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Completed

NCT Number: NCT04050501

Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke

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.

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Key information

Conditions

Ischemic Stroke Brain Diseases Brain Infarction Brain Ischemia Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders Infarction Ischemia Necrosis Nervous System Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Stroke Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Leiden University Medical Center

Leiden, Netherlands

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

non-invasive Vagus Nerve Stimulator

Device

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.

Primary outcomes

  1. Infarct volume

    Time frame: On day 5

    Final infarct volume on MRI scan

Secondary outcomes

  1. Feasibility of nVNS

    Time frame: On day 5

    Reached if more than 75% of the nVNS treated patients complete treatment for five days or until discharge

  2. Tolerability of nVNS

    Time frame: On day 5

    Reached if less than 10% of the patients treated with nVNS has to abort treatment due to side effects

  3. NIHSS (National Institutes of Health Stroke Scale) on day 5

    Time frame: On day 5

    The scale runs from 0-42 and quantifies stroke severity

  4. Clinical outcome (modified Rankin Scale, mRS) on day 90

    Time frame: 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

  5. Occurrence of seizures in the first 90 days

    Time frame: On day of admission, day 5 and day 90

    This will be asked to patients and their physician

  6. Occurrence of headache in the first 90 days

    Time frame: On day of admission, day 5 and day 90

    A questionnaire will be taken adjusted from van Os et al., neurology 2016

  7. Occurrence of depression in the first 90 days

    Time frame: On day 90

    HADS (Hospital Anxiety and Depression Scale) questionnaire will be taken. The scale runs from 0-21 and defines the risk of having a depression

  8. Quality of life after 90 days

    Time frame: On day 90

    EQ5D-5L questionnaire will be taken. This questionnaire defines a health index based on different questions

  9. Cognitive status on day 90

    Time frame: On day 90

    TICS questionnaire will be taken. This questionnaire can assess cognitive status.

  10. Penumbra recovery

    Time frame: On day 3

    Proportion of patients in whom <50% of the penumbra turned into ischemic core on non-contrast CT

  11. Blood-brain barrier measurement

    Time frame: On day 3

    Degree of blood-brain barrier leakage on day three measured with CTP

Sponsors and collaborators

Lead sponsor

Leiden University Medical Center

Other

Collaborators

  • ElectroCore INC
  • Netherlands Organisation for Scientific Research

Registry information

Acronym: NOVIS

Important dates

Study start
2019
Primary completion
2023
Study completion
2025
First posted
Aug 8, 2019
Registry last updated
May 14, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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