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Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke (NOVIS)

Primary Purpose

Ischemic Stroke

Status
Recruiting
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
non-invasive Vagus Nerve Stimulator
Sponsored by
Leiden University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ischemic Stroke focused on measuring Brain infarction, Brain ischemia, Vagus nerve stimulation, Penumbra

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Leiden University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

No Intervention

Arm Label

non-invasive Vagus Nerve Stimulation

Standard Care

Arm Description

non-invasive Vagus Nerve Stimulation on top of best medical practice

Best medical practice alone

Outcomes

Primary Outcome Measures

Infarct volume
Final infarct volume on MRI scan

Secondary Outcome Measures

Feasibility of nVNS
Reached if more than 75% of the nVNS treated patients complete treatment for five days or until discharge
Tolerability of nVNS
Reached if less than 10% of the patients treated with nVNS has to abort treatment due to side effects
NIHSS (National Institutes of Health Stroke Scale) on day 5
The scale runs from 0-42 and quantifies stroke severity
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
Occurrence of seizures in the first 90 days
This will be asked to patients and their physician
Occurrence of headache in the first 90 days
A questionnaire will be taken adjusted from van Os et al., neurology 2016
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
Quality of life after 90 days
EQ5D-5L questionnaire will be taken. This questionnaire defines a health index based on different questions
Cognitive status on day 90
TICS questionnaire will be taken. This questionnaire can assess cognitive status.
Penumbra recovery
Proportion of patients in whom <50% of the penumbra turned into ischemic core on non-contrast CT
Blood-brain barrier measurement
Degree of blood-brain barrier leakage on day three measured with CTP

Full Information

First Posted
August 5, 2019
Last Updated
March 31, 2023
Sponsor
Leiden University Medical Center
Collaborators
Netherlands Organisation for Scientific Research, ElectroCore INC
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1. Study Identification

Unique Protocol Identification Number
NCT04050501
Brief Title
Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke
Acronym
NOVIS
Official Title
Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 9, 2019 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University Medical Center
Collaborators
Netherlands Organisation for Scientific Research, ElectroCore INC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Stroke
Keywords
Brain infarction, Brain ischemia, Vagus nerve stimulation, Penumbra

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Masking Description
PROBE design
Allocation
Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
non-invasive Vagus Nerve Stimulation
Arm Type
Active Comparator
Arm Description
non-invasive Vagus Nerve Stimulation on top of best medical practice
Arm Title
Standard Care
Arm Type
No Intervention
Arm Description
Best medical practice alone
Intervention Type
Device
Intervention Name(s)
non-invasive Vagus Nerve Stimulator
Intervention Description
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 Outcome Measure Information:
Title
Infarct volume
Description
Final infarct volume on MRI scan
Time Frame
On day 5
Secondary Outcome Measure Information:
Title
Feasibility of nVNS
Description
Reached if more than 75% of the nVNS treated patients complete treatment for five days or until discharge
Time Frame
On day 5
Title
Tolerability of nVNS
Description
Reached if less than 10% of the patients treated with nVNS has to abort treatment due to side effects
Time Frame
On day 5
Title
NIHSS (National Institutes of Health Stroke Scale) on day 5
Description
The scale runs from 0-42 and quantifies stroke severity
Time Frame
On day 5
Title
Clinical outcome (modified Rankin Scale, mRS) on day 90
Description
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
Time Frame
On day 90
Title
Occurrence of seizures in the first 90 days
Description
This will be asked to patients and their physician
Time Frame
On day of admission, day 5 and day 90
Title
Occurrence of headache in the first 90 days
Description
A questionnaire will be taken adjusted from van Os et al., neurology 2016
Time Frame
On day of admission, day 5 and day 90
Title
Occurrence of depression in the first 90 days
Description
HADS (Hospital Anxiety and Depression Scale) questionnaire will be taken. The scale runs from 0-21 and defines the risk of having a depression
Time Frame
On day 90
Title
Quality of life after 90 days
Description
EQ5D-5L questionnaire will be taken. This questionnaire defines a health index based on different questions
Time Frame
On day 90
Title
Cognitive status on day 90
Description
TICS questionnaire will be taken. This questionnaire can assess cognitive status.
Time Frame
On day 90
Title
Penumbra recovery
Description
Proportion of patients in whom <50% of the penumbra turned into ischemic core on non-contrast CT
Time Frame
On day 3
Title
Blood-brain barrier measurement
Description
Degree of blood-brain barrier leakage on day three measured with CTP
Time Frame
On day 3

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anne van der Meij, PhD
Phone
0031715261899
Email
novis@lumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Marieke JH Wermer, MD PhD
Phone
0031715262197
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marieke JH Wermer, MD PhD
Organizational Affiliation
Leiden University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Leiden University Medical Center
City
Leiden
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marieke JH Wermer, MD PhD
Phone
0031715262197
Email
m.j.h.wermer@lumc.nl
First Name & Middle Initial & Last Name & Degree
Anne van der Meij, MD
Phone
0031715262197
Email
a.van_der_meij@lumc.nl

12. IPD Sharing Statement

Citations:
PubMed Identifier
33106174
Citation
van der Meij A, van Walderveen MAA, Kruyt ND, van Zwet EW, Liebler EJ, Ferrari MD, Wermer MJH. NOn-invasive Vagus nerve stimulation in acute Ischemic Stroke (NOVIS): a study protocol for a randomized clinical trial. Trials. 2020 Oct 26;21(1):878. doi: 10.1186/s13063-020-04794-1.
Results Reference
derived

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Non-invasive Vagus Nerve Stimulation in Acute Ischemic Stroke

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