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

Primary Purpose

Stroke, Acute, Stroke, Ischemic, Stroke

Status
Completed
Phase
Not Applicable
Locations
Turkey
Study Type
Interventional
Intervention
Gammacore device
Gammacore sham device
Sponsored by
Turkish Stroke Research and Clinical Trials Network
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Stroke, Acute focused on measuring vagal nerve stimulation

Eligibility Criteria

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

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.

Sites / Locations

  • Ankara University Faculty of Medicine
  • Gazi University Faculty Of Medicine
  • Hacettepe University Faculty of Medicine
  • Akdeniz University
  • Eskişehir Osmangazi Faculty of Medicine
  • Necmettin Erbakan University
  • Selcuk University
  • Ondokuz Mayıs University Faculty of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Sham Comparator

Arm Label

Standard dose vagal stimulation

High dose vagal stimulation

Sham stimulation

Arm Description

A total of 7 consecutive 2-minute trains at every 10 minutes for one hour (n=20)

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)

A total of 7 consecutive 2-minute trains at every 10 minutes for one hour (n=20)

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Full Information

First Posted
November 3, 2018
Last Updated
October 4, 2021
Sponsor
Turkish Stroke Research and Clinical Trials Network
Collaborators
Turkish Neurological Society, ElectroCore INC
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1. Study Identification

Unique Protocol Identification Number
NCT03733431
Brief Title
Non-invasive TRanscutaneous Cervical Vagus Nerve Stimulation as a Treatment for Acute Stroke; Safety and Feasibility Study
Acronym
TR-VENUS
Official Title
Non-invasive TRanscutaneous Cervical Vagus Nerve Stimulation as a Treatment for Acute Stroke; Safety and Feasibility Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
May 10, 2019 (Actual)
Primary Completion Date
December 31, 2020 (Actual)
Study Completion Date
April 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Turkish Stroke Research and Clinical Trials Network
Collaborators
Turkish Neurological Society, 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stroke, Acute, Stroke, Ischemic, Stroke, Stroke, Hemorrhagic
Keywords
vagal nerve stimulation

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
69 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard dose vagal stimulation
Arm Type
Active Comparator
Arm Description
A total of 7 consecutive 2-minute trains at every 10 minutes for one hour (n=20)
Arm Title
High dose vagal stimulation
Arm Type
Active Comparator
Arm Description
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)
Arm Title
Sham stimulation
Arm Type
Sham Comparator
Arm Description
A total of 7 consecutive 2-minute trains at every 10 minutes for one hour (n=20)
Intervention Type
Device
Intervention Name(s)
Gammacore device
Intervention Description
Transcutaneous stimulation of vagus nerve with the device positioned below the mandibular angle, medial to the sternocleidomastoid muscle and lateral to the larynx.
Intervention Type
Device
Intervention Name(s)
Gammacore sham device
Intervention Description
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.
Primary Outcome Measure Information:
Title
Cardiovascular effects, clinical worsening or death (primary safety measure)
Description
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
Time Frame
24 hours
Other Pre-specified Outcome Measures:
Title
Proportion of treatment eligible patients (feasibility measure 1)
Description
Proportion of eligible patients in whom nVNS can be started within the first 6 hours.
Time Frame
6 hours
Title
Proportion of patients completing all pre-specified treatment doses (feasibility measure 2)
Description
Proportion of enrolled patients who receive all the pre-specified treatment doses per protocol.
Time Frame
12 hours
Title
Stroke onset to treatment time (feasibility measure 3)
Description
Time from stroke onset to administration of the first dose of nVNS.
Time Frame
6 hours
Title
Early neurological outcome (efficacy measure 1)
Description
Proportion of patients with NIHSS score≤4 or improvement of baseline NIHSS score ≥8 at 24 hours
Time Frame
24 hours
Title
Early tissue outcome (efficacy measure 2)
Description
Delta infarct volume between baseline DWI and 24 hr MRI.
Time Frame
24 hours
Title
Local reaction at application site (secondary safety measure 1)
Description
Local irritation or skin reaction during treatment application
Time Frame
12 hours
Title
Acute coronary syndrome (secondary safety measure 2)
Description
Acute coronary syndrome
Time Frame
24 hours
Title
Symptomatic intracerebral hemorrhage (secondary safety measure 3)
Description
Symptomatic intracerebral hemorrhage: ≥ 4 points increase in NIH Stroke Scale Score (NIHSS) together with a PH2 (parenchymal hematoma-2) type intracerebral hemorrhage
Time Frame
24 hours
Title
Death, clinical worsening, and acute coronary syndrome (secondary safety measure 4)
Description
Combined outcome of death, clinical worsening, and acute coronary syndrome
Time Frame
24 hours
Title
New ischemic lesion or increase in hemorrhage (secondary safety measure 5)
Description
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
Time Frame
24 hours
Title
Serious adverse device event (SADE) rate (secondary safety measure 6)
Description
Serious adverse device event (SADE) rate at 24 hours
Time Frame
24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ethem M Arsava, MD
Organizational Affiliation
Hacettepe University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mehmet A Topcuoglu, MD
Organizational Affiliation
Hacettepe University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hakan Ay, MD
Organizational Affiliation
Massachusetts General Hospital, Harvard University
Official's Role
Study Chair
Facility Information:
Facility Name
Ankara University Faculty of Medicine
City
Ankara
Country
Turkey
Facility Name
Gazi University Faculty Of Medicine
City
Ankara
Country
Turkey
Facility Name
Hacettepe University Faculty of Medicine
City
Ankara
Country
Turkey
Facility Name
Akdeniz University
City
Antalya
Country
Turkey
Facility Name
Eskişehir Osmangazi Faculty of Medicine
City
Eskişehir
Country
Turkey
Facility Name
Necmettin Erbakan University
City
Konya
Country
Turkey
Facility Name
Selcuk University
City
Konya
Country
Turkey
Facility Name
Ondokuz Mayıs University Faculty of Medicine
City
Samsun
Country
Turkey

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
36356829
Citation
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.
Results Reference
derived

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

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