Vagus Nerve Stimulation ARDS Prevention Trial for COVID-19 Hospitalized Patients

This trial is designed to determine if the inflammation modulating effect of vagus nerve stimulation can improve pulmonary function and limit progression to ARDS in hospitalized COVID-19 hospitalized patients.

Study Overview

• Status: Completed
• Conditions: Severe Acute Respiratory Syndrome Coronavirus 2
• Intervention / Treatment: Device: Transcutaneous Auricular Vagus Nerve Stimulation

Detailed Description

Patients hospitalized with COVID-19 predominantly die of organ failure due to a surge of pro-inflammatory cytokines triggering the need for mechanical ventilation, often due to acute respiratory distress syndrome (ARDS). Known as a cytokine storm, the surge in cytokines is similar to the excessive inflammatory reaction associated with septic shock.

Anti-viral agents will most likely be required to reduce the molecular viral burden in COVID-19 patients, but an additional approach to control the damaging cytokine release is required to alter the course of disease in hospitalized patients and improve chances of survival. Immunosuppressant drugs may reduce inflammation and the tissue damaging cytokines, but they could also be detrimental by inhibiting natural anti-viral immune responses (i.e., suppression of interferons), thereby delaying viral clearance and increasing the risk of secondary infections and death.

The reason for the severity of the disease course in some individuals may lie in the regulation of the immune system by the vagus nerve. The vagus nerve is involved in an inflammation controlling reflex similar to the blood pressure regulating baroreflex. The vagus inflammatory reflex is triggered when the afferent vagus nerve senses inflammatory products through peripheral receptors.

Vagus nerve activity is relayed through the central nervous system to the efferent vagus nerve. This pathway involves the splenic nerve, which when activated releases norepinephrine and results in suppression of pro-inflammatory cytokine production by macrophages and alleviates inflammation in many pathological settings (e.g., endotoxemia, peritonitis, or acute kidney injury).

Electrical stimulation of the vagus nerve using VNS can improve the body's natural ability to regulate the inflammatory response and may be potent enough to suppress pro-inflammatory cytokines and prevent death from COVID-19, especially if used early enough in the course of hospitalization.

In rat models of sepsis, VNS attenuates the release of pro-inflammatory cytokines, prevents hypotension, modulates coagulation, and prevents fibrinolysis activation, decreasing organ dysfunction, and improving survival. Human studies also demonstrate that VNS suppresses the production of pro-inflammatory cytokines and improves clinical symptoms in rheumatoid arthritis, intractable epilepsy, atrial fibrillation, and Crohn's Disease.

This suggests that VNS may be effective in treating disorders characterized by cytokine dysregulation and that it has the potential to prevent hospitalized patients with COVID-19 from progressing to respiratory failure and death.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Zárate, Buenos Aires, Argentina, B2800DDF
      • Hospital Zonal Virgen del Carmen de Zárate

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients who are 18 years of age
2. Tested positive or suspected/presumed positive for COVID-19 infection
3. Patients requiring hospital admission moderate to severe pneumonia and pneumopathy
4. Patients showing fever and respiratory symptoms with radiological findings of pneumonia
5. Respiratory distress (≧30 breaths/ min) or Oxygen saturation ≤93% at rest in ambient air; or oxygen saturation ≤97 % with O2 > 5L/min
6. Patient is able to provide signed and witnessed Informed Consent

Exclusion Criteria:

1. Already enrolled in a trial for COVID-19 therapy
2. Potentially life threatening heart rhythm
3. Pregnancy or potential pregnancy
4. 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
5. History of aneurysm, intracranial hemorrhage, brain tumors, or significant head trauma
6. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Arm; Adults over 18 years of age hospitalized because of COVID-19 infection will be treated with transcutaneous auricular vagus nerve stimulation (taVNS).	Device: Transcutaneous Auricular Vagus Nerve Stimulation; Transcutaneous vagus nerve stimulation involves stimulating the auricular branch of the vagus nerve with a imperceptible electrical current within the concha of the ear.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival without need of mechanical ventilation	Survival	Day 14 since symptom onset
Cumulative incidence of successful tracheal extubation at day 14 since symptom onset.	Successful tracheal extubation	Day 14 since symptom onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival at day 14 of hospitalization	Survival	Day 14
Duration of hospitalization	Duration of hospitalization	Day 28

Collaborators and Investigators

• Sponsor: Nemechek Technologies

Publications and helpful links

General Publications

• Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
• Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020 May 1;130(5):2620-2629. doi: 10.1172/JCI137244.
• Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, Kiss A, Podesser B, Cassara AM, Tanghe E, Samoudi AM, Tarnaud T, Joseph W, Marozas V, Lukosevicius A, Istuk N, Sarolic A, Lechner S, Klonowski W, Varoneckas G, Szeles JC. Current Directions in the Auricular Vagus Nerve Stimulation I - A Physiological Perspective. Front Neurosci. 2019 Aug 9;13:854. doi: 10.3389/fnins.2019.00854. eCollection 2019.
• Tanaka S, Hammond B, Rosin DL, Okusa MD. Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway. Bioelectron Med. 2019 Aug 13;5:13. doi: 10.1186/s42234-019-0029-8. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2020
• Primary Completion (Actual): September 1, 2020
• Study Completion (Actual): November 1, 2020

Study Registration Dates

• First Submitted: May 5, 2020
• First Submitted That Met QC Criteria: May 5, 2020
• First Posted (Actual): May 7, 2020

Study Record Updates

• Last Update Posted (Actual): June 4, 2021
• Last Update Submitted That Met QC Criteria: June 1, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; Acute Respiratory Distress Syndrome; vagus nerve stimulation
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Severe Acute Respiratory Syndrome; COVID-19
• Other Study ID Numbers: NCM-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No