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

• Sponsor: Turkish Stroke Research and Clinical Trials Network
• Collaborators: Turkish Neurological Society; ElectroCore INC
• Information provided by (Responsible Party): Ethem Murat Arsava, Hacettepe University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Stroke, Acute; Stroke, Ischemic; Stroke; Stroke, Hemorrhagic	Device: Gammacore device; Device: Gammacore sham device	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Other
• Official Title: Non-invasive TRanscutaneous Cervical Vagus Nerve Stimulation as a Treatment for Acute Stroke; Safety and Feasibility Study
• Estimated Study Start Date: March 2019
• Estimated Primary Completion Date: October 2019
• Estimated Study Completion Date: December 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Cardiovascular effects, clinical worsening or death (primary safety measure) [ Time Frame: 24 hours ]

   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

Other Outcome Measures:

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Ethem M Arsava, MD; 00905323355172; arsavaem@hotmail.com

Contact: Mehmet A Topcuoglu, MD; 00905365753634; matopcuoglu@yahoo.com

Sponsors and Collaborators

Turkish Stroke Research and Clinical Trials Network

Turkish Neurological Society

ElectroCore INC

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

More Information

• Responsible Party: Ethem Murat Arsava, Professor of Neurology, Hacettepe University
• ClinicalTrials.gov Identifier: NCT03733431 History of Changes
• Other Study ID Numbers: TR-VENUS
• First Posted: November 7, 2018
• Last Update Posted: February 1, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: No
• Pediatric Postmarket Surveillance of a Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Ethem Murat Arsava, Hacettepe University:

vagal nerve stimulation

Additional relevant MeSH terms:

Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases