2278: Neuroimmune modulation for the Treatment of Rheumatoid Arthritis: Results at 12 months from a Randomized, Sham-Controlled, Double-Blind Study

Background/Purpose: Neuroimmune modulation by electrical stimulation of the left cervical vagus nerve represents a novel treatment option for rheumatoid arthritis (RA). We present 12-month efficacy and safety outcomes for an implantable vagus nerve stimulation device to treat biologic-experienced patients with RA (the RESET-RA study, ClinicalTrials.gov, NCT04539964).

Methods: In this multicenter, randomized, double-blind, sham-controlled, pivotal trial, patients with prior inadequate response or intolerance to at least one biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) were randomly assigned to stimulation (treatment) or sham. The primary endpoint of ACR20 response was assessed 3 months after randomization. After 3 months, sham crossed over to treatment, and all patients received stimulation during open-label follow-up, with results reported through 12 months. Secondary endpoints included safety measures, disease activity scores, and use of RA drugs in combination with stimulation.

Results: 242 participants across 41 US study sites were consented and underwent device implantation followed by 1:1 randomization to treatment or sham. Baseline characteristics were well-balanced with mean age of 56 years, 86% female, RA duration 12.4 years, 15 tender joints, and 10 swollen joints (28 joint count). Overall, 39% of patients had been treated with exactly 1 prior b/tsDMARD, 22% with exactly 2, and 39% with 3 or more. 43% of all patients were exposed to b/tsDMARDs with differing mechanisms of action.

At 3 months, a significantly greater percentage of patients in the treatment group were ACR20 responders (treatment 35.2% [43/122] vs. sham 24.2% [29/120], p=0.0209). Response rates continued to improve for treatment group: 52.1% at 6 months, 51.7% at 9 months, and 55.8% at 12 months (Figure 1). Disease activity scores showed a similar trend with 49.3% attaining DAS28-CRP low disease activity or remission, 47.4% attaining CDAI low disease activity or remission and 77.3% attaining EULAR good/moderate response at 12 months (Figure 2).

Augmentation of stimulation therapy with a b/tsDMARD was allowed without restriction following the 3-month, controlled portion of participation. By 12 months, only 24.8% of patients added a b/tsDMARD to stimulation therapy and 97.5% of all patients remained persistent with stimulation therapy.

The implant procedure was well-tolerated, with a serious adverse rate of 1.7%, all occurring during the perioperative period. The most common, related adverse event was transient vocal cord paresis presenting as hoarseness following the implant procedure. Stimulation was well-tolerated, with few non-serious events, such as pain or sleep disturbance. These were typically managed by adjusting the stimulation dose. No deaths or unanticipated adverse device effects occurred (Table 1).

Conclusion: RESET-RA met its primary efficacy and safety endpoints, demonstrating that vagus nerve-mediated neuroimmune modulation by electrical stimulation using an implantable device is well-tolerated with durable efficacy through 12-months among adults with active RA disease and inadequate response or intolerance to at least one b/tsDMARD.