Treatment of Acute Ischemic Stroke With Edaravone Dexborneol Sublingual Tablets in Small Vessel Disease (TASTE-SVD)

Treatment of Acute Ischemic Stroke With Edaravone Dexborneol Sublingual Tablets in Small Vessel Disease: A Randomized, Double-Blind, Placebo-Controlled Study

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.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke; Cerebral Small Vessel Disease
• Intervention / Treatment: Drug: Placebo; Drug: Edaravone Dexborneol Sublingual Tablets

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.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: YiCheng Zhu, Doctor; Phone Number: (+86)01069156380; Email: zhuych910@163.com

Study Locations

• China
  • Beijing, China
    • Recruiting
    • Peking Union Medical College Hospital
    • Contact: Fei Han; Phone Number: 8615101131416; Email: lourahan@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; One placebo tablet, to be taken sublingually, twice daily.	Drug: Placebo; One placebo tablet, to be taken sublingually, twice daily
Experimental: Edaravone Dexborneol Sublingual Tablets; One tablet of Edaravone Dexborneol Sublingual Tablet (containing 30mg Edaravone and 6mg Dexborneol) to be taken sublingually, twice daily.	Drug: Edaravone Dexborneol Sublingual Tablets; One tablet of Edaravone Dexborneol Sublingual Tablet (containing 30mg Edaravone and 6mg Dexborneol) to be taken sublingually, twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchical Composite Endpoint	This composite outcome consists of five hierarchical endpoints at 24 weeks, analyzed using the Win Ratio method: All-Cause Mortality; Modified Rankin Scale (mRS) Score ≥2; Stroke Recurrence; Change in Montreal Cognitive Assessment (MoCA) Score from Baseline; 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.	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.	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.	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	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.	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.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-stroke cognitive impairment	Number of participants with post-stroke cognitive impairment, defined as a MOCA score < 22	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.	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.	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.	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.	24 weeks
Adverse events	Adverse events, confirmed by the Clinical Event Committee.	24 weeks
Serious adverse events	Serious adverse events, confirmed by the Clinical Event Committee.	24 weeks
Liver function impairment	Number of participants with Alanine Aminotransferase level >2.0×upper limit of the normal	24 weeks
Renal function impairment	Number of participants with serum creatinine >1.5×upper limit of the normal.	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.	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.	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	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.	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.	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.	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.	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.	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	52 weeks
Composite endpoint	Composite endpoint comprising all-cause mortality, mRS ≥2, and stroke recurrence.	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.	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.	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	52 weeks
Post-stroke cognitive impairment	Number of participants with post-stroke cognitive impairment, defined as a MOCA score < 22	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.	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.	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.	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.	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	52weeks
Adverse events	Adverse events, confirmed by the Clinical Event Committee.	52weeks
Serious adverse events	Serious adverse events, confirmed by the Clinical Event Committee.	52weeks
Liver function impairment	Number of participants with Alanine Aminotransferase level >2.0×upper limit of the normal	52weeks
Renal function impairment	Number of participants with serum creatinine >1.5×upper limit of the normal.	52weeks
Composite endpoint	Composite endpoint comprising all-cause mortality, mRS ≥2, and stroke recurrence.	52weeks

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: October 23, 2024
• First Submitted That Met QC Criteria: November 3, 2024
• First Posted (Actual): November 5, 2024

Study Record Updates

• Last Update Posted (Estimated): September 26, 2025
• Last Update Submitted That Met QC Criteria: September 22, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: cognition; cerebral small vessel disease; sublingual edaravone dexborneol; acute ischemic cerebral small vessel disease
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke; Cerebral Small Vessel Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antioxidants; Protective Agents; Free Radical Scavengers; Neuroprotective Agents; Edaravone
• Other Study ID Numbers: TASTE-SVD; 2023ZD0504900 (Other Grant/Funding Number: National Science and Technology Major Project)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No