Treatment with Auricular Vagus Nerve Stimulation in Rheumatoid Arthritis

Introduction The proposed investigation is a multicenter, placebo-controlled, randomized, double-blinded, superiority, clinical study to evaluate the safety and efficacy of a novel transcutaneous auricular vagus nerve stimulator system, termed TRAVAGUS, in patients with moderate-to-severe rheumatoid arthritis (RA) who are incomplete responders or are intolerant to biologic or targeted synthetic disease modifying anti-rheumatic drugs (DMARDs). The primary efficacy endpoint is the proportion of patients achieving an ACR20 response (a composite measure of the effectiveness of arthritis treatments set forth by the American College of Rheumatology) in the treatment group compared to sham group at 12 weeks. Electrical vagus nerve stimulation is an investigational anti-inflammatory therapy targeting the nervous system to modulate immune activity. RA is a global disease associated with significant reduced quality of life and very high health care costs substantially driven by therapeutics. While many with RA have benefited from modern era biologic and small molecule therapies, unresolved chronic inflammation is common despite treatment. Therefore, non-toxic, lower cost anti-inflammatory, non-pharmacologic therapy is needed.

Purpose and aim:

The overall aim is to investigate efficacy and safety of a newly developed non-invasive auricular investigational device that electrically stimulates the auricular branch of the vagus nerve to activate the cholinergic anti-inflammatory mechanism to treat rheumatoid arthritis patients not responding to standard therapy. The mode of treatment is termed transcutaneous auricular vagus nerve stimulation (taVNS). Specifically, the investigators will address the following research questions:

1. What is the effect of taVNS on disease activity (ACR20, primary outcome) in rheumatoid arthritis?
2. What are the effects of taVNS on pain, fatigue and functional status in rheumatoid arthritis?
3. What is the safety profile of taVNS in rheumatoid arthritis? Study Design

Survey of the field There is a clinical need for improved and less expensive therapy with less serious adverse effects in rheumatoid arthritis (RA). The aim of our project is to work out such treatment using external, non-invasive activation of the endogenous cholinergic anti-inflammatory pathway, a mechanism discovered by Kevin J Tracey, who one of the founders of taVNS AB, the sponsoring company of this clinical investigation. This mechanism 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 circulating T lymphocytes capable of acetylcholine synthesis. The mobile anti-inflammatory T cells operate both within and outside compartments innervated by the vagus system. Alpha-7 nicotinic acetylcholine receptors (a7nAChR) respond to acetylcholine by guiding activities downregulating proinflammatory cytokine synthesis and redirecting the traffic of mobile inflammatory cells. Electrical vagus nerve stimulation (VNS) as well as administration of a7nAChR agonists have mediated promising therapeutic results in experimental arthritis models and in rheumatoid arthritis patients. Using a surgically implanted vagus stimulator Kevin J Tracey and Ulf Andersson (the author of this document) provided the original clinical report of successful VNS treatment in RA. Three subsequent pilot studies in RA cohorts based on similar invasive VNS technology later confirmed the encouraging therapeutic outcome of the original study.