taVNS Trial Fails to Meet End Point of Reducing Erosive Hand Osteoarthritis Pain

Transcutaneous auricular vagus nerve stimulation (taVNS) was well-tolerated but failed to meet the primary end point of pain reduction compared to placebo in people with erosive hand osteoarthritis in the ESTIVAL trial.¹

“The pathogenesis of erosive hand osteoarthritis is influenced substantially by systemic and joint inflammation, but a gap still remains in our understanding of this disease. Therefore, there is an urgent need for innovative and safe therapeutic approaches, to effectively address the challenges of treating erosive hand osteoarthritis,” study investigator Alice Courties, MD, PhD, AP-HP Hôpital Saint-Antoine, Service de Rhumatologie, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Inserm 938, Paris, France, and colleagues wrote.¹

ESTIVAL was a multicenter, randomized, double-blind, sham-controlled trial conducted across 18 hospital centers in France, including 2 secondary and 16 tertiary sites. Adults aged 18 years or older who met American College of Rheumatology criteria for hand osteoarthritis, with at least 1 erosive interphalangeal joint and ultrasound-confirmed synovitis, were randomized 1:1 to receive either daily 20-minute taVNA (VAGUSTIM, Schwa Medico) or sham stimulation with no electrical current for 12 weeks. Randomization was stratified by site and performed centrally via a web-based, computer-generated system. The primary endpoint was change in hand pain measured by visual analogue scale (VAS) from baseline to week 12, and safety was assessed through investigator-reported adverse events and serious adverse events at each visit. Primary efficacy and safety analyses were conducted in the intention-to-treat population. No individuals with lived experience of hand osteoarthritis were involved in the study design or conduct.

The trial enrolled 148 patients between April 2021, and March 2022, with 142 (96%) randomized to taVNS (n = 73; 51%) or sham stimulation (n = 69; 49%). The mean age of participants was 66.5 years (SD, 8.4), and most were female (88%), with 12% male. At week 12, primary outcome data were available for 63 (86%) patients in the taVNS group and 64 (93%) in the sham group. The median change in VAS hand pain was −16.0 mm (IQR, −32.0 to 5.0) with taVNS compared with −6.0 mm (IQR, −27.0 to 7.0) with sham, corresponding to an adjusted between-group difference of −10.0 mm (95% CI, −23.0 to 2.0; P = .22), and the primary endpoint was not met. No serious adverse events were reported, and adverse events occurred in 22 (30%) patients in the taVNS group and 16 (23%) patients in the sham group, with no new safety concerns identified.

“To our knowledge, this is the first randomized controlled study to investigate the effect of transcutaneous auricular vagus nerve stimulation in erosive hand osteoarthritis with inflammatory features. Although the primary endpoint was not met, the study suggests that transcutaneous auricular vagus nerve stimulation might provide clinical benefit in a subgroup of patients with signs of local inflammation, particularly in terms of pain relief. The study also confirms the feasibility and excellent tolerability of neuromodulation in this older population, supporting the exploration of neuroimmune pathways in the treatment of osteoarthritis,” Courties and colleagues wrote.¹

VNS is being investigated for a number of rheumatological conditions, including rheumatoid arthritis (RA). HCPLive previously spoke with John Tesser, MD, Adjunct Assistant Professor of Medicine, Midwestern University, and Arizona College of Osteopathic Medicine, and Lecturer, University of Arizona Health Sciences Center, and Arizona Arthritis & Rheumatology Associates at the American College of Rheumatology (ACR) Convergence 2024, held November 14-19 in Washington, DC, about a VNS device that was effective in improving outcomes in adults with active RA disease and inadequate response or intolerance to at least 1 biologic disease-modifying anti-rheumatic drugs (bDMARD) or targeted-synthetic DMARD (tsDMARD) in the RESET-RA trial.

“If we have a new therapy where [the] safety profile is better, that would be a real game changer for a lot of patients. Now we have to look at longer term data in a lot of patients, but we're hopeful that that will continue, because this is really resetting the neuro immune regulatory system back towards what we hope is the normal balance, and hopefully we don't allow for an over-suppression in that respect,” Tesser told HCPLive.

References

1. Courties A, Tuffet S, Cormier G, et al. Transcutaneous auricular vagus nerve stimulation versus sham stimulation in patients with erosive hand osteoarthritis (ESTIVAL): a randomised, multicentre, double-blind, sham-controlled trial. Lancet Rheumatol. Published online December 2025. doi: 10.1016/s2665-9913(25)00226-7

2. Tesser J, June J, Wickersham P, et al. Neuroimmune Modulation in Adults with Rheumatoid Arthritis and Inadequate Response or Intolerance to Biological or Targeted Synthetic DMARDs: Results at 12 and 24 Weeks from a Randomized, Sham-Controlled, Double-Blind Pivotal Study. Presented at: ACR Convergence 2024; November 14-19; Washington, DC. Abstract L10.