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

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.

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.