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

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.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke
• Intervention / Treatment: Device: non-invasive Vagus Nerve Stimulator

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne van der Meij, PhD; Phone Number: 0031715261899; Email: novis@lumc.nl
• Study Contact Backup: Name: Marieke JH Wermer, MD PhD; Phone Number: 0031715262197

Study Locations

• Netherlands
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
    • Contact: Marieke JH Wermer, MD PhD; Phone Number: 0031715262197; Email: m.j.h.wermer@lumc.nl
    • Contact: Anne van der Meij, MD; Phone Number: 0031715262197; Email: a.van_der_meij@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: non-invasive Vagus Nerve Stimulation; non-invasive Vagus Nerve Stimulation on top of best medical practice	Device: non-invasive Vagus Nerve Stimulator; 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.
No Intervention: Standard Care; Best medical practice alone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: ElectroCore INC; Netherlands Organisation for Scientific Research

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2019
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: August 5, 2019
• First Submitted That Met QC Criteria: August 7, 2019
• First Posted (Actual): August 8, 2019

Study Record Updates

• Last Update Posted (Actual): April 3, 2023
• Last Update Submitted That Met QC Criteria: March 31, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Vagus nerve stimulation; Brain infarction; Brain ischemia; Penumbra
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction
• Other Study ID Numbers: NL64702.058.18

Drug and device information, study documents

• 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