Non-invasive Vagus Nerve Stimulation for COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)

Abstract

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.

Keywords: COVID-19; biomarkers; coronavirus; inflammation; neuromodulation; non-invasive vagus nerve stimulation; randomized control trial; respiratory symptoms.

Conflict of interest statement

DC has served as a consultant and advisory board member for Medtronic, Inc. RV is director of research for the National Spine and Pain Centers, a consultant and advisory board member for Medtronic, Inc., and chief executive officer for SGX Medical, LLC. CM is an employee of NAMSA, Inc., CC is a consultant for electroCore, Inc. and an employee of Convergent Medical Technologies, Inc., EL is an employee of electroCore, Inc., and receives stock ownership. PS is an employee and was cofounder of electroCore, Inc., and receives stock ownership. Author CC was employed by company Convergent Medical Technologies, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Tornero, Pastor, Garzando, Orduña, Forner, Bocigas, Cedeño, Vallejo, McClure, Czura, Liebler and Staats.

Figures

Figure 1

Study Design. aEach stimulation was 2 min in duration. L, left side; nVNS, non-invasive vagus nerve stimulation; R, right side; SoC, standard of care.

Figure 2

The nVNS Device (gammaCore Sapphire™). Image provided courtesy of electroCore, Inc. nVNS indicates non-invasive vagus nerve stimulation.

Figure 3

Participant Disposition. aExcluded participants had missing baseline demographic and/or medical history data. nVNS, non-invasive vagus nerve stimulation; SoC, standard of care.

Figure 4

Changes From Baseline in CRP Level (A) and Percentage of Participants With Normal CRP Levels (<10 mg/L) (B) by Treatment Group Among Hospitalized Patients With COVID-19. Error bars denote 95% CIs. ap values are from F tests comparing LSM changes from baseline for the nVNS and SoC groups. b39 observations from 27 participants. c52 observations from 35 participants. dp values are from chi-squared or Fisher exact test, as appropriate. COVID-19, coronavirus disease 2019; CRP, C-reactive protein; LSM, least squares mean; nVNS, non-invasive vagus nerve stimulation; SoC, standard of care.

Figure 5

Changes From Baseline in Levels of Procalcitonin by Treatment Group Among Hospitalized Patients With COVID-19. Error bars denote 95% CIs. ap values are from F tests comparing LSM changes from baseline for the nVNS and SoC groups. b34 observations from 26 participants. c45 observations from 33 participants. COVID-19, coronavirus disease 2019; LSM, least squares mean; nVNS, non-invasive vagus nerve stimulation; SoC, standard of care.

Figure 6

Changes From Baseline in Levels of D-Dimer by Treatment Group Among Hospitalized Patients With COVID-19. Error bars denote 95% CIs. a40 observations from 28 participants. b50 observations from 34 participants. COVID-19 indicates coronavirus disease 2019; LSM, least squares mean; nVNS, non-invasive vagus nerve stimulation; SoC, standard of care.