Non-invasive TRanscutaneous Cervical Vagus Nerve Stimulation as a Treatment for Acute Stroke; Safety and Feasibility Study (TR-VENUS)

This study aims to determine safety and feasibility of non-invasive transcutaneous cervical Vagus nerve stimulation (nVNS) when delivered promptly after clinical diagnosis of acute stroke. Vagus nerve stimulation will be performed via GammaCore® device. A total of 60 patients will be randomized to each of 3 different groups; 'standard dose' vagal stimulation, 'high dose' vagal stimulation, and 'sham stimulation' (1:1:1 ratio). Adverse device events, serious adverse device events, and feasibility of vagal nerve stimulation at the setting of acute stroke will be evaluated. The study will be performed in a multi-center fashion among stroke centers within TurkStrokeNet Network.

Study Overview

• Status: Completed
• Conditions: Stroke; Stroke, Ischemic; Stroke, Acute; Stroke, Hemorrhagic
• Intervention / Treatment: Device: Gammacore device; Device: Gammacore sham device

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Turkey
  • Ankara, Turkey
    • Ankara University Faculty of Medicine
  • Ankara, Turkey
    • Gazi University Faculty of Medicine
  • Ankara, Turkey
    • Hacettepe University Faculty of Medicine
  • Antalya, Turkey
    • Akdeniz University
  • Eskişehir, Turkey
    • Eskişehir Osmangazi Faculty of Medicine
  • Konya, Turkey
    • Necmettin Erbakan University
  • Konya, Turkey
    • Selcuk University
  • Samsun, Turkey
    • Ondokuz Mayıs University Faculty of Medicine

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:

• Male or female patients who are older than 18 years old who have been admitted to neurological intensive care or stroke units with ischemic or hemorrhagic stroke
• Patients with symptom onset time within 6 hours or with unknown time of onset and no evidence of acute ischemia on fluid attenuation inversion recovery (FLAIR) imaging
• Patients who have given written informed consent prior to undertaking any study-related procedure.

Exclusion Criteria:

• Patients who have a pre-stroke disability ≥ 2 according to the modified Rankin Score
• Patients who have a NIH Stroke Scale/Score (NIHSS) ≤ 4 or ≥30
• Patients who have a NIHSS item 1a ≥2
• Patients who have experienced early dramatic neurological improvement (NIHSS score improvement ≥8) prior to study randomization suggesting resolution of signs/symptoms of stroke
• Patients with classical lacunar syndrome
• Patients who have local infection, rash or space occupying lesion at the stimulation site
• Patients with a prior injury to the vagus nerve (cervical vagotomy)
• Patients with conditions that make the positioning of the device not possible such as tonic head deviation or involuntary movements of the head and neck
• Patients using medications that can interfere with central neurotransmitter mechanisms potentially involved in the central vagal pathway (complete list is provided below under concomitant medications)
• Patients with known severe (>90% stenosis) bilateral carotid artery disease
• Patients with known carotid hypersensitivity
• Patients who had undergone bilateral carotid endarterectomy or neck surgery involving the region of carotid triangle
• Patients who have low blood pressure (Baseline SBP≤100 mmHg or DBP≤60 mmHg)
• Patients who have slow heart rate (Baseline HR≤60/min)
• Patients who have high blood pressure (SBP>220 mmHg or DBP>130 mmHg) despite initial line of treatment
• Patients who have been involved in any investigational study within the previous 90 days
• Patients who have any terminal illness such that the patient would not be expected to survive more than 90 days
• Pregnant women
• Patients with severe hypoglycemia at admission (<60 mg/dl)
• Patient experiencing seizures
• Patients with baseline ECG showing first-degree AV block; second- or third-degree atrio-ventricular block with no pacemaker/ICD in place; or ventricular tachycardia/fibrillation
• Patients with digitalis toxicity
• Patients who are suspected to have an acute coronary syndrome after clinical evaluations (Clinical, ECG, or any related biomarker)
• Patients who are scheduled to have an emergent carotid artery angioplasty stenting or endarterectomy
• Patients implanted with an electrical and/or neurostimulator device, including but not limited to cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator, or cochlear implant.
• Patients implanted with metal cervical spine hardware or having a metallic implant near the GammaCore stimulation site.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard dose vagal stimulation; A total of 7 consecutive 2-minute trains at every 10 minutes for one hour (n=20)	Device: Gammacore device; Transcutaneous stimulation of vagus nerve with the device positioned below the mandibular angle, medial to the sternocleidomastoid muscle and lateral to the larynx.
Active Comparator: High dose vagal stimulation; A total of 7 consecutive 2-minute trains applied at every 10 minutes for one hour that is followed by an additional 7 consecutive 2-minute trains interspersed at every 10 minutes applied 3 hours after completion of the initial scheme (n=20)	Device: Gammacore device; Transcutaneous stimulation of vagus nerve with the device positioned below the mandibular angle, medial to the sternocleidomastoid muscle and lateral to the larynx.
Sham Comparator: Sham stimulation; A total of 7 consecutive 2-minute trains at every 10 minutes for one hour (n=20)	Device: Gammacore sham device; Sham device which does not deliver electrical stimulation, but instead, produces a buzzing sound will be placed along the lateral border of the sternocleidomastoid muscle in order to avoid mechanical stimulation of the vagus nerve in the carotid triangle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular effects, clinical worsening or death (primary safety measure)	any of the following: severe bradycardia (HR ≤50/min) during treatment application; significant decrease in arterial blood pressure (≥20 mmHg decrease in mean arterial blood pressure) during treatment application; neurological worsening (progression of neurologic deficit as shown by ≥ 4 points increase in NIH Stroke Scale Score) within 24 hours; death within 24 hours	24 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of treatment eligible patients (feasibility measure 1)	Proportion of eligible patients in whom nVNS can be started within the first 6 hours.	6 hours
Proportion of patients completing all pre-specified treatment doses (feasibility measure 2)	Proportion of enrolled patients who receive all the pre-specified treatment doses per protocol.	12 hours
Stroke onset to treatment time (feasibility measure 3)	Time from stroke onset to administration of the first dose of nVNS.	6 hours
Early neurological outcome (efficacy measure 1)	Proportion of patients with NIHSS score≤4 or improvement of baseline NIHSS score ≥8 at 24 hours	24 hours
Early tissue outcome (efficacy measure 2)	Delta infarct volume between baseline DWI and 24 hr MRI.	24 hours
Local reaction at application site (secondary safety measure 1)	Local irritation or skin reaction during treatment application	12 hours
Acute coronary syndrome (secondary safety measure 2)	Acute coronary syndrome	24 hours
Symptomatic intracerebral hemorrhage (secondary safety measure 3)	Symptomatic intracerebral hemorrhage: ≥ 4 points increase in NIH Stroke Scale Score (NIHSS) together with a PH2 (parenchymal hematoma-2) type intracerebral hemorrhage	24 hours
Death, clinical worsening, and acute coronary syndrome (secondary safety measure 4)	Combined outcome of death, clinical worsening, and acute coronary syndrome	24 hours
New ischemic lesion or increase in hemorrhage (secondary safety measure 5)	New, spatially distinct remote ischemic lesion outside the arterial territory of the index lesion on MRI at 24 hours or greater than 30% increase in hemorrhage volume from baseline CT to 24 hour MRI in the subset with intracerebral hemorrhage	24 hours
Serious adverse device event (SADE) rate (secondary safety measure 6)	Serious adverse device event (SADE) rate at 24 hours	24 hours

Collaborators and Investigators

• Sponsor: Turkish Stroke Research and Clinical Trials Network
• Collaborators: ElectroCore INC; Turkish Neurological Society
• Investigators: Principal Investigator: Ethem M Arsava, MD, Hacettepe University; Principal Investigator: Mehmet A Topcuoglu, MD, Hacettepe University; Study Chair: Hakan Ay, MD, Massachusetts General Hospital, Harvard University

Publications and helpful links

General Publications

• Arsava EM, Topcuoglu MA, Ay I, Ozdemir AO, Gungor IL, Togay Isikay C, Nazliel B, Kozak HH, Ozturk S, Yilmaz IA, Dora B, Ay H; TR-VENUS investigators. Assessment of safety and feasibility of non-invasive vagus nerve stimulation for treatment of acute stroke. Brain Stimul. 2022 Nov-Dec;15(6):1467-1474. doi: 10.1016/j.brs.2022.10.012. Epub 2022 Nov 7.

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2019
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): April 1, 2021

Study Registration Dates

• First Submitted: November 3, 2018
• First Submitted That Met QC Criteria: November 6, 2018
• First Posted (Actual): November 7, 2018

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: October 4, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: vagal nerve stimulation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Hemorrhagic Stroke
• Other Study ID Numbers: TR-VENUS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

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