Study Assessing Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms : A Prospective, Randomized, Controlled Study Assessing Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms (SAVIORII)

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 ap....

Medienart:	Klinische Studie

Erscheinungsjahr:	2022
Erschienen:	2022

Enthalten in:	ClinicalTrials.gov - (2022) vom: 07. Nov. Zur Gesamtaufnahme - year:2022

Sprache:	Englisch

Links:	Volltext [kostenfrei]

Themen:

610 Acute Lung Injury Coronavirus Infections Medical Condition: COVID, Corona Virus Infection, Respiratory Failure, Respiratory Distress Syndrome, Adult, ARDS, Human, SARS (Severe Acute Respiratory Syndrome) Recruitment Status: Active, not recruiting Respiratory Distress Syndrome Respiratory Distress Syndrome, Newborn Respiratory Insufficiency Severe Acute Respiratory Syndrome Signs and Symptoms, Respiratory Study Type: Interventional Syndrome

Anmerkungen:	Source: Link to the current ClinicalTrials.gov record., First posted: May 11, 2020, Last downloaded: ClinicalTrials.gov processed this data on November 07, 2022, Last updated: November 09, 2022

Study ID:	NCT04382391 2020-132-AGH
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PPN (Katalog-ID):	CTG003387216