Vagus Nerve Stimulation for Moderate to Severe Rheumatoid Arthritis (RESET-RA)

Vagus Nerve Stimulation Using the SetPoint System for Moderate to Severe Rheumatoid Arthritis: The RESET-RA Study

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Procedure: Implant Procedure; Drug: Conventional Synthetic DMARD; Device: Active stimulation; Device: Non-active stimulation

Detailed Description

The RESET-RA study is an operationally seamless, 2-stage, randomized, double-blind, sham-controlled, multicenter pivotal study enrolling up to 250 subjects at up to 45 study centers across the U.S. The 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 (RA) who have had an inadequate response, loss of 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 implanted inside the left side of the neck on the vagus nerve (implant procedure). The implant delivers a small amount of electricity (stimulation) to the nerve. All eligible subjects will undergo the surgery under general anesthesia. Half of the subjects will receive active stimulation (the treatment group) and the other half will receive non-active stimulation (the control group). Stimulation will be delivered for 1 min once per day for 12 weeks. 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. Blinding will be maintained until the last enrolled and randomized subject in Stage 2 completes Week 12 assessments, and the study database is locked.

• Study Type: Interventional
• Enrollment (Actual): 243
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Mesa, Arizona, United States, 85210
      • Arizona Arthritis ans Rheumatology Research, PPLC
    • Phoenix, Arizona, United States, 85037
      • Arizona Arthritis Rheumatology & Research, PLLC
    • Tucson, Arizona, United States, 85704
      • Arizona Arthritis & Rheumatology Research, PLLC
  • California
    • Covina, California, United States, 91722
      • Medvin Clinical Research
    • Upland, California, United States, 91786
      • Inland Rheumatology Clinical Trials
    • Whittier, California, United States, 90602
      • Medvin Clinical Research
  • Colorado
    • Fort Collins, Colorado, United States, 80528
      • The Arthritis & Rheumatology Clinic of Northern Colorado
  • Connecticut
    • Stamford, Connecticut, United States, 06905
      • Stamford Therapeutics Consortium
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Delaware Arthritis
  • Florida
    • Aventura, Florida, United States, 33180
      • Arthritis & Rheumatic Disease Specialties
    • Avon Park, Florida, United States, 33825
      • HARAC Research Corporation
    • Boynton Beach, Florida, United States, 33472
      • Reciomed Clinical Research Network, Inc.
    • Clearwater, Florida, United States, 33765
      • Bay Area Rheumatology
    • Plantation, Florida, United States, 33324
      • IRIS Research and Development
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Augusta University
    • Lawrenceville, Georgia, United States, 30044
      • Parris and Associates Rheumatology
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Willowbrook, Illinois, United States, 60527
      • Willow Rheumatology and Wellness PLLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Division of Rheumatology, Allergy, and Immunology
  • Michigan
    • Lansing, Michigan, United States, 48910
      • June DO, PC
  • Minnesota
    • Eagan, Minnesota, United States, 55121
      • Saint Paul Rheumatology, P.A.
  • Missouri
    • Kansas City, Missouri, United States, 64151
      • Kansas City Physician Partners
    • St Louis, Missouri, United States, 63122
      • West County Rheumatology
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
      • Physician Research Collaboration, LLC
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Albuquerque Center for Rheumatology
  • New York
    • Babylon, New York, United States, 11702
      • Long Island Regional Arthritis & Osteoporosis Care
  • North Carolina
    • Charleston, North Carolina, United States, 28202
      • Arthritis & Osteoporosis Consultants Of The Carolinas
    • Charlotte, North Carolina, United States, 28210
      • DJL Clinical Research
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
      • Health Research of Oklahoma, PLLC
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Medical Center
  • Texas
    • Allen, Texas, United States, 75013
      • Arthritis & Rheumatology Research Institute, PLLC
    • Austin, Texas, United States, 78745
      • Tekton Research
    • Austin, Texas, United States, 78717
      • Austin Regional Clinic
    • Austin, Texas, United States, 78746
      • Central Texas Rheumatology Associates
    • Colleyville, Texas, United States, 76034
      • Precision Comprehensive Clinical Research Solutions
    • Houston, Texas, United States, 77043
      • Biopharma Informatic
    • Mesquite, Texas, United States, 75150
      • Southwest Rheumatology Research LLC
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas, Inc
  • Virginia
    • Fairfax, Virginia, United States, 22033
      • Annapolis Rheumatology
  • Washington
    • Bothell, Washington, United States, 98021
      • Sound Clinical Research, LLC
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 22-75 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Active stimulation for 1 min once per day	Procedure: Implant 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.; Other Names: Surgical placement of vagus nerve stimulator inside the neck; Drug: Conventional Synthetic DMARD; 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; Other Names: Background therapy with conventional synthetic DMARD; Device: Active stimulation; Active stimulation for 1 min once per day
Sham Comparator: Control; Non-active stimulation for 1 min once per day	Procedure: Implant 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.; Other Names: Surgical placement of vagus nerve stimulator inside the neck; Drug: Conventional Synthetic DMARD; 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; Other Names: Background therapy with conventional synthetic DMARD; Device: Non-active stimulation; Non-active stimulation for 1 min once per day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
DAS28-CRP Good or Moderate Response as Defined by European League Against Rheumatism (EULAR)	The Disease Activity Score in 28 joints calculated with C-reactive protein (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=worst), subject global assessment (0=best to 10=worst) and high-sensitivity C-reactive protein (hsCRP) concentration (mg/L). A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 A subject is considered having a moderate treatment response if: DAS28-CRP score improvement from baseline to Week 12 is > 0.6 and ≤ 1.2, and the DAS28-CRP score at Week 12 is ≤ 5.1; or; DAS28-CRP score improvement from baseline to Week 12 is > 1.2, and the DAS28-CRP score at Week 12 is > 3.2. A subject is considered having a good treatment response if: • DAS28-CRP score improvement from baseline to Week 12 is > 1.2 and the DAS28-CRP score at Week 12 is ≤ 3.2	Week 12
DAS28-CRP Response (MCID -1.2) at Week 12	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) response is based on the minimal clinically important difference (MCID) of -1.2 from baseline. DAS28-CRP is based on a composite score of 4 items: tender and swollen joint counts of 28 joints (scale 0=best to 28=worst), subject global assessment (0=best to 10=worst) and high-sensitivity C-reactive protein (hsCRP) concentration (mg/L). A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96	Week 12
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22)	HAQ-DI response based on the MCID of -0.22 from baseline. The HAQ-DI is a questionnaire validated for RA self-assessment by subjects that contains 20 questions in the following 8 functional areas: Dressing and grooming; Arising; Eating; Walking; Hygiene; Reach; Grip; Common daily activities Scoring within each functional area is from 0 (without any difficulty) to 3 (unable to do). The total score is obtained by summing 8 area scores and dividing by 8. The total HAQ-DI score ranges from 0 to 3 and corresponds to the current degree of disability: 0 to < 1 Mild difficulties to moderate disability; 1 to < 2 Moderate disability; 2 to 3 Severe to very severe disability	Week 12
ACR20 Response at Week 12 From Day 0	Response is defined as achieving at least 20% improvement from Day 0 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=worse), 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/mL).	Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bone Erosion Progression, All Completers	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand. A total score for each pathology is generated by the summation of individual joint/bone scores as follows: Synovitis: 8 joints each scored on a scale from 0 = normal to 3 = severe, resulting in a total score from 0 to 24.; Bone erosion: 25 bones each scored on a scale from 0 (0-10% eroded volume) to 10 (91-100% eroded volume), resulting in a total score from 0 to 250.; Osteitis: 25 bones scored on a scale from 0 (no osteitis) to 3 (68-100% of bone volume involved), resulting in a total score from 0 to 75.; CARLOS (cartilage loss): 25 joints each scored on a scale from 0 (no damage) to 4 (complete ankylosis or fusion), resulting in a total score from 0 to 100. The proportion of bone erosion progressors is the % subjects with an increase of > 0.5 on the bone erosion score, comparing baseline to Week 12. An increase of > 0.5 represents disease progression.	Week 12
Bone Erosion Progression, All Completers With Erosive Phenotype	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand. A total score for each pathology is generated by the summation of individual joint/bone scores as follows: Synovitis: 8 joints each scored on a scale from 0 = normal to 3 = severe, resulting in a total score from 0 to 24.; Bone erosion: 25 bones each scored on a scale from 0 (0-10% eroded volume) to 10 (91-100% eroded volume), resulting in a total score from 0 to 250.; Osteitis: 25 bones scored on a scale from 0 (no osteitis) to 3 (68-100% of bone volume involved), resulting in a total score from 0 to 75.; CARLOS (cartilage loss): 25 joints each scored on a scale from 0 (no damage) to 4 (complete ankylosis or fusion), resulting in a total score from 0 to 100. The proportion of bone erosion progressors is the % subjects with an increase of > 0.5 on the bone erosion score, comparing baseline to Week 12. An increase of > 0.5 represents disease progression.	Week 12
Bone Erosion Progression, All Completers That Previously Only Failed 1 b/tsDMARD	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand. A total score for each pathology is generated by the summation of individual joint/bone scores as follows: Synovitis: 8 joints each scored on a scale from 0 = normal to 3 = severe, resulting in a total score from 0 to 24.; Bone erosion: 25 bones each scored on a scale from 0 (0-10% eroded volume) to 10 (91-100% eroded volume), resulting in a total score from 0 to 250.; Osteitis: 25 bones scored on a scale from 0 (no osteitis) to 3 (68-100% of bone volume involved), resulting in a total score from 0 to 75.; CARLOS (cartilage loss): 25 joints each scored on a scale from 0 (no damage) to 4 (complete ankylosis or fusion), resulting in a total score from 0 to 100. The proportion of bone erosion progressors is the % subjects with an increase of > 0.5 on the bone erosion score, comparing baseline to Week 12. An increase of > 0.5 represents disease progression.	Week 12
Change in Erosion Score, All Completers	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Bone erosion: 25 bones each scored on a scale from 0 (0-10% eroded volume) to 10 (91-100% eroded volume), resulting in a total score from 0 to 250.	Week 12
Change in Erosion Score, All Completers With Erosive Phenotype	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Bone erosion: 25 bones each scored on a scale from 0 (0-10% eroded volume) to 10 (91-100% eroded volume), resulting in a total score from 0 to 250.	Week 12
Change in Erosion Score, All Completers That Previously Only Failed 1 b/tsDMARD	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Bone erosion: 25 bones each scored on a scale from 0 (0-10% eroded volume) to 10 (91-100% eroded volume), resulting in a total score from 0 to 250.	Week 12
Change in Synovitis Score, All Completers	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Synovitis: 8 joints each scored on a scale from 0 = normal to 3 = severe, resulting in a total score from 0 to 24.	Week 12
Change in Synovitis Score, All Completers With Erosive Phenotype	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Synovitis: 8 joints each scored on a scale from 0 = normal to 3 = severe, resulting in a total score from 0 to 24.	Week 12
Change in Synovitis Score, All Completers That Previously Only Failed 1 b/tsDMARD	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Synovitis: 8 joints each scored on a scale from 0 = normal to 3 = severe, resulting in a total score from 0 to 24.	Week 12
Change in Osteitis Score, All Completers	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Osteitis: 25 bones scored on a scale from 0 (no osteitis) to 3 (68-100% of bone volume involved), resulting in a total score from 0 to 75.	Week 12
Change in Osteitis Score, All Completers With Erosive Phenotype	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Osteitis: 25 bones scored on a scale from 0 (no osteitis) to 3 (68-100% of bone volume involved), resulting in a total score from 0 to 75.	Week 12
Change in Osteitis Score, All Completers That Previously Only Failed 1 b/tsDMARD	RAMRIS is a standardized system for RA MRI scoring of 4 different types of joint pathologies in the wrist and the hand (synovitis, bone erosion, osteitis, and cartilage loss). A total score for each pathology is generated by the summation of individual joint/bone scores: • Osteitis: 25 bones scored on a scale from 0 (no osteitis) to 3 (68-100% of bone volume involved), resulting in a total score from 0 to 75.	Week 12
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission	The CDAI score is based on 4 items: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); EGA, evaluator's global assessment (0=best to 10=worst) The CDAI score is calculated as follows and ranges from 0 to 76: • CDAI = TJC28 + SJC28 + SGA + EGA The CDAI score corresponds to the current RA activity: 0 to ≤ 2.8 Remission; >2.8 to ≤ 10 Low disease activity (LDA); >10 to ≤ 22 Moderate disease activity; > 22 High disease activity	Week 12
DAS28-CRP Low Disease Activity (LDA) or Remission	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) score is a composite index providing a measure of disease activity, comprising: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); hsCRP (mg/L), high sensitivity C-reactive protein concentration (mg/L) A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 The DAS28-CRP score corresponds to the current RA activity: 0 to < 2.6 Remission; 2.6 to < 3.2 LDA; 3.2 to ≤ 5.1 Moderate activity; > 5.1 High activity	Week 12
the American College of Rheumatology (ACR) 20 Response, All Completers	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 24
the American College of Rheumatology (ACR) 20 Response, Non-augmented	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 24
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, All Completers	The CDAI score is based on 4 items: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); EGA, evaluator's global assessment (0=best to 10=worst) The CDAI score is calculated as follows and ranges from 0 to 76: • CDAI = TJC28 + SJC28 + SGA + EGA The CDAI score corresponds to the current RA activity: 0 to ≤ 2.8 Remission; >2.8 to ≤ 10 Low disease activity (LDA); >10 to ≤ 22 Moderate disease activity; > 22 High disease activity	Week 24
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, Non-augmented	The CDAI score is based on 4 items: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); EGA, evaluator's global assessment (0=best to 10=worst) The CDAI score is calculated as follows and ranges from 0 to 76: • CDAI = TJC28 + SJC28 + SGA + EGA The CDAI score corresponds to the current RA activity: 0 to ≤ 2.8 Remission; >2.8 to ≤ 10 Low disease activity (LDA); >10 to ≤ 22 Moderate disease activity; > 22 High disease activity	Week 24
DAS28-CRP Low Disease Activity (LDA) or Remission, All Completers	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) score is a composite index providing a measure of disease activity, comprising: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); hsCRP (mg/L), high sensitivity C-reactive protein concentration (mg/L) A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 The DAS28-CRP score corresponds to the current RA activity: 0 to < 2.6 Remission; 2.6 to < 3.2 LDA; 3.2 to ≤ 5.1 Moderate activity; > 5.1 High activity	Week 24
DAS28-CRP Low Disease Activity (LDA) or Remission, Non-augmented	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) score is a composite index providing a measure of disease activity, comprising: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); hsCRP (mg/L), high sensitivity C-reactive protein concentration (mg/L) A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 The DAS28-CRP score corresponds to the current RA activity: 0 to < 2.6 Remission; 2.6 to < 3.2 LDA; 3.2 to ≤ 5.1 Moderate activity; > 5.1 High activity	Week 24
Health Assessment Questionnaire Disability Index (HAQ-DI) MCID Response, All Completers	HAQ-DI response based on the MCID of -0.22 from baseline. The HAQ-DI is a questionnaire validated for RA self-assessment by subjects that contains 20 questions in the following 8 functional areas: Dressing and grooming; Arising; Eating; Walking; Hygiene; Reach; Grip; Common daily activities Scoring within each functional area is from 0 (without any difficulty) to 3 (unable to do). The total score is obtained by summing 8 area scores and dividing by 8. The total HAQ-DI score ranges from 0 to 3 and corresponds to the current degree of disability: 0 to < 1 Mild difficulties to moderate disability; 1 to < 2 Moderate disability; 2 to 3 Severe to very severe disability	Week 24
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22), Non-augmented	HAQ-DI response based on the MCID of -0.22 from baseline. The HAQ-DI is a questionnaire validated for RA self-assessment by subjects that contains 20 questions in the following 8 functional areas: Dressing and grooming; Arising; Eating; Walking; Hygiene; Reach; Grip; Common daily activities Scoring within each functional area is from 0 (without any difficulty) to 3 (unable to do). The total score is obtained by summing 8 area scores and dividing by 8. The total HAQ-DI score ranges from 0 to 3 and corresponds to the current degree of disability: 0 to < 1 Mild difficulties to moderate disability; 1 to < 2 Moderate disability; 2 to 3 Severe to very severe disability	Week 24
Study Participants That Are Somewhat to Very Satisfied With the SetPoint System for Treatment of Rheumatoid Arthritis	Patient satisfaction was assessed at Week 24 using five-point Likert rating scale: I am very dissatisfied; I am somewhat dissatisfied; I am neither satisfied nor dissatisfied; I am somewhat satisfied; I am very satisfied	Week 24
Study Participants That Are Neither Satisfied Nor Dissatisfied With the SetPoint System for Treatment of Rheumatoid Arthritis	Patient satisfaction was assessed at Week 24 using five-point Likert rating scale: I am very dissatisfied; I am somewhat dissatisfied; I am neither satisfied nor dissatisfied; I am somewhat satisfied; I am very satisfied	Week 24
Study Participants That Are Somewhat to Very Dissatisfied With the SetPoint System for Treatment of Rheumatoid Arthritis	Patient satisfaction was assessed at Week 24 using five-point Likert rating scale: I am very dissatisfied; I am somewhat dissatisfied; I am neither satisfied nor dissatisfied; I am somewhat satisfied; I am very satisfied	Week 24
Study Participants That Would Recommend the SetPoint System to a Family Member or Friend	Patients were asked a question about whether they would recommend the SetPoint System to family and friends	Week 24
the American College of Rheumatology (ACR) 20 Response, All Completers	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 36
the American College of Rheumatology (ACR) 20 Response, Non-augmented	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 36
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, All Completers	The CDAI score is based on 4 items: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); EGA, evaluator's global assessment (0=best to 10=worst) The CDAI score is calculated as follows and ranges from 0 to 76: • CDAI = TJC28 + SJC28 + SGA + EGA The CDAI score corresponds to the current RA activity: 0 to ≤ 2.8 Remission; >2.8 to ≤ 10 Low disease activity (LDA); >10 to ≤ 22 Moderate disease activity; > 22 High disease activity	Week 36
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, Non-augmented	The CDAI score is based on 4 items: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); EGA, evaluator's global assessment (0=best to 10=worst) The CDAI score is calculated as follows and ranges from 0 to 76: • CDAI = TJC28 + SJC28 + SGA + EGA The CDAI score corresponds to the current RA activity: 0 to ≤ 2.8 Remission; >2.8 to ≤ 10 Low disease activity (LDA); >10 to ≤ 22 Moderate disease activity; > 22 High disease activity	Week 36
DAS28-CRP Low Disease Activity (LDA) or Remission, All Completers	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) score is a composite index providing a measure of disease activity, comprising: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); hsCRP (mg/L), high sensitivity C-reactive protein concentration (mg/L) A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 The DAS28-CRP score corresponds to the current RA activity: 0 to < 2.6 Remission; 2.6 to < 3.2 LDA; 3.2 to ≤ 5.1 Moderate activity; > 5.1 High activity	Week 36
DAS28-CRP Low Disease Activity (LDA) or Remission, Non-augmented	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) score is a composite index providing a measure of disease activity, comprising: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); hsCRP (mg/L), high sensitivity C-reactive protein concentration (mg/L) A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 The DAS28-CRP score corresponds to the current RA activity: 0 to < 2.6 Remission; 2.6 to < 3.2 LDA; 3.2 to ≤ 5.1 Moderate activity; > 5.1 High activity	Week 36
Health Assessment Questionnaire Disability Index (HAQ-DI) MCID Response, All Completers	HAQ-DI response based on the MCID of -0.22 from baseline. The HAQ-DI is a questionnaire validated for RA self-assessment by subjects that contains 20 questions in the following 8 functional areas: Dressing and grooming; Arising; Eating; Walking; Hygiene; Reach; Grip; Common daily activities Scoring within each functional area is from 0 (without any difficulty) to 3 (unable to do). The total score is obtained by summing 8 area scores and dividing by 8. The total HAQ-DI score ranges from 0 to 3 and corresponds to the current degree of disability: 0 to < 1 Mild difficulties to moderate disability; 1 to < 2 Moderate disability; 2 to 3 Severe to very severe disability	Week 36
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22), Non-augmented	HAQ-DI response based on the MCID of -0.22 from baseline. The HAQ-DI is a questionnaire validated for RA self-assessment by subjects that contains 20 questions in the following 8 functional areas: Dressing and grooming; Arising; Eating; Walking; Hygiene; Reach; Grip; Common daily activities Scoring within each functional area is from 0 (without any difficulty) to 3 (unable to do). The total score is obtained by summing 8 area scores and dividing by 8. The total HAQ-DI score ranges from 0 to 3 and corresponds to the current degree of disability: 0 to < 1 Mild difficulties to moderate disability; 1 to < 2 Moderate disability; 2 to 3 Severe to very severe disability	Week 36
the American College of Rheumatology (ACR) 20 Response, All Completers	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 48
the American College of Rheumatology (ACR) 20 Response, Non-augmented	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 48
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, All Completers	The CDAI score is based on 4 items: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); EGA, evaluator's global assessment (0=best to 10=worst) The CDAI score is calculated as follows and ranges from 0 to 76: • CDAI = TJC28 + SJC28 + SGA + EGA The CDAI score corresponds to the current RA activity: 0 to ≤ 2.8 Remission; >2.8 to ≤ 10 Low disease activity (LDA); >10 to ≤ 22 Moderate disease activity; > 22 High disease activity	Week 48
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, Non-augmented	The CDAI score is based on 4 items: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); EGA, evaluator's global assessment (0=best to 10=worst) The CDAI score is calculated as follows and ranges from 0 to 76: • CDAI = TJC28 + SJC28 + SGA + EGA The CDAI score corresponds to the current RA activity: 0 to ≤ 2.8 Remission; >2.8 to ≤ 10 Low disease activity (LDA); >10 to ≤ 22 Moderate disease activity; > 22 High disease activity	Week 48
DAS28-CRP Low Disease Activity (LDA) or Remission, All Completers	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) score is a composite index providing a measure of disease activity, comprising: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); hsCRP (mg/L), high sensitivity C-reactive protein concentration (mg/L) A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 The DAS28-CRP score corresponds to the current RA activity: 0 to < 2.6 Remission; 2.6 to < 3.2 LDA; 3.2 to ≤ 5.1 Moderate activity; > 5.1 High activity	Week 48
DAS28-CRP Low Disease Activity (LDA) or Remission, Non-augmented	The Disease Activity Score in 28 joints calculated with C-reactive protein (DAS28-CRP) score is a composite index providing a measure of disease activity, comprising: TJC28, tender joint count of 28 joints (scale 0=best to 28=worst); SJC28, swollen joint count of 28 joints (scale 0=best to 28=worst); SGA, subject global assessment (0=best to 10=worst); hsCRP (mg/L), high sensitivity C-reactive protein concentration (mg/L) A total score ranges from 0 to 10 and is computed as follows: DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96 The DAS28-CRP score corresponds to the current RA activity: 0 to < 2.6 Remission; 2.6 to < 3.2 LDA; 3.2 to ≤ 5.1 Moderate activity; > 5.1 High activity	Week 48
Health Assessment Questionnaire Disability Index (HAQ-DI) MCID Response, All Completers	HAQ-DI response based on the MCID of -0.22 from baseline. The HAQ-DI is a questionnaire validated for RA self-assessment by subjects that contains 20 questions in the following 8 functional areas: Dressing and grooming; Arising; Eating; Walking; Hygiene; Reach; Grip; Common daily activities Scoring within each functional area is from 0 (without any difficulty) to 3 (unable to do). The total score is obtained by summing 8 area scores and dividing by 8. The total HAQ-DI score ranges from 0 to 3 and corresponds to the current degree of disability: 0 to < 1 Mild difficulties to moderate disability; 1 to < 2 Moderate disability; 2 to 3 Severe to very severe disability	Week 48
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22), Non-augmented	HAQ-DI response based on the MCID of -0.22 from baseline. The HAQ-DI is a questionnaire validated for RA self-assessment by subjects that contains 20 questions in the following 8 functional areas: Dressing and grooming; Arising; Eating; Walking; Hygiene; Reach; Grip; Common daily activities Scoring within each functional area is from 0 (without any difficulty) to 3 (unable to do). The total score is obtained by summing 8 area scores and dividing by 8. The total HAQ-DI score ranges from 0 to 3 and corresponds to the current degree of disability: 0 to < 1 Mild difficulties to moderate disability; 1 to < 2 Moderate disability; 2 to 3 Severe to very severe disability	Week 48
the American College of Rheumatology (ACR) 20 Response, Subjects With 1 Prior b/tsDMARD	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
the American College of Rheumatology (ACR) 20 Response, Subjects With 2 Prior b/tsDMARD	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
the American College of Rheumatology (ACR) 20 Response, Subjects With 3 Prior b/tsDMARD	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
the American College of Rheumatology (ACR) 20 Response, Subjects With >=4 Prior b/tsDMARD	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

Collaborators and Investigators

• Sponsor: SetPoint Medical Corporation
• Investigators: Principal Investigator: Mark Richardson, MD PhD, Massachusetts General Hospital; Principal Investigator: John Tesser, MD, Arizona Arthritis and Rheumatology Research, P.C.

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2021
• Primary Completion (Actual): May 16, 2024
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: August 31, 2020
• First Submitted That Met QC Criteria: August 31, 2020
• First Posted (Actual): September 7, 2020

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis; Vagus nerve; implant; vagus nerve stimulating device; drug refractory; permanent implantable
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Skin and Connective Tissue Diseases; Arthritis, Rheumatoid; Pharmaceutical Preparations; Dosage Forms; Delayed-Action Preparations; Drug Implants
• Other Study ID Numbers: SPM-020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No sharing data is planned.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes