Clinical trial NCT06674460: Treatment of Acute Ischemic Stroke with Edaravone Dexborneol Sublingual Tablets in Small Vessel Disease
Official title: Treatment of Acute Ischemic Stroke with Edaravone Dexborneol Sublingual Tablets in Small Vessel Disease: a Randomized, Double-Blind, Placebo-Controlled Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Cerebral Small Vessel Disease
Ischemic Stroke
Keywords: sublingual edaravone dexborneol
cerebral small vessel disease
acute ischemic cerebral small vessel disease
cognition
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
First posted: 2024-11-05
Enrollment: 600
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 1. Inclusion Criteria:

1. Age: Between 30 and 80 years .
2. MRI-confirmed recent small subcortical infarct (RSSI): A lesion in the small penetrating artery territory, detected as DWI hyperintensity and ADC hypointensity, with a maximum axial diameter ≤20 mm.
3. White Matter Hyperintensity (WMH) Burden: Fazekas score ≥2 (total score range: 0-6).
4. Time from Stroke Onset: ≤3 weeks from symptom onset to randomization.
5. Pre-stroke Functional Status: Modified Rankin Scale (mRS) ≤1 before the index stroke.
6. Cognitive Function: No prior diagnosis of cognitive impairment or dementia.
7. Education Level: At least primary school education and capable of completing cognitive assessments as judged by the investigator.
8. 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.
9. Informed Consent: Participants or their legal representatives must voluntarily sign an informed consent form (ICF).

2. Exclusion Criteria:

1. Intracranial Hemorrhagic Diseases: Evidence of hemorrhagic stroke, epidural hematoma, subarachnoid hemorrhage, or other bleeding disorders detected by head imaging (MRI/CT).However, hemorrhagic transformation may be assessed by the investigator for potential inclusion.
2. Severe Consciousness Disturbance: NIHSS item 1a score \>1 (indicative of significant impairment in consciousness).
3. Cortical Infarcts or Other Brain Abnormalities:Co-existing cortical infarcts, hydrocephalus, or other non-vascular white matter diseases (e.g., multiple sclerosis, carbon monoxide poisoning-related leukoencephalopathy).
4. Severe Carotid Artery Stenosis: Requiring surgical intervention (\>50% stenosis).
5. Systemic Conditions Affecting Cognition:Endocrine disorders, vitamin deficiencies, systemic autoimmune diseases that can cause cognitive impairment.
6. Neurological Disorders Associated with Cognitive Decline:CNS infections, Creutzfeldt-Jakob disease, primary Parkinson's disease, epilepsy, brain tumors, or severe traumatic brain injury.
7. Pre-existing Severe Psychiatric Disorders:Diagnosed with major depressive disorder, vascular cognitive impairment, Alzheimer's disease, Parkinson's disease dementia, Lewy body dementia, frontotemporal dementia, or any cognitive dysfunction unrelated to stroke.
8. Severe Physical Disability or Language Impairment:Severe hemiplegia or aphasia that significantly affects cognitive assessment.
9. Use of Cognitive-Enhancing Medications:Within 4 weeks prior to screening, including but not limited to:Cholinesterase inhibitors (donepezil, rivastigmine, galantamine), NMDA receptor antagonists (memantine),Other neuroprotective agents (sodium oligomannate, lecanemab)
10. Severe Liver or Kidney Dysfunction:Active liver disease (acute hepatitis, chronic active hepatitis, cirrhosis) or ALT/AST \>2× ULN.
11. Severe renal impairment (serum creatinine \>1.5× ULN).
12. Life Expectancy \<1 year due to severe systemic diseases.
13. Contraindications to MRI:Participants with MRI-incompatible implants, severe claustrophobia, or inability to undergo MRI.
14. Known Allergies:History of hypersensitivity to Dexborneol, natural borneol, edaravone, or any excipients (e.g., mannitol, copovidone, microcrystalline cellulose, silica, magnesium stearate).
15. Pregnancy and Lactation:Pregnant or lactating women, or those planning pregnancy during the study period.
16. Participation in Other Clinical Trials:Enrolled in another clinical trial within the last 30 days.
17. Other Investigator-Determined Factors:Any other medical, psychological, or social condition that, in the investigator's judgment, makes the patient unsuitable for participation.

Primary outcomes:
measure: Hierarchical Composite Endpoint
timeFrame: 24 weeks
measure: All-Cause Mortality
timeFrame: 24weeks
measure: Modified Rankin Scale (mRS) Score ≥2
timeFrame: 24 weeks
measure: Stroke Recurrence
timeFrame: 24 weeks
measure: Change in Montreal Cognitive Assessment (MoCA) Score from Baseline
timeFrame: 24 weeks
measure: Change in Vascular Dementia Assessment Scale-Cognitive Subscale (VaDAS-Cog) Score from Baseline
timeFrame: 24 weeks
Secondary outcomes:
measure: All cause mortality
timeFrame: 24 weeks
measure: Modified Rankin Scale (mRS) Score ≥2
timeFrame: 24 weeks
measure: Stroke recurrence
timeFrame: 24 weeks
measure: Post-stroke cognitive impairment
timeFrame: 24 weeks
measure: Cognitive function (MMSE)
timeFrame: 24 weeks
measure: Cognitive function (MoCA)
timeFrame: 24 weeks
measure: Cognitive function (VaDAS-Cog)
timeFrame: 24 weeks
measure: Depression (HAMD)
timeFrame: 24 weeks
measure: Activity of Daily Living
timeFrame: 24 weeks
measure: Adverse events
timeFrame: 24 weeks
measure: Serious adverse events
timeFrame: 24 weeks
measure: Liver function impairment
timeFrame: 24 weeks
measure: Renal function impairment
timeFrame: 24 weeks
measure: Change in White Matter Hyperintensity Fazekas Score from Baseline
timeFrame: 52 weeks
measure: Number of New MRI-Confirmed Infarcts
timeFrame: 52 weeks
measure: Change in Number of Microbleeds from Baseline
timeFrame: 52 weeks
measure: Change in White Matter Hyperintensity Volume from Baseline
timeFrame: 52 weeks
measure: Change in Brain Atrophy Index from Baseline
timeFrame: 52 weeks
Other outcomes:
Locations:
Study officials:
References:
citation: Fu Y, Wang A, Tang R, Li S, Tian X, Xia X, Ren J, Yang S, Chen R, Zhu S, Feng X, Yao J, Wei Y, Dong X, Ling Y, Yi F, Deng Q, Guo C, Sui Y, Han S, Wen G, Li C, Dong A, Sun X, Wang Z, Shi X, Liu B, Fan D. Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial. JAMA Neurol. 2024 Feb 19;81(4):319-26. doi: 10.1001/jamaneurol.2023.5716. Online ahead of print.
citation: Xu J, Wang Y, Wang A, Gao Z, Gao X, Chen H, Zhou J, Zhao X, Wang Y. Safety and efficacy of Edaravone Dexborneol versus edaravone for patients with acute ischaemic stroke: a phase II, multicentre, randomised, double-blind, multiple-dose, active-controlled clinical trial. Stroke Vasc Neurol. 2019 Apr 22;4(3):109-114. doi: 10.1136/svn-2018-000221. eCollection 2019 Sep.
citation: Xu J, Wang A, Meng X, Yalkun G, Xu A, Gao Z, Chen H, Ji Y, Xu J, Geng D, Zhu R, Liu B, Dong A, Mu H, Lu Z, Li S, Zheng H, Chen X, Wang Y, Zhao X, Wang Y; TASTE Trial Investigatorsdagger. Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke: A Phase III, Randomized, Double-Blind, Comparative Trial. Stroke. 2021 Mar;52(3):772-780. doi: 10.1161/STROKEAHA.120.031197. Epub 2021 Feb 16.