CADASIL
Conditions
Brief summary
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).
Detailed description
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.
Interventions
One tablet (containing edaravone 30 mg and dexborneol 6 mg) is taken sublingually twice daily for the 6-month treatment period.
Sponsors
Huashan Hospital
Jiangsu Simcere Pharmaceutical Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 1\. Genetically Confirmed CADASIL: Diagnosis of CADASIL confirmed by NOTCH3 genetic testing. * 2\. Age: Between 18 and 80 years. * 3\. Lacunar Lesion Requirement: Presence of ≥1 lacune on brain MRI. * 4\. No acute ischemic stroke or intracerebral hemorrhage within the past 3 months. * 5\. Modified Rankin Scale (mRS) score of 0 to 3. * 6\. Contraception Requirements: Women of childbearing potential and male participants with female partners of childbearing potential must agree to use effective contraception during the study and 30 days after the last dose of the investigational drug.Female participants must have a negative pregnancy test before enrollment. * 7\. Informed Consent: Participants or their legal representatives must voluntarily sign an informed consent form (ICF).
Exclusion criteria
* 1\. Presence of other major neurological disorders: Non-vascular white matter diseases (e.g., multiple sclerosis, carbon monoxide encephalopathy), central nervous system infections, Creutzfeldt-Jakob disease, primary Parkinson's disease, traumatic brain injury, or intracranial tumors. * 2\. Severe Liver Dysfunction: Active liver disease (acute hepatitis, chronic active hepatitis, cirrhosis) or ALT/AST \>2× ULN. * 3\. Severe renal impairment (serum creatinine \>1.5× ULN). * 4\. Life Expectancy \<1 year due to severe systemic diseases. * 5\. Contraindications to MRI: Participants with MRI-incompatible implants, severe claustrophobia, or inability to undergo MRI. * 6\. Known Allergies: History of hypersensitivity to Dexborneol, natural borneol, edaravone, or any excipients (e.g., mannitol, copovidone, microcrystalline cellulose, silica, magnesium stearate). * 7\. Pregnancy and Lactation: Pregnant or lactating women, or those planning pregnancy during the study period. * 8\. Participation in Other Clinical Trials * 9\. Other Investigator-Determined Factors: Any other medical, psychological, or social condition that, in the investigator's judgment, makes the patient unsuitable for participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in whole-brain blood-brain barrier water exchange rate (kw) measured by DP-pCASL MRI | Baseline, Month 6, and Month 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Stroke Events | 12 months | Number and proportion of participants experiencing any stroke event, including ischemic stroke and hemorrhagic stroke, recorded throughout the study. |
| Change in Montreal Cognitive Assessment (MoCA) Score | Baseline, Month 6, and Month 12 | 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. |
| Change in Auditory Verbal Learning Test (AVLT) Score | Baseline, Month 6, and Month 12 | 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. |
| Change in Boston Naming Test Score | Baseline, Month 6, and Month 12 | 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. |
| Change in Stroop Color-Word Test completion time | Baseline, Month 6, and Month 12 | 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. |
| Change in Stroop Color-Word Test number of correct responses | Baseline, Month 6, and Month 12 | 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. |
| Change in Symbol Digit Modalities Test (SDMT) Score | Baseline, Month 6, and Month 12 | 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. |
| Change in Trail Making Test (TMT) Score | Baseline, Month 6, and Month 12 | 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. |
| Change in Digit Span Test (DST) Score | Baseline, Month 6, and Month 12 | 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. |
| Change in Hamilton Anxiety Rating Scale (HAMA) score | Baseline, Month 6, and Month 12 | 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. |
| Change in Hamilton Depression Rating Scale (HAMD) score | Baseline, Month 6, and Month 12 | 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. |
| Change in number of lacunes | Baseline, Month 6, and Month 12 | 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. |
| Change in Number of Microbleeds | Baseline, Month 6, and Month 12 | 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. |
| Change in White Matter Hyperintensity Volume | Baseline, Month 6, and Month 12 | 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. |
| Change in perivascular space (PVS) score | Baseline, Month 6, and Month 12 | 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. |
| Change in total brain volume | Baseline, Month 6, and Month 12 | 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. |
| Change in fractional anisotropy (FA) | Baseline, Month 6, and Month 12 | 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. |
| Change in mean diffusivity (MD) | Baseline, Month 6, and Month 12 | 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. |
| Change in peak width of skeletonized mean diffusivity (PSMD) | Baseline, Month 6, and Month 12 | 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. |
| Change in Tinetti Balance and Gait Assessment score | Baseline, Month 6, and Month 12 | 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. |
| Changes in Short Physical Performance Battery (SPPB) score | Baseline, Month 6, and Month 12 | Changes in Short Physical Performance Battery (SPPB) score (range 0-12, with higher score indicating better physical performance). |
| Change in modified Rankin Scale (mRS) score | Baseline, Month 6, and Month 12 | 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. |
| Change in Instrumental Activities of Daily Living (IADL) scale score | Baseline, Month 6, and Month 12 | 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. |
| Change in serum neurofilament light chain (NfL) | Baseline, Month 6, and Month 12 | The change in serum neurofilament light chain (NfL) concentration. NfL is a biomarker of neuroaxonal injury; higher levels may indicate greater neuronal damage. |
| Change in serum high-sensitivity C-reactive protein (hs-CRP) | Baseline, Month 6, and Month 12 | 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. |
| Change in serum interleukin-6 (IL-6) | Baseline, Month 6, and Month 12 | The change in serum interleukin-6 (IL-6) concentration. IL-6 is a pro-inflammatory cytokine; higher levels may indicate a greater inflammatory burden. |
| Change in serum interleukin-8 (IL-8) | Baseline, Month 6, and Month 12 | The change in serum interleukin-8 (IL-8) concentration. IL-8 is a pro-inflammatory chemokine; higher levels may indicate a greater inflammatory burden. |
| Change in serum interleukin-10 (IL-10) | Baseline, Month 6, and Month 12 | The change in serum interleukin-10 (IL-10) concentration. IL-10 is an anti-inflammatory cytokine; higher levels reflect an anti-inflammatory response. |
| Change in serum tumor necrosis factor-alpha (TNF-α) | Baseline, Month 6, and Month 12 | 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. |
| Change in serum glial fibrillary acidic protein (GFAP) | Baseline, Month 6, and Month 12 | 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. |
| Adverse events | 12 months | Adverse events, confirmed by the Clinical Event Committee. |
| Serious adverse events | 12 months | Serious adverse events, confirmed by the Clinical Event Committee. |
| Liver function impairment | 12 months | Number of participants with Alanine Aminotransferase level \>2.0×upper limit of the normal |
| Renal function impairment | 12 months | Number of participants with serum creatinine \>1.5×upper limit of the normal. |
Countries
China
Contacts
CONTACTXin Cheng
Outcome results
None listed