Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study

Mark C Genovese; Norman B Gaylis; David Sikes; Alan Kivitz; Diane Lewis Horowitz; Charles Peterfy; Emmett V Glass; Yaakov A Levine; David Chernoff

doi:10.1016/S2665-9913(20)30172-7

Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study

Lancet Rheumatol. 2020 Sep;2(9):e527-e538. doi: 10.1016/S2665-9913(20)30172-7. Epub 2020 Jul 28.

Authors

Mark C Genovese¹, Norman B Gaylis², David Sikes³, Alan Kivitz⁴, Diane Lewis Horowitz⁵, Charles Peterfy⁶, Emmett V Glass⁷, Yaakov A Levine⁷, David Chernoff⁷

Affiliations

¹ Division of Immunology and Rheumatology, Stanford University, Palo Alto, CA, USA. Electronic address: genovese@stanford.edu.
² Arthritis and Rheumatic Disease Specialties, Aventura, FL, USA.
³ Department of Rheumatology, Florida Medical Clinic, Zephyrhills, FL, USA.
⁴ Altoona Center for Clinical Research, Duncansville, PA, USA.
⁵ Division of Rheumatology, Northwell Health, Great Neck, NY, USA.
⁶ Spire Sciences, Boca Raton, FL, USA.
⁷ SetPoint Medical, Valencia, CA, USA.

PMID: 38273617
DOI: 10.1016/S2665-9913(20)30172-7

Abstract

Background The inflammatory reflex plays a role in regulating innate and adaptive immunity by modulating cellular and molecular inflammatory pathways. The vagus nerve is a major constituent of the inflammatory reflex and studies have shown that the reflex can be activated by electrical stimulation of the vagus nerve. In this first in-human pilot study, we assessed the safety and efficacy of a novel miniaturised vagus nerve stimulation (VNS) device for the treatment of multidrug-refractory rheumatoid arthritis.

Methods: Participants with moderately to severely active rheumatoid arthritis and prior insufficient response to two or more biological disease-modifying anti-rheumatic drugs or Janus kinase inhibitors with at least two different modes of action were enrolled in a two-stage study done at five clinical research sites in the USA. Stage 1 was open label; participants were implanted with a miniaturised VNS device, which was activated for 1 min once a day. In stage 2, participants were randomly assigned (1:1:1) to receive active stimulation (1 min once a day or 1 min four times a day) or sham stimulation (device implanted but not activated), with the sites and participants masked to treatment assignment. The primary outcome was incidence of treatment-emergent adverse events. Clinical efficacy was assessed as a key secondary outcome. The study was registered with ClinicalTrials.gov, NCT03437473.

Findings: 14 patients were enrolled between March 13 and Aug 8, 2018. Three patients received stimulation in stage 1 and, following safety review board approval, the remaining 11 patients were implanted during stage 2 and randomly assigned to receive 1 min of stimulation once daily (n=3), 1 min of stimulation four times daily (n=4), or no stimulation (n=4) for 12 weeks. There were no device-related or treatment-related serious adverse events. Surgery-related adverse events were Horner's syndrome and vocal cord paralysis (in one patient each), which resolved without clinically significant sequelae. No deaths were recorded.

Interpretation: VNS with a miniaturised neurostimulator was safe and well tolerated and reduced signs and symptoms of rheumatoid arthritis in patients with multidrug-refractory disease. These results support further evaluation in a larger randomised sham-controlled study.

Funding: SetPoint Medical.

Associated data

ClinicalTrials.gov/NCT03437473