Safety, Feasibility, and Efficacy of Non-invasive Vagus Nerve Stimulation (nVNS) in the Treatment of Aneurysmal Subarachnoid Hemorrhage

Study Overview
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Brief Summary
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This is a single-site, single-arm, open-label pilot study assessing the safety, feasibility, and efficacy of non-invasive vagus nerve stimulation (nVNS), gammaCore, for the acute treatment of aneurysmal subarachnoid hemorrhage (SAH) subjects in a neurocritical care setting. 25 patients will be enrolled, all treated with an active device. The primary efficacy outcomes are reduced aneurysm rupture rate, reduced seizure and seizure-spectrum activity, minimized hemorrhage grades, and increased survival.

Detailed Description
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This is a single-site, single-arm, open-label pilot study assessing the safety, feasibility, and efficacy of non-invasive vagus nerve stimulation (nVNS), gammaCore, for the acute treatment of aneurysmal subarachnoid hemorrhage (SAH). The hypothesis is that two 2-minute non-invasive stimulations of the cervical branch of the vagus nerve with nVNS, 3 times daily (TID), is a safe, practical, and potentially effective treatment after SAH in the neurocritical care setting. After diagnosis and surgical repair of the SAH, patients admitted to the Neuroscience Intensive Care Unit (NeuroICU) at Massachusetts General Hospital (MGH) will be screened for eligibility. Upon providing informed consent, eligible patients will be enrolled, begin the treatment protocol, and will be monitored. Data collection will be completed using automated systems, electronic reports, and manual collection before, during, and after nVNS. The primary objective is to examine the safety, feasibility, and possible efficacy of nVNS as a treatment after aneurysmal subarachnoid hemorrhage (SAH). Safety will be assessed by the incidence of severe adverse device events (SADEs) following nVNS. Feasibility of the nVNS implementation will be evaluated by the ability to deliver >85% of doses per protocol, report of minimal interference with current standard of care treatments and procedures in in the NeuroICU, and beginning of treatment within 72 hours of presumed aneurysm rupture. Efficacy of nVNS will be explored using the following assessments: subject disability measured using mRS at 10 days (or discharge) and 90 days after SAH effects on EEG, TCD, and ICP before, during, and after nVNS DCI/ischemic stroke detected by CT scans and/or angiography HR (heart rate), HR variability, and BP before, during, and after nVNS The study period starts within 72 hours of presumed aneurysm rupture and ends at 10 days or discharge, if sooner. The PI and co-investigators will conduct safety monitoring of this small, single-site, low-risk pilot study on a continuous basis, ensuring adherence to the Mass General Brigham (MGB) Institutional Review Board (IRB) guidelines accordingly.

Official Title
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STORM: Safety, Feasibility, and Efficacy of Non-invasive Vagus Nerve Stimulation (nVNS) in the Treatment of Aneurysmal Subarachnoid Hemorrhage

Conditions
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Subarachnoid Hemorrhage, Aneurysmal

Intervention / Treatment
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* Device: gammaCore


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18-85 years of age Ruptured aneurysmal SAH confirmed by angiography and repaired by neurosurgical clipping or endovascular occlusion (coiling) Modified Glasgow Coma Scale (mGCS) score ≥ 10 and Hunt Hess 1-4 within 72 hours of presumed aneurysm rupture Enrollment and initiation of nVNS treatment must occur within 72 hours of presumed aneurysm rupture Provide a legally obtained informed consent form from the participant or the legally authorized representative (LAR); telephonic consent is acceptable Female participants of reproductive age must have a negative pregnancy test result (urine or blood) Exclusion Criteria: Use of any concomitant electrostimulation device, including a pacemaker, defibrillator, or deep brain stimulator No plan to secure aneurysm, defined as aneurysm that has not been surgically or endovascularly treated Previous neck dissection or radiation History of carotid artery disease or carotid surgery/dissection History of secondary or tertiary heart blocks, ventricular tachycardia, or supraventricular tachycardia (SVT; including atrial fibrillation) Screws, metals, or devices in the neck Currently participating in an investigational drug or device clinical trial with potential to confound data collection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>The gammaCore device supplies non-invasive stimulation to the cervical branch of the vagus nerve. | Device: gammaCore<br>* Participants will receive two 2-minute non-invasive stimulations to the cervical branch of the vagus nerve (nVNS) three times daily with gammaCore, an FDA cleared device for the acute treatment and prevention of migraine and cluster headache. Intervention will begin within 72 hours post-rupture and end at 10 days post-rupture or discharge, whichever occurs first. The dosing regimen is supported by preclinical models and clinical data.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The presentation of severe adverse device events (SADEs) within 30 minutes of nVNS first treatment dose. | The rate of serious adverse events, such as bradycardia, hypotension, and decline in modified Glasgow Coma Scale grade. Events are determined through continuous monitoring of vital signs, including but not limited to: blood pressure, O2 saturation, heart rate, routine blood work, EKG, and alarm trigger frequency. | up to 10 days post-rupture | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The feasibility of nVNS in SAH subjects in the critical care setting. | The ability to deliver >85% of nVNS doses as scheduled, report of interference with NeuroICU standard of care, and nVNS initiation within 72 hours of enrollment. | up to 10 days post-rupture | 
| The frequency of alarm triggers peri-nVNS. | The monitoring of alarm trigger frequency due to significant clinical decline in blood pressure, O2 saturation, and EKG. The multiple alarm triggers will be aggregated to report one value, the frequency of total alarm triggers peri-nVNS. | up to 10 days post-rupture | 
| The measure of subject disability using a modified Rankin Score at baseline, intervention completion (10 days), and follow up (90 days). | The clinician will document a modified Rankin Score (mRS) at baseline, intervention completion at 10 days or discharge, and follow up at 90 days. A modified Rankin Score (mRS) is on a scale from 0-6 and is used to measure the level of disability after subarachnoid hemorrhage (SAH) or other neurological injury. The score increases as the level of disability and need for continuous care increases. A score of 0 indicates that a patient has no residual symptoms, while a score of 6 indicates that a patient has died. | at 10 days and 90 days post-rupture | 
| The rate of established predictors of delayed cerebral ischemia (DCI) and outcome. | The rate of DCI related events such as seizure, vasospasm, elevated intracranial pressure (ICP), heart rate variability, and blood pressure variability. These events are monitored by electroencephalogram (EEG), angiography, transcranial doppler (TCD) ultrasound, computerized tomography (CT), and medical record review. | up to 10 days post-rupture | 
| The occurrence of ischemic complications. | Delayed cerebral ischemia (DCI) and ischemic stroke will be detected by routine CT scans and/or angiography. | up to 10 days post-rupture | 
| The self-reported assessment for the quality of life of patients with neurological disorders at follow up (90 days). | The Quality of Life in Neurological Disorders (NeuroQOL Cognitive 6a) assessment is a self-reported 6-question survey to score the health-related quality of life of patients with neurological disorders. Questions are answered on a scale from 1 to 5. A score of 1 is considered a poor self-assessment, while a score of 5 is very good. The NeuroQOL Cognitive 6a assessment will be completed by each participant at follow up, 90 days post-rupture. | at 90 days post-rupture | 
| The self-reported assessment for physical, mental, and social health at follow up (90 days). | The Patient-Reported Outcomes Measurement Information System (PROMIS-10 Global) self-assessment is a 10-question survey that evaluates physical, mental, and social health of patients. Self-assessment scores range from 1 to 5 or 0 to 10. A score of 1 is considered a poor self-assessment, while a score of 5 is excellent. A score of 0 is considered no pain, while a score of 10 is the worst pain imaginable. The PROMIS-10 Global assessment will be completed by each participant at follow up, 90 days post-rupture. | at 90 days post-rupture | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aneurysm, Hemorrhage, Intracranial Hemorrhages, Cerebrovascular Disorders, Intracranial Aneurysm, Vascular Diseases, Aneurysm, Brain, Brain Diseases, Central Nervous System Diseases, Aneurysm, Ruptured