Vagus Nerve Stimulation for Moderate to Severe Rheumatoid Arthritis

Study Overview
=================
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 250 subjects at 40 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 180-week open-label follow-up with all subjects (treatment and control) receiving active stimulation to evaluate long-term safety.

Detailed Description
-----------------
The RESET-RA study is an operationally seamless, 2-stage, randomized, double-blind, sham-controlled, multicenter pivotal study enrolling 250 subjects at 40 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 180-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.

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

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Procedure: Implant Procedure
* Drug: Conventional Synthetic DMARD
* Device: Active stimulation
* Device: Non-active stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 22 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the American College of Rheumatology (ACR) 20 response | Difference between treatment and control groups in the proportion of subjects who achieve at least 20% improvement from baseline to Week 12 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 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 12 | 
| DAS28-CRP response (MCID -1.2) at Week 12 | DAS28-CRP response based on the minimal clinically important difference (MCID) of -1.2 from baseline | 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 | Week 12 | 
| ACR20 response at Week 12 from Day 0 | Difference between treatment and control groups in the proportion of subjects who achieve at least 20% improvement from Day 0 to Week 12 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 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rheumatoid Arthritis, Vagus nerve, vagus nerve stimulating device, drug refractory, permanent implantable, implant