Vagus Nerve Stimulation for Moderate to Severe Rheumatoid Arthritis

NCT04539964 | Active Not Recruiting Phase 3 Results DMC FDA Device

• 1 other identifier: SPM-020
• Study Type: interventional
• Target: 243
• Locations: 1 country
• Sites: 42

Brief Summary

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.

Conditions

Rheumatoid Arthritis

Keywords

Rheumatoid Arthritis; Vagus nerve; vagus nerve stimulating device; drug refractory; permanent implantable; implant

Outcome Measures

Primary Outcomes (1)

• the American College of Rheumatology (ACR) 20 Response

  Response is defined as achieving at least 20% improvement from baseline to Week 12 in tender and swollen joint counts of 28 joints (scale 0=best to 28=worst) 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=worst), subject pain (0=no pain to 10=worst), evaluator's global assessment (0=best to 10=worst), or high sensitivity C-reactive protein (hsCRP) concentration (mg/L).

  Week 12

Secondary Outcomes (4)

• DAS28-CRP Good or Moderate Response as Defined by European League Against Rheumatism (EULAR)

  Week 12

• DAS28-CRP Response (MCID -1.2) at Week 12

  Week 12

• Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22)

  Week 12

• ACR20 Response at Week 12 From Day 0

  Week 12

Other Outcomes (46)

• Bone Erosion Progression, All Completers

  Week 12

• Bone Erosion Progression, All Completers With Erosive Phenotype

  Week 12

• Bone Erosion Progression, All Completers That Previously Only Failed 1 b/tsDMARD

  Week 12

Study Arms (2)

Treatment

EXPERIMENTAL

Active stimulation for 1 min once per day

Procedure: Implant Procedure; Drug: Conventional Synthetic DMARD; Device: Active stimulation

Control

SHAM COMPARATOR

Non-active stimulation for 1 min once per day

Procedure: Implant Procedure; Drug: Conventional Synthetic DMARD; Device: Non-active stimulation

Interventions

Implant Procedure PROCEDURE

The SetPoint System (study device) contains a miniaturized stimulator (implant) that is surgically implanted inside the left side of the neck on the vagus nerve (implant procedure). All eligible subjects will undergo the surgery under general anesthesia in outpatient settings.

Also known as: Surgical placement of vagus nerve stimulator inside the neck

Control; Treatment

Conventional Synthetic DMARD DRUG

All subjects will continue to take at least one type of conventional synthetic DMARD at the same stable dose as for 4 weeks prior to consent

Also known as: Background therapy with conventional synthetic DMARD

Control; Treatment

Active stimulation DEVICE

Active stimulation for 1 min once per day

Treatment

Non-active stimulation DEVICE

Non-active stimulation for 1 min once per day

Control

Eligibility Criteria

• Age: 22 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age at screening
• Active moderate or severe RA, defined as at least 4/28 tender and 4/28 swollen joints
• Demonstrated an inadequate response, loss of response, or intolerance to 1 or more approved for rheumatoid arthritis biologic or targeted synthetic Disease-Modifying Anti-Rheumatic Drugs (DMARDs), including Janus kinase inhibitors (JAKi)
• Receiving treatment with at least 1 conventional synthetic DMARD for at least 12 weeks and on a continuous non-changing dose and route of administration for at least 4 weeks prior to Screening and able to continue the same stable dose through Week 12

You may not qualify if:

• Untreated or poorly controlled psychiatric illness or history of substance abuse
• Significant immunodeficiency due to underlying illness
• History of stroke or transient ischemic attack, or diagnosis of cerebrovascular fibromuscular dysplasia
• Clinically significant cardiovascular disease
• Neurological syndromes, including multiple sclerosis, Alzheimer's disease, or Parkinson's disease
• Uncontrolled fibromyalgia
• History of left or right carotid surgery
• History of unilateral or bilateral vagotomy, partial or complete splenectomy
• Recurrent vasovagal syncope episodes
• Current, regular use of tobacco products
• Hypersensitivity/allergy to MRI contrast agents and/or unable to perform MRI

Sponsors & Collaborators

• SetPoint Medical Corporation: lead

Study Sites (42)

Arizona Arthritis ans Rheumatology Research, PPLC

Mesa, Arizona, 85210, United States

Location

Arizona Arthritis Rheumatology & Research, PLLC

Phoenix, Arizona, 85037, United States

Location

Arizona Arthritis & Rheumatology Research, PLLC

Tucson, Arizona, 85704, United States

Location

Medvin Clinical Research

Covina, California, 91722, United States

Location

Inland Rheumatology Clinical Trials

Upland, California, 91786, United States

Location

Medvin Clinical Research

Whittier, California, 90602, United States

Location

The Arthritis & Rheumatology Clinic of Northern Colorado

Fort Collins, Colorado, 80528, United States

Location

Stamford Therapeutics Consortium

Stamford, Connecticut, 06905, United States

Location

Delaware Arthritis

Lewes, Delaware, 19958, United States

Location

Arthritis & Rheumatic Disease Specialties

Aventura, Florida, 33180, United States

Location

HARAC Research Corporation

Avon Park, Florida, 33825, United States

Location

RecioMed Clinical Research Network, Inc.

Boynton Beach, Florida, 33472, United States

Location

Bay Area Rheumatology

Clearwater, Florida, 33765, United States

Location

IRIS Research and Development

Plantation, Florida, 33324, United States

Location

Augusta University

Augusta, Georgia, 30912, United States

Location

Parris and Associates Rheumatology

Lawrenceville, Georgia, 30044, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Willow Rheumatology and Wellness PLLC

Willowbrook, Illinois, 60527, United States

Location

Massachusetts General Hospital Division of Rheumatology, Allergy, and Immunology

Boston, Massachusetts, 02114, United States

Location

June DO, PC

Lansing, Michigan, 48910, United States

Location

Saint Paul Rheumatology, P.A.

Eagan, Minnesota, 55121, United States

Location

Kansas City Physician Partners

Kansas City, Missouri, 64151, United States

Location

West County Rheumatology

St Louis, Missouri, 63122, United States

Location

Physician Research Collaboration, LLC

Lincoln, Nebraska, 68516, United States

Location

Albuquerque Center for Rheumatology

Albuquerque, New Mexico, 87102, United States

Location

Long Island Regional Arthritis & Osteoporosis Care

Babylon, New York, 11702, United States

Location

Arthritis & Osteoporosis Consultants Of The Carolinas

Charleston, North Carolina, 28202, United States

Location

DJL Clinical Research

Charlotte, North Carolina, 28210, United States

Location

Health Research of Oklahoma, PLLC

Oklahoma City, Oklahoma, 73103, United States

Location

Lehigh Valley Health Network

Allentown, Pennsylvania, 18103, United States

Location

University of Pennsylvania Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

Arthritis & Rheumatology Research Institute, PLLC

Allen, Texas, 75013, United States

Location

Austin Regional Clinic

Austin, Texas, 78717, United States

Location

Tekton Research

Austin, Texas, 78745, United States

Location

Central Texas Rheumatology Associates

Austin, Texas, 78746, United States

Location

Precision Comprehensive Clinical Research Solutions

Colleyville, Texas, 76034, United States

Location

Biopharma Informatic

Houston, Texas, 77043, United States

Location

Southwest Rheumatology Research LLC

Mesquite, Texas, 75150, United States

Location

Clinical Trials of Texas, Inc

San Antonio, Texas, 78229, United States

Location

Annapolis Rheumatology

Fairfax, Virginia, 22033, United States

Location

Sound Clinical Research, LLC

Bothell, Washington, 98021, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

Related Publications (2)

• Tesser JRP, Crowley AR, Box EJ, June JP, Wickersham PB, Valenzuela GJ, Gaylis NB, Lam GKW, Pacheco LA, Ridley DJ, Pinto-Patarroyo GP, Novack SN, Churchill MA, Kohler M, Lee EC, Pando JA, Parris GR, Peterson JR, Shah T, Singhal AK, Vuong V, Levine YA, Evangelista ML, Derosier AA, Curtis JR, Richardson RM, Chernoff D. Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial. Nat Med. 2026 Jan;32(1):369-378. doi: 10.1038/s41591-025-04114-7. Epub 2025 Dec 22.

  PMID: 41429981 DERIVED

• Peterson D, Van Poppel M, Boling W, Santos P, Schwalb J, Eisenberg H, Mehta A, Spader H, Botros J, Vrionis FD, Ko A, Adelson PD, Lega B, Konrad P, Calle G, Vale FL, Bucholz R, Richardson RM. Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study. Bioelectron Med. 2024 Mar 13;10(1):8. doi: 10.1186/s42234-023-00138-x.

  PMID: 38475923 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Drug Implants

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Delayed-Action Preparations; Dosage Forms; Pharmaceutical Preparations

Limitations and Caveats

A possible limitation was a 3-month controlled phase, which did not capture peak therapeutic response, known to evolve over longer periods for some patients based on prior experience with vagus nerve stimulation. This is likely influenced by modulation of innate neuroimmune pathways vs. inhibition of discrete inflammatory pathways, the mechanism of most pharmaceutical interventions. Nevertheless, consistency of outcomes across multiple visits thru Wk 48 supports durability of treatment effect.

Results Point of Contact

• Title: VP of Clinical Affairs
• Organization: SetPoint Medical

info@setpointmedical.com

661.750.6140

Study Officials

• John Tesser, MD

  Arizona Arthritis and Rheumatology Research, P.C.

  PRINCIPAL INVESTIGATOR

• Mark Richardson, MD PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: All subjects, investigators, joint evaluators and study staff will be blinded. Blinding of subjects, joint evaluators and investigators will be assessed at Weeks 4 and 12.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: An operationally seamless, 2-stage, randomized, double-blind, sham-controlled, multicenter study. Subjects will be assigned randomly in a 1:1 ratio into either a treatment or control group. Subjects assigned to the treatment group will receive active stimulation for 1 min once per day, and those assigned to the control group will receive non-active stimulation for 1 min once per day.

Study Record Dates

• First Submitted: August 31, 2020
• First Posted: September 7, 2020
• Study Start: January 11, 2021
• Primary Completion: May 16, 2024
• Study Completion (Estimated): October 1, 2027
• Last Updated: April 14, 2026
• Results First Posted: December 19, 2025

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (42)