Transcutaneous vagus nerve stimulation in erosive hand osteoarthritis: protocol for the randomised, double-blind, sham-controlled ESTIVAL trial

Abstract

Introduction: Patients with erosive hand osteoarthritis (EHOA) experience pain and inflammation, two features that can be targeted by vagus nerve stimulation using electrical auricular transcutaneous vagus nerve stimulation (tVNS). A pilot study demonstrated the feasibility of the procedure, so we designed a randomised sham-controlled trial to determine the safety and efficacy of tVNS in EHOA.

Methods and analysis: ESTIVAL Study (Essai randomisé comparant la STImulation auriculaire transcutanée du nerf Vague versus sham stimulation dans l'Arthrose DigitaLe Érosive symptomatique et inflammatoire) is a superiority, randomised, double-blind sham-controlled trial comparing two parallel arms: active and sham tVNSs in a 1:1 ratio. Patients with symptomatic EHOA (score ≥40/100 mm on a visual analogue scale (VAS) for pain of 0-100 mm) and inflammatory EHOA (≥1 clinical and ultrasonography-determined interphalangeal synovitis) are included in 18 hospital centres (17 rheumatology and 1 rehabilitation departments) in France. Active and sham tVNSs use an auricular electrode connected to the Vagustim device, with no electric current delivered in the sham group. Patients undergo stimulation for 20 min/day for 12 weeks. The follow-up visits take place at weeks 4, 8 and 12. The enrolment duration is 2 years and started in April 2021; 156 patients are scheduled to be included. The primary outcome is the difference in self-reported hand pain in the previous 48 hours measured on a VAS of 0-100 mm between baseline and week 12. Secondary outcomes include other pain outcomes, function, quality of life, serum biomarker levels, compliance and tolerance. For a subset of patients, MRI of the hand is performed at baseline and week 12 to compare the change in Outcome Measures in Rheumatology/Hand Osteoarthritis MRI Scoring System subscores. The primary analysis will be performed at the end of the study according to the intent-to-treat principle.

Ethics and dissemination: Ethics approval was obtained from the institutional review board (Comité de Protection des Personnes, 2020-A02213-36). All participants will be required to provide written informed consent. The findings will be published in peer-reviewed journals.

Trial registration number: NCT04520516; Pre-results.

Protocol version and number: V.2 of 11 March 2021.

Keywords: pain management; protocols & guidelines; rheumatology.

Conflict of interest statement

Competing interests: AC declares grants or contracts with Institut Servier, support for attending meetings and/or travel from Pfizer, Novartis, MSD, BMS and UCB. EM declares grants or contracts with Expanscience, Meda-Mylan, Sublimed, Pierre Fabre Labs, Fidia and Tand RB Chemedica; consulting fees from Fidia, Sublimed Expanscience and Meda-Mylan; payment or honoraria for lectures from Pierre Fabre and Fidia; and support for attending meetings and/or travel from Pfizer. TS declares grants from AstraZeneca, Bayer, Boehringer, Daiichi-Sanky, Eli Lilly, GSK and Sanofi, and personal fess from AstraZeneca, Ablative Solutions, Bayer, Novartis and Sanofi. FB reports other conflicts from 4MovingG Biotech; personal fees from 4P Pharma during the conduct of the study; personal fees from Boehringer, Bone Therapeutics, CellProthera, Expanscience, Galapagos, Gilead, GSK, Lilly, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB and Peptinov; and grants from TRB Chemedica outside the submitted work; in addition, FB has a patent (WO2020104833A1); the co-inventors are R Rattenbach and Francis Berenbaum Composition, and methods for regulating chondrocyte proliferation and increasing of cartilage matrix production were issued. JS declares grants from Pfizer and Schwa-Medico.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Schematic flow of the design of the randomised study comparing symptomatic effects of auricular tVNS versus sham tVNS in patients with symptomatic and inflammatory EHOA. Patients with symptomatic EHOA and inflammatory clinical and ultrasonography-evidenced synovitis are randomised (1:1) to active tVNS (n=65) or sham tVNS (n=65) for 20 min each day for 12 weeks. The two treatment arms are assessed at 4, 8 and 12 weeks. The primary outcome is assessed at 12 weeks. ß-hCG, ß-human Chorionic Gonadotropin; EHOA, erosive hand osteoarthritis; tVNS, transcutaneous vagus nerve stimulation.

Figure 2

Description of the Vagustim device, the cymba concha, auricular electrode applied on the left cymba concha and the conductive gel provided to patients at the beginning of the study.