A Prospective, Randomized, Controlled Study Assessing Vagus Nerve Stimulation in CoViD-19 Respiratory Symptoms (SAVIORII)
Trial Snapshot
- Phase
- Not Applicable
- Status
- Terminated
- Sponsor
- Enrollment
- 21
- Locations
- 4
- Primary Endpoint
- Number of Participants With Clinical Events
Study Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients (age 18 years and older) who have tested positive or suspected/presumed positive for CoViD-19 using PCR real time test
- •Patients with cough, shortness of breath or respiratory compromise (RR>24/min, increased work of breathing.)
- •O2 Saturation less than or equal to 96% on room air or sensation
- •Agrees to use the gammaCore Sapphire device as intended and to follow all of the requirements of the study including recording required study data
- •Permission for early am blood draw to freeze for subsequent lab tests and sequencing as related to CoViD-19 sequelae
- •Patient is able to provide signed and witnessed Informed Consent
Exclusion Criteria
- •On home/therapy oxygen (i.e. for chronic obstructive pulmonary disease (COPD) patients) at baseline prior to development of CoViD-19
- •Already using gammaCore® (nVNS) for other medical conditions
- •A history of aneurysm, intracranial hemorrhage, brain tumors, or significant head trauma
- •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)
- •Patients with clinically significant hypertension, hypotension, bradycardia, or tachycardia (as per investigator discretion)
- •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
- •Current implantation of metal cervical spine hardware or a metallic implant near the gammaCore® stimulation site
- •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)
- •Compromised access to peripheral veins for blood sampling.
- •Pregnant women
- •Patients with active cancer or those who have had recent cancer treatment
Outcomes
Primary Outcomes
Number of Participants With Clinical Events
Time Frame: From baseline to 90 days post-discharge
compare clinical events between the control group and active group for patients admitted to the hospital for CoViD-19.
Secondary Outcomes
- Evaluate C-reactive Protein (CRP) Trends(From baseline to discharge from hospital or death while hospitalized (patients had data for up to 6.2 days on average after baseline for these outcomes))
- Evaluate Supplemental Oxygen Requirements(From baseline to discharge from hospital or death while hospitalized (patients had data for up to 6.2 days on average after baseline for these outcomes))
- Compare Clinical Improvement in Participants(From baseline to discharge from hospital or death while hospitalized (data not collected during the study for this outcome))
- Evaluate D-dimer Trends/Levels(From baseline to discharge from hospital or death while hospitalized (patients had data for up to 6.2 days on average after baseline for these outcomes))
- Number of Participant Deaths(From baseline to discharge from hospital or death while hospitalized (patients had data for up to 6.2 days on average after baseline for these outcomes))
- Time to Onset of Mechanical Ventilation(From baseline to discharge from hospital or death while hospitalized)
- Evaluate Cytokine Trends (Serum/Plasma Level of TNF-α)(From baseline up to 7 days, discharge or death (whichever occurred first))
- Evaluate Ferritin Levels/Trends(From baseline to discharge from hospital or death while hospitalized (patients had data for up to 6.2 days on average after baseline for these outcomes))
- Evaluate Cytokine Trends (Serum/Plasma Level of IL-1β)(From baseline up to 7 days, discharge or death (whichever occurred first))
- Evaluate Cytokine Trends (Serum/Plasma Level of IL-6)(From baseline up to 7 days, discharge or death (whichever occurred first))
- Evaluate Pro-Calcitonin (PCT) Levels/Trends(From baseline to discharge from hospital or death while hospitalized (patients had data for up to 6.2 days on average after baseline for these outcomes))
Investigators
Tariq Cheema
Associate Division Director, AHN Pulmonary, Critical Care and Sleep Medicine
Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)