Ultrasound Neuroimmune Modulation in Adults With Rheumatoid Arthritis

Stage 1 is an open-label pilot study of 6-10 participants. To maintain a seropositive-enriched cohort, enrollment of seronegative participants (those with RF ≤14 IU/mL and Anti-CCP \<20 U/mL) is capped at 3 participants in Stage 1. All participants will receive daily active SUSTAIN therapy for 8 weeks. The initial active ultrasound parameter set (Experimental Treatment 1) will be based on the best available evidence at the start of the trial. If interim review of early efficacy data from the first 3-5 participants, specifically, the magnitude and direction of change in DAS28-CRP from Baseline to Week 4, suggests that a second parameter set may be warranted, the Sponsor may elect to enroll an additional 3-5 participants to receive a second active ultrasound parameter set (Experimental Treatment 2). This decision will be made by the Sponsor prior to enrollment of the first participant assigned to Experimental Treatment 2 and will be documented in a protocol decision memo. If the Sponsor determines that Experimental Treatment 1 demonstrates sufficient early signal, Stage 1 will be completed using a single parameter set. The primary objective of Stage 1 is to assess feasibility, defined as ≥70% adherence to scheduled treatment sessions, and safety, defined by the absence of device-related serious adverse events (SAEs) or Grade ≥2 adverse events (AEs) requiring medical intervention per CTCAE criteria. Data from Stage 1 will be used to refine trial procedures and confirm readiness for Stage 2. Stage 2 consists of a double-blind, randomized, sham-controlled study enrolling 30-40 participants, randomized 1:1 to receive daily active or sham SUSTAIN therapy for 8 weeks. Selection of the Stage 2 active treatment ultrasound parameter set will be based on the safety profile and magnitude/direction of the DAS28-CRP change from Baseline to Week 4 of the two experimental treatments. Enrollment of seronegative participants is capped at 10 in Stage 2, such that at least 75% of enrolled participants are seropositive. Randomization is stratified by serostatus to maintain balance across arms. This stage is designed to further characterize safety and adherence in a larger cohort, and to estimate treatment effect size using clinical and biomarker-based secondary endpoints. All participants will be followed through Week 12 to assess post-treatment safety and durability of clinical and immunologic effects.