Time frame: Baseline, Month 6, and Month 12
Change in serum tumor necrosis factor-alpha (TNF-α)
The change in serum tumor necrosis factor-alpha (TNF-α) concentration. TNF-α is a pro-inflammatory cytokine; higher levels may indicate a greater inflammatory burden.
Time frame: Baseline, Month 6, and Month 12
Change in serum glial fibrillary acidic protein (GFAP)
The change in serum glial fibrillary acidic protein (GFAP) concentration. GFAP is a biomarker of astroglial activation and injury; higher levels may indicate greater astrocytic damage.
Time frame: Baseline, Month 6, and Month 12
Adverse events
Adverse events, confirmed by the Clinical Event Committee.
Time frame: 12 months
Serious adverse events
Serious adverse events, confirmed by the Clinical Event Committee.
Time frame: 12 months
Liver function impairment
Number of participants with Alanine Aminotransferase level \>2.0×upper limit of the normal
Time frame: 12 months
Renal function impairment
Number of participants with serum creatinine \>1.5×upper limit of the normal.
Time frame: 12 months
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