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
About this trial
This is an interventional other trial for Stroke, Acute focused on measuring vagal nerve stimulation
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.
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
NCT ID
NCT03733431
First Posted
November 3, 2018
Last Updated
October 4, 2021
Sponsor
Turkish Stroke Research and Clinical Trials Network
Collaborators
Turkish Neurological Society, ElectroCore INC
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
Learn more about this trial
Non-invasive TRanscutaneous Cervical Vagus Nerve Stimulation as a Treatment for Acute Stroke; Safety and Feasibility Study
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