Sacral Nerve Stimulation for Mild-to-Moderate or Refractory Rheumatoid Arthritis

Study Overview
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Brief Summary
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This pilot study will assess the efficacy of sacral never stimulation (SNS) for the treatment of adult patients with active, mild-to-moderate rheumatoid arthritis or those with refractory disease. The study will enroll 60 subjects in a single center. All eligible subjects will be randomly divided into two groups at a ratio of 1:1. Half of the subjects will receive SNS (treatment) and the other half will receive sham stimulation (control). Subjects will be followed up for 2-4 weeks, according to their response to the treatment. Disease activity score, patient report outcomes and serum inflammatory cytokines will be observed before and after treatment.

Detailed Description
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Studies have shown that vagus nerve stimulation (VNS) may exert an anti-inflammatory effect through mechanisms like cholinergic anti-inflammatory pathway (CAP). This anti-inflammatory function of VNS has been verified in collagen induced arthritis (CIA) rats, RA patients, and animal models of inflammatory bowel disease (IBD). In recent years, it was reported that sacral nerve stimulation (SNS) is a safer way to exert a similar anti-inflammatory effect as VNS. Therefore, this study aims to explore the therapeutic effect of SNS on RA patients. This is a randomized controlled clinical trial which will enroll 60 eligible RA patients. These subjects will be divided into two groups at a ratio of 1:1, the treatment group (Group 1) who will receive SNS and the control group (Group 2) who will receive sham stimulation. The patients will lie in prone position. In Group 1, a senior acupuncture doctor will pierce filiform needles through the sacral foramen into the S3 and S4 sacral nerves. These sites correspond to the Zhongliao and Xialiao acupoints in Traditional Chinese Medicine. In Group 2, shallow acupuncture stimulation will be performed at sites 8-10cm away from the acupoints in Group 1. In both groups, electrodes will be clamped on the filiform needles and an electrical current of 0.5 mA will be delivered. The stimulation will last for 60 minutes every time, once a day for 2 weeks. If the subjects respond to the treatment well, SNS treatment will be continued for 2 weeks. The following parameters will be measured before and 2-4 weeks after treatment: Disease activity-related indexes of RA: swelling joint number (SJC), tender joint number (TJC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP); Serum levels of inflammatory cytokines, including IL-6, IL-17, TNF-α, etc; Patient report outcomes: Visual Analogue Scale (VAS) pain score, Health Assessment Questionnaire Disability Index (HAQ-DI) ; Indexes of autonomic nervous function: serum level of norepinephrine (NE), heart rate variability (HRV).

Official Title
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A Randomized, Sham-Controlled, Double-Blind Study of Sacral Nerve Stimulation for Mild-to-Moderate or Refractory Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Device: Sacral nerve stimulation
* Device: Sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-65 years of age at screening Met the American College of Rheumatology criteria (2010) for RA Active mild to moderate RA (defined as 3.2 < DAS28-CRP< 5.1) naïve to any medication; or refractory RA who demonstrated an inadequate response or loss of response to 2 or more conventional synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) after treatment for at least 6 months. Exclusion Criteria: Any severe chronic or uncontrolled comorbid disease, such as important organ failure, degree II and III heart block, clinically significant cardiovascular disease, severe infection, tumor, etc; Combined with other connective tissue diseases Cognitive impairment and can't cooperate Pregnancy or breastfeeding Bleeding or coagulation disorders Localized skin infections Intra-articular corticosteroid or pulse steroid within 2 weeks preceding the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Sacral nerve stimulation | Device: Sacral nerve stimulation<br>* A senior acupuncture doctor will pierce filiform needles through the sacral foramen into the S3 and S4 sacral nerves. These sites correspond to the Zhongliao and Xialiao acupoints in Traditional Chinese Medicine. Electrodes will be clamped on the filiform needles and an electrical current of 0.5 mA will be delivered. The stimulation will last for 60 minutes every time, once a day for 2 weeks.<br>|
| Sham Comparator: Control<br>Sham stimulation | Device: Sham stimulation<br>* Shallow acupuncture stimulation will be performed at sites 8-10cm away from the acupoints in Group 1. Electrodes will be clamped on the filiform needles and an electrical current of 0.5 mA will be delivered. The stimulation will last for 60 minutes every time, once a day for 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The American College of Rheumatology (ACR) 20 response at Week 2 from Day 0 | Difference between treatment and control groups in the proportion of subjects who achieve at least 20% improvement from baseline to Week 2 in tender and swollen joint counts of 28 joints (scale 0=best to 28=worse) and 3 out of the following 5 measures: Health Assessment Questionnaire Disability Index (HAQ-DI) score (scale 0=no difficulty to 3=unable to do), subject global assessment (0=best to 10=worse), subject pain (0=no pain to 10=worse), evaluator's global assessment (0=best to 10=worse), or high sensitivity C-reactive protein (hsCRP) concentration (mg/mL) with higher values representing worse outcome. | Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. The Disease Activity Score 28-C-reactive protein (DAS28-CRP) good or moderate response as defined by European League Against Rheumatism (EULAR) | The DAS28-CRP good or moderate response as defined by EULAR based on a composite score of 4 items: tender and swollen joint counts of 28 joints (scale 0=best to 28=worse), subject global assessment (0=best to 10=worse) and high-sensitivity C-reactive protein (hsCRP) concentration (mg/L) with higher values representing worse outcome | week 2 | 
| DAS28-CRP response (MCID -1.2) at Week 2 | DAS28-CRP response based on the minimal clinically important difference (MCID) of -1.2 from baseline | wee 2 | 
| 3. Health Assessment Questionnaire Disability Index (HAQ-DI) response (MCID -0.22) | HAQ-DI response based on the MCID of -0.22 from baseline | week 2 | 
| Pain Visual Analogue Scale (scoring range 0   10) | Changes from baseline to week 2. | week 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rheumatoid arthritis, Sacral nerve, Sacral nerve stimulation, Neuromodulation, randomized clinical trial, drug refractory