Vagus Nerve Stimulation for Rheumatoid Arthritis

(RESET-RA Trial)

Recruiting at 45 trial locations

Overseen By Jamie Latos, DO

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 3

Sponsor: SetPoint Medical Corporation

Must be taking: Conventional DMARDs

Disqualifiers: Psychiatric illness, Cardiovascular disease, Neurological syndromes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 12 weeks

243 Participants Needed

Trial Summary

What is the purpose of this trial?

The RESET-RA study will assess the safety and efficacy of the SetPoint System (study device) for the treatment of adult patients with active, moderate to severe rheumatoid arthritis who have had an inadequate response or intolerance to biologic or targeted synthetic Disease-Modifying Anti-Rheumatic Drugs (DMARDs). The study device contains a miniaturized stimulator (implant) that is surgically placed under general anesthesia on the vagus nerve through a small incision on the left side of the neck (implant procedure). The study will enroll up to 250 subjects at up to 45 sites. All eligible subjects will undergo the implant procedure. Half of the subjects will receive active stimulation (treatment) and the other half will receive non-active stimulation (control). After completing primary endpoint assessments at Week 12, there will be a one-way crossover of control subjects to active stimulation and a 252-week open-label follow-up with all subjects (treatment and control) receiving active stimulation to evaluate long-term safety.

Will I have to stop taking my current medications?

The trial requires that you continue taking at least one conventional synthetic DMARD (a type of medication for rheumatoid arthritis) at a stable dose through Week 12. The protocol does not specify if you need to stop other medications, so it's best to discuss this with the trial team.

What data supports the effectiveness of the treatment SetPoint System for rheumatoid arthritis?

Research suggests that vagus nerve stimulation (VNS) can reduce inflammation in rheumatoid arthritis by lowering levels of certain inflammatory markers. Studies in both humans and animal models have shown that VNS may decrease disease activity and improve symptoms in patients with rheumatoid arthritis. ^{1 2 3 4 5}

Is vagus nerve stimulation safe for humans?

Vagus nerve stimulation (VNS) has been used safely in humans for various conditions, including rheumatoid arthritis, epilepsy, and other inflammatory diseases. Studies have shown that both invasive and non-invasive VNS are generally well tolerated, with no major safety concerns reported in the trials. ^{2 3 5 6 7}

How does vagus nerve stimulation treatment differ from other rheumatoid arthritis treatments?

Vagus nerve stimulation (VNS) is unique because it uses electrical impulses to stimulate the vagus nerve, which can reduce inflammation by decreasing the production of pro-inflammatory cytokines (proteins that promote inflammation). Unlike traditional drug treatments for rheumatoid arthritis, which often involve medications like corticosteroids or biological agents, VNS is a non-drug, neuromodulatory approach that targets the body's nervous system to help manage the disease. ^{2 3 4 5 8}

Research Team

JOHN R TESSER

Principal Investigator

Arizona Arthritis and Rheumatology Research, P.C.

Mark Richardson, MD PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults aged 22-75 with active, moderate to severe rheumatoid arthritis who haven't responded well or can't tolerate certain advanced RA medications. Participants must be on a stable dose of conventional synthetic DMARD for at least 12 weeks before the trial and continue it through Week 12. People with recurrent fainting episodes, significant psychiatric or substance abuse history, stroke/TIA, serious heart disease, neurological disorders like MS/Alzheimer's/Parkinson's, uncontrolled fibromyalgia, past carotid surgery/splenectomy/vagotomy or tobacco users are excluded.

Inclusion Criteria

I have rheumatoid arthritis and treatments like biologics or JAK inhibitors haven’t worked for me.

I have active rheumatoid arthritis with at least 4 tender and 4 swollen joints.

I have been on a stable dose of a DMARD for my condition for at least 12 weeks.

Exclusion Criteria

I have a condition that significantly weakens my immune system.

I frequently faint due to sudden drops in my heart rate and blood pressure.

I have had surgery on my carotid artery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Implant Procedure

Surgical implantation of the miniaturized stimulator on the vagus nerve under general anesthesia

1 day

1 visit (in-person)

Treatment

Participants receive either active or non-active stimulation for 1 minute once per day

12 weeks

Weekly visits (in-person or virtual)

Crossover

Control subjects crossover to receive active stimulation

1 day

Open-label Follow-up

All subjects receive active stimulation to evaluate long-term safety

252 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• SetPoint System

Trial Overview The RESET-RA study is testing the SetPoint System device that stimulates the vagus nerve to treat rheumatoid arthritis. The device is implanted via surgery under general anesthesia. Of the enrolled participants, half will receive actual stimulation while the other half will get non-active stimulation as a control group initially; after Week 12 all subjects will receive active stimulation for long-term safety assessment.

Participant Groups

Group I: Treatment Experimental Treatment 3 Interventions

Active stimulation for 1 min once per day

Group II: Control Placebo Group 3 Interventions

Non-active stimulation for 1 min once per day

Who Is Running the Clinical Trial?

SetPoint Medical Corporation

Lead Sponsor

Trials

8

Recruited

400+

Findings from Research

Abdominal vagus nerve stimulation (VNS) significantly reduced disease severity in a collagen-induced arthritis rat model, showing decreased inflammatory scores and ankle swelling compared to unstimulated rats.

Stimulated rats had undetectable levels of tumor necrosis factor-alpha (TNF-α) and significantly lower receptor activator of NFκB ligand (RANKL) levels, indicating that abdominal VNS may be an effective therapeutic approach for rheumatoid arthritis patients resistant to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats. Payne, SC., Romas, E., Hyakumura, T., et al.[2022]

In a randomized, double-blind, sham-controlled trial involving 113 patients with rheumatoid arthritis, auricular vagus nerve stimulation (VNS) did not show a significant improvement in disease activity compared to sham treatment, with ACR20 response rates of 25.0% for active stimulation versus 26.9% for sham.

While there were some changes in secondary endpoints like the Health Assessment Questionnaire-Disability Index (HAQ-DI), the overall results suggest that VNS alone is not effective for managing rheumatoid arthritis, indicating the need for larger studies to explore its potential benefits in combination with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Double-Blind, Sham-Controlled, Clinical Trial of Auricular Vagus Nerve Stimulation for the Treatment of Active Rheumatoid Arthritis. Baker, MC., Kavanagh, S., Cohen, S., et al.[2023]

In a pilot study involving two patients with active rheumatoid arthritis who did not respond adequately to methotrexate, vagal nerve stimulation significantly improved clinical symptoms and inflammatory markers over a 42-day period.

After stopping the stimulation, both patients experienced a worsening of their symptoms, indicating that the effects of vagal stimulation may be temporary and highlighting the need for further research with more participants to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[VAGAL NERVE STIMULATION IN THE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS – RESULTS THROUGH DAY 84 OBTAINED AT THE CROATIAN CENTER OF AN INTERNATIONAL PILOT STUDY]. Doko, I., Grazio, S., Grubišić, F., et al.[2018]

Vagus nerve stimulation (VNS) has shown promise in reducing inflammation and pain in various musculoskeletal diseases, including rheumatoid arthritis, with pilot studies indicating significant decreases in disease activity.

Both invasive and non-invasive VNS methods have been associated with benefits in conditions like Sjogren's syndrome and fibromyalgia, but further randomized controlled trials are needed to confirm these findings and determine optimal treatment parameters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in musculoskeletal diseases. Courties, A., Berenbaum, F., Sellam, J.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

A Randomized, Double-Blind, Sham-Controlled, Clinical Trial of Auricular Vagus Nerve Stimulation for the Treatment of Active Rheumatoid Arthritis. [2023]

3. Croatia pubmed.ncbi.nlm.nih.gov

[VAGAL NERVE STIMULATION IN THE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS – RESULTS THROUGH DAY 84 OBTAINED AT THE CROATIAN CENTER OF AN INTERNATIONAL PILOT STUDY]. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Vagal influences in rheumatoid arthritis. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study. [2021]

6. France pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in musculoskeletal diseases. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Modulating Heart Rate Variability through Deep Breathing Exercises and Transcutaneous Auricular Vagus Nerve Stimulation: A Study in Healthy Participants and in Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. [2022]