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

Official title

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

Overview

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

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.

Interventions

• Device gammaCore
  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.

Primary outcome measures

• The presentation of severe adverse device events (SADEs) within 30 minutes of nVNS first treatment dose. [Time frame: up to 10 days post-rupture]

Secondary outcome measures (7)

• The feasibility of nVNS in SAH subjects in the critical care setting. [Time frame: up to 10 days post-rupture]
• The frequency of alarm triggers peri-nVNS. [Time frame: 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). [Time frame: at 10 days and 90 days post-rupture]
• The rate of established predictors of delayed cerebral ischemia (DCI) and outcome. [Time frame: up to 10 days post-rupture]
• The occurrence of ischemic complications. [Time frame: 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). [Time frame: at 90 days post-rupture]
• The self-reported assessment for physical, mental, and social health at follow up (90 days). [Time frame: at 90 days post-rupture]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Massachusetts General Hospital — Boston

Publications

• 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
• 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: 10.100 PMID 29659050
• 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
• 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 PMID 22556195
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT05103566 · 2021p002016

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗