Outcomes of Treatment With Vagal Nerve Stimulation in Post-COVID Syndrome: A Pilot Study
Phase: NA
Conditions: Post COVID Syndrome, Fatigue, Headache
Sponsor: Mayo Clinic

VNS in LC: Pilot Study 
PI: RT Hurt, MD, PhD 
Mayo Clinic - NCT05445427 
 
 
 
 
 
Outcomes of Treatment with  
Vagal Nerve Stimulation  
in Post-COVID Syndrome: 
A Pilot Study  
 
NCT05445427 
 
 
29 May 2024 
 

Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
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General Study Information 
 
Principal Investigator:    Ryan T. Hurt MD, PhD   
  
Study Title:    Outcomes of Treatment with Vagal Nerve Stimulation in Post-COVID Syndrome: A Pilot Study 
 
Mayo Clinic IRB approved as of:   29 May 2024 
 
Research Question and Aims 
Hypothesis: Vagal nerve stimulation improves outcomes in patients with post-COVID syndrome.  
 
Aims, purpose, or objectives: 
1. To evaluate the impact of vagal nerve stimulation in the treatment of post-COVID syndrome 
 
Background:  
 
Post-COVID syndrome is a constellation of symptoms that persist greater than 28 days after the initial onset of 
symptoms of SARS-CoV-2 infection.(1) The constellation of symptoms bears a striking resemblance to the 
“central sensitization syndromes”, a group that includes fibromyalgia, chronic fatigue syndrome, and postural 
orthostatic tachycardia syndrome (POTS).(1, 2) This syndrome is likely to occur in upward of 10% of the 
population who has been infected with COVID-19, likely affecting hundreds of millions across the world.(2, 3) 
The etiology of this condition is poorly understood at this time, but it has been linked to immune dysregulation, 
which likely mediates its effects via neuroinflammation, as demonstrated by the strikingly consistent 
hypometabolic pattern seen on brain PET.(3-7)  
 
At this time, we have no effective treatment options for post-COVID syndrome. Sympathetic hyperactivity has 
been a reliable feature of these central sensitization conditions and many of our treatment modalities are 
directed at reducing the sympathetic drive.(8) Parasympathetic nervous system activation thereby presents an 
attractive therapeutic intervention.  
 
The Gammacore vagal nerve stimulator has been used in several clinical settings and has demonstrated 
decreased frequency and severity of headaches. Some studies have also shown a decrease in fatigue.(9-11) We 
hypothesize that VNS may also decrease post-COVID symptoms, particularly fatigue. If this proves beneficial, 
these findings could drive an individualized approach to treating post-COVID syndrome.  
 
Whereas multiple studies have previously described common Point-of-Care Ultrasound (POCUS) findings in 
acute COVID-19, to date no description has been made of POCUS findings in the post-COVID syndrome. In 
the acute setting, POCUS has been shown to perform similarly to CT for diagnostic and prognostic purposes 
both in COVID-19 and other pulmonary conditions. POCUS has also previously been shown to usefully 
augment the physical exam for volume status and left ventricular function. In the post-COVID setting, questions 
often exist regarding ongoing pulmonary parenchymal disease, cardiac disease, and cardiovascular 
manifestations of autonomic dysfunction. Often the evaluation for these problems requires multiple outpatient 
imaging studies which are costly and time consuming.  As such, the use of POCUS in the post-COVID 

Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
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syndrome evaluation may provide an opportunity to simplify and expedite the patient evaluation while reducing 
cost.  
 
Study Design and Methods 
Methods:   
 
20 patients will be recruited from the Post-COVID Care Clinic (PCOCC) at the Mayo Clinic in Rochester. After 
providing informed consent to this study as well as our post-COVID patient registry and biorepository, patients 
will perform baseline clinical questionnaires including the Post-COVID Functional Status Score, PHQ-9, GAD-
7, PROMIS-F, and COMPASS and have a blood sample taken for analysis for cytokine panel including high 
sensitivity IL-6, DHEA, and am cortisol.  A Point-of-Care Ultrasound (POCUS) will be performed, if one has 
not been performed clinically within the previous two weeks,  and enrollees will have PET-CT of the brain 
performed to evaluate brain metabolism.  
 
They will then be randomized to either receive VNS treatment or not to receive VNS treatment. For those 
randomized to use the Gammacore, the device will be applied to the neck (by the study participant) for 2-minute 
intervals, two sets, administered three times daily. The people who contact the patients for follow-up as part of 
the PCOCC treatment program (nurses and health coaches) will be blinded, but patients will not be blinded in 
this open-label study. All patients will complete the above questionnaires at 2, 4, 6, and 12 weeks, lab draws at 
6 and 12 weeks, and a repeat POCUS will be completed as well as a PET-CT of the brain at 12 weeks.   
 
Study Outline 
 
Subject Information 
Target accrual: 20 
 
Subject population:  Adult Patients from the Post COVID Care Clinic at Mayo Clinic, Rochester MN 
 
Inclusion Criteria:  
1. Age ≥ 18 years old 
2. Presence of fatigue with post exertional malaise 
3. Presence of headache 
4. Clinical diagnosis of post COVID syndrome 
5. They have consented to participate in the study 
6. Have the ability to participate in all aspects of the study 
PoCOS 
diagnosis 
confirmed
Study 
consent
0 weeks
•Blood 
draw
•Question
naires
•POCUS
•PET-CT
2 weeks 
•Question
naires
4 weeks
•Question
naires
6 weeks
•Blood 
draw
•Question
naires
12 weeks 
•Blood 
draw
•Question
naires
•POCUS
•PET-CT

Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
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Exclusion Criteria:   
1. Age < 18 years old 
2. Pregnant 
3. Prior adverse reaction to 14FDG 
4. Active implantable medical device e.g., pacemaker, hearing aid implant 
5. Metallic device e.g., stent, orthopedic hardware in neck 
6. Using another electronic device at the same time e.g., TENS, mobile phone 
7. Any other condition deemed exclusionary by the study principal investigator 
 
Biospecimens 
From healthy, non-pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk application, 
the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period and collection may 
not occur more frequently than 2 times per week. 
Volume per blood draw: _30_ml   
Frequency of blood draw _every 6 weeks x 3 occurrences 
 
Review of medical records, images, specimens  
 
  The study involves data that exist at the time of IRB submission and data that will be generated after IRB 
submission.  
 
Data Analysis 
Data Analysis Plan:  
 
Data will be collected and stored in a de-identified RedCAP database. Data to be abstracted from the electronic 
health record includes demographics, medical history, and laboratory results. Experimental data will be added 
to the database as generated.  
 
Outcomes will be compared across groups. Changes from baseline to week 12 will be analyzed using analysis 
of covariance, with the baseline value included as the covariate.  Distributional assumptions will be assessed 
and transformations or nonparametric methods used as appropriate.  A p-value of <0.05 will be considered 
significant. Power calculations were not performed as this is a pilot study for use in post COVID syndrome and 
there is limited data to base these calculations upon. 
 
Endpoints 
1. Primary: Post-COVID Functional Status Score  
2. Secondary: PROMIS_F 
3. Exploratory:  
a. PET-CT 
b. Lab values – cytokine panel, high sensitivity IL-6, DHEA, cortisol 
c. PHQ-9, GAD-7, and COMPASS 
d. Point-of-Care Ultrasound 
 

Minimal Risk Protocol Template [IRB 10429.010] 
 
Effective: 9/20/2017 
 
 
 
 
 
 
 
 
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References 
1. 
Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, Group WCCDW. A clinical case definition of post-
COVID-19 condition by a Delphi consensus. The Lancet Infectious Diseases. 2021. 
2. 
Bierle DM, Aakre CA, Grach SL, Salonen BR, Croghan IT, Hurt RT, et al. Central sensitization 
phenotypes in post acute sequelae of SARS-CoV-2 infection (PASC): defining the post COVID 
syndrome. Journal of Primary Care & Community Health. 2021;12:21501327211030826. 
3. 
Ganesh R, Grach SL, Ghosh AK, Bierle DM, Salonen BR, Collins NM, et al., editors. The female-
predominant persistent immune dysregulation of the post-COVID syndrome. Mayo Clinic Proceedings; 
2022: Elsevier. 
4. 
Guedj E, Campion J, Dudouet P, Kaphan E, Bregeon F, Tissot-Dupont H, et al. 18F-FDG brain PET 
hypometabolism in patients with long COVID. European journal of nuclear medicine and molecular 
imaging. 2021;48(9):2823-33. 
5. 
Guedj E, Lazarini F, Morbelli S, Ceccaldi M, Hautefort C, Kas A, et al. Long COVID and the brain 
network of Proust's madeleine: targeting the olfactory pathway. Clinical Microbiology and Infection. 
2021;27(9):1196-8. 
6. 
Guedj E, Morbelli S, Kaphan E, Campion J-Y, Dudouet P, Ceccaldi M, et al. From early limbic 
inflammation to long COVID sequelae. Brain. 2021;144(8):e65-e. 
7. 
Grach SL, Ganesh R, Messina SA, Hurt RT. Post-COVID-19 syndrome: persistent neuroimaging changes 
and symptoms 9 months after initial infection. BMJ Case Reports CP. 2022;15(4):e248448. 
8. 
Martínez-Martínez L-A, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous 
system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial 
cystitis: a review of case-control studies. JCR: Journal of Clinical Rheumatology. 2014;20(3):146-50. 
9. 
McIntire LK, McKinley RA, Goodyear C, McIntire JP, Brown RD. Cervical transcutaneous vagal nerve 
stimulation (ctVNS) improves human cognitive performance under sleep deprivation stress. 
Communications biology. 2021;4(1):1-9. 
10. Tarn J, Legg S, Mitchell S, Simon B, Ng W-F. The effects of noninvasive vagus nerve stimulation on 
fatigue and immune responses in patients with primary Sjögren’s Syndrome. Neuromodulation: 
Technology at the Neural Interface. 2019;22(5):580-5. 
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