Can External Vagus Nerve Stimulation Reduce Systemic Levels of Inflammatory Mediators in Duchenne Muscular Dystrophy Patients?

Official title

A Pilot Study to Evaluate Safety and Ability of the Transcutaneous Auricular Vagus Nerve Stimulator the Travagus One System to Decrease Inflammatory Mediators in Patients With Duchenne Muscular Dystrophy.

Overview

The intended investigation is a pilot study to evaluate the safety and efficacy of a novel transcutaneous auricular vagus nerve stimulator system, termed TRAVAGUS ONE, to reduce systemic levels of inflammatory mediators in patients with Duchenne muscular dystrophy (DMD). Electrical vagus nerve stimulation is an investigational anti-inflammatory therapy targeting the nervous system to modulate dysregulated inflammation. DMD is a severe genetic disorder characterized by progressive muscle degeneration and weakness due to the alterations of a protein named dystrophin that helps keep muscle cells intact. The disease affects male children, and the symptom onset is in early childhood. In addition to the muscle degeneration all patients suffer from severe systemic inflammation and express increased systemic levels of proinflammatory molecules, which can be quantified in peripheral blood samples. Daily, systemic corticosteroid therapy with high doses is the standard of care in DMD to control symptoms and to slow disease progression through potent anti-inflammatory activity. Unfortunately, high dosage and long-term use of corticosteroids are typically also accompanied by severe adverse effects that reduce the quality of life in DMD patients. There is thus a great need for improved anti-inflammatory treatment with less severe adverse effects. In the planned pilot study involving 20 DMD patients aged 5-17 years, the investigators intend to treat each patient for one week in their home environment using transcutaneous auricular vagus nerve stimulation (taVNS) with a novel device named Travagus One to find out whether this intervention is safe and may reduce systemic levels of proinflammatory molecules. Venous blood samples will be collected at three different time points before and after the taVNS treatment period. Note: This study relates to an FDA-nonregulated Device. There are no U.S. Locations for the study. The study was approved by the Swedish Medical Products Agency.

Detailed description

Purpose and aim:

The overall aim is to investigate efficacy and safety of a newly developed non-invasive, auricular, investigational equipment named the TRAVAGUS ONE System that electrically stimulates the auricular branch of the vagus nerve to activate the cholinergic anti-inflammatory mechanism to study possible inhibiting effects on increased levels of systemic inflammatory mediators in DMD patients. The mode of treatment is termed transcutaneous auricular vagus nerve stimulation (taVNS). Specifically, we will address the following research questions:

1. Can taVNS treatment for a week reduce systemic levels of inflammatory molecules? 2. What is the safety profile of taVNS? Survey of the field Several thousand children with epilepsy have over the past 10 years been treated with invasive or external taVNS therapy with no or mild adverse effects. There is a clinical need for improved anti-inflammatory therapy with less serious adverse effects in DMD. The aim of our planned study is to investigate whether taVNS treatment via the cholinergic anti-inflammatory mechanism may reduce systemic levels of inflammatory molecules involved in the pathogenesis of DMD. If so, that would motivate future extended therapeutic taVNS studies in DMD patients. Therapy using taVNS is based on non-invasive activation of the endogenous cholinergic anti-inflammatory pathway, a mechanism discovered by Kevin Tracey, one of the founders of taVNS AB, which is the sponsoring company of the present clinical investigation. The cholinergic anti-inflammatory pathway is the efferent part of the inflammatory reflex, a neural circuit that counteracts exaggerated dysfunctional inflammatory responses. The anti-inflammatory effects are mediated via acetylcholine released via the vagus system and a subset of mobile T lymphocytes (T ChAT-cells) capable of acetylcholine synthesis. These anti-inflammatory T cells operate both within and outside compartments innervated by the vagus system. Alpha-7 nicotinic acetylcholine receptors (alpha-7nAChR) respond to acetylcholine by guiding activities downregulating proinflammatory cytokine synthesis, redirecting the traffic of mobile inflammatory cells, and converting pro-inflammatory macrophages to healing macrophages. Using a surgically implanted vagus nerve stimulator Kevin Tracey and Ulf Andersson (the author of this document) provided the original clinical report in 2012 of successful VNS treatment in a chronic inflammatory disease. Multiple pilot studies using either invasive or external VNS in various inflammatory diseases have supported the validity of the original discovery. FDA approved an implantable vagus nerve stimulating device for treatment of rheumatoid arthritis in July 2025 as a result of a successful randomized, placebo-controlled multicenter study with rheumatoid arthritis patients refractory to conventional therapy.

The auricular branch of the vagus nerve is a sensory nerve to the external ear including the cymba conchae region. Stimulation of this auricular nerve branch delivers afferent neuronal impulses, whereas cervically implanted devices deliver both efferent and afferent vagus nerve stimulation. Extended experience from therapeutic epilepsy studies has provided reassuring safety results regarding taVNS therapy. Functional magnetic resonance imaging demonstrates that taVNS activates the main vagal afferent pathway through the brainstem to upstream cortical projections in a similar way to implanted cervical VNS electrodes, confirming this nerve as a suitable non-invasive target to administer vagus nerve stimulation.

Study design:

The study plan is to include 20 boys with DMD treated at Astrid Lindgren Children´s Hospital (ALB), which is the pediatric unit of the Karolinska University Hospital in Stockholm, Sweden. The study will comprise a pilot investigation performed for one week in each DMD patient aged 5-17 years. The therapeutic intervention is electrical taVNS with the TRAVAGUS ONE device in the auricular cymba conchae/cavum conchae regions of the left ear for 5 minutes/twice daily for one week. Venous blood samples will be collected in EDTA-tubes at the first visit before taVNS, and after 24 and 168 hours, respectively. Plasma samples will be frozen for later quantitative analysis of inflammatory mediators.

Interventions

• Device Transcutaneous auricular vagus nerve stimulation
  The transcutaneous auricular vagus nerve stimulation will be performed for 5 minutes twice daily for one week in a home environment using the TRAVAGUS ONE system, which encompasses two investigational device components connected via an electrical cable. The components include a headset (class I medical device) with auricular electrodes connected to a pulse generator (class II a medical device), both manufactured by the sponsoring company taVNS AB. The system delivers safe, charge-balanced, curre

Primary outcome measures

• The dynamic changes in plasma levels of multiple inflammatory molecules in response to taVNS therapy will be studied [Time frame: From enrollment to end of treatment at 1 week]

Eligibility criteria

Inclusion criteria

• Confirmed DMD diagnosis
• Informed consent signed by the legal guardian and the patient

Exclusion criteria

• Age <5 years
• Wounds, skin irritation, or infection in the left auricle
• Previous vagotomy or other interventions that may have hampered vagus nerve functions
• Inability, even with the assistance of a guardian, to acquire adequate technique for ear stimulation
• Previous partial or complete splenectomy
• Severe cardiac disease

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Sweden · 1 center

• Astrid Lindgren Children´s Hospital — Stockholm

Publications

• Andersson U, Tracey KJ. Neural reflexes in inflammation and immunity. J Exp Med. 2012 Jun 4;209(6):1057-68. doi: 10.1084/jem.20120571. PMID 22665702
• Gaylis NB, Sikes D, Kivitz A, Horowitz DL, Evangelista M, Levine YA, Chernoff D. Neuroimmune Modulation for Drug-Refractory Rheumatoid Arthritis: Long-Term Safety and Efficacy in Patients Enrolled in a Pilot Vagus Nerve Stimulation Study. Rheumatol Ther. 2025 Dec;12(6):1125-1136. doi: 10.1007/s40744-025-00798-y. Epub 2025 Oct 10. PMID 41071520
• De Pasquale L, D'Amico A, Verardo M, Petrini S, Bertini E, De Benedetti F. Increased muscle expression of interleukin-17 in Duchenne muscular dystrophy. Neurology. 2012 Apr 24;78(17):1309-14. doi: 10.1212/WNL.0b013e3182518302. Epub 2012 Apr 11. PMID 22496194
• Andersson U, Tracey KJ. Vagus nerve SARS-CoV-2 infection and inflammatory reflex dysfunction: Is there a causal relationship? J Intern Med. 2024 Jan;295(1):91-102. doi: 10.1111/joim.13746. Epub 2023 Nov 29. PMID 38018736
• Villaldama-Soriano MA, Rodriguez-Cruz M, Hernandez-De la Cruz SY, Almeida-Becerril T, Cardenas-Conejo A, Wong-Baeza C. Pro-inflammatory monocytes are increased in Duchenne muscular dystrophy and suppressed with omega-3 fatty acids: A double-blind, randomized, placebo-controlled pilot study. Eur J Neurol. 2022 Mar;29(3):855-864. doi: 10.1111/ene.15184. Epub 2021 Nov 26. PMID 34779542
• Rosas-Ballina M, Olofsson PS, Ochani M, Valdes-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011 Oct 7;334(6052):98-101. doi: 10.1126/science.1209985. Epub 2011 Sep 15. PMID 21921156
• Andersson U, Tracey KJ. A new approach to rheumatoid arthritis: treating inflammation with computerized nerve stimulation. Cerebrum. 2012 Mar;2012:3. Epub 2012 Mar 21. PMID 23447789
• Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol. 2012;30:313-35. doi: 10.1146/annurev-immunol-020711-075015. Epub 2012 Jan 6. PMID 22224768

Identifiers

NCT: NCT07543302 · CIV-SE-25-06-053095 · Dnr: 5.1.1-2025-067582

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗