Safety and Efficacy of Non-invasive Vagus Nerve Stimulation in the Treatment of Headache in Subarachnoid Hemorrhage

NCT ID: NCT04126408

Last Updated: 2024-01-09

Study Results

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Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

40 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-01-13

Study Completion Date

2022-06-20

Brief Summary

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This is a single site, randomized, sham-controlled, double blinded pilot study assessing the feasibility, safety, tolerability, and efficacy of non-invasive VNS (nVNS), gammaCore, in the treatment of headache in subarachnoid hemorrhage (SAH). 40 participants will be enrolled, 20 in the active device arm and 20 in the sham arm. The primary efficacy outcome is the the difference between the active and sham treatment groups in morphine equivalence dosage.

Detailed Description

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This is a single site, randomized, sham-controlled, double-blind study assessing the feasibility, safety, tolerability, and efficacy of non-invasive VNS (nVNS) in the treatment of headache in subarachnoid hemorrhage (SAH). The hypothesis is that two-two minute noninvasive stimulations of the cervical branch of the Vagus nerve, every 5 hours, is efficacious in safely reducing headache intensity and frequency in patients with headache due to SAH, during the patient's intensive care unit (ICU) stay. After screening and obtaining informed consent, eligible patients diagnosed with SAH on head scans, admitted to the Neurosurgical Intensive Care Unit (NSCU) at Northshore University Hospital will be randomized to either the treatment (stimulation of the cervical branch of the Vagus nerve) or sham (inactive stimulation) group. Pain intensity will be evaluated every 4 hours. Non-invasive stimulation will be performed every 5 hours. Device related adverse events, mean headache intensity, and mean and peak morphine equivalence dosage during the study period will be compared between the VNS group and the sham group.

The primary objective of this study is to examine the safety and effectiveness of nVNS as a treatment for headache in subarachnoid hemorrhage (SAH).

The primary safety endpoint for this study is the incidence of device related serious adverse events.

The primary outcome measurements for effectiveness is the difference between the active and sham treatment groups in morphine equivalence dosage

Secondary endpoints include descriptive comparisons between the active and sham treatment groups in:

* The difference between the active and sham treatment groups in the mean daily headache intensity
* The difference between total overall morphine equivalence dosage between the active and sham group per subject during study
* Opiate related adverse events (such as urinary retention, constipation, sedation, respiratory depression, nausea, vomiting and pruritis)
* The difference in CSF and blood inflammatory markers before and after VNS
* Difference in vessel diameter during angiogram for cerebral vasospasm before and after VNS

Study period is 14 days starting 24-72 hours post successful treatment of the aneurysm and extubation.

Conditions

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Subarachnoid Hemorrhage, Aneurysmal

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Outcome Assessors

Study Groups

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Sham arm

gammaCore sham device which will not provide stimulation of the vagus nerve

Group Type SHAM_COMPARATOR

gammaCore

Intervention Type DEVICE

The intervention consists of a transcutaneous non-invasive stimulation of the cervical branch of the vagus nerve (nVNS) using gammaCore, an FDA approved device for the treatment of migraine and cluster headache. This will be compared to the sham device, which is the same device which will not provide stimulation to the nerve. Stimulation frequency will be identical to the frequency used in previous nVNS studies for the treatment of migraine headache.

Treatment group

Active gammaCore device that supplies non-invasive stimulation of the cervical branch of the Vagus nerve

Group Type ACTIVE_COMPARATOR

gammaCore

Intervention Type DEVICE

The intervention consists of a transcutaneous non-invasive stimulation of the cervical branch of the vagus nerve (nVNS) using gammaCore, an FDA approved device for the treatment of migraine and cluster headache. This will be compared to the sham device, which is the same device which will not provide stimulation to the nerve. Stimulation frequency will be identical to the frequency used in previous nVNS studies for the treatment of migraine headache.

Interventions

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gammaCore

The intervention consists of a transcutaneous non-invasive stimulation of the cervical branch of the vagus nerve (nVNS) using gammaCore, an FDA approved device for the treatment of migraine and cluster headache. This will be compared to the sham device, which is the same device which will not provide stimulation to the nerve. Stimulation frequency will be identical to the frequency used in previous nVNS studies for the treatment of migraine headache.

Intervention Type DEVICE

Eligibility Criteria

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Inclusion Criteria

* Established signed and dated informed consent form
* CT of the head revealing blood in the subarachnoid space
* Subject is male or female, 18 to 80 years of age
* Subject alert to be able to verbalize pain level. If alertness improves after placement of an external ventricular drain, or once extubated, and the patient becomes alert , the patient will be enrolled
* Subject reports pain of \> =7 on 10 Point Pain numeric rating scale
* Female of reproductive age must have a negative pregnancy test (Urine or blood test)

Exclusion Criteria

* Use of any concomitant electrostimulation devices (Pacemaker, defibrillator, deep brain stimulation.)
* Unsecured aneurysm defined as aneurysm that has not been surgically or endovascularly treated.
* Previous carotid surgeries or known history of carotid artery disease
* Screws, metals or device in the neck
* History of secondary or tertiary heart blocks, ventricular tachycardia, Supra-Ventricular Tachycardia (including atrial fibrillation)
* Alcoholics (CAGE scale of 2 or greater). If patients are on Clinical Institute Withdrawal Assessment for Alcohol (CIWA) protocol for alcohol withdrawal, the patient will be excluded from the study.
* Drug addicts or chronic opioid users confirmed by history or with urine toxicology showing opiates or cocaine
* small traumatic SAH
Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Northwell Health

OTHER

Sponsor Role lead

Responsible Party

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Tania Rebeiz

Assistant Professor, MD

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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Northshore University Hospital

Manhasset, New York, United States

Site Status

Countries

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United States

References

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Magalhaes JE, Azevedo-Filho HR, Rocha-Filho PA. The risk of headache attributed to surgical treatment of intracranial aneurysms: a cohort study. Headache. 2013 Nov-Dec;53(10):1613-23. doi: 10.1111/head.12165. Epub 2013 Jun 28.

Reference Type BACKGROUND
PMID: 23808965 (View on PubMed)

Rumalla K, Smith KA, Arnold PM, Mittal MK. Subarachnoid Hemorrhage and Readmissions: National Rates, Causes, Risk Factors, and Outcomes in 16,001 Hospitalized Patients. World Neurosurg. 2018 Feb;110:e100-e111. doi: 10.1016/j.wneu.2017.10.089. Epub 2017 Oct 26.

Reference Type BACKGROUND
PMID: 29107164 (View on PubMed)

Glisic EK, Gardiner L, Josti L, Dermanelian E, Ridel S, Dziodzio J, McCrum B, Enos B, Lerwick P, Fraser GL, Muscat P, Riker RR, Ecker R, Florman J, Seder DB. Inadequacy of Headache Management After Subarachnoid Hemorrhage. Am J Crit Care. 2016 Mar;25(2):136-43. doi: 10.4037/ajcc2016486.

Reference Type BACKGROUND
PMID: 26932915 (View on PubMed)

Morad AH, Tamargo RJ, Gottschalk A. The Longitudinal Course of Pain and Analgesic Therapy Following Aneurysmal Subarachnoid Hemorrhage: A Cohort Study. Headache. 2016 Nov;56(10):1617-1625. doi: 10.1111/head.12908. Epub 2016 Oct 5.

Reference Type BACKGROUND
PMID: 27704534 (View on PubMed)

Dorhout Mees SM, Bertens D, van der Worp HB, Rinkel GJ, van den Bergh WM. Magnesium and headache after aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2010 May;81(5):490-3. doi: 10.1136/jnnp.2009.181404. Epub 2009 Oct 13.

Reference Type BACKGROUND
PMID: 19828484 (View on PubMed)

Oshinsky ML, Murphy AL, Hekierski H Jr, Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain. 2014 May;155(5):1037-1042. doi: 10.1016/j.pain.2014.02.009. Epub 2014 Feb 14.

Reference Type BACKGROUND
PMID: 24530613 (View on PubMed)

Akerman S, Simon B, Romero-Reyes M. Vagus nerve stimulation suppresses acute noxious activation of trigeminocervical neurons in animal models of primary headache. Neurobiol Dis. 2017 Jun;102:96-104. doi: 10.1016/j.nbd.2017.03.004. Epub 2017 Mar 9.

Reference Type BACKGROUND
PMID: 28286178 (View on PubMed)

Frangos E, Komisaruk BR. Access to Vagal Projections via Cutaneous Electrical Stimulation of the Neck: fMRI Evidence in Healthy Humans. Brain Stimul. 2017 Jan-Feb;10(1):19-27. doi: 10.1016/j.brs.2016.10.008. Epub 2016 Oct 20.

Reference Type BACKGROUND
PMID: 28104084 (View on PubMed)

Bosche B, Graf R, Ernestus RI, Dohmen C, Reithmeier T, Brinker G, Strong AJ, Dreier JP, Woitzik J; Members of the Cooperative Study of Brain Injury Depolarizations (COSBID). Recurrent spreading depolarizations after subarachnoid hemorrhage decreases oxygen availability in human cerebral cortex. Ann Neurol. 2010 May;67(5):607-17. doi: 10.1002/ana.21943.

Reference Type BACKGROUND
PMID: 20437558 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26645547 (View on PubMed)

Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003 May-Aug;9(5-8):125-34.

Reference Type BACKGROUND
PMID: 14571320 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 30943885 (View on PubMed)

George MS, Ward HE Jr, Ninan PT, Pollack M, Nahas Z, Anderson B, Kose S, Howland RH, Goodman WK, Ballenger JC. A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders. Brain Stimul. 2008 Apr;1(2):112-21. doi: 10.1016/j.brs.2008.02.001. Epub 2008 Mar 28.

Reference Type BACKGROUND
PMID: 20633378 (View on PubMed)

Breit S, Kupferberg A, Rogler G, Hasler G. Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. Front Psychiatry. 2018 Mar 13;9:44. doi: 10.3389/fpsyt.2018.00044. eCollection 2018.

Reference Type BACKGROUND
PMID: 29593576 (View on PubMed)

Lendvai IS, Maier A, Scheele D, Hurlemann R, Kinfe TM. Spotlight on cervical vagus nerve stimulation for the treatment of primary headache disorders: a review. J Pain Res. 2018 Aug 27;11:1613-1625. doi: 10.2147/JPR.S129202. eCollection 2018.

Reference Type BACKGROUND
PMID: 30214271 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

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19-0837

Identifier Type: -

Identifier Source: org_study_id

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