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Background: Severe coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various biomarkers of inflammation. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156). Methods: Participants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-min doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events. Results: Of the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n = 47; SoC, n = 50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (i.e., all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study. Conclusions: nVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential use earlier in the course of COVID-19 and its potential to mitigate some of the symptoms associated with post-acute sequelae of COVID-19 is warranted.
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OBJECTIVES: Primary Objective: The primary objective is to reduce initiation of mechanical ventilator dependency in patients with moderate to severe CoViD- 19. This will be measured as the difference between the control group and active group for subjects admitted to the hospital for CoViD-19. Secondary Objectives: ⢠To evaluate cytokine trends / Prevent cytokine storms ⢠To evaluate supplemental oxygen requirements ⢠To decrease mortality of CoViD-19 patients ⢠Delay onset of ventilation TRIAL DESIGN: The study is a single centre, 2-arm, prospective, randomized (ratio 1:1), controlled trial with parallel groups design to compare the reduction of respiratory distress in a CoViD-19 population, using the intervention of the gammaCore®-Sapphire device plus standard of care (active) vs. standard of care alone (SoC) - the control group. The gammaCore® treatments will be used acutely and prophylactically. The active and control groups will be matched for disease and severity. PARTICIPANTS: i. Inclusion Criteria The subjects have to meet all of the following criteria to be eligible to enter the trial: 1.Patient older than 18 years2.Been tested positive or suspected/presumed positive for CoViD-19 Has a cough, shortness of breath or respiratory O2 Saturation less than or equal to 92% without need for mechanical ventilation or acute respiratory failure 3.Agree to use the gammaCore®-Sapphire device as intended and to follow all of the requirements of the study including recording required study data4.Patient is able to provide signed and witnessed Informed Consent ii. Exclusion Criteria Subjects meeting any of the following criteria cannot be included in this research study: 1.Pregnant women2.On home/therapy oxygen (i.e. for patients with Chronic Obstructive Pulmonary Disease) at baseline prior to development of CoViD-193.Patient already enrolled in a clinical trial using immunotherapeutic regimen for CoViD-194.History of aneurysm, intracranial hemorrhage, brain tumors, or significant head trauma5.Known or suspected severe atherosclerotic cardiovascular disease, severe carotid artery disease (eg, bruits or history of transient ischemic attack or cerebrovascular accident), congestive heart failure, known severe coronary artery disease, or recent myocardial infarction6.Uncontrolled high blood pressure (>140/90)7.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 implant8.Current implantation of metal cervical spine hardware or a metallic implant near the gammaCore stimulation site9.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) Participants will be recruited from Hospital Clínico Universitario de Valencia in Spain. INTERVENTION AND COMPARATOR: Intervention: Prophylactic: Administer 2 doses (at 2 minutes each) of gammaCore®-Sapphire, one dose on each side of the neck scheduled three times a day (morning, mid-day and 1 hour before bed at night).Acute respiratory failure or shortness of breath: Administer 2 doses (at 2 minutes each) of gammaCore®-Sapphire, one on each side of the neck. If shortness of breath (SOB) persists 20 minutes after the start of the first treatment, a second dose will be administered. Max doses per day is 9 or 18 stimulations.Plus standard of care Control: Standard of care: oxygen therapy, antibiotics and ventilatory support if necessary depending on the clinic MAIN OUTCOMES: Primary Endpoint: Initiation of mechanical ventilation, from randomization until ICU admission or hospital discharge, whatever occurs first Secondary Endpoints: Safety; ascertainment of Adverse Effects/Serious Adverse Events, from randomisation to ICU admission or hospital discharge, whatever occurs firstCytokine Storm measured by: Tumor necrosis factor α, Interleukin 6, Interleukin 1ß. Days 1,3,5,10,15 and/or at hospital dischargeMortality and/or need for Critical Care admission, from randomisation until ICU admission or hospital discharge, whatever occurs first,O2 saturation levels , from randomization until ICU admission or hospital discharge, whatever occurs firstNeed for supplemental oxygen, from randomisation until ICU admission or hospital discharge, whatever occurs first RANDOMISATION: The patients are classified according to their oxygen levels as mild, moderate and severe and randomized according to their classification to the intervention and control in a ratio of 1:1. The randomization will be stratified for gender and age. BLINDING (MASKING): This is an open label study, it is not possible to blind the participants and healthcare providers to the intervention. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The total number of patients to be included in the study is 90, with 45 in each study group TRIAL STATUS: The protocol version is 8.0 from 07th April 2020. The recruitment began 20th April 2020 and is expected to be complete 31st July 2020. TRIAL REGISTRATION: The study is registered in clinicaltrials.gov on 29th April 2020 with the identification number: NCT04368156 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.