Ultrasound Neuroimmune Modulation in Adults With Rheumatoid Arthritis: Feasibility and Safety in a Multicenter, Randomized, Double-Blind, Sham-Controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 40
- 试验地点
- 3
- 主要终点
- Adherence to Therapy
研究概览
简要总结
This two-stage, multicenter clinical trial is designed to evaluate the feasibility, safety, and preliminary efficacy of splenic ultrasound stimulation to activate immune-neuromodulation (SUSTAIN) in patients with rheumatoid arthritis (RA) and at least moderate disease activity. The findings from this trial will directly inform the design and power calculations for a future pivotal trial by identifying an appropriate effect size and confirming protocol feasibility and safety.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
In addition the laboratory personnel analyzing the blood samples, and the statistician analyzing the trial data will be blinded to treatment group.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •At least 18 years old
- •Diagnosis of rheumatoid arthritis as defined by ACR/EULAR 2010 classification criteria
- •At least moderate disease activity, defined as ≥4 tender joints (28-joint count) and ≥4 swollen joints (28-joint count) and a DAS28-CRP >3.2 at the baseline visit
- •hsCRP > 0.3 mg/dL at the last qualifying visit, baseline or retest
- •If on background DMARD therapy, must be on stable dose (see
排除标准
- •Able and willing to comply with all study-related procedures, including daily treatment sessions in the study vehicle, research site visits, and assessments
- •Exclusion Criteria:
- •Unable to provide informed consent
- •Current or planned participation in another interventional clinical trial
- •Inflammatory joint disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis. Current diagnosis of secondary Sjogren's Syndrome is permitted.
- •Prior use of >2 biologic or targeted synthetic DMARDs for RA where the primary reason for discontinuation was efficacy
- •Conventional synthetic DMARDs:
- •Initiation within 12 weeks prior to enrollment
- •Dose adjustment or discontinuation within 4 weeks prior to enrollment
- •If on a stable dose, inability to maintain the stable dose during the study period
- •Biologic DMARDs:
- •Initiation or dose adjustment within 12 weeks prior to enrollment
- •Discontinuation within 4 weeks prior to enrollment
- •If on a stable dose, inability to maintain the stable dose during the study period
- •JAK inhibitors:
- •Initiation, dose adjustment, or discontinuation within 4 weeks prior to enrollment
- •If on a stable dose, inability to maintain the stable dose during the study period
- •Corticosteroids:
- •Initiation, dose adjustment, or discontinuation within 4 weeks prior to enrollment
- •Current dose >10 mg/day prednisone (or equivalent)
- •If on a stable dose, inability to maintain the stable dose during the study
- •Initiation, dose adjustment, or discontinuation of high-dose NSAIDs (≥1200 mg/day ibuprofen) within 14 days of informed consent. Over-the-counter use of NSAIDs is permissible.
- •Pregnant or planning to become pregnant during the study period
- •Known hypersensitivity to ultrasound gel or membrane components
- •History of splenic disorders, including splenectomy, congenital asplenia, or splenomegaly on baseline visit ultrasound
- •Rash, wound, or skin infection overlying the spleen
- •History of vagal nerve injury, vagotomy, or known autonomic neuropathy
- •Recent abdominal surgery or trauma within 30 days of screening
- •Skin to spleen hilum depth >7 cm as measured by ultrasound at the baseline visit
- •Abdominal anatomy or condition precluding adequate ultrasound targeting of the spleen
- •Uncontrolled fibromyalgia or other diffuse pain syndromes that may confound symptom reporting
- •Any condition that, in the investigator's judgment, would preclude safe participation or compliance with study procedures
研究组 & 干预措施
Treatment
Daily active stimulation for 8 weeks
干预措施: Active treatment (Device)
Control
Daily sham stimulation, for 8 weeks, which will look and feel the same as active stimulation, but with no ultrasound energy entering the body
干预措施: Sham (No Treatment) (Device)
结局指标
主要结局
Adherence to Therapy
时间窗: 8 weeks
Proportion of patients adherent to treatment, defined by completing ≥70% of the 56 scheduled ultrasound treatments
Change in high sensitivity CRP (hsCRP)
时间窗: 8 weeks
The primary endpoint is the change in hsCRP from baseline to weeks 2, 4, 6 and 8. The baseline value will be calculated as the average of the screening and baseline visits, both of which must be ≥ 10 mg/L.
Incidence of Adverse Events
时间窗: 12 weeks
All adverse events (AEs) regardless of treatment group that occur over the 12 week enrollment period will be coded and summarized by frequency, severity, and relatedness using the latest MedDRA version (v28.1).
次要结局
- Change in high sensitivity CRP (hsCRP)(Weeks 2, 4, 6, and 8)
- American College of Rheumatology (ACR) 20, 50 and 70 response rates(Week 8)
- Change in Heath Assessment Questionnaire Disability Index (HAQ-DI)(Week 8)
- Change in Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP).(Week 8)
- Change in Clinical Disease Activity Index (CDAI) score for Rheumatoid Arthritis(Week 8)
- Change in Simplified Disease Activity Index (SDAI) for Rheumatoid Arthritis (RA)(Week 8)