Safety and Efficacy of Non-invasive Vagus Nerve Stimulation in the Treatment of Headache in Subarachnoid Hemorrhage
Phase: NA
Conditions: Subarachnoid Hemorrhage, Aneurysmal
Sponsor: Northwell Health

 
 
Safety and efficacy of non-invasive Vagus Nerve Stimulation (nVNS) in the 
treatment of headache in Subarachnoid Hemorrhage (SAH) (the VANQUISH  
study) 
Principal Investigator: Tania Rebeiz 
 
Version Number:  6 
12 January 2023 
 
 
 

  
1 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ................................................................................................ 1 
1 
PROTOCOL SUMMARY ..................................................................................................... 1 
1.1 
Synopsis ...............................................................................................................................1 
1.2 
Schedule of Activities (SoA)...................................................................................................3 
2 
INTRODUCTION ............................................................................................................... 4 
2.1 
Study Rationale ....................................................................................................................4 
2.2 
Background ..........................................................................................................................5 
2.3 
Risk/Benefit Assessment ..................................................................................................... 10 
2.3.1 
Known Potential Risks .......................................................................................................................... 10 
2.3.2 
Known Potential Benefits ..................................................................................................................... 11 
2.3.3 
Assessment of Potential Risks and Benefits......................................................................................... 12 
3 
OBJECTIVES AND ENDPOINTS ......................................................................................... 12 
4 
STUDY DESIGN ............................................................................................................... 14 
4.1 
Overall Design .................................................................................................................... 14 
4.2 
Scientific Rationale for Study Design ................................................................................... 16 
4.3 
Justification for Dose .......................................................................................................... 15 
4.4 
End of Study Definition ....................................................................................................... 16 
5 
STUDY POPULATION ...................................................................................................... 17 
5.1 
Inclusion Criteria ................................................................................................................ 17 
5.2 
Exclusion Criteria ................................................................................................................ 18 
5.3 
Lifestyle Considerations ...................................................................................................... 20 
5.4 
Pre-Screen Failures ............................................................................................................. 20 
5.5 
Strategies for Recruitment and Retention ........................................................................... 20 
6 
STUDY INTERVENTION ................................................................................................... 20 
6.1 
Study Intervention(s) Administration .................................................................................. 20 
6.1.1 
Study Intervention Description ............................................................................................................ 20 
6.1.2 
Dosing and Administration................................................................................................................... 21 
6.2 
Preparation/Handling/Storage/Accountability .................................................................... 21 
6.2.1 
Acquisition and accountability ............................................................................................................. 21 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................................................ 22 
6.2.3 
Product Storage and Stability............................................................................................................... 22 

  
6.2.4 
Preparation........................................................................................................................................... 22 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................... 23 
6.4 
Study Intervention Compliance ........................................................................................... 23 
6.5 
Concomitant Therapy ......................................................................................................... 23 
6.5.1 
Rescue Medication ............................................................................................................................... 23 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...................................................................................... 23 
7.1 
Discontinuation of Study Intervention ................................................................................. 23 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................... 24 
7.3 
Lost to Follow-Up ............................................................................................................... 24 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................... 24 
8.1 
Efficacy Assessments .......................................................................................................... 24 
8.2 
Safety and Other Assessments ............................................................................................ 27 
8.3 
Adverse Events and Serious Adverse Events ........................................................................ 29 
8.3.1 
Definition of Adverse Events (AE) ........................................................................................................ 29 
8.3.2 
Definition of Serious Adverse Events (SAE) ......................................................................................... 30 
8.3.3 
Time Period and Frequency for Event Assessment and Follow-Up ..................................................... 32 
8.3.4 
Adverse Event Reporting...................................................................................................................... 32 
8.3.5 
Serious Adverse Event Reporting ......................................................................................................... 33 
8.3.6 
Reporting Events to Participants.......................................................................................................... 34 
8.3.7 
Events of Special Interest ..................................................................................................................... 34 
8.3.8 
Reporting of Pregnancy ........................................................................................................................ 34 
8.4 
Unanticipated Problems ..................................................................................................... 34 
8.4.1 
Definition of Unanticipated Problems (UP) ......................................................................................... 34 
8.4.2 
Unanticipated Problem Reporting ....................................................................................................... 35 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................................................. 35 
9 
STATISTICAL CONSIDERATIONS ...................................................................................... 35 
9.1 
Statistical Hypotheses ......................................................................................................... 35 
9.2 
Sample Size Determination ................................................................................................. 36 
9.3 
Populations for Analyses..................................................................................................... 36 
9.4 
Statistical Analyses ............................................................................................................. 36 
9.4.1 
General Approach ................................................................................................................................ 36 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s)........................................................................................ 37 
9.4.3 
Analysis of the Secondary Endpoint(s)................................................................................................. 37 
9.4.4 
Safety Analyses..................................................................................................................................... 37 
9.4.5 
Baseline Descriptive Statistics .............................................................................................................. 38 
9.4.6 
Planned Interim Analyses ..................................................................................................................... 38 

  
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 38 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .................................................. 38 
10.1.1 
Informed Consent Process ................................................................................................................... 38 
10.1.2 
Study Discontinuation and Closure ...................................................................................................... 40 
10.1.3 
Confidentiality and Privacy .................................................................................................................. 40 
10.1.4 
Future Use of Stored Specimens and Data .......................................................................................... 41 
10.1.5 
Key Roles and Study Governance......................................................................................................... 41 
10.1.6 
Safety Oversight ................................................................................................................................... 41 
10.1.7 
Clinical Monitoring healthcare providor .............................................................................................. 41 
10.1.8 
Quality Assurance and Quality Control ................................................................................................ 42 
10.1.9 
Data Handling and Record Keeping ..................................................................................................... 43 
10.1.10 
Protocol Deviations .......................................................................................................................... 43 
10.1.11 
Publication and Data Sharing Policy................................................................................................. 44 
10.1.12 
Conflict of Interest Policy ................................................................................................................. 44 
10.2 
Protocol Amendment History .......................................................................................... 47 
11 
REFERENCES ............................................................................................................... 48 
11.1 
Adverse Events/Adverse Device Effects and Device Deficiencies ....................................... 50 
11.1.1 
Adverse Event/Adverse Device Effect Definitions ............................................................................... 50 
11.1.2 
Serious Adverse Event/Serious Adverse Device Effect/Unanticipated Adverse Device Effect 
Definitions ............................................................................................................................................................ 50 
11.1.3 
Unanticipated serious adverse device effect (USADE) ........................................................................ 51 
11.1.4 
Reporting of Adverse Events/Adverse Device Effects ......................................................................... 51 
11.1.5 
Reporting of Serious Adverse Event/Serious Adverse Device Effects ................................................. 60 
 

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STATEMENT OF COMPLIANCE 
 
 The trial will be carried out in accordance with International Conference on Harmonisation      
Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who 
are responsible for the conduct, management, or oversight of NIH-funded clinical trials 
have completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the Institutional Review Board (IRB) for review and 
approval.  Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  In addition, all 
changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Safety and efficacy of non-invasive Vagus Nerve Stimulation (nVNS) 
in the treatment of headache in Subarachnoid Hemorrhage (SAH)  
 
Study Description: 
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). We hypothesize 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 

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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. Patients will be on continuous telemetry with frequent 
vital sign measurement. Opiate related adverse events will also be 
monitored.  
 
Locations                         
  
 
 
 
 
 
Objectives: 
 
 
North Shore University Hospital  
Lenox Hill Hospital  
Yale University Hospital- for specimen processing  
  
 
The primary objective of this study is to examine the safety and 
efficacy of nVNS as a treatment for headache in subarachnoid 
hemorrhage (SAH).  
 
 
 
Endpoints: 
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) 
  
Study Population: 
This is a pilot study of 40 subjects. We will enroll men and woman 
18 – 75 years of age. Patients with alcohol and drug addiction will be 

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excluded. Our patient population mostly represents the New York 
state area, mostly Long island and Queens as we are the main 
referral hospital to that area. 
 
Phase: 
 
N/A 
 
Description of 
Sites/Facilities 
Enrolling Participants: 
 
 
The Northwell system has a policy that most subarachnoid 
hemorrhages admitted to our affiliated hospitals get transferred to 
the Northshore University Hospital Neurosurgical Care Unit as it is 
the tertiary Neuro-interventional and Neurosurgical Unit of the 
system. As a result, those patients are automatically transferred to 
our unit, where screening and enrollment can be initiated.  
  
Description of Study 
Intervention: 
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 does not stimulate the nerve. 
Stimulation frequency will be identical to the frequency used in 
previous nVNS studies for the treatment of migraine headache. 
Dosing will be as described in this protocol. The IRB approved 
healthcare provider will show the subject how to  stimulate the 
cervical branch of the Vagus nerve transcutaneously, and will 
increase the amplitude/intensity gradually. If pain or discomfort is 
felt, the amplitude will be decreased to a comfortable level. Rescue 
pain killers (acetaminophen, opiates) will be given as needed. In the 
sham group, the sham device will be applied in the same location 
and at the same frequency as in the treatment group.  
 
Study Duration: 
Study period is up to 10 days starting 24 hours post successful 
treatment of the aneurysm.  
 
 
1.2 
SCHEDULE OF ACTIVITIES (SOA) 
 
 

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Procedures 
Screening and 
randomization 
Days -1-5 
Enrollment/Baseline 
Days 2-5 till discharge 
from  NSCU 
 
Step down unit 
Neurosurgical floor 
Final Study  
discharge  
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Administer study intervention 
 
X 
X 
 
Concomitant medication 
review 
X 
X 
X 
X 
Physical exam (including 
height and weight) 
X 
X 
X 
X 
Vital signs (temperature, BP, 
HR, Oxygen saturation) 
X 
 Hourly and as 
needed 
X 
X 
Height 
X 
 
 
 
Weight 
X 
X 
 
X 
Performance status 
X 
X 
x 
X 
Hematology  
X 
X 
X 
 
serum chemistry  
X 
X 
X 
 
Pregnancy test  
X 
 
 
 
EKG (as indicated) 
X 
x  
As needed 
 
Daily narcotic use 
x 
x 
x 
 
Adverse event review and 
evaluation 
x 
x 
x 
x 
Radiologic/Imaging 
assessment (CT, MRI, 
CTA/CTP, angiogram) 
X 
x 
x 
x 
Patient satisfaction 
assessment 
 
 
  
x 
Complete Case Report Forms 
(CRFs) 
X 
X 
X 
X 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Subarachnoid hemorrhage (SAH) is a devastating condition, most commonly due to trauma and 
aneurysm rupture, and carries significant mortality and morbidity. About half of the survivors 
are left with disability. Some of the known complications are aneurysm re-rupture, seizures, 
central fever, delayed cerebral ischemia (DCI) and hydrocephalus (ref). SAH induces a systemic 
inflammatory immune response (SIRS) and over activated sympathetic nervous system. As a 
result, patients are monitored carefully in the intensive care unit, with frequent neurologic 
examination. The most common presenting sign is headache, which worsens in the first 
week.(1) The hallmark of this headache in SAH is that it is often described as “the worst 
headache of my life”. Evaluating a cohort of patients with aneurysmal SAH, Magalhães et al., 
showed that headache lasts on average 12.5 days, and that anxiety was a risk factor for 
persistent headache.(2) In addition, headache is one of the most common cause of readmission 
in SAH, leading to an increase in healthcare cost.(3) Non-enhanced cat scan (CT) of the head 

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showing blood in the subarachnoid space confirms the diagnosis of SAH. Unfortunately, there 
are no guidelines on the management of headache due to SAH, this is possibly due to the 
limited therapeutic interventions. Most pain killers fail to control headache intensity and carry 
risks. Physicians resort to opiates which can cause central nervous system (CNS) depression, 
alter the neurologic examination and lead to unnecessary tests, increasing hospital length of 
stay and healthcare cost. Opiates can cause ileus and urinary retention which are commonly 
seen in the Intensive Care Unit (ICU) setting. In addition, the over usage of opiates due to its 
potent analgesic effect has led to what we are currently experiencing in the United States, an 
opiate epidemic. A recent study showed that on day 4-5 post SAH ictus, patients use a daily 
mean morphine equivalent dose of 18 mg intravenously. In addition, some patients were 
prescribed a maximum total daily dose of 16 mg of Decadron.(4) There is lack of strong 
evidence advocating the use of Decadron in the management of headache due to SAH. 
However, it is frequently used given the assumption that it decreases the inflammation caused 
by the blood products, thought to be involved in the pathogenesis of headache, as a result, 
decrease headache intensity. However, steroids can cause immunosuppression, hyperglycemia, 
decrease wound healing, peptic ulcers, and has been shown to increase mortality in traumatic 
brain injury. Acetaminophen is frequently used, but not effective in controlling pain, and care 
should be taken to avoid toxic levels.(1) In a prospective study, Morad et al., showed that 
continuous usage of opiates and acetaminophen failed to attenuate severe headache in SAH 
patients, even though the daily mean intravenous morphine equivalence of 15.7 mg was used, 
with no significant decline in usage during the hospital stay. The authors suggest the need for a 
more effective and safe therapeutic intervention.(5) Headache is the major complaint in 
patients with SAH and is very disabling, leading to days of pain and suffering. Unfortunately 
until today, there are no effective treatments. Vagus nerve stimulation has been shown to have 
nociceptive effect and could potentially help safely manage headache in this patient 
population. In addition, vagus nerve stimulation activates the parasympathetic nervous system 
(SAH is a hyperactive sympathetic response) and has anti-inflammatory properties that could 
potentially prevent secondary brain injury (DCI and stroke) seen in aneurysmal SAH (a-SAH). 
The FDA recently approved the noninvasive form, which has been proven to be safe and 
efficacious in controlling different types of headaches, which share similar pathophysiology to 
SAH related headache, making it an attractive therapeutic option for this patient population. 
 
2.2 
Background   
 
Headache related to SAH is thought to be due to meningeal irritation from the blood products 
which activates an inflammatory cascade, leading to pain. SAH causes upregulation of the 
NMDA receptors as a result magnesium, an antagonist of the NMDA receptor is being 
investigated as a treatment for SAH related headache.(6) Cortical spreading depression 
commonly seen in SAH patients could also be involved in headache pathogenesis. It is 
frequently seen in migraine with aura. Vagus Nerve Stimulation (VNS) has been FDA approved 
for many years for the treatment of refractory seizures and depression. Recently, the FDA 
approved the transcutaneous form, which stimulates the cervical branch of the vagus nerve for 
the treatment of migraine and cluster headaches, pathologies that share similar 

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pathophysiology (inflammation, cortical spreading depression) to headache and secondary 
brain injury caused by subarachnoid hemorrhage. This is a very attractive way of stimulating the 
nerve avoiding the surgical complications of the invasive form, with strong evidence showing 
safety and efficacy in multiple patient populations. 
Some of the potential beneficial effects of nVNS in subarachnoid hemorrhage patients are 
(Figure 1): 
1-Analgesic Effect: Oshinsky et al showed that nVNS could reverse allodynia in animal model, by 
reversing the rise in extracellular glutamate levels in the trigeminal nucleus seen when the 
meninges are infused with inflammatory mediators.(7) VNS has also been shown to inhibit 
trigeminal nerve firing when animal dura was stimulated.(8) Functional imaging in individuals 
receiving nVNS shows the deactivation of the spinal trigeminal nucleus.(9) The trigeminal 
nucleus is the major sensory nucleus for pain.  
2- Cortical spreading depression (CSD) is a wave of electrical depolarization often seen in 
patients with traumatic brain injury, strokes, subarachnoid hemorrhage and migraine. A recent 
study detected 120 CSD with subdural electroencephalogram (ECoG) in 8 out of 9 patients with 
aneurysmal SAH. The frequency of CSD peaked between days 5 and 7. Clustering of CSD 
correlated with the hypoxemia and development of delayed ischemic neurologic deficit.(10) It is 
postulated that inhibiting cortical spreading depression could provide neuroprotection.  In SAH 
animal model, noninvasive VNS has been shown to significantly reduce CSD.(11) Patients with 
migraine with aura are at increased risk of having strokes, this is thought to be due to CSD. 
Inhibiting CSD with VNS could potentially help reduce headache in SAH and prevent delayed 
cerebral ischemia and strokes.  
3- Inflammation: Vagus nerve has been shown to control the neuroendocrine immune axis. It 
regulates the immune system through the Hypothalamus Pituitary Adrenal (HPA) pathway and 
modulates the release of inflammatory mediators through the spleen and immune cells.(12) 
There are multiple ongoing human studies using VNS for the treatment of autoimmune diseases 
like rheumatoid arthritis and Crohn's disease. These inflammatory mediators are thought to be 
involved in the pathogenesis of headache and secondary brain injury in SAH patients. nVNS has 
been shown to decrease the rate of aneurysm rupture and improve outcome  in a mouse model 
of intracranial aneurysm. (13) 
4- Psychiatric disorders: A recent pilot study revealed that VNS could have a potential beneficial 
effect in the treatment of anxiety.(14) In addition, there is an ongoing study evaluating nVNS in 
generalized anxiety disorder, chronic pain, depression and PTSD.(15, 16) Magalhães et al. 
showed that anxiety is a risk factor for persistent headache in SAH .(2)  
5- Seizures: VNS is FDA approved for the treatment of refractory seizures. Seizures are 
commonly seen in SAH, and often physicians use prophylactic antiepileptic’s in SAH, although 
this is not recommended due to the side effects of the antiepileptic’s. nVNS could potentially 
prevent seizures in patients with SAH. 

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In summary, through the deactivation of the pain centers, inhibition of CSD, reduction of 
inflammatory markers and glutamate levels, and being an antagonist of the NMDA receptors 
thought to be involved in SAH headache pathogenesis, nVNS could be an effective analgesic in 
patients with SAH. (Figure1)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Mechanism of action of Vagus nerve stimulation 

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• 
 
 
 
 
A recent meta-analysis reviewing 3 randomized controlled trials for cluster headache, one 
randomized trial for migraine, and multiple observational studies, concluded that nVNS is 
effective and safe in the treatment of headache.(17)  
 
 
 
 
 
 
Table taken from a systematic review on the clinical evidence of devices in the treatment of migraine and cluster 
headache (18) 
nVNS
Anxiety 
Centers of 
pain control 
(Trigeminal 
nucleus, 
glutamate)
Cortical 
spreading 
depression 
Inflammation
 
Stroke 
Delayed cerebral 
ischemia 
Seizures 

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Device 
Study 
Authors 
CE 
marked 
FDA 
cleared 
AAN 
Classification of 
Evidence 
GRADE 
nVNS 
Acute 
migraine 
treatment* 
Tassorelli et 
al 21 
Yes 
Yes 
I 
High 
Migraine 
prevention*† 
Silberstein et 
al (EVENT)31 
Yes 
No 
II 
Low 
Acute CH 
treatment 
Silberstein et 
al (ACT1)22 
Yes 
Yes¶ 
NA 
High 
Goadsby et al 23 
NA 
High 
CH prevention‡ 
Gaul et al 24 
Yes 
Yes 
NA 
High 
Marin et al 25 
NA 
Moderate
e-TNS 
Acute 
migraine 
treatment 
Chou et al 26 
Yes 
Yes 
NA 
Moderate
Migraine 
prevention* 
Schoenen et 
al 27 
Yes 
Yes 
III 
Moderate
Acute CH 
treatment§ 
NA 
No 
No 
NA 
NA 
CH prevention§ 
NA 
No 
No 
NA 
NA 
sTMS 
Acute 
migraine 
treatment 
Lipton et al 28 
Yes 
Yes 
NA 
Moderate
Migraine 
prevention 
Starling et al 29 
Yes 
Yes 
NA 
Low 
Acute CH 
treatment§ 
NA 
No 
No 
NA 
NA 
CH prevention§ 
NA 
No 
No 
NA 
NA 
 

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Given the potential benefits and its safety profile, nVNS could potentially help control headache 
and secondary brain injury due to SAH.  
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Major side effects of VNS historically have been due to the surgical procedure or the continuous 
on-off stimulation. With transcutaneous VNS, one can avoid these side effects. Per the 
gammaCore instructions for use (IFU), some of the potential reversable complications are 
dyspnea,  dysgusia, and muscle twitching or pain during the stimulation.(19) Per the IFU, other 
mild to moderate complications are: “Paresthesia or dysesthesias lasting beyond the treatment 
period, skin irritation due to allergic reaction to gel, diarrhea, nausea/vomiting, or loss of 
appetite, sweating, fatigue, depressed mood, tinnitus, progression of headache symptom, 
abnormal heart rhythm. Potential risks associated with non-invasive vagus nerve stimulation 
that may be moderate to severe: progression of headache symptoms, syncope, light-
headedness, and/or dizziness”.(19)  
 
A recent systematic review of 51 studies evaluating the safety of noninvasive VNS, revealed 
that it is safe and well tolerated with minimal side effects. Skin irritation was the most common 
side effect, followed by headache accounting for 3.6% and nasopharyngitis in 1.7% .(20) Cardiac 
side effects are one of the most feared complications of invasive VNS. However, the review, 
which included patients with previous cardiac disease, found that cardiac side effects from 
nVNS on either side are minimal, accounting for only 1 out of the 1322 patients. The individual 
developed symptomatic bradycardia after nVNS.(20) In addition, there are ongoing studies 
evaluating the usefulness of nVNS in heart failure. Other rare complications are dizziness, facial 
palsy, nausea and vomiting. In addition, Redgrave et al could not show that side effects 
correlated with nVNS dose.(20) nVNS has not been studied in patients with subarachnoid 
hemorrhage or brain aneurysms, however the invasive form has been used in patients with 
cerebral vascular malformations, and we are unaware of any cases in the literature of 
intracranial hemorrhage due to VNS. There is an ongoing clinical trial on safety of noninvasive 
VNS, in moderate traumatic brain injury which include “operative intracranial lesions”.(21) A 
recent pilot study with invasive VNS in chronic stroke showed that it was feasable, tolerable and 
safe.(22) Given the lack of human studies in aneurysmal SAH, only patients with completely 
treated aneurysms will be part of the study. It is important to include this patient population 
given the potential benefits of VNS in controlling secondary brain injury ( strokes and delayed 
cerebral ischmia) thought to be due to inflammation and cortical spreading depression. These 
secondary complications seen in a-SAH are not typically seen in other causes of SAH. In 
addition, a recent study on  nVNS in a mouse model with cerebral aneurysm ahowed that daily 
stimulation of the vagus nerve could be actually protective and decreased the risk of 
aneurysmal rupture(13). Other vascular malformations will be excluded, given that their 
interventional treatment is more complicated.  It is unknown if nVNS has long-term side effects, 
however, studies have shown that most common long-term complications seen in the invasive 

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form were due to recurrent surgeries for device malfunction (battery and lead replacement). 
This is bypassed with the nVNS.  
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
gammaCore has been successfully studied for the acute and preventive treatment of cluster 
and migraine headache.(19) It has been proven to decrease headache intensity, and prevent 
migraine attacks. To this point it has not been studied in patients with headache due to SAH. 
Given the shared pathophysiology (inflammation, cortical spread depression) and the potential 
of deactivating the nociceptive center, nVNS could potentially alleviate SAH related headache, 
decreasing the usage of opiates and steroids and thereby decreasing their side effects. This 
could potentially decrease the ICU and hospital length of stay, decrease the readmission rate 
from headache due to SAH, decrease the outpatient usage of opiates and prevent opiate 
dependency. 
In addition, nVNS could also provide neuroprotection against stroke, one of the most feared 
complication in a-SAH. Stroke in a-SAH is thought to be due to vasospasm of blood vessels 
caused by inflammation and cortical spreading depression leading to ischemia. In animal model, 
noninvasive VNS has been shown to significantly reduce CSD.(11) In addition, nVNS has anti-
inflammatory properties. Experimental animal studies have shown that VNS has the potential of 
improving outcome in critical illnesses through its anti-inflammatory effects which could 
potentially extend to sepsis, intracranial hemorrhage, ventilator related lung injury, 
postoperative cognitive dysfunction, myocardial ischemia and reperfusion injury. One of the 
postulated mechanisms, is that it regulates α7nAChR which regulates inflammation.(23) Animal 
studies have shown that stimulating the α7nACh decreases inflammatory markers.(24) Through 
inhibiting CSD and controlling inflammation, nVNS could potentially prevent secondary brain 
injury (strokes and DCI) seen in a-SAH patients. 
 
Studies have also shown that VNS enhances neuroplasticity, which could fasten recovery. 
Animal studies on intracranial hemorrhage showed that VNS improves functional recovery.(25) 
Multiple ongoing studies are evaluating the beneficial effects of VNS in improving functional 
recovery during rehabilitation of patients with strokes.(22) nVNS could potentially help 
recovery from SAH.  
 
In Summary, some of the immediate potential benefits of non-invasive VNS could include: 
control of headache intensity, decreasing the side effects of narcotic and steroid use, prevent 
DCI and strokes due to SAH, prevent seizures, decrease the SIRS response by regulating the 
sympathetic nervous system and regulating α7nAChR, and decrease ICU and hospital length of 
stay due to decrease usage of opiates leading to loss of neurologic examination and leading to 
unnecessary testing.  
 
Some of the long-range potential benefits might include decreased readmission rates from 
headache due to SAH, decrease outpatient usage of opiates, and prevent opiate dependency 
and improving recovery through enhancing neuroplasticity.  

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2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Although the risks of nVNS in SAH population are unknown, a recent study in a mouse model of 
SAH showed that it decreased aneurysmal rupture rate and improved outcomes in those with 
ruptured aneurysm. The authors noted the potential for nVNS in humans and the ability to 
translate their research to human studies.(13) To minimize risks, if an aneurysm has been 
identified to be the cause of the SAH, patients will only be enrolled when the aneurysm has 
been completely treated. In addition, while in the NSCU, patients will be continuously 
monitored via telemetry, with frequent BP measurement. Studies conducted on patients with 
migraine and cluster headache were conducted as outpatient. Our patients are continuously 
monitored, and the medical staff are well equipped to treat any medical emergency. Vagus 
nerve stimulation will only be administered if the vital signs are stable (SBP>100 mmHg, 
MAP>60 mmHg, HR>60, Oxygen saturation > 90%). 
 
 
 
3 
OBJECTIVES AND ENDPOINTS 
   
The primary outcome measurement for effectiveness is: 
 
-The difference between the active and sham treatment groups in mean daily morphine 
equivalence dosage during study 
 
Secondary endpoints include descriptive comparisons between the active and sham treatment 
groups in: 
 
- The difference in mean daily headache intensity during the study 
- The difference between total overall morphine equivalence dosages per subject during study  
 -Opiate related adverse events (such as urinary retention, constipation, sedation, nausea, 
vomiting and pruritis) 
- The difference in cytokines levels and brain permeability markers in the blood and/or CSF 
 before and after stimulation and between the sham and active device group  
- Effects of VNS on brain permeability measured through CT perfusion studies 
-The difference in modified rankin scale at hospital discharge and during outpatient follow up. 
This will be collected retrospectively from the follow up outpatient visit. 
 
Exploratory analyses will include descriptive comparisons of the rates of stroke, vasospasm, DCI, 
seizure, central fever and severity of vasospasm between the active and sham treatment groups. 
 
 
OBJECTIVES 
ENDPOINTS 
Primary Objective:  
 

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Incidence of device related 
serious adverse events. 
 
 
The difference between the 
active and sham treatment 
groups in mean daily morphine 
equivalence dosage during study  
 
 
 
 
Secondary Objectives 
 
The difference between the 
active and sham treatment 
groups in the mean daily 
headache intensity during the 
study 
 
 
 
The difference between total 
overall morphine equivalence 
dosage between the active and 
sham group per subject during 
study  
 
 
Incidence of opiate related 
adverse events (such as urinary 
retention, constipation, sedation, 
respiratory depression, nausea, 
vomiting and pruritis) 
 
 
The difference in cytokines 
levels and blood brain 
permeability markers in the 
blood and/or CSF before and 
after stimulation and between the 
sham and active group 
 
Proportion of patients with device related adverse 
events 
 
 
 
Morphine equivalence dosage will be calculated per day. 
 
 
 
 
 
 
 
 
 
Headache intensity will be measured throughout the day 
and a mean daily headache intensity will be calculated. 
 
 
 
 
 
 
Total morphine equivalence dosage for the duration of 
the study will be calculated. 
 
 
 
 
 
Number of patients with of urinary retention, 
constipation, sedation, nausea, respiratory depression, 
vomiting and pruritis.  
 
 
 
 
When possible, cytokines levels and permeability 
markers will be measure in the blood and/or serum just 
before the first vagus nerve stimulation and 
approximately 24 hours later,  after the 11:30 AM 
stimulation session. If possible, this will be repeated on 
day 5 and  7 post-ictus as it is the period of cerebral 
vasospasm  

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Immunologic investigations include but not limited to, 
measurement of inflammatory protein levels, RNA 
sequencing of leukocyte and stimulation assays.  
Evaluate the effects of VNS on 
blood brain barrier integrity  
The integrity of the blood brain barrier will be evaluated 
through CT perfusion if performed as standard of care. 
Exploratory objectives 
 
Comparisons of the rates of 
stroke, vasospasm, DCI, seizure, 
and central fever between the 
active and sham treatment 
groups 
 
 
 
 
 
 
 
 
 
 
Effect of nVNS on severity of 
cerebral vasospasm during DSA 
 
 
 
 
 
 
 
Neuroimaging upon admission and at discharge will be 
compared and evidence of new strokes will be noted. 
The presence of DCI (change in neurologic examination 
thought to be due to vasospasm) will be evaluated.  
 
Transcranial doppler velocities will be compared 
between the active and sham groups 
 
The number of days with central fever will be compared 
between the active and sham groups 
 
Incidence of seizures will be compared between the 
active and sham groups   
 
 
Rate of change in the severity of cerebral vasospasm will 
be noted before and during or after  nVNS 
 
 
 
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This is a single site, randomized sham controlled, double blinded, and parallel group study 
comparing the efficacy and safety of transcutaneous VNS in the management of headache 

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related to subarachnoid hemorrhage. We will screen patients diagnosed with subarachnoid 
hemorrhage who are admitted to Northshore University Hospital Neurosurgical Critical Care Unit. 
These are patients admitted under our care. Eligible patients will be enrolled after signing the 
informed consent. Enrollment will be performed between days 1 and 5 of aneurysm treatment. 
Subjects will be randomized into one of the two groups below: 
1.    Group 1: Control (patients will receive treatment using an inactive VNS device) 
2.    Group 2: Treatment (patients will receive treatment using an active VNS device) 
  
The Biostatistics Unit at the Feinstein Institute for Medical Research [BU-FIMR] will develop a 
randomization plan for the study using the Biostatistics Randomization Management System 
[BRMS]. BRMS is a secure, HIPAA-compliant, web-based application that allows investigators to 
randomize subjects into randomized clinical trials (RCTs) using a personal computer with internet 
access. A randomization allocation will be generated by the BU-FIMR using the method of 
permuted blocks. Details of the randomization procedure, including required record keeping will 
be further developed upon approval of the protocol. The treatment group will receive 2, 2 minute 
stimulations every 5 hours delivered by a blinded provider. The person assessing the pain 
intensity, vital signs, and giving pain killers and the participants will be blinded. Pain will be rated 
pre and post stimulation by the blinded caregiver. During NSCU stay at each stimulation, patients 
will be on continuous telemetry, and vital signs will be recorded before and at the end of the 
treatment and hourly for the rest of the day by the blinded caregiver. The control group will 
receive a sham device, the device is physically identical to the active device, and however no 
stimulation will be delivered. Patients in either group will be informed that they might feel a 
tingling sensation or muscle twitch with either device. Before the stimulation is initiated, vital 
signs will be checked. This includes HR, SBP, MAP, and oxygen saturation. If vital signs are stable, 
defined as HR>60 beats per minute, SBP> 100 mmHg, MAP> 60 mm HG, and saturation > 90% on 
room air, nasal cannula or face mask, the stimulation will be provided. In addition, both groups 
will receive standard of care abortive medications. Pain is usually assessed every 4 hours and as 
needed, and abortive medications are given depending on the intensity of the headache.  40 
patients will be enrolled, and VNS will be performed for up to 10 days.  
 
 
Figure: Protocol  
 
 
 
 
2-2 min VNS stimulation  
40 SAH  
20 n-VNS + Standard of care  
Every 5 hours 

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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This is a randomized sham-controlled pilot study. The patients and the person assessing the 
patient’s response will be blinded. Standard medical care treatment will be provided to both 
arms of the study.  
 
4.3 
JUSTIFICATION FOR DOSE 
This will be a transcutaneous stimulation of the cervical branch of the Vagus nerve to avoid the 
operative complications of invasive VNS. Stimulation frequency will be similar  to what was has 
been used in studies on headache.(17) Patients will receive a dosage based on the instructions 
from the gammaCore IFU: the physician or patient will start stimulating the cervical branch of 
the Vagus nerve and will gradually increase the amplitude to the most comfortable stimulation 
level.  
 
 
 
4.4 
END OF STUDY DEFINITION 
 
The study intervention will be up to 10 days in length. Vagus stimulation will be performed 4 
times daily (approximately at 6:30AM, 11:30AM, 4:30PM and 9:30PM).  Data collection will 
continue till hospital discharge. If the participant becomes hemodynamically unstable, defined 
as hypotension requiring vasopressors the VNS will be held for safety purposes. However, it will 
be resumed, once the patient is stabilized, off vasopressors for 48 hours. If the patient is being 
hemodynamically augmented for symptomatic vasospasm, n-VNS will not be withheld as the 
beneficial effects of n-VNS on symptomatic vasospasm will be investigated in this study.  
 
20 sham + Standard of care 
Every 5 hours 
2-2 min Sham 

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Figure: Study Timeline 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
Participants must fulfill all of the inclusion criteria in order to be eligible for the study:  
Screening and informed 
consent and randomization
ICU
VNS every 5 hours
Neurosurgery floor
VNS every 5 hours
Days 1-5  
Days2-10 

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- 
Established signed and dated informed consent form 
- 
Can be enrolled within 5 days of cerebral aneurysm treatment.  
- 
CT of the head revealing blood in the subarachnoid space 
- 
Subject has ruptured cerebral aneurysm or SAH patients who do not have vascular 
malformation on cerebral angiogram.  
- 
Subject is male or female 18 -75 years of age  
- 
Subject is alert able to verbalize pain at the time of enrollment  
- 
Subject reports pain of 7 and greater on a 10 Point Pain numeric rating scale or 
presenting with severe headache.  
- 
Female of reproductive age must have a negative pregnancy test (Urine or blood test) 
 
 
nVNS will only be performed if vital signs are stable (HR>60, SBP> 100 mmHg, MAP> 60 
mmhg, and saturation > 90% on room, nasal cannula or face mask). Then the vagus 
nerve will be stimulated.  
 
 
 
 
 
 
5.2 
EXCLUSION CRITERIA 
 
 
Patient who meets any of the following criteria will be excluded: 
- 
Use of any concomitant electrostimulation devices (Pacemaker, defibrillator, deep brain 
stimulation.)  
- 
Unsecured ruptured 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, SVT (including 
atrial fibrillation)  
- 
Alcoholics (CAGE scale of 2 or greater). If patients are on 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  
- 
Traumatic subarachnoid hemorrhage  
- 
Thin cortical subarachnoid hemorrhage not due to a cerebral aneurysm  
 
 
 
 

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Fria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.3 
LIFESTYLE CONSIDERATIONS 
There will be no lifestyle modification related to the study  
 
5.4 
PRE-SCREEN FAILURES 
Individuals who do not meet the criteria for participation in this trial (pre-screen failure) 
because of unsecured aneurysm intubated or has symptomatic hydrocephalus or symptomatic 
bradycardia may be rescreened once the aneurysm is secured, patient is extubated and 
stabilized, and EVD is placed. Rescreened participants should be assigned the same participant 
number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The neurosurgical critical care unit (NSCU) at Northshore University Hospital is the main referral 
unit for the healthcare system for patients with subarachnoid hemorrhage. All transferred 
patients  
are admitted to the NSCU, as a result, patients can be easily identified by the research team on 
a daily basis. Every day, the neurointensivist or the research coordinator will evaluate which 
patients admitted to the NSCU have been diagnosed with subarachnoid hemorrhage. If an 
aneurysm is found to be the cause of the SAH, surgical or endovascular treatment of the 
aneurysm is typically performed within 72 hours of diagnosis. Patients will be included in the 
study once the aneurysm has been treated. The primary investigator, or sub investigators will 
take consent from the patient. The primary investigator will ensure that the sub investigators 
and research assistants are trained and knowledgeable of the research protocol. Patients 
enrolled in the study will be followed up to 10 days starting 24 hours post successful treatment 
of the aneurysm unless discharged earlier from the hospital.  
 
We admit on average 110 SAH cases a year. If we assume that 50% satisfy our inclusion criteria, 
and that 70% will sign the inform consent, we should be able to reach our target number in 
approximately 12 months. Patients identified in the NSCU will be approached by the research 
team, and the study will be explained tothem.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 

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GammaCore has received FDA approval/clearance for the treatment of acute migraine and 
acute or preventive treatment of cluster headache. It has not been studied for the treatment of 
headache in SAH. Given the shared pathogenesis of headache in SAH and migraine, we would 
like to test the device in SAH patient population. Per the GammaCore IFU: “gammaCore 
Sapphire™ (non-invasive vagus nerve stimulator) is a multi-use, hand-held, rechargeable, 
portable device consisting of a rechargeable battery, signal-generating and -amplifying 
electronics, and a control button for the subject to adjust the signal amplitude. GammaCore 
Sapphire provides visible (display) and audible (beep) feedback on the device and stimulation 
status. A pair of stainless steel surfaces, which are the skin contact surfaces (stimulation 
surfaces), allows the delivery of a proprietary electrical signal. Tubes of electroCore-approved 
gel are provided with each unit. The subject applies the gel to the stimulation surfaces to 
maintain an uninterrupted conductive path from the stimulation surfaces to the skin on the 
neck. The stimulation surfaces are capped when not in use. gammaCore Sapphire produces a 
low-voltage electric signal consisting of five 5000-Hz pulses that are repeated at a rate of 25 Hz. 
The waveform of the electric pulses is approximately a sine wave with a peak voltage limited to 
24 V when placed on the skin and a maximum output current of 60 mA.(19). Each stimulation is 
designed to be applied for two minutes (120 seconds), after which the device automatically 
turns off. Each device allows for multiple stimulations”.(19) 
6.1.2 DOSING AND ADMINISTRATION 
Two-two minute transcutaneous stimulations will be administered every 5 hours 
(approximately 6:30AM, 11:30 AM, 4:30 PM and 9:30 PM) with no relation to meals. Some 
patients might miss few stimulations as they might be getting a procedure, have unstable vital 
signs, or refuse the stimulation, amongst other reasons that might make stimulation not 
feasible. If vital signs are stable (HR > 60 beats/minute, and SBP> 100 mmHg and MAP> 60 
mmhg and saturation > 90% on room, nasal cannula or face mask,), nVNS or Sham will be 
initiated. We will start by placing gel on the skin of the neck, the device will be placed in direct 
contact with the gel and the skin. The stimulation will be performed by the patient, with 
assistance from an IRB approved personnel if the patient is uncomfortable performing it. The 
stimulation intensity will be increased as directed by the gammaCore pamphlet. Patients will be 
informed that they may or may not feel a tingling sensation with the investigational device and 
the sham device. Two 2 minutes stimulation will be provided. Tolerance will be assessed during 
and directly after stimulation and every 5 hours afterwards as directed by the intensivist on call. 
 
If a digital subtraction angiography is being performed for vasospasm, nVNS will be delivered to 
assess its effect on cerebral vasospasm. 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 

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Electrocore is providing gammaCore devices, providing expertise related to study design and 
execution and will provide device training prior to study initiation.  ElectroCore will not be 
involved in the acquisition of data. Devices will be tracked using a device accountability log. 
  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
 
gammaCore (nVNS) Sapphire(19)   
 
 
 
 
 
 
 
 
The device or its immediate package will bear a label with the following information: 
1- The name and place of business of the manufacturer, packer, or distributer 
2- The quantity of contents  
3- The following statement “CAUTION-Investigational device. Limited by Federal (or United States) 
law to investigational use”  
4- The labels will describe all relevant contraindications, hazards, adverse effects, interfering 
substances or devices, warnings, and precautions  
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
 “gammaCore should be stored at room temperature away from moisture • Range: 0°C to 38°C 
(32°F to 100°F),  Humidity: 10% to 90%, Barometric Pressure: 80 to 101 kPa Replace cap after 
each use, Store the device in such a way (eg, drawer or shelf) that the cap remains in place and 
are not accidentally removed”. (19) 
 
 
 
6.2.4 PREPARATION 

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Per the gammaCore pamphlet “Charge your device before first use. Allow 6 to 7 hours for a full 
charge. High temperatures may increase the charging time. If the device has no charge, it takes 
only a few minutes to charge an additional two to three treatments. Monitor battery life and 
charge as needed to maintain adequate number of treatments on device”(19) 
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
To minimize bias, this will be a randomized controlled trial. Patients will be randomized using 
variable block design, assigning patients 1:1 to the treatement group n-VNS and sham group, 
with concealment of allocation. Participants and the provider assessing the pain scale, providing 
the pain killers and assessing for adverse events will be blinded.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
The trial will be evaluated on a daily basis if there are active patients enrolled. The principle 
investigator will meet monthly with the study coordinator, research assistant and co-
investigators evaluating the adherence with the study protocol.  
 
The vital signs, medication administered, and pain assessment will be recorded as standard of  
care in our electronic medical record SUNRISE.  
 
 
6.5 
CONCOMITANT THERAPY 
 
Patients will be given standard of care medication for delayed cerebral ischemia prophylaxis 
and opiates and acetaminophen for pain control. Opiate addicts and patients on chronic opiates 
at home will be excluded.  
 
6.5.1 RESCUE MEDICATION 
 
Rescue pain killers will be given per standard of care in both groups. 
   
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
The study intervention will be held during procedure days, or if the participant gets intubated, 
or is in shock (cardiogenic, distributive or septic). During non-procedure days, or once 
extubated and stabilized and participant becomes alert the study intervention can be resumed.  
 

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In addition, as stated earlier, if HR< 60 beats/min, SBP<100 mm HG, or MAP< 60 mm HG and 
oxygen saturation < 90 %, the intervention will be postponed.  
 
If hemodynamic instability or unstable arrhythmia occur during the VNS, and is thought to be 
due to the VNS by the investigator, the participant will be discontinued from the study 
procedure, however, will be followed until discharge from the hospital.  
 
If a clinically significant finding is identified (including, but not limited to changes from baseline) 
after enrollment, the investigator or qualified designee will determine if any change in 
participant management is needed. Any new clinically relevant finding will be reported as an 
adverse event (AE). 
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
• Significant study intervention non-compliance  
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• Disease progression which requires discontinuation of the study intervention 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• Participant unable to receive the study intervention for more than 3 consecutive days 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form but do not receive the 
study intervention may be replaced.  Subjects who sign the informed consent form, and receive 
the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 
There should be no loss of follow up as this is an inpatient study.  The study will last for up to 10 
days. 
 
8 
 STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Per standard of care, patients presenting with signs of SAH like acute severe headache, will get 
a diagnostic head CT which confirms blood in the subarachnoid space. If patients have 
symptomatic hydrocephalus (altered mental status with CT head consistent with 

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hydrocephalus) an external ventricular drain will be placed. Most patients will get either a CT 
angiogram or a conventional angiogram to rule out a vascular malformation, especially if there 
is no history of trauma. If an aneurysm is detected, the standard of care is to treat it as soon as 
possible. Usually, an aneurysm iseither coiled or clipped (craniectomy or craniotomy). Every 
patient admitted with subarachnoid hemorrhage will get graded accordingly to their headache 
intensity, level of consciousness and neurologic deficits with the Hunt Hess grade (table 2). 
Their CT scans also get graded (modified fisher scale mFS) according to the thickness and 
location of blood (table 3). All subarachnoid hemorrhage (unless there is minimal amount of 
blood and no vascular malformation) are admitted to the Neurosurgical care unit (NSCU). 
Detailed physical examination, including the NIHSS, history, including medication history, past 
medical, surgical history, and social history are recorded in the medical records. North Shore 
University hospital NSCU is the referral center for most of the hospitals in Northwell health care 
system. Most aneurysmal SAH patients get transferred to our unit. Per standard of care, all 
women of child bearing age, admitted to the NSCU get a urine or blood pregnancy test, patients 
suspected of abusing drugs get urine toxicology. Once in the NSCU, patients get vital signs and 
neurologic assessment every hour, and pain assessment every 4 hours and as needed. The 
length of stay in the intensive care unit depends on the amount of blood on the head scan 
(mFS). Patients with higher mFS are more prone to get delayed cerebral ischemia. As a result, 
per standard of care, patients with SAH get almost daily transcranial dopplers to monitor for 
cerebral vasospasm, frequent head scans, occasionally brain perfusion studies and MRI of the 
brain. Patients are monitored for central fever (vital signs, blood cultures), cerebral salt wasting 
with frequent BMP and urine output measurements, seizures with PRN electroencephalograms 
(EEG). Once out of the critical care period, (vasospasm usually starts at day 3 post bleeding and 
peaks at day 10), patients get transferred to a regular neurosurgical floor before being 
discharged home or to rehabilitation. On average patients stay in the NSCU between 2-21 days. 
All patients admitted to the NSCU with SAH will be screened and evaluated for the inclusion 
and exclusion criteria after obtaining an informed consent. 
 
Screening involves reviewing the medical records following HIPPA regulation for: Age, gender, 
ethnicity, presence of aneurysm, day of rupture, etiology of the SAH if not aneurysmal, 
radiologic ( Angiogram, CT head) and medical history before and after the aneurysm is secured, 
Glasgow coma score before and after aneurysm repair, modified fisher scale (mFS), Hunt-Hess 
grade ( HHS), time of ictus, history of alcohol and drug abuse, presence of hydrocephalus on 
head CT, presence of an external ventricular drain ( EVD) , date of EVD placement, new HHS 
after EVD placement, clipping or coiling.  Medical records will be reviewed for the past medical 
history (pacemaker, defibrillator, history of CHF, arrhythmias, cervical carotid disease, history of 
a headache disorder like migraine or cluster headache), physical examination, labs will be 
reviewed which includes but not limited to pregnancy test and urine toxicology. Headache 
intensity and opiate, steroids and acetaminophen usage are recorded in the electronic medical 
record. The presence of vasospasm and delayed cerebral ischemia will be noted.  
Once found eligible satisfying the inclusion and exclusion criteria, and informed consent signed, 
patients will be randomized to either the treatment group or the control group. The same data 
will be recorded for both groups. The treatment period will start once admitted in the NSCU 
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During the NSCU stay, patients areevaluated for pain every 4 hours. If vital signs are stable 
(SBP> 100 mmHg and HR> 60 beats per minutes with no arrhythmia on telemetry, MAP> 60 
mmHg and oxygen saturation > 90%) patient will receive either the treatment (nVNS) or the 
Sham device every 5 hours. Headache intensity will be evaluated every four hours. In addition, 
vital signs will be noted just after stimulation, and hourly afterwards or as ordered by the 
physician. The daily mean morphine equivalence dosage will be recorded. Concomitant 
medications will be recorded.  
 
During the ICU length of stay, the following will be assessed and recorded per standard of care : 
• Transcranial dopplers (TCD) 
• Neuroimaging (CT head, MRI brain, angiograms, CT perfusion with permeability study)  
• EVD weaning and day of start of weaning 
• Presence of vasospasm, delayed cerebral ischemia, Central fever, Cerebral salt wasting. 
These are usually recorded in the medical record. 
• Urinary retention documented as frequent straight catheterization for more than 3 days  
• Constipation evaluated by the need for enema, suppository, lactulose or magnesium 
oxide administered   
• Blood tests, CSF studies 
• EEG results  
• Neurologic examination including Glasgow coma score, and NIHSS 
• Delirium score  
 
When Transcranial dopplers are being done as per standard of care, we will assess the 
changes in transcranial velocities around the time of the stimulation of the Vagus nerve. 
 
When possible, we will draw blood or in case there is an EVD we will also collect CSF for 
biomarkers. Not more than 5 ml of blood will be drawn  before the 11:30 am stimulation 
session of the Vagus nerve. This will be repeated approximately 24 hours later, at 11:30 
am post VNS stimulation session. This might be repeated on days 5 and 7  post-ictus  
In case there is an EVD, 2 cc of CSF from the drain and 20 cc of CSF that is otherwise 
discarded will be drawn before the 11:30 am stimulation session of the Vagus nerve. 
Another 2 cc of CSF from the drain and 20 cc of CSF that is otherwise discarded will be 
drawn approximately 24 hours later, at around 11:30 am post VNS stimulation session. 
This might be repeated on days 5 and 7 post-ictus.  
The CSF will not be taken from the proximal port of the EDV unless it is being tested for 
CSF cell count or cultures as per standard of care. This is in order not to increase the risk 
of infection.  
Deidentified blood and CSF will be sent to Dr. Lauren Sansing, academic chief in the 
department of stroke and vascular neurology, Yale, 300 George St suite 353, 06511. 
 

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IF CT perfusion is being performed per standard of care between days 3-10, blood brain 
permeability will be evaluated and results will be compared between the sham group 
and the active device group.  
 
 
During the period of the study after the patients are discharged from the ICU to the 
Neurosurgical floor, we will evaluate their daily headache intensity and morphine 
equivalence dosage, in addition to their TCD results, Neuroimaging and EEG results, 
neurologic examination and vital signs. 
 
Table 2: Hunt-Hess Score in aneurysmal SAH: (26, 27) 
1. Asymptomatic, mild headache, slight nuchal rigidity 
2. Moderate to severe headache, nuchal rigidity, no neurologic deficit other than cranial 
nerve palsy 
3. Drowsiness, confusion, mild focal neurologic deficit 
4. Stupor, moderate-severe hemiparesis 
5. Coma, decerebrate posturing 
Table 3: Modified Fisher Scale:(28) 
• grade 0: no subarachnoid hemorrhage (SAH), no intraventricular hemorrhage (IVH) 
• grade 1 focal or diffuse, thin SAH, no IVH 
• grade 2 thin focal or diffuse SAH, IVH present 
• grade 3 thick focal or diffuse SAH, no IVH 
grade 4: thick focal or diffuse SAH, IVH present 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
nVNS has been proven to be safe. However, the risks of VNS in SAH population are not known. 
In order to minimize the risks, if an aneurysm has been identified to be the cause of the SAH, 
patients will only be enrolled if the aneurysm has been completely treated. This information 
will be pulled from the medical record. Past medical and surgical history, respiratory and 
hemodynamic state will be pulled from the medical record. Vital signs and neurologic 
examinations are usually performed every 1 to 4 hours depending on the acuity of each case, 
and pain assessment evaluated every 4 hours and as needed. In the NSCU, patients are on 
continuous ECG analyzes via telemetry. Stimulation will only be given if HR >60 and the 
SBP>100 mmHg, MAP> 60 mmHg and oxygen saturation is >90% for safety concerns. The 
presence of intolerable pain at the stimulation site, skin irritation, hoarseness, and change in 
the taste, shortness of breath, chest pain, nausea, and vomiting will be evaluated.   
 
Safety outcomes: 

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- 
Rate of Symptomatic bradycardia defined as a drop in HR to less than 60 beats per 
minutes with symptoms, not due to nimodipine. The timing of nimodipine relative to 
the VNS will be recorded. All patients are on telemetry during the stimulation. 
- 
Rate of drop in blood pressure, defined as a drop in blood pressure requiring fluid 
resuscitation or vasopressor support thought to be due to the device. 
- 
Rate of side effects: presence of intolerable pain at the stimulation site, skin irritation, 
nasopharyngitis, hoarseness, dysgeusia, shortness of breath, chest pain, nausea and 
vomiting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 
 

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of the nVNS 
and/or Standard of Care Treatments, whether or not considered device-related or drug-related. 
 
 
Screening
Days 1-3
• Total n=40
• Obtain informed consent
• Screen potential participants by inclusion and exclusion criteria
• Obtain history, document
• Randomize 
Baseline assessments/ Study Intervention
Days 2-4 till discharge 
from ICU
• Administer initial dose of study intervention 
• Obtain daily cumulative dosage of all pain medication
• Evaluate presence of evolving stroke on head CT or MRI brain
• Evaluate seizures documented on EEG
• Complete vital signs before and after each stimulation and daily trend 
• Questionaire for side effects from VNS post every stimulation
• Trend in daily Transcranial dopplers (TCD) 
• Incidence of symptomatic vasospaspm
• Presence of central fever
• Patient satisfaction
End of the study
Discharge from the 
hospital or day 10 
post-ictus

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8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
Serious adverse event is defined as in the view of the investigator, the occurrence of any of the 
following complications: 
 
Death 
A life-threatening adverse event such as any hemodynamically unstable arrhythmia 
Prolongs existing hospitalization 
Results in persistent or significant incapacity or disability 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
8.3.2.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity.  
 
• Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities like skin irritation, transient dysgeusia, transient hoarseness, 
vomiting, mild pain at the stimulation site during stimulation.  
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning, 
like mild shortness of breath, chest pain and reversible facial palsy. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
Like hypotension requiring treatement, hemodynamic stable arrhythmia, severe 
dyspnea requiring medical treatment  
 
 
 
8.3.2.2 RELATIONSHIP TO STUDY INTERVENTION 
 
Using the investigator clinical judgment, the relation of the adverse events to the use of the 
device will be reported as,  
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 

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chemicals. The response to withdrawal of the study intervention (dechallenge) should 
be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and later 
be upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There 
must be an alternative, definitive etiology documented by the clinician. 
 
8.3.2.3 EXPECTEDNESS  
Some of the expected adverse events are: application site discomfort, application site 
irritation/redness, local pain, face/head/neck area (including toothache), muscle twitching 
and/or contractions, face/head/neck area (including facial droop and/or lip pull), 
headache/migraine, dizziness, tingling, pricking, or a feeling of “pins and needles” on the skin 
where the device is applied (paresthesia/dysesthesia) 
 
Additional expected adverse events, which have been associated with other VNS devices, are 
cough, gastrointestinal discomfort, hoarseness or change in voice, irregular heart beat 
(arrhythmia), metallic taste, nausea, shortness of breath (dyspnea)  
 
The principle investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention. 
 
 

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8.3.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may arise at any time. 
As a result, the patient will be evaluated directly after each stimulation. The neurointensivist in 
charge will determine the frequency of vital signs and neurologic examination checks.  
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity and relatedness to the study 
device, and time of resolution/stabilization of the event. All AEs occurring while in the study 
must be documented appropriately regardless of the relationship to the device. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The principal investigators will record all reportable events with start dates occurring any time 
after informed consent is obtained until 3 days after the last day of study participation (Vagus 
nerve is stimulated), or until discharge from hospital (whatever comes first) .  Events will be 
followed for outcome information until resolution or stabilization. 
 
8.3.4 ADVERSE EVENT REPORTING  
Given that patients with SAH experience many known complications, like hydrocephalus, 
strokes, delayed cerebral ischemia, cerebral vasospasm, fever, electrolyte disturbance, post-
operative complications, only adverse effects that are thought to be related to the study device 
or are unexpected as part of the natural course of subarachnoid hemorrhage will be reported. 
The Neurointensivist in charge of the patient will evaluate all side effects and deem its 
seriousness and relatedness to the device.  
 
All adverse effects thought to be part of the natural history of SAH, or mild side effects that are 
expected to occur during the VNS such as skin irritation, muscle twitch, transient dyspnea 
during stimulation, transient hoarseness during stimulation, mild pain at the stimulation site 
will be recorded in the participant’s medical record and will be collected as secondary 
endpoints. All serious or severe or unexpected side effects related to the device will be 
reported to the IRB within 7 days of the PI’s knowledge. Any unknown adverse event thought to 
be related to the device will also be reported to the IRB.  
 

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Adverse Events reporting: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.5 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will report to the IRB any serious adverse event related or potentially related 
to the study intervention. All serious adverse events (SAEs) will be followed until satisfactory 
resolution or until the site investigator deems the event to be chronic or the participant is 
stable.  
 
 
POTENTIAL SERIOUS ADVERSE EVENT mentioned in section 8.3.2 
Monitoring: Participants will be on continuous telemetry recording continuously the 
EKG, respiratory rate, oxygen saturation, Blood pressure will be recorded one-hour 
post-stimulation and 1-4 hours afterwards. Vital signs will be recorded before and 
directly after stimulation, the medical professional will be at bedside during the 
stimulation monitoring any side effect. Vital signs and neurologic examination are 
evaluated every 1-4 hours and as needed afterwards. The VNS will be performed in 
the intensive care unit setting, where personnel are trained in cardiopulmonary 
resuscitation and treating hemodynamically unstable patients.  
 Is the adverse Event Serious related or 
potentially related to the device 
Record in the medical 
records  
Unexpected in frequency  
Unexpected Adverse 
Report to the IRB within 7 day 
of PI’s knowledge   
YES 
YES 
YES 
NO 
NO 
NO 

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Actions: 
o Participants must have stable vital signs (SBP> 100mmHg, MAP>60 mmHg, HR> 
60 beats/minute, oxygen saturation > 90%, not on mechanical ventilation) 
before the vagus nerve is stimulated. If unstable vital signs, the stimulation will 
be skipped, until the patient is more stable.  
o If the participants develop a life-threatening arrhythmia thought to be due to the 
VNS, subject will be taken off therapy, but will continue to be followed until end 
of study. 
o If the participants get intubated or develops hemodynamic shock due to the 
natural history of the disease, the subject will be taken off the therapy.  
The study investigator shall complete an Unanticipated Adverse Device Effect Form and 
submit to the reviewing Institutional Review Board (IRB) as soon as possible, but in no 
event later than 7 working days after the investigator first learns of the effect.  The 
principle investigator is responsible for conducting and evaluating any unanticipated 
adverse device effect and shall report the results of such evaluation to the reviewing IRB 
and participating investigators within 7 working days of the event.  
 
 
8.3.6 REPORTING EVENTS TO PARTICIPANTS  
Participants will be directly informed of side effects considered to be related to the VNS.  
 
8.3.7 EVENTS OF SPECIAL INTEREST  
Not applicable. 
8.3.8 REPORTING OF PREGNANCY  
 
Not applicable, only woman with negative pregnancy test will be enrolled in this inpatient trial 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
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• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB). The UP report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• UPs that are serious adverse events (SAEs) will be reported to the IRB within 2 days of 
the investigator becoming aware of the event.  
• Any other UP will be reported to the IRB within 7 days of the investigator becoming 
aware of the problem.  
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
The participant will be individually informed of any UP. Given that the patients are in the 
intensive care unit and that most side effects occur during stimulation, the individual will be 
informed directly (within 3 days) of the unanticipated problems. 3 days in order to make sure 
that the UP is due to the VNS.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
There are no statistical hypotheses in this study. This is a feasibility pilot study that will allow us to 
better calculate the sample size for a large randomized control study comparing VNS to sham 
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The primary outcome measurements for effectiveness will be: 
 
-The difference between the active and sham treatment groups in mean daily morphine 
equivalence dosage during the study period 
 
 
 
Secondary endpoints include descriptive comparisons between the active and sham treatment 
groups in: 
 
- The difference between the active and sham treatment groups in mean daily headache 
intensity during the study period 
- 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, nausea, 
vomiting and pruritis) 
 
Exploratory analyses will include comparisons of the rates of stroke, vasospasm, DCI, seizure, 
central fever and severity of vasospasm between the active and sham treatment groups. 
  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
There are no statistical hypotheses in this study, and therefore there is no sample size 
justification for this study. This is a feasibility pilot study that will allow us to better calculate 
the sample size for a large randomized control study comparing VNS to sham device.  
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Participants who received at least 1 stimulation will be included in the Intent To Treat (ITT) 
population. Opiate usage and pain intensity during the days of procedures in which patients are 
intubated and unconscious will be excluded from the analysis. The days of EDV weaning will be 
noted, given that hydrocephalus can cause headache due to high ICP. A modified Intent-to-treat 
(mITT) population inclusive of all subjects who treat at least 7 days with at least 3 stimulations 
of the study device; and a per-protocol (PP) population of people who are compliant with the 
treatment regimen for the duration of the study will be analyzed.   
 
9.4 
STATISTICAL ANALYSES 
9.4.1 General Approach 
Discrete variables will be tabulated by frequency and proportion of subjects falling in each 
category.  

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Continuous variables will be summarized using mean, standard deviation, median, minimum 
and maximum values. 
 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
-The difference between the active and sham treatment groups in daily mean morphine 
equivalence dosage during the study 
 
Repeated measures mixed models will be used to describe the difference between the active 
and sham treatment groups in morphine equivalence dosage during NSCU length of stay. 
Morphine equivalence dosage will be modeled as a function of treatment group and 
measurement time. Subject will be included as a random effect. Least squared means will be 
used to estimate the treatment effect. 
 
 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S)  
 
- The difference between the active and sham treatment groups in mean headache intensity 
during study period 
 
Repeated measures mixed models will be used to describe the difference between the active 
and sham treatment groups in mean headache intensity during NSCU length of stay. Pain will be 
modeled as a function of treatment group and measurement time. Subject will be included as a 
random effect. Least squared means will be used to estimate the treatment effect. 
 
- The difference between total overall morphine equivalence dosage between the active and 
sham group per subject during study  
 
Total overall morphine equivalence dosage in the active and sham treatment groups will be 
compared using analysis of covariance (ANCOVA) with adjustment for number of days in study. 
 
-Opiate related adverse events (such as urinary retention, constipation, sedation, nausea, 
vomiting and pruritis) 
 
 
 
9.4.4 SAFETY ANALYSES 
The primary safety endpoint of this clinical investigation is the overall incidence of device-
related serious AEs. The primary safety analysis will be summarized and presented as 
proportions and respective 95% exact binomial confidence intervals (CIs).  The rate of opiate 

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related adverse events will similarly be presented as proportions and respective 95% exact 
binomial confidence intervals. 
Frequency and percentage of subjects experiencing a specific adverse event will be tabulated 
by system organ class, preferred term, and treatment group. Summary tables and subject data 
listings will be provided. 
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
NA 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
A safety interim analysis may be considered if deemed necessary by the principal investigator  
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
 
10.1.1.1 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
If the patient is physical disabled and is unable to sign the informed consent, oral consent process for 
more than minimal risk research will be followed as stated in the HRPP Policy and Procedures Manual. If 
patient decision capacity is in doubt, a mini mental state examination will be performed, and if the score 
is <24, the signature of a healthcare Agent, guardian or next of kin will be required with an assent 
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Via Telephone/Email/Mail (one or in combination) for LAR’s that are off-site: 
 
Investigator may contact (or be contacted by) a potential LAR by telephone or email to 
discuss participation in a research study. Investigator must provide LAR with all the 
information contained in the consent form. Investigator will answer any questions regarding 
the research study and giveLAR ample time to consider participation in the study. (May 
require follow-up email/phone conversation). IfLAR indicates interest in participating in the 
research study, the LAR will be informed of the next steps necessary to provide informed 
consent   
a. A consent form will be sent to the LAR by regular mail ( if no email access), an email 
attachment  
b. The LAR must read the consent form and call or email the investigator if he/she 
wishes to discuss the research and resolve issues/questions 
 
If LAR agrees to participate in research, he/she should sign the consent form and return it to 
the investigator by one the following methods: 
c. Mail or fax hard copy to the site 
d. Return a picture/image of signed consent form  
e. Scan the signed consent form and return it to the investigator as an email 
attachment.  
f. If the LAR received the consent electronically but does not have access to printing, 
the following will apply 
i. The LAR will verbally consent (with a witness on the phone) and respond via 
email documenting the confirmation he/she consents.  
ii. A copy of the email confirming consent will be filed in the subject’s binder.  
iii. LAR may sign and return the ICF on a future date. 
An enrollment note must be written by the investigator documenting all phone conversations 
with the subject. Printouts of any email correspondence must be placed in the subject’s file. 
After the signed consent form is received, investigator will sign the consent form and date the 
signature with the current date. The investigator should add a note detailing the date 
discrepancy of the signatures. A copy will be made and sent to the LAR for his/her records.  
   
If a consent form is returned missing a signature, the participant will be notified by phone or 
email. A copy will be made and kept in the participant’s file and the original will be sent back to 
the participant for completion and resubmission to the investigator. 
 

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1. Documentation required 
a. How was the ICF transmitted to the LAR (email, mail, fax ) 
b. How was the LAR signature obtained (e-signature, scanned and email back, mailed 
back, took a picture of signature page emailed/text back, verbal assent with witness 
present and subsequent email confirmation) 
c. Enrollment note written by investigator documenting consent discussions by phone 
with the LAR 
d. Statement describing how fully signed consent copy was given to LAR 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Verbal notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and will provide the reason(s) 
for the termination or suspension.   
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and their interventions. This confidentiality is extended to clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the primary investigator. 
 
All research activities will be conducted in as private a setting as possible. 
 
Representatives of the Institutional Review Board (IRB) may inspect all documents and records required 
to be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study.  
 

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The study participant’s contact information will be securely stored for internal use during the study. At 
the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB, Institutional policies.  
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored in Northwell database This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a 
unique study identification number. The study data entry and study management systems used by 
clinical sites and by Northwell research staff will be secured and password protected. At the end of the 
study, all study databases will be de-identified and archived at the Northwell data base 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
NA 
 
 
 
 
 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator and 
medical monitor 
Tania Rebeiz, MD, Assistant 
professor  
Northshore University Hopsital  
 
3126228808 
trebeiz@northwell.edu 
 
10.1.6 SAFETY OVERSIGHT 
 
The principle investigator will be responsible in collecting any adverse event and reporting it to the IRB. 
An un-blinded co-investigator not involved in the study procedure will review aggregate safety data on a 
weekly basis. 
 
10.1.7 CLINICAL MONITORING HEALTHCARE PROVIDER 
The principle investigator will ensure that the rights and well-being of trial participants are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s) 
 
• 
Monitoring for this study will be performed by the principle investigator, co-investigators the 
research coordinator and research assistants.  

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• 
At the start of the intervention, the principle investigator or co-investigators will be performing 
the vagus nerve stimulation and teaching the patients andIRB approved personnel  on how to 
use the device. This will be done for the first 3 episodes of headache. On site assessment will be 
performed daily by the research team.   
• 
An unblinded investigator not involved in the study will be review unexpected adverse events or 
serious adverse events  
• 
uPhysical examination Neurologic examination will be recorded, including the NIHS scale as part 
of standard of care. 
• 
Vital signs (e.g., temperature, pulse, respirations, blood pressure, oxygen saturation) every hour 
or as ordered by the physician, and before and after each stimulation.  
• 
Electrocardiograms (EKGs): EKG will be performed at baseline. Patients will be on continuous 
cardiac monitoring, (telemetry) during the study. If any changes detected on telemetry 
(arrhythmia) or chest pain or dyspnea during the stimulation, an emergent EKG will be done. 
The EKG will be printed on a paper and stored in SUNRISE and will be read directly. EKG will also 
be done as needed per physician’s request.  
• 
Radiographic or other imaging assessments. Reports of CT scan, MRI brain, CT angiogram, CT 
perfusion, conventional angiogram, transcranial dopplers done as standard of care diagnosis will 
be collected.  
• 
Biological specimen collection and laboratory evaluations. Standard of care blood tests 
including CBC, BMP, LFT, cultures, procalcitonin when done will be evaluated.   
 
Assessment of study intervention adherence or see Study Intervention Compliance, section 6.4 
Headache: headache intensity and quality will be evaluated as part of the standard of care every 4 
hours.  
 
Assessment of adverse events. Side effects are evaluated during the stimulation, directly afterwards 
until resolution as appropriate. The neurointensivist will evaluate the need for more frequent vital signs 
assessment.  
• 
Patient’s satisfaction with using the VNS in managing the headache intensity will be evaluated: 
Satisfaction will be rated on a 5-point scale: 1- very unsatisfied, 2- mild unsatisfied, 3- 
indifferent, 4- satisfied, 5 very satisfied. 
 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
We will perform internal quality management of study conduct and data collection, 
documentation and completion.   
 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be evaluated by the principle investigator.  
 
The primary investigator, and research coordinator will verify that the clinical trial is conducted 
and data are generated and documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP), and 

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applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)).  
 
A protocol on when to use the VNS and abortive medications will be given to all healthcare 
providers taking care of the patients.  
All study personnel will be trained on how to collect the data. The principle investigator will 
check the data on a weekly basis. The principle investigator and the electrocore company will 
train the healthcare providers on how to use the device. Data will be recorded in redcap. Most 
of the information is pulled from our electronic medical records, SUNRISE.  
 
 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff. The investigators are responsible 
for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.   
 
Hardcopies of the study work sheets will be provided for use as source document worksheets 
for recording data for each participant enrolled in the study.  Data recorded in the electronic 
case report form (eCRF) derived from source documents should be consistent with the data 
recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be recorded in paper CRFs and transcribed into 
the redcap database for statistical analysis purposes. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents.  
 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for 10 years after completion of the study.  These 
documents should be retained for a longer period, however, if required by local regulations. 
Permission is not required prior to destruction of records.  
 
 
10.1.10 
PROTOCOL DEVIATIONS  

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A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) 
requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working 
days of the scheduled protocol-required activity.  Protocol deviations must be sent to the 
reviewing Institutional Review Board (IRB) per their policies. The investigator is responsible for 
knowing and adhering to the reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will 
be made to publish results in peer-reviewed journals.  Data from this study may be requested 
from other researchers x years after the completion of the primary endpoint by contacting 
<specify person or awardee institution, or name of data repository. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in 
the design and conduct of this trial.  The study leadership in conjunction with the IRB has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest 

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10.2 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
 
1. 
Swope R, Glover K, Gokun Y, Fraser JF, Cook AM. Evaluation of headache severity after aneurysmal 
subarachnoid hemorrhage. Interdisciplinary Neurosurgery. 2014;1(4):119-22. 
2. 
Magalhães JE, Azevedo-Filho HR, Rocha-Filho PA. The risk of headache attributed to surgical treatment of 
intracranial aneurysms: a cohort study. Headache. 2013;53(10):1613-23. 
3. 
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;110:e100-e11. 
4. 
Glisic EK, Gardiner L, Josti L, Dermanelian E, Ridel S, Dziodzio J, et al. Inadequacy of Headache 
Management After Subarachnoid Hemorrhage. Am J Crit Care. 2016;25(2):136-43. 
5. 
Morad AH, Tamargo RJ, Gottschalk A. The Longitudinal Course of Pain and Analgesic Therapy Following 
Aneurysmal Subarachnoid Hemorrhage: A Cohort Study. Headache. 2016;56(10):1617-25. 
6. 
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;81(5):490-3. 
7. 
Oshinsky ML, Murphy AL, Hekierski H, Jr., Cooper M, Simon BJ. Noninvasive vagus nerve stimulation as 
treatment for trigeminal allodynia. Pain. 2014;155(5):1037-42. 
8. 
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;102:96-104. 
9. 
Frangos E, Komisaruk BR. Access to Vagal Projections via Cutaneous Electrical Stimulation of the Neck: 
fMRI Evidence in Healthy Humans. Brain Stimul. 2017;10(1):19-27. 
10. 
Bosche B, Graf R, Ernestus RI, Dohmen C, Reithmeier T, Brinker G, et al. Recurrent spreading 
depolarizations after subarachnoid hemorrhage decreases oxygen availability in human cerebral cortex. Ann 
Neurol. 2010;67(5):607-17. 
11. 
Chen SP, Ay I, de Morais AL, Qin T, Zheng Y, Sadeghian H, et al. Vagus nerve stimulation inhibits cortical 
spreading depression. Pain. 2016;157(4):797-805. 
12. 
Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a 
missing link in neuroimmunomodulation. Mol Med. 2003;9(5-8):125-34. 
13. 
Suzuki T, Takizawa T, Kamio Y, Qin T, Hashimoto T, Fujii Y, et al. Noninvasive Vagus Nerve Stimulation 
Prevents Ruptures and Improves Outcomes in a Model of Intracranial Aneurysm in Mice. Stroke. 
2019:STROKEAHA118023928. 
14. 
George MS, Ward HE, Ninan PT, Pollack M, Nahas Z, Anderson B, et al. A pilot study of vagus nerve 
stimulation (VNS) for treatment-resistant anxiety disorders. Brain Stimul. 2008;1(2):112-21. 
15. 
Pascal G. Transcutaneous Vagus Nerve Stimulation in Private Healthcare Center  [ 
16. 
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;9:44. 
17. 
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;11:1613-25. 

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18. 
Reuter U, McClure C, Liebler E, Pozo-Rosich P. Non-invasive neuromodulation for migraine and cluster 
headache: a systematic review of clinical trials.  J Neurol Neurosurg Psychiatry. 90. England: Author(s) (or their 
employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. 
Published by BMJ.; 2019. p. 796-804. 
19. 
Gammacore. https://gammacorecom/wp-content/themes/gammacore-p2/pdf/gammacore_IFUpdf. 
20. 
Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R, et al. Safety and tolerability of Transcutaneous Vagus 
Nerve stimulation in humans; a systematic review. Brain Stimul. 2018. 
21. 
Burgman T, Samadani U. Vagus Nerve Stimulation to Treat Moderate Traumatic Brain Injury 2016 
[https://clinicaltrials.gov/ct2/show/NCT02974959]. 
22. 
Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, et al. Safety, Feasibility, and Efficacy of 
Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke. Stroke. 2016;47(1):143-50. 
23. 
Steinberg BE, Sundman E, Terrando N, Eriksson LI, Olofsson PS. Neural Control of Inflammation: 
Implications for Perioperative and Critical Care. Anesthesiology. 2016;124(5):1174-89. 
24. 
Duris K, Manaenko A, Suzuki H, Rolland WB, Krafft PR, Zhang JH. alpha7 nicotinic acetylcholine receptor 
agonist PNU-282987 attenuates early brain injury in a perforation model of subarachnoid hemorrhage in rats. 
Stroke. 2011;42(12):3530-6. 
25. 
Hays SA, Khodaparast N, Hulsey DR, Ruiz A, Sloan AM, Rennaker RL, 2nd, et al. Vagus nerve stimulation 
during rehabilitative training improves functional recovery after intracerebral hemorrhage. Stroke. 
2014;45(10):3097-100. 
26. 
Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. 
J Neurosurg. 1968;28(1):14-20. 
27. 
Hunt WE, Meagher JN, Hess RM. Intracranial aneurysm. A nine-year study. Ohio State Med J. 
1966;62(11):1168-71. 
28. 
Frontera JA, Claassen J, Schmidt JM, Wartenberg KE, Temes R, Connolly ES, et al. Prediction of 
symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59(1):21-
7; discussion -7. 
 
 
 

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POSSIBLE ALTERNATIVE AE SECTION 
11.1 
ADVERSE EVENTS/ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES  
The definitions and procedures for reporting adverse events (AE), adverse device effects (ADE), 
serious adverse events (SAE), serious adverse device effects (SADE) and are presented in the 
sections below. It is of utmost importance that all staff involved in the investigation are familiar 
with the definitions and procedures and it is the responsibility of the Clinical Investigator to 
ensure this.  
11.1.1 
ADVERSE EVENT/ADVERSE DEVICE EFFECT DEFINITIONS 
Adverse Event 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal findings) in subjects, users or other persons, whether or not related to the 
study device. 
Note1: This definition includes events related to the investigational medical device or 
comparator. 
Note 2: This definition includes events related to the procedures involved 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical device 
Adverse Device Effect 
Adverse event related to the use of an investigational medical device  
Note 1: This definition includes any event resulting from insufficiencies or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. 
Note 2: This definition includes any event that is a resulting from a user error or from 
intentional misuse of the investigational medical device. 
11.1.2 
SERIOUS 
ADVERSE 
EVENT/SERIOUS 
ADVERSE 
DEVICE 
EFFECT/UNANTICIPATED ADVERSE DEVICE EFFECT DEFINITIONS 
Serious Adverse Event 
Adverse event that: 
a) Leads to a death 
b) Led to a serious deterioration in the health of the subject that either resulted in: 

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1. a life-threatening illness or injury or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient hospitalisation or prolonged  hospitalisation,  
4. medical or surgical intervention to prevent life-threatening illness or permanent         
impairment to a body structure or a body function 
c) Led to foetal distress, foetal death or a congenital abnormality or birth defect 
Serious Adverse Device Effect 
A SADE is an ADE that results in any of the consequences characteristic of an SAE or that might 
lead to any of these consequences if suitable action is not taken, if intervention is not made or 
if circumstances are less opportune.  
11.1.3 
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
 
11.1.4 
REPORTING OF ADVERSE EVENTS/ADVERSE DEVICE EFFECTS 
11.1.4.1 
METHODS FOR ELICITING ADVERSE EVENTS/ADVERSE DEVICE EFFECTS 
All subjects will be carefully monitored for the occurrence of AEs during the investigation period 
from the run-in to the completion of follow up.  The Clinical Investigator will collect AE 
information using non-leading questions such as “have you experienced any new health 
problems or worsening of existing conditions”. Events directly observed or spontaneously 
volunteered by subjects will also be recorded. 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
All AEs including but not limited to events reported by the subject or reported in response to an 
open question by the Clinical Investigator or member of this team, which fall into any of the 
above definitions must be recorded as an AE in the CRF and should include the following 
information. 
• Brief description of the event (diagnosis) 

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• Start date (and time, if relevant) 
• Stop date (and time, if relevant) (or resolution) 
• Severity 
• Action taken regarding the medical device 
• Opinion on causality 
• Seriousness 
• Outcome 
Severity 
Severity describes the intensity of an event and will be assessed as: 
 
Mild 
The AE does not interfere in a significant manner with the subject’s normal functioning level. It 
may be an annoyance. 
 
Moderate 
The AE produces some impairment of function but not hazardous to health. It is uncomfortable 
and/or an embarrassment. 
 
Severe 
The AE produces significant impairment of functioning or incapacitation and/or it is a hazard to 
the subject. 
 
If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description. 
Causality (Adverse Device Effects/ADE) 
Causality will be assessed as: 

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Related (definitely, possible or probable) 
 
A causal relationship between the clinical investigational medical device and the AE is at least a 
reasonable possibility, i.e. there is evidence or argument suggesting a causal relationship.  
 
Not related 
There is no indication that the AE was caused by the clinical investigational medical device. 
 
ADEs will be reported by ticking the “yes” box for ADEs on the CRF page for AEs/ADEs.  
The procedures described for AEs above will be followed for documenting ADEs.  
11.1.4.2 
FOLLOW-UP OF SUBJECTS WITH ADVERSE EVENTS 
Any AE that is ongoing when the subject is withdrawn from the investigation should be 
followed-up until the AE is resolved or the Clinical Investigator decides that the AE is stable and 
needs no further follow-up. The date when the Clinical Investigator considers one of these 
outcomes to have occurred for the last ongoing AE for a subject will be considered the last visit 
for this subject, and the outcome should be recorded in the CRF.