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

Study Overview
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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.

Official Title
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Safety and Efficacy of Non-invasive Vagus Nerve Stimulation in the Treatment of Headache in 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: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham arm<br>gammaCore sham device which will not provide stimulation of the vagus nerve | Device: gammaCore<br>* 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.<br>|
| Active Comparator: Treatment group<br>Active gammaCore device that supplies non-invasive stimulation of the cervical branch of the Vagus nerve | Device: gammaCore<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference between the active and sham treatment groups in morphine equivalence dosage | Daily morphine equivalence dosage will be calculated and compared between the active and Sham group | up to 14 days of admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference between the active and sham treatment groups in the mean daily headache intensity | Headache intensity is measured every 4 hours per standard of care. The pain intensity is reported using a 0 to 10 numeric rating scale, o being no pain, and 10 being severe pain. The mean daily headache intensity will be measured and compared between the active and sham group | up to 14 days of admission | 
| The difference between total overall morphine equivalence dosage between the active and sham group per subject during study |  | up to 14 days of admission | 
| The difference in opiate related adverse events | The rate of opiate related adverse events such as urinary retention, constipation, respiratory depression, central nervous system depression will be compared between the 2 groups | up to 14 days of admission | 
| The difference in CSF and blood inflammatory markers before and after VNS. When possible, if there is an EVD, 2 cc of CSF and 5 cc of blood will be analyzed for inflammatory markers. | CSF and blood samples will be collected before the first stimulation and 24 hours after stimulation and during the vasospasm period. The blood and CSF will be analyzed for Interleukins, TNF, blood brain permeability markers like MMP. Immunologic investigations include but not limited to, measurement of inflammatory protein levels, RNA sequencing of leukocyte and stimulation assays. | up to 14 dats of admission | 
| The difference in CSF and blood Blood brain permeability markers before and after VNS. When possible, if there is an EVD, 2 cc of CSF and 5 cc of blood will be analyzed for inflammatory markers. | CSF and blood samples will be collected before the first stimulation and 24 hours after stimulation and during the vasospasm period. The blood and CSF will be analyzed for Blood brain permeability markers like MMP | up to 14 dats of admission | 
| The difference in vessel diameter during cerebral vasospasm during cerebral angiography before and after VNS | VNS will be delivered during angiography to evaluate the effect on cerebral vasospasm | up to 14 dats of admission |