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

NCT05103566 | Recruiting FDA Device

• 1 other identifier: 2021p002016
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Subarachnoid Hemorrhage, Aneurysmal

Keywords

Aneurysm; Hemorrhage; Intracranial Hemorrhages; Cerebrovascular Disorders; Intracranial Aneurysm; Vascular Diseases; Aneurysm, Brain; Brain Diseases; Central Nervous System Diseases; Aneurysm, Ruptured

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• The feasibility of nVNS in SAH subjects in the critical care setting.

  up to 10 days post-rupture

• The frequency of 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).

  at 10 days and 90 days post-rupture

• The rate of established predictors of delayed cerebral ischemia (DCI) and outcome.

  up to 10 days post-rupture

• The occurrence of ischemic complications.

  up to 10 days post-rupture

Study Arms (1)

Treatment group

EXPERIMENTAL

The gammaCore device supplies non-invasive stimulation to the cervical branch of the vagus nerve.

Device: gammaCore

Interventions

gammaCore DEVICE

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.

Treatment group

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• ElectroCore INC: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

Related Publications (21)

• Suzuki T, Takizawa T, Kamio Y, Qin T, Hashimoto T, Fujii Y, Murayama Y, Patel AB, Ayata C. Noninvasive Vagus Nerve Stimulation Prevents Ruptures and Improves Outcomes in a Model of Intracranial Aneurysm in Mice. Stroke. 2019 May;50(5):1216-1223. doi: 10.1161/STROKEAHA.118.023928.

  PMID: 30943885 BACKGROUND

• Rosenthal ES, Biswal S, Zafar SF, O'Connor KL, Bechek S, Shenoy AV, Boyle EJ, Shafi MM, Gilmore EJ, Foreman BP, Gaspard N, Leslie-Mazwi TM, Rosand J, Hoch DB, Ayata C, Cash SS, Cole AJ, Patel AB, Westover MB. Continuous electroencephalography predicts delayed cerebral ischemia after subarachnoid hemorrhage: A prospective study of diagnostic accuracy. Ann Neurol. 2018 May;83(5):958-969. doi: 10.1002/ana.25232. Epub 2018 May 16.

  PMID: 29659050 BACKGROUND

• Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G; European Stroke Organization. European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis. 2013;35(2):93-112. doi: 10.1159/000346087. Epub 2013 Feb 7.

  PMID: 23406828 BACKGROUND

• Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012 Jun;43(6):1711-37. doi: 10.1161/STR.0b013e3182587839. Epub 2012 May 3.

  PMID: 22556195 BACKGROUND

• Lissak IA, Zafar SF, Westover MB, Schleicher RL, Kim JA, Leslie-Mazwi T, Stapleton CJ, Patel AB, Kimberly WT, Rosenthal ES. Soluble ST2 Is Associated With New Epileptiform Abnormalities Following Nontraumatic Subarachnoid Hemorrhage. Stroke. 2020 Apr;51(4):1128-1134. doi: 10.1161/STROKEAHA.119.028515. Epub 2020 Mar 11.

  PMID: 32156203 BACKGROUND

• Lissak IA, Locascio JJ, Zafar SF, Schleicher RL, Patel AB, Leslie-Mazwi T, Stapleton CJ, Koch MJ, Kim JA, Anderson K, Rosand J, Westover MB, Kimberly WT, Rosenthal ES. Electroencephalography, Hospital Complications, and Longitudinal Outcomes After Subarachnoid Hemorrhage. Neurocrit Care. 2021 Oct;35(2):397-408. doi: 10.1007/s12028-020-01177-x. Epub 2021 Jan 22.

  PMID: 33483913 BACKGROUND

• Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R, Majid A. Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review. Brain Stimul. 2018 Nov-Dec;11(6):1225-1238. doi: 10.1016/j.brs.2018.08.010. Epub 2018 Aug 23.

  PMID: 30217648 BACKGROUND

• Chen SP, Ay I, Lopes de Morais A, Qin T, Zheng Y, Sadeghian H, Oka F, Simon B, Eikermann-Haerter K, Ayata C. Vagus nerve stimulation inhibits cortical spreading depression. Pain. 2016 Apr;157(4):797-805. doi: 10.1097/j.pain.0000000000000437.

  PMID: 26645547 BACKGROUND

• Ay I, Ay H. Ablation of the sphenopalatine ganglion does not attenuate the infarct reducing effect of vagus nerve stimulation. Auton Neurosci. 2013 Mar;174(1-2):31-5. doi: 10.1016/j.autneu.2012.12.001. Epub 2012 Dec 27.

  PMID: 23273773 BACKGROUND

• Ay I, Lu J, Ay H, Gregory Sorensen A. Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. Neurosci Lett. 2009 Aug 14;459(3):147-51. doi: 10.1016/j.neulet.2009.05.018. Epub 2009 May 13.

  PMID: 19446004 BACKGROUND

• Ay I, Sorensen AG, Ay H. Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia: an unlikely role for cerebral blood flow. Brain Res. 2011 May 25;1392:110-5. doi: 10.1016/j.brainres.2011.03.060. Epub 2011 Mar 31.

  PMID: 21458427 BACKGROUND

• Ay I, Nasser R, Simon B, Ay H. Transcutaneous Cervical Vagus Nerve Stimulation Ameliorates Acute Ischemic Injury in Rats. Brain Stimul. 2016 Mar-Apr;9(2):166-73. doi: 10.1016/j.brs.2015.11.008. Epub 2015 Dec 1.

  PMID: 26723020 BACKGROUND

• van der Meij A, van Walderveen MAA, Kruyt ND, van Zwet EW, Liebler EJ, Ferrari MD, Wermer MJH. NOn-invasive Vagus nerve stimulation in acute Ischemic Stroke (NOVIS): a study protocol for a randomized clinical trial. Trials. 2020 Oct 26;21(1):878. doi: 10.1186/s13063-020-04794-1.

  PMID: 33106174 BACKGROUND

• Jay RM. Biofix absorbable system. J Foot Surg. 1992 Sep-Oct;31(5):477. No abstract available.

  PMID: 1430829 BACKGROUND

• Dreier JP, Woitzik J, Fabricius M, Bhatia R, Major S, Drenckhahn C, Lehmann TN, Sarrafzadeh A, Willumsen L, Hartings JA, Sakowitz OW, Seemann JH, Thieme A, Lauritzen M, Strong AJ. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain. 2006 Dec;129(Pt 12):3224-37. doi: 10.1093/brain/awl297. Epub 2006 Oct 25.

  PMID: 17067993 BACKGROUND

• Hartings JA, Watanabe T, Bullock MR, Okonkwo DO, Fabricius M, Woitzik J, Dreier JP, Puccio A, Shutter LA, Pahl C, Strong AJ; Co-Operative Study on Brain Injury Depolarizations. Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma. Brain. 2011 May;134(Pt 5):1529-40. doi: 10.1093/brain/awr048. Epub 2011 Apr 7.

  PMID: 21478187 BACKGROUND

• Struck AF, Westover MB, Hall LT, Deck GM, Cole AJ, Rosenthal ES. Metabolic Correlates of the Ictal-Interictal Continuum: FDG-PET During Continuous EEG. Neurocrit Care. 2016 Jun;24(3):324-31. doi: 10.1007/s12028-016-0245-y.

  PMID: 27169855 BACKGROUND

• Claassen J, Perotte A, Albers D, Kleinberg S, Schmidt JM, Tu B, Badjatia N, Lantigua H, Hirsch LJ, Mayer SA, Connolly ES, Hripcsak G. Nonconvulsive seizures after subarachnoid hemorrhage: Multimodal detection and outcomes. Ann Neurol. 2013 Jul;74(1):53-64. doi: 10.1002/ana.23859. Epub 2013 Jun 27.

  PMID: 23813945 BACKGROUND

• Witsch J, Frey HP, Schmidt JM, Velazquez A, Falo CM, Reznik M, Roh D, Agarwal S, Park S, Connolly ES, Claassen J. Electroencephalographic Periodic Discharges and Frequency-Dependent Brain Tissue Hypoxia in Acute Brain Injury. JAMA Neurol. 2017 Mar 1;74(3):301-309. doi: 10.1001/jamaneurol.2016.5325.

  PMID: 28097330 BACKGROUND

• Nonis R, D'Ostilio K, Schoenen J, Magis D. Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: An electrophysiological study in healthy volunteers. Cephalalgia. 2017 Nov;37(13):1285-1293. doi: 10.1177/0333102417717470. Epub 2017 Jun 26.

  PMID: 28648089 BACKGROUND

• O'Connor KL, Westover MB, Phillips MT, Iftimia NA, Buckley DA, Ogilvy CS, Shafi MM, Rosenthal ES. High risk for seizures following subarachnoid hemorrhage regardless of referral bias. Neurocrit Care. 2014 Dec;21(3):476-82. doi: 10.1007/s12028-014-9974-y.

  PMID: 24723663 BACKGROUND

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Aneurysm; Hemorrhage; Intracranial Hemorrhages; Cerebrovascular Disorders; Intracranial Aneurysm; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Aneurysm, Ruptured

Condition Hierarchy (Ancestors)

Nervous System Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Intracranial Arterial Diseases

Study Officials

• Aman B Patel, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Aman B Patel, MD

CONTACT

617-726-3303; abpatel@mgh.harvard.edu

Austin R Birmingham, BS

CONTACT

617-643-5547; abirmingham@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Neurosurgery

Study Record Dates

• First Submitted: September 16, 2021
• First Posted: November 2, 2021
• Study Start: October 4, 2022
• Primary Completion: December 1, 2025
• Study Completion: April 1, 2026
• Last Updated: May 9, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)