Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial
John R. P. Tesser, A Crowley, Emily Jane Box, Joshua P. June, Pendleton Brewster Wickersham, Guillermo J. Valenzuela, Norman Gaylis, G. Lam, Leroy A. Pacheco, David J. Ridley, Gineth Paola Pinto-Patarroyo, Stuart Novack, Melvin A. Churchill, Minna J. Kohler, Eric C. Lee, Jose A. Pando, Glenn R. Parris, Jeff Peterson, Tina Shah, Atul K. Singhal, Victoria Vuong, Yaakov A. Levine, Melissa Evangelista, Amy A. Derosier, Jeffrey R. Curtis, R. Mark Richardson, David Chernoff
Abstract
The inflammatory reflex, in which vagus nerve signaling modulates cytokine production, is dysregulated in rheumatoid arthritis (RA). RESET-RA, a pivotal, double-blind, randomized, sham-controlled trial, evaluated a vagus nerve-targeted neuromodulation system for RA in 242 patients with inadequate response/intolerance to biological/targeted synthetic disease-modifying antirheumatic drugs. Patients were randomized to active or sham stimulation for 3 months, and then all received open-label stimulation with results reported to 12 months. The primary end point was 3-month American College of Rheumatology 20% (ACR20) response. ACR20 rates were higher with active simulation than with sham at 3 months (35.2% versus 24.2%, P = 0.0209), which further improved in open-label to 50.0% at 6 months and 52.8% at 12 months (all-completers). Adverse events occurred in a similar proportion of patients in both arms. Related serious adverse events (rate = 1.6%) were all perioperative, and resolved. Vagus nerve-mediated neuroimmune modulation for RA achieved its primary efficacy end point and produced durable clinical benefits with a favorable safety profile. ClinicalTrials.gov registration: NCT04539964 .