Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke

Study Overview
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Brief Summary
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The main objective of the study will be to investigate whether treatment with non-invasive vagus nerve stimulation (nVNS) on top of best medical practice in acute ischemic stroke patients results in less infarct growth in the penumbra and smaller infarct volumes compared with those of patients not treated with nVNS. The study will be a prospective randomized clinical trial with blinded outcome assessment (PROBE design). 150 patients will be randomized to nVNS with the gammaCore Sapphire™ device on top of best medical practice versus best medical practice alone (including intravenous thrombolysis and/or thrombectomy if indicated). If patients are randomized to nVNS, two stimulations of two minutes each will be applied in the neck every 15 minutes in the first 3 hours. Thereafter two stimulations will be applied every 8 hours over the next 5 days or until discharge, whichever occurs first. The stimulation side in the neck will be the radiological side of the stroke. The primary endpoint will be the final infarct volume on MRI scan on day 5 of patients treated with nVNS compared with those of patients not treated with VNS.

Official Title
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Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Device: non-invasive Vagus Nerve Stimulator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ischemic stroke NIHSS ≥1 Perfusion deficit on the admission CTP scan; the penumbra must comprise at least 1/3 of the total ischemic area (ischemic core and penumbra) The infarct has to comprise the anterior circulation Treatment has to start <12 hours after stroke onset Patients or their representatives need to give their informed consent Exclusion Criteria: A life expectancy of less than three months mRS >2 prior to admission Contra-indication for contrast CT Contra-indications for VNS: An active implantable medical device such as a pacemaker, deep brain stimulator, or any implanted electronic device Symptomatic stenosis or dissection of the carotid artery (in these patients the other side will be stimulated unless a significant stenosis on the other side is present as well) Structural abnormality e.g. lymphadenopathy, previous surgery or abnormal anatomy (in these patients the other side will be stimulated) Metal cervical spine hardware or metallic implant near the stimulation site Cervical vagotomy (in these patients the other side will be stimulated) Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: non-invasive Vagus Nerve Stimulation<br>non-invasive Vagus Nerve Stimulation on top of best medical practice | Device: non-invasive Vagus Nerve Stimulator<br>* Two stimulations of two minutes each will be applied in the neck every 15 minutes in the first 3 hours. Thereafter two stimulations will be applied every 8 hours over the next 5 days or until discharge, whichever occurs first. The stimulation side in the neck will be the radiological side of the stroke.<br>|
| No Intervention: Standard Care<br>Best medical practice alone | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infarct volume | Final infarct volume on MRI scan | On day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of nVNS | Reached if more than 75% of the nVNS treated patients complete treatment for five days or until discharge | On day 5 | 
| Tolerability of nVNS | Reached if less than 10% of the patients treated with nVNS has to abort treatment due to side effects | On day 5 | 
| NIHSS (National Institutes of Health Stroke Scale) on day 5 | The scale runs from 0-42 and quantifies stroke severity | On day 5 | 
| Clinical outcome (modified Rankin Scale, mRS) on day 90 | The scale runs from 0-6 and quantifies disabilities: 0 - No symptoms - No significant disability. Able to carry out all usual activities, despite some symptoms - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities - Moderate disability. Requires some help, but able to walk unassisted - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted - Severe disability. Requires constant nursing care and attention, bedridden, incontinent - Dead | On day 90 | 
| Occurrence of seizures in the first 90 days | This will be asked to patients and their physician | On day of admission, day 5 and day 90 | 
| Occurrence of headache in the first 90 days | A questionnaire will be taken adjusted from van Os et al., neurology 2016 | On day of admission, day 5 and day 90 | 
| Occurrence of depression in the first 90 days | HADS (Hospital Anxiety and Depression Scale) questionnaire will be taken. The scale runs from 0-21 and defines the risk of having a depression | On day 90 | 
| Quality of life after 90 days | EQ5D-5L questionnaire will be taken. This questionnaire defines a health index based on different questions | On day 90 | 
| Cognitive status on day 90 | TICS questionnaire will be taken. This questionnaire can assess cognitive status. | On day 90 | 
| Penumbra recovery | Proportion of patients in whom <50% of the penumbra turned into ischemic core on non-contrast CT | On day 3 | 
| Blood-brain barrier measurement | Degree of blood-brain barrier leakage on day three measured with CTP | On day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain infarction, Brain ischemia, Vagus nerve stimulation, Penumbra