Study Assessing Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms
Study Assessing Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms
The study is a prospective, randomized, controlled investigation designed for comparison of
 two groups for the reduction of respiratory distress in a CoViD-19 population, using
 gammaCore Sapphire (nVNS) plus standard of care (active) vs. standard of care alone (SoC),
 the control group. The gammaCore® (nVNS) treatments will be used acutely and
 prophylactically. The aims of this study are to summarize and compare the incidence of
 clinical events and pro-inflammatory cytokine levels in patients randomized to use of
 gammaCore Sapphire plus standard of care vs standard of care alone in patients hospitalized
 for CoViD-19. Secondary objectives are demonstrate the safety of gammaCore Sapphire use in
 patients hospitalized for CoViD-19.
Vagus nerve stimulation (VNS) has an established history of reducing airway distress. VNS has
 at least two mechanisms of action that may profoundly affect respiratory function in patients
 with respiratory distress due to CoViD-19.

 First, vagus nerve stimulation modulates bronchoconstriction, acute stimulation has
 demonstrated a marked improvement in Work of Breathing (WOB) as well as Forced Expiratory
 Volume (FEV1) in patients with severe respiratory distress due to airway reactivity. This
 effect appears to occur via an afferent response to stimulation of the vagus nerve.

 Second, and perhaps more importantly, VNS has been shown to be a potent moderator of
 pathologic immune reactions, specifically suppressing pro-inflammatory cytokine levels via
 activation of the Cholinergic Anti-inflammatory Pathway (CAP). VNS is currently being studied
 to modulate pro-inflammatory cytokines patterns and concentrations in a variety of acute and
 progressive inflammatory conditions, ranging from septic shock and asthma to stroke,
 rheumatoid arthritis and Inflammatory Bowel Disease. VNS has been studied in animal models of
 acute septic shock, consistently demonstrating life-saving potential. In one such study,
 cecal ligation and puncture was used to induce a septic state in an animal model. VNS reduced
 the expression of cytokines which was tightly associated with survival. Specifically, in
 animal and human models, this neuromodulatory therapy has the capacity to reduce the
 expression of inflammatory mediators, including TNF-α, IL-6 and IL-1β. These are precisely
 the same cytokines which are elevated in ARDS and other inflammatory disorders. In all cases,
 the therapy has shown considerable promise as a potential alternative to steroids (having
 potent anti-inflammatory activity but without the adverse side effects of steroids) and
 biologic therapies targeting pro-inflammatory cytokines (broadly - e.g., tofacitinib, or
 specifically - e.g., adalimumab, etanercept, and infliximab).

 Viral-induced acute respiratory distress syndrome (ARDS), including those caused by SARS
 CoV-1 and MERS are characterized by a massive systemic pro-inflammatory state. Although a
 pro-inflammatory environment is required to control the rate of infection as well as the
 eradication of infected and compromised cells, the massive response to these viruses,
 primarily due to leukocytes of the innate arm of the immune system, is part of the problem as
 a significant number of tissues are damaged and lost secondary to the infected tissues in a
 by-stander and collateral manner. A simple, drug-free approach to attenuate this systemic
 inflammation would be of significant benefit to the progression of the syndrome and
 potentially improve the overall recovery of the patients.

 For these reasons, the investigators propose that VNS may ameliorate the over-activity of the
 pro-inflammatory immune condition in CoViD-19 patients, thus conferring a superior
 therapeutic option especially for elderly patients and those presenting with respiratory
 illness in setting of co-morbid conditions who experience severe symptoms. These groups are
 at particularly high risk of requiring mechanical ventilation, developing ARDS, experiencing
 severe cytokine storm and have a higher mortality rate.

 Non-Invasive Vagus Nerve Stimulation (nVNS) - Historically, VNS was delivered using implanted
 signal generators coupled to leads having electrodes that wrap around the vagus nerve. The
 vagus nerve is located within the carotid sheath, and thus the implantation surgery is
 complicated with inherent risks, particularly in the critically ill. More recently, a
 non-invasive approach to vagus nerve stimulation (nVNS) was cleared by the FDA for the acute
 treatment of pain associated episodic cluster and migraine headaches and the prevention of
 cluster headaches and migraine headaches. This device, gammaCore (electroCore, Inc., Basking
 Ridge, NJ) is handheld and requires no surgery or implants. The device is applied by
 healthcare providers or patients to the skin at the neck over the vagus nerve to deliver
 periodic doses of VNS non-invasively.

 With respect to bronchoconstriction, early studies demonstrated modulation of airway
 reactivity in hospitalized asthmatic patients, improving various measures of airway patency.

 Non-invasive VNS (nVNS) is a safe method of stimulating the vagus nerve, with minimal side
 effects. It does not require surgery or an invasive procedure that would otherwise limit its
 utility in the critically ill. The stimulation can be either self-administered or
 administered by a health care practitioner. There are numerous studies with both implanted
 and nVNS in multiple animal models and humans that have demonstrated a modulation of the
 inflammatory cascade with an improvement in survival.

 gammaCore® (nVNS) has been studied in approximately 2,000 patients as part of clinical trials
 with an excellent safety profile. It is available through commercial insurers and the private
 pay market, and is listed on the federal supply schedule available for purchase by the VA and
 Department of Defense and also carries a CE mark for distribution abroad. More than ten
 thousand patients have been successfully treated in the United States and abroad.

 CoViD-19 Respiratory Issues Involve Virally-triggered Severe (Lethal) Cytokine Expression -
 CoViD-19 (coronavirus disease 2019) is caused by SARS CoV-2 (severe acute respiratory
 syndrome coronavirus 2) and is related to the coronavirus which caused SARS in 2003 (SARS
 CoV-1). The virus is transmitted either through airborne droplets (e.g. coughing or sneezing)
 or direct contact (e.g. through a surface containing the virus), with a mean incubation
 period between 4 and 7 days (range 2 days to > 2 weeks). As of April 3, 2020, there are over
 a million confirmed cases and rising with 55,000 individuals deceased to date. This gives a
 current mortality rate of 5.3 %, although the base case of confirmed cases may be markedly
 underestimated. Elderly and those with co-morbid conditions including heart disease,
 diabetes, and asthma seem to have a higher mortality rate.

 Many CoViD-19 patients experience moderate to severe respiratory symptoms, including
 shortness of breath and impaired oxygen saturation. Eighty-eight percent (88%) of patients
 present with respiratory symptoms. A significant and increasing number of CoViD-19 patients
 require hospitalization, and progress to being intubated and/or ventilator dependent. Given
 the rapid spread of this contagion, concern exists that the international healthcare systems
 do not have the number of ventilators and/or ICU beds to meet the expected demand in the
 coming months.

 The most critically afflicted can experience pneumonia and/or ARDS. Accumulating evidence
 suggests that this subgroup with severe CoViD-19 likely have a cytokine storm syndrome, a
 hallmark of ARDS that includes dramatic increase in the expression of pro-inflammatory
 cytokines, mainly TNF-α, IL-6 and IL-1β among others. Elevations in IL-6 seem to be a
 particularly poor outcome indicator of respiratory compromise. It is believed that the
 mortality of ARDS is at least partially the result of an over activity of the patient's
 immune system.30 Predictors of fatality from a recent retrospective, multi-center study of
 150 confirmed CoViD-19 cases in Wuhan, China, included elevated ferritin (mean 1297•6 ng/ml
 in non-survivors vs 614•0 ng/ml in survivors; p<0•001) and IL-6 (p<0•0001)31, suggesting that
 mortality and respiratory decompensation may be due to virally-driven hyperinflammation.

 Therapies that could block the cytokine storm may help improve survival and decrease the need
 for ventilator use and prolonged respiratory support. Other companies are in fact developing
 pharmaceutical approaches for the treatment of cytokine storm, or plasma infusions from those
 who have recovered from the virus. At this point there is no cure or vaccine for the virus
 and neither is there a treatment approach to dampen the systemic inflammation.

 Given the CE mark and excellent safety profile, including the twenty year history of the use
 of VNS to block the over production of pro-inflammatory mediators via the CAP (cholinergic
 anti-inflammatory pathway), and the lack of other effective or reasonable options during this
 pandemic the investigators propose deploying gammaCore® (nVNS) devices for prophylactic use
 to those who have been diagnosed as infected with the virus, but before the cytokine storm
 begins to cause and/or exacerbate the severe respiratory distress syndrome. The hypothesis is
 that the administration of non-invasive VNS using gammaCore®, during and following severe
 infection with CoViD-19 may prevent the worsening inflammatory response and acute injury
 associated, thus decreasing ventilator dependence and mortality of the virus. If utilized
 early enough in the course of disease the investigators hope to reduce ventilator dependence
 and improve survival with a scientifically driven safe and cost-effective approach.
 Furthermore, through additional acute utility of gammaCore® (nVNS) in cases of ARDS and
 cytokine storm the investigators can effectively blunt the pro inflammatory response, reduce
 mortality and liberate patients from mechanical ventilation earlier which will assist in
 deploying the ventilator to other patients in need during the CoViD-19 pandemic.

 electroCore has designed a non-invasive vagus nerve stimulation (nVNS) device called
 gammaCore®. The gammaCore® (nVNS) device is a handheld, battery-powered unit that produces a
 proprietary electrical waveform in the vicinity of the vagus nerve in the neck. Each
 treatment, or dose, is relatively brief (120 seconds) and the user maintains control over the
 stimulation intensity.

 gammaCore® is currently commercially available for the treatment of cluster and migraine
 headaches, and broad safety data with thousands of patients treated in the US Europe and the
 UK in both clinical trials and routine clinical care.

 Treatment paradigms have been developed and tested in clinical trials to support FDA
 clearance for the acute treatment of pain associated with episodic cluster and migraine
 headaches, and the prevention of cluster and migraine headache. This experience demonstrates
 that nVNS may be administered safely in up to 24 two-minute doses per day. The investigators
 thus have data to draw on as to how to effectively stimulate the vagus nerve. Given the
 multiple modes of action with blocking the CAP, and acute bronchodilatation, using a similar
 treatment paradigm for a trial to evaluate nVNS treatment of ARDS is reasonable. The device
 should be used both prophylactically and acutely early in the course of the disease prior to
 mechanical ventilation, and once trained, treatment can be fully managed by either a
 healthcare professional or the patient. If one waits until mechanical ventilation has
 started, it is less likely that a therapy will be able to block the cytokine storm and
 outcomes will be less profound.

 With respect to the theoretical cardiac and respiratory side effects of non-invasive
 treatment, historically, stimulation of the vagus nerve is associated with adverse side
 effects, including bradycardia and bronchoconstriction. These effects were shown to be the
 result of in discriminant stimulation of all fibers in the vagal bundle (the vagus nerve is
 primarily comprised of A and C fibers), which could be avoided by specifically tuning the
 electrical signals to selectively stimulate only the A fibers. This is possible because of
 the difference in electric field strengths necessary to activate the different fiber types.

 The intensity, pulse duration and frequency of gammaCore® (nVNS) stimulation parameters have
 been optimized to induce signals in the large, myelinated Aβ fibers of the cervical branch of
 the vagus nerve. Since gammaCore® activates only the low threshold afferent Aβ fibers, versus
 the high threshold efferent C-fibers that innervate the heart, there is no known risk for
 adverse cardiac or other systemic parasympathetic effects.

 electroCore has conducted pre-clinical studies to assess the potential risk of vagus nerve
 over-stimulation on the heart and airways. Several studies were conducted in beagle dogs with
 hypersensitized airways (worst case for airway reactivity) at maximum stimulation output for
 2 minutes. Review of heart rate and airway resistance before, during and after stimulation
 indicated that there were no significant adverse changes associated with stimulation. These
 results are consistent with the human clinical experience with the gammaCore® device.

 Regarding the theorized mechanism of action, afferent fibers from the vagus nerve enter the
 brain and synapse onto the nucleus tractus solitarius (NTS) in the brain stem , making
 connections with many structures in the brain including the locus coeruleus (LC), the
 periaqueductal gray (PAG) and the raphe nucleus (RN). These structures are known to control
 the release of key inhibitory neurotransmitters. Numerous animal and clinical studies over
 the last 25 years have implicated the activity of these structures, in particular the LC, in
 the mechanism of action of VNS to inhibit seizures.

 Clinical Use for Clinical Care - Given the lack of other effective and/or reasonable options
 for a patient with CoViD-19 respiratory distress and the anticipated demands on our
 healthcare system, considering gammaCore® (nVNS) therapy, the investigators propose, is a
 reasonable approach. To achieve goal of decreasing health care burden with patient benefit of
 decreasing ventilator dependency, inflammatory response and mortality, plan to use it early
 in course of disease i.e. prior to severe respiratory distress and the need for mechanical
 ventilation.

 The presumptive mechanisms of bronchodilatation and modulation of the cytokine storm would
 suggest that early intervention is ideal in improving pulmonary function and avoiding
 respiratory depression.

 1. Prevention. Mitigation of pro-inflammatory immunokine release would be best achieved
 with two doses, consisting of a two-minute stimulation, on each side of the neck three
 times a day (am, afternoon and an hour before bed). This would be a total of 6
 treatments (2 stimulations x 3 times per day) of stimulation as a
 prophylactic/preventive measure. This dosage is well below the known safety dosage
 threshold

 2. In addition, patients may receive additional treatments when experiencing acute
 respiratory distress. Similarly, one treatment is two doses. Each treatment (a
 two-minute stimulation on each side of the neck) is performed on the neck. If shortness
 of breath (SOB) persists 20 minutes after start of first treatment, administer a second
 treatment. Maximum number of treatments per day is 9. This is symptomatic control and
 can be used to improve FEV1, Work of Breathing or dyspnea.
Inclusion Criteria:

 1. Patients (age 18 years and older) who have tested positive or suspected/presumed
 positive for CoViD-19 using PCR real time test

 2. Patients with cough, shortness of breath or respiratory compromise (RR>24/min,
 increased work of breathing.)

 3. O2 Saturation less than or equal to 96% on room air or sensation

 4. Agrees to use the gammaCore Sapphire device as intended and to follow all of the
 requirements of the study including recording required study data

 5. Permission for early am blood draw to freeze for subsequent lab tests and sequencing
 as related to CoViD-19 sequelae

 6. Patient is able to provide signed and witnessed Informed Consent

 Exclusion Criteria:

 1. On home/therapy oxygen (i.e. for chronic obstructive pulmonary disease (COPD)
 patients) at baseline prior to development of CoViD-19

 2. Already using gammaCore® (nVNS) for other medical conditions

 3. A history of aneurysm, intracranial hemorrhage, brain tumors, or significant head
 trauma

 4. Known or suspected severe atherosclerotic cardiovascular disease, severe carotid
 artery disease (e.g., bruits or history of transient ischemic attack or
 cerebrovascular accident), congestive heart failure, known severe coronary artery
 disease, myocardial infarction documented within past 90 days, or current or recent
 history of life-threatening arrhythmia (sustained ventricular tachycardia, ventricular
 fibrillation, second or third-degree heart block, uncontrolled atrial fibrillation or
 uncontrolled atrial flutter)

 5. Patients with clinically significant hypertension, hypotension, bradycardia, or
 tachycardia (as per investigator discretion)

 6. Current implantation of an electrical and/or neurostimulator device, including but not
 limited to a cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain
 stimulator, spinal stimulator, bone growth stimulator, or cochlear implant

 7. Current implantation of metal cervical spine hardware or a metallic implant near the
 gammaCore® stimulation site

 8. Belongs to a vulnerable population or has any condition such that his or her ability
 to provide informed consent, comply with the follow-up requirements, or provide
 self-assessments is compromised (e.g. homeless, developmentally disabled and prisoner)

 9. Compromised access to peripheral veins for blood sampling.

 10. Pregnant women

 11. Patients with active cancer or those who have had recent cancer treatment