Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial

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 .

Fig. 1. CONSORT diagram.

Patient disposition through month 12. BMI, body mass index; CVA, cerebrovascular accident; TIA, transient ischemic attack; JAKi, Janus kinaseinhibitor, NSAID, nonsteroidal anti-inflammatory drug.

Fig. 2. Integrated neuromodulation system.

The integrated neuromodulation system consists of an implant and pod. The implant is placed in the pod to position and hold it in place on the left cervical vagus nerve to ensure direct contact for precise stimulation. The implant is approximately 2.5 cm in length and weighs 2.6 g. To charge the implant, patients wear a wireless device (charger) around the neck for a few minutes, once a week. The implant is programmed by healthcare providers (HCPs) using a proprietary application (programmer). Adapted from ref. , by permission of Cold Spring Harbor Laboratory Press.

Fig. 3. Clinical composite outcomes and disease activity.

a, The percentage of patients who had an ACR20 response at 3 months, the primary efficacy end point of this study. Patients with missing data or who received rescue treatment were imputed as nonresponders. Stimulation, n = 122; sham, n = 120. b, The percentage of patients who had an ACR20 response through 12 months. Within double-blind period; stimulation, n = 122; sham, n = 120. At 6, 9 and 12 months, n = 97, 89, 77 in arm 1, respectively, and n = 98, 87, 81 in arm 2, respectively. c, The percentage of patients who had a DAS28-CRP good or moderate response according to the EULAR criteria. At 3, 6, 9 and 12 months, n = 118, 95, 85, 75 in arm 1, respectively, and n = 117, 98, 82, 79 in arm 2, respectively. d, The percentage of patients who had achieved LDA or remission by DAS28-CRP criteria (score < 3.2). At 3, 6, 9 and 12 months, n = 118, 95, 85, 75 in arm 1, respectively, and n = 117, 98, 82, 79 in arm 2, respectively. All data are presented as the percentage of each group with s.e. Formal statistical analyses were only performed at the 3-month study visit (double-blind) with the Cochran–Mantel–Haenszel (CMH) test using stratification factors based on prespecified criteria (prior inadequate or lost response to a tsDMARD, prior inadequate or lost response to ≥4 biological DMARDs with ≥2 mechanisms of action and RA disease severity defined as either <4 TJC28 or <4 SJC28 at day 0), at a one-sided significance level of 0.025. P = 0.0209, 95% CI = 0.6–23.1 (a,b). P = 0.0048, 95% CI = 7.3–31.7 (c). P = 0.0154, 95% CI = 1.2–21.6 (d). After 3 months (open-label stimulation), patients were permitted to augment therapy with adjunctive drugs without restriction. Data presented at 6, 9 and 12 months in b–d include all patients completing the visit who had not used augmented therapy. Percent of patients with augmented therapy—6 months = 17.8%, 9 months = 24.8%, 12 months = 32.2%. BL, baseline. *P < 0.025, **P < 0.01.

Fig. 4. Treatment impact on the joints.

a,b, The mean change and s.e. in the number of tender and swollen joints and as compared to baseline are shown in a (tender-joint count) and in b (swollen-joint count). The vertical line at 3 months indicates the end of the double-blind period of the study and the beginning of open-label stimulation. For a and b, within double-blind period: stimulation, n = 116; sham, n = 114. At 6, 9 and 12 months, n = 96, 88 and 77 in arm 1, respectively, and n = 98, 87 and 80 in arm 2, respectively. c–f, The cumulative probability of a change in erosion score, as assessed via the OMERACT RAMRIS. The right part of the curve (positive values on the y axis) represents erosion progression (worsening), the left part of the curve represents erosion regression (improvement) and the flat line at y = 0 represents no change in erosion score. c,e, Plot change from baseline to 3 months during the controlled-blind period. d,f, Plot change from 3 months to 6 months during open-label stimulation. Patients who completed the 3-month and 6-month visits without augmented therapy are included in c and d. Patients at risk for erosion progression are included in e and f. g,h, The percentage of patients who had erosion progression, defined as >0.5 increase in RAMRIS erosion score by MRI. The vertical line at 3 months demarcates the double-blind period between baseline and 3 months and the open-label stimulation period between 3 months and 6 months. Data are presented as the mean (a,b) or the percentage of each group (g,h) with s.e. Statistical analyses were only performed at points through 3 months; a and b with mixed-effect model repeated measures and g and h with the CMH test. All tests use one-sided significance level of 0.025. In a, P = 0.0021, 0.0004 and 0.0014 at month 1, 2 and 3, respectively. In b, P = 0.0097, 0.0009 and 0.0131 at month 1, 2 and 3, respectively. *P < 0.025, **P < 0.01, ***P < 0.001.

Extended Data Fig. 1. Schematic of study design.

Adapted from ref. , licensed under a Creative Commons Attribution 4.0 International License.