Trial Outcomes & Findings for Vagus Nerve Stimulation for Moderate to Severe Rheumatoid Arthritis (NCT NCT04539964)

Last Updated: 2025-12-19

Results Overview

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).

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

243 participants

Primary outcome timeframe

Week 12

Results posted on

2025-12-19

Participant Flow

In total, 405 subjects were consented, and 162 subjects were screen failures. Of the 243 subjects meeting eligibility, 1 subject did not complete the implant procedure per Sponsor decision; the remaining 242 subjects were implanted and subsequently randomly assigned to either treatment with active stimulation (n=122) or control with sham, non-active stimulation (n=120).

Participant milestones

Participant milestones
Measure	Treatment Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day
Overall Study STARTED	122	120
Overall Study Week 12 (Primary Endpoint)	122	120
Overall Study Week 24	119	117
Overall Study Week 36	119	115
Overall Study Week 48	119	114
Overall Study COMPLETED	120	116
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day
Overall Study device malfunction	1	0
Overall Study Withdrawal by Subject	1	2
Overall Study Adverse Event	0	2

Baseline Characteristics

Vagus Nerve Stimulation for Moderate to Severe Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. Conventional Synthetic Disease-Modifying Antirheumatic Drug (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 Active stimulation: Active stimulation for 1 minute once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 minute once per day	Total n=242 Participants Total of all reporting groups
Age, Continuous	55.8 years STANDARD_DEVIATION 10.28 • n=8 Participants	55.5 years STANDARD_DEVIATION 10.49 • n=6 Participants	55.7 years STANDARD_DEVIATION 10.36 • n=6 Participants
Sex: Female, Male Female	98 Participants n=8 Participants	110 Participants n=6 Participants	208 Participants n=6 Participants
Sex: Female, Male Male	24 Participants n=8 Participants	10 Participants n=6 Participants	34 Participants n=6 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	23 Participants n=8 Participants	22 Participants n=6 Participants	45 Participants n=6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	98 Participants n=8 Participants	95 Participants n=6 Participants	193 Participants n=6 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=8 Participants	3 Participants n=6 Participants	4 Participants n=6 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=8 Participants	0 Participants n=6 Participants	1 Participants n=6 Participants
Race (NIH/OMB) Asian	4 Participants n=8 Participants	5 Participants n=6 Participants	9 Participants n=6 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=8 Participants	1 Participants n=6 Participants	1 Participants n=6 Participants
Race (NIH/OMB) Black or African American	10 Participants n=8 Participants	12 Participants n=6 Participants	22 Participants n=6 Participants
Race (NIH/OMB) White	102 Participants n=8 Participants	93 Participants n=6 Participants	195 Participants n=6 Participants
Race (NIH/OMB) More than one race	5 Participants n=8 Participants	9 Participants n=6 Participants	14 Participants n=6 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=8 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants
Region of Enrollment United States	122 participants n=8 Participants	120 participants n=6 Participants	242 participants n=6 Participants
Body Mass Index	30.7 kg/m2 STANDARD_DEVIATION 7.25 • n=8 Participants	29.8 kg/m2 STANDARD_DEVIATION 6.71 • n=6 Participants	30.3 kg/m2 STANDARD_DEVIATION 6.98 • n=6 Participants
Rheumatoid arthritis (RA) duration	13.0 years STANDARD_DEVIATION 10.59 • n=8 Participants	11.8 years STANDARD_DEVIATION 10.45 • n=6 Participants	12.4 years STANDARD_DEVIATION 10.52 • n=6 Participants
Clinical Disease Activity Index (CDAI) score	36.1 score on a scale STANDARD_DEVIATION 12.60 • n=8 Participants	38.2 score on a scale STANDARD_DEVIATION 12.75 • n=6 Participants	37.1 score on a scale STANDARD_DEVIATION 12.69 • n=6 Participants
Disease Activity Score-28 with C-reactive protein (DAS28-CRP) score	5.3 score on a scale STANDARD_DEVIATION 0.91 • n=8 Participants	5.4 score on a scale STANDARD_DEVIATION 0.96 • n=6 Participants	5.3 score on a scale STANDARD_DEVIATION 0.93 • n=6 Participants
Rheumatoid Factor (RF) Negative	73 Participants n=8 Participants	64 Participants n=6 Participants	137 Participants n=6 Participants
Rheumatoid Factor (RF) Positive	49 Participants n=8 Participants	56 Participants n=6 Participants	105 Participants n=6 Participants
Anti-Citrullinated Protein Antibodies (ACPA) Negative	57 Participants n=8 Participants	61 Participants n=6 Participants	118 Participants n=6 Participants
Anti-Citrullinated Protein Antibodies (ACPA) Positive	61 Participants n=8 Participants	59 Participants n=6 Participants	120 Participants n=6 Participants
Anti-Citrullinated Protein Antibodies (ACPA) Missing	4 Participants n=8 Participants	0 Participants n=6 Participants	4 Participants n=6 Participants
Serology Negative	56 Participants n=8 Participants	54 Participants n=6 Participants	110 Participants n=6 Participants
Serology Positive	62 Participants n=8 Participants	66 Participants n=6 Participants	128 Participants n=6 Participants
Serology Missing	4 Participants n=8 Participants	0 Participants n=6 Participants	4 Participants n=6 Participants
Prior b/tsDMARDs	2.5 number of b/tsDMARDs STANDARD_DEVIATION 1.98 • n=8 Participants	2.7 number of b/tsDMARDs STANDARD_DEVIATION 1.87 • n=6 Participants	2.6 number of b/tsDMARDs STANDARD_DEVIATION 1.92 • n=6 Participants
Number of prior b/tsDMARDs 1	52 Participants n=8 Participants	42 Participants n=6 Participants	94 Participants n=6 Participants
Number of prior b/tsDMARDs 2	25 Participants n=8 Participants	28 Participants n=6 Participants	53 Participants n=6 Participants
Number of prior b/tsDMARDs 3	15 Participants n=8 Participants	16 Participants n=6 Participants	31 Participants n=6 Participants
Number of prior b/tsDMARDs 4	15 Participants n=8 Participants	15 Participants n=6 Participants	30 Participants n=6 Participants
Number of prior b/tsDMARDs 5	7 Participants n=8 Participants	8 Participants n=6 Participants	15 Participants n=6 Participants
Number of prior b/tsDMARDs 6	2 Participants n=8 Participants	5 Participants n=6 Participants	7 Participants n=6 Participants
Number of prior b/tsDMARDs 7	2 Participants n=8 Participants	4 Participants n=6 Participants	6 Participants n=6 Participants
Number of prior b/tsDMARDs 8	2 Participants n=8 Participants	1 Participants n=6 Participants	3 Participants n=6 Participants
Number of prior b/tsDMARDs 9	0 Participants n=8 Participants	0 Participants n=6 Participants	0 Participants n=6 Participants
Number of prior b/tsDMARDs 10+	2 Participants n=8 Participants	1 Participants n=6 Participants	3 Participants n=6 Participants
Tender Joint Count (out of 28 joints)	14.1 number of joints STANDARD_DEVIATION 6.94 • n=8 Participants	15.0 number of joints STANDARD_DEVIATION 7.26 • n=6 Participants	14.6 number of joints STANDARD_DEVIATION 7.10 • n=6 Participants
Swollen Joint Count (out of 28 joints)	9.6 number of joints STANDARD_DEVIATION 5.46 • n=8 Participants	10.5 number of joints STANDARD_DEVIATION 4.98 • n=6 Participants	10.0 number of joints STANDARD_DEVIATION 5.23 • n=6 Participants
HAQ-DI Score	1.4 score on a scale STANDARD_DEVIATION 0.59 • n=8 Participants	1.3 score on a scale STANDARD_DEVIATION 0.61 • n=6 Participants	1.4 score on a scale STANDARD_DEVIATION 0.60 • n=6 Participants
Pain (0-10)	5.5 score on a scale STANDARD_DEVIATION 2.00 • n=8 Participants	5.7 score on a scale STANDARD_DEVIATION 2.23 • n=6 Participants	5.6 score on a scale STANDARD_DEVIATION 2.12 • n=6 Participants
Subject's Global Assessment (0-10)	6.2 score on a scale STANDARD_DEVIATION 2.07 • n=8 Participants	6.0 score on a scale STANDARD_DEVIATION 2.25 • n=6 Participants	6.1 score on a scale STANDARD_DEVIATION 2.16 • n=6 Participants
Evaluator's Global Assessment (0-10)	6.3 score on a scale STANDARD_DEVIATION 1.88 • n=8 Participants	6.7 score on a scale STANDARD_DEVIATION 1.72 • n=6 Participants	6.5 score on a scale STANDARD_DEVIATION 1.80 • n=6 Participants
hsCRP	8.41 mg/L STANDARD_DEVIATION 12.338 • n=8 Participants	8.01 mg/L STANDARD_DEVIATION 12.762 • n=6 Participants	8.21 mg/L STANDARD_DEVIATION 12.526 • n=6 Participants

PRIMARY outcome

Timeframe: Week 12

Population: ITT

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response	43 Participants	29 Participants	—

SECONDARY outcome

Timeframe: Week 12

Population: ITT

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

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
DAS28-CRP Good or Moderate Response as Defined by European League Against Rheumatism (EULAR)	74 Participants	50 Participants	—

SECONDARY outcome

Timeframe: Week 12

Population: ITT

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

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
DAS28-CRP Response (MCID -1.2) at Week 12	55 Participants	39 Participants	—

SECONDARY outcome

Timeframe: Week 12

Population: ITT

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

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22)	56 Participants	44 Participants	—

SECONDARY outcome

Timeframe: Week 12

Population: ITT

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).

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
ACR20 Response at Week 12 From Day 0	38 Participants	27 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=108 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=105 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Bone Erosion Progression, All Completers	18 Participants	21 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

Outcome measures

Outcome measures
Measure	Treatment n=53 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=45 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Bone Erosion Progression, All Completers With Erosive Phenotype	10 Participants	17 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

Outcome measures

Outcome measures
Measure	Treatment n=46 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=36 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Bone Erosion Progression, All Completers That Previously Only Failed 1 b/tsDMARD	3 Participants	9 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=108 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=105 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Erosion Score, All Completers	0.2 score on a scale Standard Deviation 0.85	0.5 score on a scale Standard Deviation 1.74	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

Outcome measures

Outcome measures
Measure	Treatment n=53 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=45 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Erosion Score, All Completers With Erosive Phenotype	0.3 score on a scale Standard Deviation 1.09	1.1 score on a scale Standard Deviation 2.51	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

Outcome measures

Outcome measures
Measure	Treatment n=46 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=36 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Erosion Score, All Completers That Previously Only Failed 1 b/tsDMARD	0.0 score on a scale Standard Deviation 0.60	0.8 score on a scale Standard Deviation 2.57	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=108 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=105 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Synovitis Score, All Completers	0.0 score on a scale Standard Deviation 1.64	0.1 score on a scale Standard Deviation 1.51	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=53 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=45 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Synovitis Score, All Completers With Erosive Phenotype	-0.1 score on a scale Standard Deviation 2.27	0.0 score on a scale Standard Deviation 1.77	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=46 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=36 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Synovitis Score, All Completers That Previously Only Failed 1 b/tsDMARD	0.1 score on a scale Standard Deviation 0.81	0.6 score on a scale Standard Deviation 1.78	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=108 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=104 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Osteitis Score, All Completers	0.1 score on a scale Standard Deviation 2.61	0.8 score on a scale Standard Deviation 4.13	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=53 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=45 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Osteitis Score, All Completers With Erosive Phenotype	0.2 score on a scale Standard Deviation 3.74	1.8 score on a scale Standard Deviation 6.18	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT with MRI images at both Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Treatment n=46 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=36 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Change in Osteitis Score, All Completers That Previously Only Failed 1 b/tsDMARD	-0.3 score on a scale Standard Deviation 2.22	1.1 score on a scale Standard Deviation 4.92	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT, 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

Outcome measures

Outcome measures
Measure	Treatment n=120 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=119 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission	28 Participants	19 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT, 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

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=119 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
DAS28-CRP Low Disease Activity (LDA) or Remission	31 Participants	18 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=117 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=236 Participants Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, All Completers	53 Participants	65 Participants	118 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=96 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=98 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=194 Participants Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, Non-augmented	50 Participants	52 Participants	102 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=117 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=236 Participants Combination of TOL and COL populations
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, All Completers	33 Participants	36 Participants	69 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=96 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=98 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=194 Participants Combination of TOL and COL populations
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, Non-augmented	33 Participants	31 Participants	64 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=118 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=117 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=235 Participants Combination of TOL and COL populations
DAS28-CRP Low Disease Activity (LDA) or Remission, All Completers	36 Participants	37 Participants	73 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=95 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=98 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=193 Participants Combination of TOL and COL populations
DAS28-CRP Low Disease Activity (LDA) or Remission, Non-augmented	35 Participants	32 Participants	67 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=117 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=236 Participants Combination of TOL and COL populations
Health Assessment Questionnaire Disability Index (HAQ-DI) MCID Response, All Completers	64 Participants	72 Participants	136 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=96 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=98 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=194 Participants Combination of TOL and COL populations
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22), Non-augmented	56 Participants	62 Participants	118 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

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

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=114 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=233 Participants Combination of TOL and COL populations
Study Participants That Are Somewhat to Very Satisfied With the SetPoint System for Treatment of Rheumatoid Arthritis	90 Participants	92 Participants	182 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=114 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=233 Participants Combination of TOL and COL populations
Study Participants That Are Neither Satisfied Nor Dissatisfied With the SetPoint System for Treatment of Rheumatoid Arthritis	14 Participants	12 Participants	26 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=114 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=233 Participants Combination of TOL and COL populations
Study Participants That Are Somewhat to Very Dissatisfied With the SetPoint System for Treatment of Rheumatoid Arthritis	15 Participants	10 Participants	25 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 24

Population: ITT, all completers

Patients were asked a question about whether they would recommend the SetPoint System to family and friends

Outcome measures

Outcome measures
Measure	Treatment n=118 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=114 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=232 Participants Combination of TOL and COL populations
Study Participants That Would Recommend the SetPoint System to a Family Member or Friend	108 Participants	110 Participants	218 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=115 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=234 Participants Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, All Completers	57 Participants	64 Participants	121 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=89 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=87 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=176 Participants Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, Non-augmented	46 Participants	54 Participants	100 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=117 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=114 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=231 Participants Combination of TOL and COL populations
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, All Completers	39 Participants	40 Participants	79 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=87 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=87 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=174 Participants Combination of TOL and COL populations
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, Non-augmented	34 Participants	35 Participants	69 Participants

POST_HOC outcome

Timeframe: Week 24

Population: ITT

Therapy persistence means continuation of therapy after it is initiated.

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System as a Stand-alone Therapy	96 Participants	99 Participants	195 Participants

POST_HOC outcome

Timeframe: Week 24

Population: ITT

Therapy persistence means the continuation of therapy after it is initiated. Augmentation of study therapy means the addition of treatment for RA therapy to active stimulation applied after completion of Week 12 assessments, during open-label, long-term follow-up. Augmented therapy may be applied at any time during long-term follow-up. The decision about the need, type and timing of treatment is left to the discretion of the Co-PI Rheumatologist and the subject. Subjects combining active stimulation with the following additions to RA therapy fall into the augmented therapy subgroup for analysis of response rates for key efficacy endpoints at specific timepoints: * Prednisone equivalent \>10 mg/day. If average daily corticosteroid use exceeds 10 mg/day prednisone after a period (time from previous visit up to the day before the current visit), the subject is assigned to the augmented therapy subgroup for that visit. * Corticosteroid injection. If subject received a corti

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy Augmented With a b/tsDMARD	17 Participants	12 Participants	29 Participants

POST_HOC outcome

Timeframe: Week 24

Population: ITT

Therapy persistence means continuation of therapy after it is initiated. Augmentation of study therapy means the addition of treatment for RA therapy to active stimulation applied after completion of Week 12 assessments, during open-label, long-term follow-up. Augmented therapy may be applied at any time during long-term follow-up. The decision about the need, type and timing of treatment is left to the discretion of the Co-PI Rheumatologist and the subject. Subjects combining active stimulation with the following additions to RA therapy fall into the augmented therapy subgroup for analysis of response rates for key efficacy endpoints at specific timepoints: * Prednisone equivalent \>10 mg/day. If average daily corticosteroid use exceeds 10 mg/day prednisone after a period (time from previous visit up to the day before the current visit), the subject is assigned to the augmented therapy subgroup for that visit. * Corticosteroid injection. If subject received a corticosteroi

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy Augmented With a csDMARD and/or Steroid	9 Participants	8 Participants	17 Participants

POST_HOC outcome

Timeframe: Week 24

Population: ITT

Therapy persistence is defined as the continuation of therapy after it is initiated.

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy as a Stand-alone or Augmented Thereapy	120 Participants	118 Participants	238 Participants

POST_HOC outcome

Timeframe: Week 24

Population: ITT

Discontinuation means active stimulation was suspended or the SetPoint System Implant was removed

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Discontinuation of SetPoint System Therapy	2 Participants	2 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=114 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=107 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=221 Participants Combination of TOL and COL populations
DAS28-CRP Low Disease Activity (LDA) or Remission, All Completers	38 Participants	40 Participants	78 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=85 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=82 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=167 Participants Combination of TOL and COL populations
DAS28-CRP Low Disease Activity (LDA) or Remission, Non-augmented	31 Participants	35 Participants	66 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=118 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=115 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=233 Participants Combination of TOL and COL populations
Health Assessment Questionnaire Disability Index (HAQ-DI) MCID Response, All Completers	68 Participants	67 Participants	135 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 36

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=89 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=87 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=176 Participants Combination of TOL and COL populations
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22), Non-augmented	53 Participants	51 Participants	104 Participants

POST_HOC outcome

Timeframe: Week 36

Population: ITT

Therapy persistence means continuation of therapy after it is initiated.

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System as a Stand-alone Therapy	89 Participants	88 Participants	177 Participants

POST_HOC outcome

Timeframe: Week 36

Population: ITT

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy Augmented With a b/tsDMARD	25 Participants	22 Participants	47 Participants

POST_HOC outcome

Timeframe: Week 36

Population: ITT

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy Augmented With a csDMARD and/or Steroid	7 Participants	9 Participants	16 Participants

POST_HOC outcome

Timeframe: Week 36

Population: ITT

Therapy persistence is defined as the continuation of therapy after it is initiated.

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy as a Stand-alone or Augmented Thereapy	120 Participants	116 Participants	236 Participants

POST_HOC outcome

Timeframe: Week 36

Population: ITT

Discontinuation means active stimulation was suspended or the SetPoint System Implant was removed

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Discontinuation of SetPoint System Therapy	2 Participants	4 Participants	6 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=114 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=233 Participants Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, All Completers	61 Participants	62 Participants	123 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=77 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=80 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=157 Participants Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, Non-augmented	43 Participants	48 Participants	91 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=118 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=114 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=232 Participants Combination of TOL and COL populations
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, All Completers	47 Participants	41 Participants	88 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=76 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=81 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=156 Participants Combination of TOL and COL populations
Clinical Disease Activity Index (CDAI) Low Disease Activity (LDA) or Remission, Non-augmented	36 Participants	33 Participants	69 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=117 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=111 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=228 Participants Combination of TOL and COL populations
DAS28-CRP Low Disease Activity (LDA) or Remission, All Completers	50 Participants	42 Participants	92 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=75 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=78 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=153 Participants Combination of TOL and COL populations
DAS28-CRP Low Disease Activity (LDA) or Remission, Non-augmented	37 Participants	32 Participants	69 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: ITT, all completers

Outcome measures

Outcome measures
Measure	Treatment n=119 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=113 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=232 Participants Combination of TOL and COL populations
Health Assessment Questionnaire Disability Index (HAQ-DI) MCID Response, All Completers	66 Participants	67 Participants	133 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48

Population: Subgroup of subjects receiving active stimulation for 1 min once per day, whose study therapy has not been augmented, who completed assessment.

Outcome measures

Outcome measures
Measure	Treatment n=77 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=80 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=157 Participants Combination of TOL and COL populations
Health Assessment Questionnaire Disability Index (HAQ-DI) Response (MCID -0.22), Non-augmented	41 Participants	49 Participants	90 Participants

POST_HOC outcome

Timeframe: Week 48

Population: ITT

Therapy persistence means continuation of therapy after it is initiated.

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System as a Stand-alone Therapy	77 Participants	81 Participants	158 Participants

POST_HOC outcome

Timeframe: Week 48

Population: ITT

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy Augmented With a b/tsDMARD	32 Participants	28 Participants	60 Participants

POST_HOC outcome

Timeframe: Week 48

Population: ITT

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy Augmented With a csDMARD and/or Steroid	16 Participants	12 Participants	28 Participants

POST_HOC outcome

Timeframe: Week 48

Population: ITT

Therapy persistence is defined as the continuation of therapy after it is initiated.

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Persistence With SetPoint System Therapy as a Stand-alone or Augmented Thereapy	120 Participants	116 Participants	236 Participants

POST_HOC outcome

Timeframe: Week 48

Population: ITT

Discontinuation means active stimulation was suspended or the SetPoint System Implant was removed

Outcome measures

Outcome measures
Measure	Treatment n=122 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=120 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) n=242 Participants Combination of TOL and COL populations
Discontinuation of SetPoint System Therapy	2 Participants	4 Participants	6 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT, subgroup of subjects that previously failed 1 b/tsDMARD

Outcome measures

Outcome measures
Measure	Treatment n=52 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=42 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, Subjects With 1 Prior b/tsDMARD	23 Participants	8 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT, subgroup of subjects that previously failed 2 b/tsDMARD

Outcome measures

Outcome measures
Measure	Treatment n=25 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=28 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, Subjects With 2 Prior b/tsDMARD	8 Participants	3 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT, subgroup of subjects that previously failed 3 b/tsDMARD

Outcome measures

Outcome measures
Measure	Treatment n=15 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=16 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, Subjects With 3 Prior b/tsDMARD	3 Participants	6 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 12

Population: ITT, subgroup of subjects that previously failed \>=4 b/tsDMARD

Outcome measures

Outcome measures
Measure	Treatment n=30 Participants Active stimulation for 1 min once per day 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. 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 Active stimulation: Active stimulation for 1 min once per day	Control n=34 Participants Non-active stimulation for 1 min once per day 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. 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 Non-active stimulation: Non-active stimulation for 1 min once per day	All (TOL+COL) Combination of TOL and COL populations
the American College of Rheumatology (ACR) 20 Response, Subjects With >=4 Prior b/tsDMARD	9 Participants	12 Participants	—

Adverse Events

Treatment

Serious events: 22 serious events

Other events: 74 other events

Deaths: 0 deaths

Control

Serious events: 29 serious events

Other events: 79 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

VP of Clinical Affairs

SetPoint Medical

Phone: 661.750.6140

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60