Splenic neuromodulation as monotherapy and in combination with biologic or targeted synthetic DMARDs for difficult-to-treat rheumatoid arthritis (ConsiderRAte): a randomised, sham-controlled, early feasibility trial.

Background: Preclinical and early human evidence indicate that splenic neuromodulation modulates immune activity either independently or in conjunction with biologic or targeted synthetic (b/ts) disease modifying antirheumatic drugs (DMARDs). This study evaluated the safety, tolerability, and preliminary effectiveness of splenic nerve stimulation (SpNS) as monotherapy and in combination with b/tsDMARDs in adult patients with difficult-to-treat rheumatoid arthritis. Methods: ConsideRAte was an early-feasibility, multicentre, randomised sham-controlled trial of an implantable device (Galvani System) delivering SpNS conducted across six centres in the USA and Netherlands. Adults with difficult-to-treat rheumatoid arthritis, defined by inadequate response to at least two b/tsDMARDs, were implanted and randomised 1:1 to active (STIM ON) or sham (STIM OFF) stimulation following five sentinel patients. Participants received 12 weeks of stimulation in the monotherapy phase, defined as stimulation added to stable conventional synthetic DMARDS (csDMARDs) and/or low dose corticosteroids. Participants with Disease Activity Score using Erythrocyte Sedimentation Rate (DAS28-ESR) improvement of ≥1.2 continued stimulation for an additional 12 weeks; non-responders discontinued stimulation and received baricitinib for 12 weeks. Thereafter, participants who were not in remission could receive adjunct tsDMARDs (baricitinib) together with SpNS in an open-label phase for six months, after which the participants moved to long-term-follow-up. The primary objective was to assess safety and tolerability of the Galvani System, its implantation and subsequent stimulation; key secondary outcomes included assessment of disease activity Disease Activity Score using C-Reactive Protein (DAS28-CRP) and patient-reported outcomes. This study is registered with ClinicalTrials.gov (NCT05003310). Findings: Between January 2022 and November 2024, eleven participants (Five Open Label STIM ON, six randomised to STIM ON (n = 3) and STIM OFF (n = 3)) were successfully implanted with the Galvani System. No device-related serious adverse events, or unanticipated adverse device effects occurred. During the 12-week monotherapy phase, mean DAS28-CRP decreased by 1.02 ± 0.45 (mean ± Standard Error, [SE]) in the STIM ON group compared with -0.34 ± 0.14 in the STIM OFF group. Five of eight (62.5%) STIM ON participants achieved a clinically meaningful improvement (≥1.0-point reduction). Nine participants entered the adjunct phase, with mean (±SE) DAS28-CRP decreasing with -2.95 ± 0.56 points at week 12 and -2.28 ± 0.69 points at week 24; 55.6% (5/9) achieved low disease activity (LDA) and 33.3% (3/9) remission. Two participants remained on monotherapy. In exploratory analysis, biomarkers were assessed in the monotherapy phase at the end of 12 weeks and trends for systemic proinflammatory cytokine reductions and in TH17 (T-helper 17) cell populations were observed in responders as defined by DAS28-CRP changes. Interpretation: SpNS demonstrated a favourable safety profile and was well tolerated in this small cohort. Clinical improvements were observed for monotherapy, and enhanced outcomes were observed for adjunct treatment resulting in multiple participants reaching LDA or remission. By engaging neuro-immune pathways rather than targeting single cytokines, this approach represents a novel therapeutic option that warrants further evaluation as stand-alone therapy or to complement existing pharmacological treatments for difficult-to-treat rheumatoid arthritis patients. Funding: Galvani Bioelectronics.