Vagus Nerve Stimulation Using the SetPoint System for Moderate to Severe Rheumatoid Arthritis: The RESET-RA Study
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: SetPoint Medical Corporation

Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
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May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
CLINICAL INVESTIGATIONAL PROTOCOL 
1 
TITLE PAGE 
Study Title 
Vagus Nerve Stimulation Using the SetPoint System for Moderate to 
Severe Rheumatoid Arthritis: The RESET-RA Study 
Protocol Number 
SPM-020 
ClinicalTrials.gov ID  
NCT04539964 
Investigational Device 
The SetPoint System 
Indication for Use / 
Breakthrough Device Designation 
(Q240179) 
The SetPoint system is indicated for the treatment of adult patients 
with moderately to severely active RA who have had an inadequate 
response, loss of response or intolerance to one (1) or more biological 
or targeted synthetic DMARDs 
Study Design 
An operationally seamless, 2-stage, randomized, sham-controlled, 
double-blind, multicenter, pivotal study with a 12-week follow-up for 
the primary efficacy endpoint, followed by one-way crossover of the 
control group and a 252-week open-label follow-up of all subjects on 
active stimulation for long-term safety 
Study Sponsor’s Name and Address 
SetPoint Medical, Inc. 
25101 Rye Canyon Loop 
Valencia, CA 91355 U.S.A. 
National  
Co-Principal Investigators 
Rheumatology: 
John Tesser, MD 
Arizona Arthritis and Rheumatology Research, P.C. 
9520 W. Palm Lane, Suite 220 
Phoenix AZ, 85037 
 
Surgery: 
Mark Richardson, MD PhD 
Director, Functional Neurosurgery 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 U.S.A. 
Data Management and Monitoring 
SetPoint Medical, Inc. 
Biostatistics and Data Analysis 
SetPoint Medical, Inc. 
This study will be conducted under the guidance of the International Council on Harmonisation (ICH) Good Clinical Practice 
(GCP), Clinical investigation of medical devices for human subjects – GCP (BS EN ISO 14155), and other applicable local 
and federal regulations, including the archiving of essential documents. 
 
The study-related COVID-19 contingency measures to assure the safety of study subjects, maintain compliance with GCP, 
and minimize risks to study integrity for the duration of the COVID-19 pandemic are detailed in Section 19. 
 
CONFIDENTIALITY STATEMENT 
This document is the property of SetPoint Medical, Inc. The document is highly confidential and is to be used only in 
connection with matters authorized by a senior representative of SetPoint Medical, and no part of it is to be disclosed to a 
third party without prior written permission from SetPoint Medical. 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
2 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision History 
 
Revision 
Revision Date 
Summary of Changes 
A 
13MAR2020 
Acquisition of document number 
B 
21MAY2020 
Initial release 
C 
08OCT2020 
• 
Moved baseline assessments for the primary and key secondary 
efficacy endpoints from Day 0 to the day of consent, as 
recommended by the FDA. 
• 
Moved baseline assessments, including MRI, for the exploratory 
endpoints from Day 0 to Screening, as recommended by the FDA. 
• 
Expanded prior b/tsDMARD from 1-3 to 1 or more (p. 35) 
• 
Removed Confirmation of RA Severity visit 
• 
Shortened window between Implant Procedure and Day 0 visit 
• 
Opened Titration 1-3 visit windows 
• 
Added pregnancy test to Titration 1-3 
• 
Added blood collection for CBC 
• 
Changed Principal Investigator to Co-Principal Investigator 
Rheumatologist and Sub-Investigator to Co-Primary Investigator 
Surgeon  
• 
Adjusted sample size from 70 to 60 in Stage 1 and from 180 to 190 
in Stage 2 (p. 15, 34) 
• 
Reduced the maximum number of subjects per site from 40 to 20 
(p. 34) 
• 
Added subject washout status to Screening (p. 40) 
• 
Removed Early Termination Visit 
• 
Updated statistical section with power calculations for 250 subjects 
and a broader range of sham effect (p. 61)  
• 
Updated definitions of analysis populations (p. 63) 
• 
Defined major procedural protocol deviations (p. 64) 
• 
Added authorship requirements (p. 73) 
• 
Added COVID-19 contingency measures (p. 73) 
D 
17NOV2020 
• 
Added definitions of EGA, SGA and subject’s pain assessment 
under Definitions and removed them from text (pp. 12, 15) 
• 
Added CBC to Screening in Schedule of Assessments (p. 21) 
• 
Added ACR20 at Week 12 from Day 0 to key secondary endpoints 
(p. 35) 
• 
Moved HAQ-DI score change from baseline to Week 12 from key 
secondary to exploratory endpoints (p. 35) 
• 
Modified exclusion #3 for corticosteroid injections from within 28 
to 30 days of Implant Procedure (p. 37) 
• 
Modified exclusions #4 and #5 to change timepoint by when 
concomitant use of glucocorticoids and NSAIDs must be stable 
from Implant Procedure to informed consent (p. 37) 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
3 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
• 
Modified exclusion #6 to restrict subjects not agreeing to abstain 
from nicotine products throughout study (p. 38) 
• 
Updated exclusion #17 to include pre-surgical X-ray (p. 38) 
• 
Updated exclusion #35 to specify investigational drug for RA (p. 
39) 
• 
Added exclusion # 40 for subjects that work or reside in areas with 
high RF (p. 39) 
• 
Clarified options for explant or decommissioning upon withdrawal 
(p. 41) 
• 
Included collection of vital signs, height, and weight to Screening 
and baseline assessments (p. 42)  
• 
Added final evaluation of eligibility to end of Screening and 
baseline assessments (p. 43) 
• 
Listed X-ray views required for pre-surgical clearance (p. 43) 
• 
Clarified that pregnancy test is done, as required, at titration visits 
(p. 46) 
• 
Added unblinding after completion of Week 12 to inform decision 
about participation in the long-term extension study (pp. 47, 71) 
• 
Added figure showing study visit timeline (p. 49) 
• 
Removed female sterilization as a method of birth control (p. 49) 
• 
Updated required period of stability for allowed medications (p. 53) 
• 
Updated reporting schedule to sponsor for device-related AEs from 
10 working days to 24-48 hours (p. 56) 
• 
Added scarring to risks associated with surgical implantation (p. 59) 
• 
Added risk of concomitant csDMARDs and VNS therapy (p. 59) 
• 
Updated training requirements (p. 66) 
• 
Clarified role of unblinded technicians (p. 70) 
• 
Updated COVID-19 Contingency Measures to allow only Week 4 
or Week 8, not both, to be conducted remotely, allow virtual re-
consent and include CBC to blood collection under Study 
Procedures During COVID-19 (p. 77) 
E 
05MAY2021 
• 
Updated study title (pp. 1, 21) 
• 
Changed “moderate-to-severe” to “moderate to severe” throughout 
document   
• 
Added ClinicalTrials.gov identifier (p. 1) 
• 
Updated description of study design to include one-way crossover 
and open-label, long-term follow-up (pp. 1, 21-22, 44, 56) 
• 
Added abbreviations bDMARD, csDMARD, MMP3, PMA, SAA, 
and tsDMARD and removed PCB (pp. 12-14) 
• 
Added definitions for crossover, crossover PTE population, open-
label PTE population and rescue treatment; separated definition of 
EULAR response criteria from DAS28-CRP; updated definition of 
PTE population (pp.15-18) 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
4 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
• 
Added that blinding will be maintained until all subjects have 
completed Week 12 assessments and database is locked (pp. 21, 43, 
83-84) 
• 
Clarified that pause between Stage 1 and Stage 2 pertains to a pause 
in enrollment (pp. 21, 43, 59) 
• 
Added statement that initial 12-week follow-up data will support 
PMA application and additional follow-up will evaluate long-term 
safety (pp. 21, 43)  
• 
Removed term “therapeutic” from description of active stimulation 
and replaced “non-therapeutic” with “non-active” to describe sham 
stimulation (pp. 21, 44, 53) 
• 
Removed reference to offering participation in a separate, long-
term, open-label extension study in which all subjects receive active 
stimulation. (pp. 21, 56) 
• 
Added that control group will crossover to active stimulation after 
completion of Week 12 assessments (pp. 1, 21-22, 43, 44) 
• 
Under study population, updated note to state that 10% reflects 
JAKi usage in the “target” RA population, instead of “general” (pp. 
22, 45) 
• 
Added allowance to miss up to 2 doses of csDMARD due to 
COVID-19 vaccination, except in the 4 weeks prior to informed 
consent (pp. 22, 45, 63) 
• 
Removed reference to equivalent dose of methotrexate for required 
background RA therapy (pp. 22, 45) 
• 
For allowed concomitant medications, clarified that mild oral 
opiates taken on a regular basis may be continued and those taken 
only as needed are allowed except 24 hours prior to assessments 
(pp. 23, 64) 
• 
Removed reference to subject being eligible for rescue therapy in a 
separate, extension study if they do not achieve ACR20 
improvement (pp. 23, 57)  
• 
Added that rescue treatment is allowed after subject completes 
Week 12 assessments and that the need, timing, and type of rescue 
treatment are at the discretion of the Co-PI Rheumatologist and the 
subject (pp.23, 44, 65-66) 
• 
For allowed concomitant medications, clarified that dose must 
remain stable through completion of Week 12 assessments and 
subjects not taking these at the time of informed consent should not 
start until completion of Week 12 assessments (pp. 23, 64) 
• 
Extended duration of study participation by adding 18 visits as part 
of open-label, long-term follow-up after completion of Week 12 
(pp. 23, 56) 
• 
Added resuming stimulation and implant decommissioning as 
reasons for an unscheduled visit (pp. 23, 57) 
• 
Added Co-Primary Rheumatologist’s blinding assessment at Week 
4 and 12 (pp. 23, 25, 27, 55, 84, 92) 
• 
Extended duration of study participation by 3.5 years to reflect 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
5 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
addition of long-term follow-up (pp. 24, 59) 
• 
Updated study flow diagram to add crossover of the control group 
after Week 12 assessments, open-label, long-term follow-up, 
requirements on application of rescue treatment, and optional 
explant procedure; clarify allowed concomitant medications; and to 
include changes to schedule of assessments noted below (pp. 25-26) 
• 
Updated schedule of assessment to remove reference to Week 12 as 
EOS; added vital signs to Screening, Day 0 and Week 12; added 
SF-36 and EQ-5D-5L to Day 0; added 12-lead ECG to Week 12; 
add blinding assessment for Co-PI rheumatologist; and added dose 
titration to Week 12 (pp. 27, 55, 56) 
• 
Added schedule for assessments for open-label, long-term follow-
up (pp. 28, 56) 
• 
Updated Figure 1 reference to study device from “NCAP” to 
“SetPoint System” and correct typo (p. 31) 
• 
Indicated range of output currents (p. 33) 
• 
Added description of Energizer Wireless Charger (p. 33) 
• 
Editorial changes to description of SPM-008 (pp. 39) 
• 
Updated status of SPM-011 to current (p. 41) 
• 
Added exploratory endpoints for open-label, long term follow-up 
(pp. 42-43) 
• 
Updated examples of biomarkers to be analyzed (p. 43, 61) 
• 
Updated period of reporting for incidence of AEs and device 
deficiencies to include open-label, long-term follow-up (pp. 43, 78) 
• 
Added types and dosages for csDMARDs permitted as RA 
background therapy and included allowance for lower doses in the 
case of dose limiting toxicity (pp. 45, 63) 
• 
Modified exclusion #10 by adding an exception for infections 
cleared before Implant Procedure (pp. 46, 50) 
• 
Added statement that in the event subject becomes or wants to 
become pregnant, implant will be decommissioned, and subject 
followed for safety (pp. 46, 59)  
• 
Corrected definition for subject status of “screen failure” and 
updated definition of “completed study” to include period of open-
label, long-term follow-up (p. 48) 
• 
Added information on the possible need for re-consent (p. 50) 
• 
Added a heading for information on device check and dose 
titration/adjustment (p. 54) 
• 
Added information on monitoring implant charge level and possible 
decommissioning in the event 0% charge level is observed (pp. 54, 
57-58) 
• 
Added requirement for subjects that have their implant 
decommissioned to continue adhering to study visits and 
procedures. Subjects that choose to end participation after 
decommissioning are asked to contact the investigator in the event 
of a safety issue (p. 58) 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
6 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
• 
Added requirement to record the need, type and timing of rescue 
treatment to follow-up visits after Week 12 (p. 56) 
• 
Added instruction for Co-PI Rheumatologist to discuss subject 
options during open-label long-term follow-up and to document 
decision made (pp. 55-56) 
• 
Added information on re-registering MicroRegulator and crossover 
of control group to active stimulation following week 12 
assessments (p. 56) 
• 
Changed referenced to “Clinician Standby Mode” to “Suspending 
Therapy” (p. 56, 58) 
• 
Added requirement to decommission implant at end of study (p. 56) 
• 
Added section describing suspending and resuming stimulation 
including information on when stimulation must and can be 
suspended, how to perform suspension and study treatment during 
period of suspension (p. 57)  
• 
Removed list of visits and visit windows in section 11.6 since 
redundant with schedule of assessments (pp. 55-56) 
• 
Added information on risk of using csDMARD during pregnancy 
(p. 59) 
• 
Expanded type and corrected categorization of contraception 
methods (p. 60)  
• 
Added that clinical laboratory samples will be analyzed centrally 
through Week 24 and locally from Week 36 through Week 192 (p. 
61) 
• 
Added allowance for dose adjustments to background therapy for 
the management of toxicity and requirement to record toxicity as an 
adverse event (pp. 63)  
• 
Added allowance for perioperative changes to background RA 
therapy and allowed concomitant medications at discretion of 
investigator to manage risks associated with implant procedure (pp. 
63, 64) 
• 
Added that risks associated with use of csDMARDs should be 
discussed with subject (p. 63) 
• 
Added that restriction on concomitant use of steroid pulse therapy, 
b/tsDMARDs, and steroid injections applies only through 
completion of Week 12 assessments (p. 64) 
• 
Added possible need to suspend stimulation, decommission implant 
or surgically remove implant in the event subject requires a 
prohibited medical intervention (p. 65) 
• 
Added that results from RA disease activity assessments collected 
at follow-up visit can be used for decision making on rescue (p. 65) 
• 
Added that subjects that are rescued may continue their assigned 
study treatment and that rescued subjects should continue to follow 
the study visit schedule, adhere to all study procedures and be 
monitored for safety (p. 66) 
• 
Added “indeterminate” as a relationship classification for AEs (pp. 
66, 67) 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
7 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
• 
Added section on AE expectedness (p. 67) 
• 
Added section on AE adjudication (pp. 67-68) 
• 
Removed format for reporting of a death, SAE, and device-related 
AE (p. 69) 
• 
Added potential risks: eructation, constipation, vomiting or 
gagging, seroma, weight change and neutropenia (pp. 71-72) 
• 
Included rescue treatment with potential risks related to 
concomitant use of VNS with csDMARDs (p. 72) 
• 
Added analysis of exploratory endpoints to gather additional 
efficacy and long-term safety data (pp. 42-43, 78) 
• 
Clarified how decisions on rescue are made, types of medications 
are considered as rescue, how data are handled (pp. 65-66) 
• 
Added that subjects initiating rescue treatment during open-label 
long-term follow-up are treated as non-responders (p. 66, 78) 
• 
Added definitions for open-label and crossover PTE populations (p. 
79) 
• 
DMC meeting schedule updated to specify frequency during Stage 
1 enrollment, Stage 2 enrollment and open-label, long-term follow-
up (p. 82) 
• 
Removed allowance for investigator to directly obtain treatment 
assignment and added process for requesting unblinding in 
exceptional circumstances in which knowledge of treatment 
assignment is necessary to manage the subject (pp. 83-84) 
• 
Clarified blinding and unblinding rules (pp. 83-84) 
• 
Removed revealing treatment assignment to subject and Co-PI 
Rheumatologist upon completion of Week 12 assessments (p. 84) 
• 
Added responsibility of Co-PIs to ensure timely delivery of source 
documentation required for adjudication and reporting of AEs (p. 
85) 
• 
Added information on COVID vaccination with concomitant 
immunomodulatory therapies (p. 92)  
• 
Made minor clarifications, edits and editorial changes throughout 
F 
19OCT2021 
• 
Identified study as breakthrough device (p. 1) 
• 
Increased number of Stage 1 sites to 25 (pp. 22, 44) 
• 
Clarified prior JAKi use conditions upon which stratification and 
population limits are based (pp. 22. 47, 77, 78) 
• 
Clarified background csDMARD requirements (p. 46, 64) 
• 
Clarified that exclusion for significant cardiovascular disease 
applies to current, clinically significant conditions (p. 47) 
• 
Corrected description of inclusion criterion on kidney function and 
adding requirement that eligibility be confirmed prior to screening 
MRI (p. 48, 52, 74) 
• 
Added uncontrolled sleep apnea as an example of a pulmonary 
disease that would render a patient ineligible for participation (p. 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
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May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
48) 
• 
Correct exclusion #41 to replace reference to a 12-week study with 
more specific information about 6-7 week screening and post-
surgical clearance and 192 weeks of follow up (p. 49) 
• 
Require that the Co-PI Surgeon perform Pre-surgical Clearance, as 
opposed to a designee (p. 53) 
• 
Added detail describing pre-surgical clearance (p. 53) 
• 
Require that the Co-PI Surgeon or designee at the surgical site, as 
opposed to the rheumatology site, perform Post-surgical Clearance 
(p. 54) 
• 
Clarified meaning of childbearing potential and conditions under 
which a pregnancy test is not necessary (p. 60) 
• 
Require that the same joint evaluator conduct the Tender and 
Swollen Joint Counts and Evaluator Global Assessment at 
Screening and Week 12 (p. 62) 
• 
Removed DMC’s role in making treatment recommendations in 
order to preserve study blind. In the event Co-PI Rheumatologist 
believes knowledge of treatment assignment is essential for 
management of a subject, they must request and receive 
authorization from Sponsor CMO. The decision and rationale to 
unblind will be documented and presented for review by the DMC 
to ensure concurrence with the recommendation. If unblinding is 
recommended and the DMC concurs, the CMO with authorize the 
Co-PI Rheumatologists access to the treatment assignment in IRT 
(p. 85) 
G 
10FEB2022 
 
• 
Removed 10% study population limit on subjects with JAKi 
intolerance (limit on JAKi failure or loss of response is maintained) 
(pp. 22, 23, 46, 47, 77, 78) 
• 
Added statement that in the case of full discharge, the 
MicroRegulator battery cannot be recharged and must be 
decommissioned. Once decommissioned, the subject must return 
their Energizer and Wireless Charger (pp. 55, 59) 
• 
Added requirement for Co-PI Rheumatologist to review risks, 
particularly black box risks, that are associated with any rescue 
treatment prescribed. Also, to discuss any additional tests or 
monitoring required to mitigate such risks (pp. 67, 74)  
• 
Added Appendix B:  FDA Drug Safety Communication (DSC) 
issued on 09/01/2021 about JAK inhibitor (pp. 101-107) 
H 
10MAR2022 
• 
Added the risk of aspiration as a result of swallowing difficulty (pp. 
73, 74) 
I 
29SEP2022 
• 
Add 5 U.S. study centers, for a total of 45 sites (pp. 23, 45) 
• 
Add stratification for subjects with inadequate response or loss of 
response to ≥4 biological DMARDs (bDMARDs) with ≥ 2 
mechanisms of action (pp. 23, 79)   
• 
Limit the total number of subjects who have experienced JAKi 
failure or loss of response from 10% of the study population (i.e., 
25 subjects) to a total of 6 subjects (already enrolled in Stage 1) (pp. 
24, 47, 48, 80) 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
9 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
• 
Provide additional guidance on the exclusion of subjects with 
cervical spine disorder or instability to include subjects that, in the 
opinion of the investigator, could be exacerbated by the 
investigational implant procedure (p. 49) 
• 
Provide additional guidance on medical conditions that could put 
subject at increased risk for surgical complications (pp. 49-50) 
• 
Extend use of central laboratory for entire duration of study (p. 64) 
• 
Add Energizer to the list of options for assessment of AE 
relationship (p. 69)  
• 
Removed detail not relevant to power calculation from footnote of 
Table 4 (p. 80) 
• 
Clarify how interim analysis data is submitted to FDA (to reflect 
what was done for Stage 1 report submission) (p. 81) 
• 
Add exploratory analysis of subjects combining rescue therapy with 
VNS (p. 82) 
J 
07NOV2022 
• 
Added indication to Title Page (p. 1) 
• 
Clarified 5th bullet under Revision History, Summary of Changes 
(p. 9) 
• 
Updated MicroRegulator charge level threshold for counseling 
subject on importance of regular charging from 85% to 75% to 
align with modifications made to Energizer LED and audible 
indicators for MicroRegulator state of charge which was approved 
per FDA submission G170231/S026 (pp. 56, 60) 
• 
Added “to reduce the risk of potential…post-operative pain” as an 
allowed reason for making temporary, perioperative changes to 
allowed concomitant medications (p. 67) 
K 
15MAY2023 
• 
Removed indication for Breakthrough Device Designation from 
title page (p. 1) 
• 
Replaced National Co-PI Rheumatologist (from Dr. Curtis to Dr. 
Tesser) (p. 1) 
• 
Clarified total number of study centers in Stage 1 and 2 as a limit, 
not an actual (pp. 23, 45) 
• 
Updated exclusion criterion #6 to exclude regular use of and 
dependency on nicotine product within the past two years. 
Previously exclusion was for current use (p. 48) 
• 
Added additional examples of outcome measures that could be 
confounded by fibromyalgia to exclusion criterion #15 (p. 48) 
• 
Added exclusion of patients with BMI at screening of  35kg/m2 (p. 
50) 
• 
Added exclusion for use of high potency opioids (p. 50) 
• 
Added exclusion of patients with inflammatory joint disease other 
than RA (p. 50) 
• 
Added examples of mild oral opiates that are allowed (p. 67) 
• 
Updated frequency of DMC meetings to be consistent with charter 
(p. 86) 
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Clinical Investigational Protocol SPM-020 (The RESET-RA Study) 
Doc# CLP-001 Rev M, 16JUL2024 
 
 
CONFIDENTIAL 
10 of 111 
May not be reproduced outside of SetPoint Medical without written permission from Document Control. 
Revision 
Revision Date 
Summary of Changes 
L 
29JAN2024 
• 
Updated enrollment from “up to 250 randomized subjects” to “at 
least 240 and up to 250 randomized subjects” and included 
information for 240 subjects in power analysis (pp. 24, 46, 82 and 
83)  
• 
Introduced and defined new term “augmented therapy” to describe 
the addition of treatment for RA therapy after completion of Week 
12 assessments (pp. 18, 70, 71, 84) 
• 
Updated units for hsCRP to reflect how central lab reporting results 
(p. 21) 
• 
Added details on the specific types of treatments that are considered 
“rescue,” along with the data imputation rule specified for subjects 
receiving rescue (pp. 22, 70) 
• 
Added Energizer as a relationship classification for consistency 
with categories specified in section 15.1, Specification of Safety 
Parameters (p. 71) 
• 
Added detail on adjudication of stimulation-related adverse events 
once the study is unblinded. If subject has AE classified as 
stimulation-related but was assigned to the control group, 
classification will be updated to “not related” (p. 72) 
• 
Updated to reflect communication procedures that took place for 
the Interim analysis, consistent with G170231/S028 (p. 83) 
• 
Renamed “Open label PTE population” to “Treatment to Open 
Label (TOL) population” and “Crossover PTE population” to 
“Control to Open Label (COL)” for clarity and for consistency with 
SAP (pp.19, 23, 84)  
• 
Removed “If a subject decides to discontinue from the study, every 
attempt will be made to continue to collect the safety data according 
to the protocol procedures” from definition of safety population 
since no allowed mechanism exists for collecting safety data after a 
subject withdraws from the study (p. 84) 
• 
Described locking of the primary dataset (versus entire dataset) 
when referencing the point at which the study will be unblinded 
(pp. 24, 46, 70, 89) 
M 
16JUL2024 
• 
Extended duration of study participation by adding 6 visits as part 
of open-label, long-term follow-up after completion of Week 12 
(pp. 25, 26, 27, 28, 47, 59, 61, 64) 
• 
Updated Sections 5.2 and 6.2 Long-Term Follow-up to include 
visits from Week 204 through Week 264 (EOS) (pp. 30, 32) 
• 
Updated the evaluation period of incidence of AEs, SAEs, and 
device malfunctions through Week 264 (EOS) (p. 47, 72, 85) 
• 
Updated Figure 12: SPM-020 Study Schematic to extend Open-
label, Long-term follow-up to 252 weeks with end of study at Week 
264 (p. 48) 
• 
Updated Figure 13: SPM-020 Study Timeline to extend Open-label, 
Long-term follow-up to 252 weeks with end of study at Week 264 
(p. 64) 
• 
Added that blood samples from Week 204 through Week 264 
(EOS) will be analyzed locally (p. 66) 
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Revision 
Revision Date 
Summary of Changes 
• 
Updated procedure for distribution of Unblinding information (p. 
90) 
 
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TABLE OF CONTENTS 
1 
TITLE PAGE............................................................................................................... 1 
2 
LIST OF ABBREVIATIONS ................................................................................... 16 
3 
DEFINITIONS OF TERMS ..................................................................................... 19 
4 
PROTOCOL SUMMARY ........................................................................................ 25 
5 
STUDY FLOW DIAGRAM ..................................................................................... 29 
5.1 
Informed Consent to Week 12 (Primary Endpoint) ........................................ 29 
5.2 
Long-Term Follow-up ..................................................................................... 30 
6 
SCHEDULE OF ASSESSMENTS ........................................................................... 31 
6.1 
Informed Consent to Week 12 (Primary Endpoint) ........................................ 31 
6.2 
Long-Term Follow-Up .................................................................................... 32 
7 
BACKGROUND INFORMATION ......................................................................... 33 
7.1 
Rheumatoid Arthritis, Treatment Options and Unmet Clinical Need ............. 33 
7.2 
Investigational Device ..................................................................................... 34 
7.3 
Summary of Prior Clinical Experience ........................................................... 38 
8 
STUDY OBJECTIVE AND ENDPOINTS ............................................................. 45 
9 
STUDY DESIGN ....................................................................................................... 47 
9.1 
Overall Design................................................................................................. 47 
9.2 
Rationale for Study Design ............................................................................. 48 
10 
STUDY POPULATION ............................................................................................ 49 
10.1 
Inclusion Criteria ............................................................................................. 49 
10.2 
Exclusion Criteria ............................................................................................ 49 
10.3 
Subject Status .................................................................................................. 52 
10.4 
Subject Withdrawal ......................................................................................... 53 
11 
SUBJECT TREATMENT AND STUDY PROCEDURES ................................... 54 
11.1 
Pre-screening ................................................................................................... 54 
11.2 
Informed Consent and Screening .................................................................... 54 
11.3 
Enrollment and Implant Procedure ................................................................. 57 
11.4 
Post-Surgical Clearance .................................................................................. 57 
11.5 
Day 0 Assessments, Randomization, and Initiation of Stimulation ................ 57 
11.6 
Follow-up ........................................................................................................ 59 
11.7 
Unscheduled Visits .......................................................................................... 61 
11.8 
Suspending and Resuming Stimulation........................................................... 62 
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11.9 
Explant Procedure ........................................................................................... 63 
11.10 Duration of Study Period................................................................................. 63 
12 
STUDY PROCEDURES ........................................................................................... 64 
12.1 
Pregnancy Test and Birth Control Methods .................................................... 64 
12.2 
RA Disease Activity Assessments .................................................................. 65 
12.3 
Clinical Laboratory Tests ................................................................................ 66 
12.4 
Hand MRI ........................................................................................................ 67 
13 
STUDY SUPPLIES AND DEVICE ACCOUNTABILITY ................................... 67 
14 
PRIOR AND CONCOMITANT MEDICATION .................................................. 68 
14.1 
Prior RA Medication ....................................................................................... 68 
14.2 
Required Background RA Therapy ................................................................. 68 
14.3 
Allowed Medications ...................................................................................... 68 
14.4 
Prohibited Medications and Interventions....................................................... 69 
14.5 
Rescue Treatment ............................................................................................ 70 
15 
ASSESSMENT OF SAFETY ................................................................................... 72 
15.1 
Specifications of Safety Parameters ................................................................ 72 
15.2 
Classification of AEs ....................................................................................... 72 
15.3 
AE Adjudication .............................................................................................. 73 
15.4 
Guidelines for Reporting of AEs ..................................................................... 74 
16 
RISK/BENEFIT ASSESSMENT ............................................................................. 75 
16.1 
Assessment of Risks for the Proposed Investigation ...................................... 75 
16.2 
Potential Risks with VNS Therapy ................................................................. 76 
16.3 
Potential Risks with Surgical Implantation ..................................................... 77 
16.4 
Potential Risk Due to Concomitant Use of csDMARDs and/or Additional 
RA Treatment .................................................................................................. 78 
16.5 
Potential Risk Due to Contrast Enhanced MRI ............................................... 78 
16.6 
Risk Analysis of the SetPoint System ............................................................. 79 
16.7 
Benefit Assessment of the Proposed Investigation ......................................... 79 
16.8 
Consideration of Patient Preference ................................................................ 80 
16.9 
Assessment of Uncertainty .............................................................................. 81 
17 
STATISTICAL CONSIDERATIONS..................................................................... 81 
17.1 
Randomization ................................................................................................ 81 
17.2 
Primary Efficacy Endpoint .............................................................................. 82 
17.3 
Interim Analysis .............................................................................................. 83 
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17.4 
Analysis of Key Secondary Endpoints ............................................................ 84 
17.5 
Analysis of Exploratory Endpoints ................................................................. 85 
17.6 
Analysis of Safety Measures ........................................................................... 85 
17.7 
Handling of Rescue Treatment ........................................................................ 85 
17.8 
Analysis Populations ....................................................................................... 85 
18 
STUDY MANAGEMENT ........................................................................................ 86 
18.1 
Ethical Considerations..................................................................................... 86 
18.2 
Sponsor Responsibilities ................................................................................. 86 
18.3 
Blinding ........................................................................................................... 90 
18.4 
Unblinding ....................................................................................................... 90 
18.5 
Investigator Responsibilities ........................................................................... 91 
18.6 
Protection of Subject Confidentiality .............................................................. 93 
18.7 
Study Suspension or Early Termination.......................................................... 94 
18.8 
Site Closeout ................................................................................................... 95 
18.9 
Quality Assurance and Supervision by Authorities ........................................ 95 
18.10 IRB Approved ICF and Protection of Study Subjects..................................... 95 
18.11 IRB Approval .................................................................................................. 95 
18.12 Other Investigator Reports .............................................................................. 96 
18.13 Final Clinical Study Report ............................................................................. 96 
18.14 Publication Policy ........................................................................................... 96 
19 
COVID-19 CONTINGENCY MEASURES............................................................ 96 
19.1 
Study Procedures During COVID-19 ............................................................. 97 
19.2 
Contingency Measures for Study Management .............................................. 99 
20 
REFERENCES ........................................................................................................ 100 
21 
APPENDICES ......................................................................................................... 104 
 
LIST OF FIGURES 
Figure 1: Stimulation of the Cholinergic Anti-Inflammatory Pathway .................................. 35 
Figure 2: SetPoint System Implantable Components .............................................................. 36 
Figure 3: Cyberonics VNS Therapy System ........................................................................... 38 
Figure 4: SPM-005 Study Design ........................................................................................... 39 
Figure 5: SPM-005 DAS28-CRP Change from Baseline ....................................................... 40 
Figure 6: SPM-005 ACR20 Response in Subjects with ≥ 4 Prior bDMARDs Compared to 
JAKi Trials ............................................................................................................ 40 
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Figure 7: SPM-005/006 DAS28-CRP Change from Baseline ................................................ 41 
Figure 8: SPM-005/006 CDAI Change from Baseline ........................................................... 42 
Figure 9: SPM-008 Study Design ........................................................................................... 43 
Figure 10: SPM-008 DAS28-CRP Change from Baseline ..................................................... 44 
Figure 11: SPM-008 CDAI Change from Baseline ................................................................ 44 
Figure 12: SPM-020 Study Schematic .................................................................................... 48 
Figure 13: SPM-020 Study Timeline ...................................................................................... 64 
Figure 14: SPM-008 Individual DAS28-CRP Score Change from Baseline to Week 12 ...... 80 
Figure 15: SPM-008 Change in RAMRIS Bone Erosion Score by DAS28-CRP Response .. 80 
 
LIST OF TABLES 
Table 1: Microregulator Stimulation Pulse Parameters .......................................................... 37 
Table 2: SPM-008 Treatment Emergent AEs Related to the Implantation Procedure............ 45 
Table 3: Study Objectives and Endpoints ............................................................................... 46 
Table 4: Power Calculations for ACR Response Based on Pooled Data from Stage 1 and 2 83 
Table 5: True Probability of Stopping after Stage 1 and Power of Study Success Based on 
Pooled Data ........................................................................................................... 84 
Table 6: Blinding Matrix ......................................................................................................... 90 
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2 
LIST OF ABBREVIATIONS 
Abbreviation 
Expansion 
ACh 
Acetylcholine 
ACPA 
Anti-citrullinated peptide antibody 
ACR 
American College of Rheumatology 
AE 
Adverse event 
7nAChR 
Alpha 7 nicotinic acetylcholine receptor 
bDMARD 
Biologic DMARD 
BS EN 
British Standard European Norm 
CAP 
Cholinergic anti-inflammatory pathway 
CARLOS 
Cartilage loss score 
CBC 
Complete blood count 
CDAI 
Clinical Disease Activity Index 
ChAT+ 
Choline acetyltransferase 
CIA 
Collagen-induced arthritis 
Co-PI 
Co-principal investigator 
CRF 
Case report form 
CRP 
C-reactive protein 
csDMARD 
Conventional synthetic DMARD 
CTA 
Clinical trial agreement 
DAS 
Disease Activity Score 
DMARD 
Disease-modifying anti-rheumatic drug 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EGA 
Evaluator’s global assessment 
eGFR 
Estimated glomerular filtration rate 
ELISA 
Enzyme-linked immunosorbent assay 
EMR 
Electronic medical records 
EQ-5D-5L 
EuroQol 5 domains 5 levels  
EULAR 
European League Against Rheumatism 
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Abbreviation 
Expansion 
GBCA 
Gadolinium-based contrast agents 
GCP 
Good clinical practice 
HAQ-DI 
Health Assessment Questionnaire Disability Index 
hsCRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
IFU 
Instructions for use 
IL 
Interleukin 
IRB 
Institutional review board 
IRT 
Interactive response technology 
ISO 
International Organization for Standardization 
ITT 
Intent to treat 
JAKi 
Janus kinase inhibitor 
LDA 
Low disease activity 
LED 
Light emitting diode 
LPS 
Lipopolysaccharide 
MCID 
Minimal clinically important difference 
MCS 
Mental component summary 
MMP3 
Matrix metalloproteinase-3 
MRI 
Magnetic resonance imaging 
NCAP 
Neurostimulation of the cholinergic anti-inflammatory pathway 
NRS 
Numerical rating scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
PCS 
Physical component summary 
PMA 
Premarket Approval 
POD 
Positioning and Orientation Device 
PTE 
Per-treatment evaluable 
QD 
Every day 
QID 
4 times a day 
RA 
Rheumatoid arthritis 
RAMRIS 
Rheumatoid Arthritis MRI Scoring System 
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Abbreviation 
Expansion 
RCT 
Randomized controlled trial 
RF 
Rheumatoid factor 
SAA 
Serum amyloid A 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SF-36 
Short Form Survey with 36 items 
SGA 
Subject’s global assessment 
SJC28 
Swollen joint count in 28 joints 
Sub-I 
Sub-investigator 
TEAE 
Treatment emergent adverse event 
TENS 
Transcutaneous electrical nerve stimulation 
TJC28 
Tender joint count in 28 joints 
TNF 
Tumor necrosis factor 
tsDMARD 
Targeted synthetic DMARD 
UADE 
Unanticipated adverse device effect 
UAT 
User acceptance testing 
UI 
User interface 
USADE 
Unanticipated serious adverse device effect 
VNS 
Vagus nerve stimulation 
 
 
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DEFINITIONS OF TERMS 
Term 
Definition 
ACR20/50/70 
A composite measure defined as improvement of 20, 50 or 70% in:  
• 
TJC28 
• 
SJC28 
And 3 out of the following 5 criteria:  
• 
Subject’s pain assessment 
• 
SGA 
• 
HAQ-DI 
• 
EGA 
• 
hsCRP (mg/mL)  
Adverse device effect 
AE related to the use of an investigational medical device. This definition 
includes adverse events resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. This definition includes any event resulting 
from use error or from intentional misuse of the investigational medical device. 
[BS EN ISO 14155] 
AE 
Any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device.  
[BS EN ISO 14155] 
Augmented therapy 
Additional treatment for RA therapy 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 stimulation with the following additions to 
RA therapy will 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 corticosteroid injection 
within 30 days prior to a study visit, the subject is assigned to the 
augmented therapy subgroup for that visit. 
• 
b/ts/csDMARD.  Subjects who receive treatment with biologic, targeted 
synthetic, or additional conventional synthetic DMARD, or increased dose 
of background conventional synthetic DMARD will be assigned to the 
augmented therapy subgroup for all subsequent visits. 
Baseline 
Information and values collected during Screening. The RA disease activity 
assessments that serve as the baseline assessments used for determination of the 
primary and key secondary efficacy endpoints must be performed on the day of 
informed consent.  
CDAI 
The CDAI score is based on 4 items: 
• 
TJC28 
• 
SJC28 
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Term 
Definition 
• 
SGA 
• 
EGA 
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 
The MCID is a score reduction by 12 if starting in high activity, 6 if starting in 
moderate activity, and 1 if starting in low activity. 
Control to Open Label 
(COL) population 
Control subjects from ITT population who received non-active (sham) 
stimulation through Week 12, switched to active stimulation after completing 
Week 12 assessments, continued to receive active stimulation during open-label 
follow-up, and for whom follow-up data are available. 
Crossover 
The process of switching from an initially assigned treatment to the other 
treatment being studied. 
DAS28-CRP 
The DAS28-CRP score is a composite index providing a measure of disease 
activity, comprising: 
• 
TJC28 
• 
SJC28 
• 
SGA 
• 
hsCRP (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 
 A DAS28-CRP score reduction by 1.2 represents the MCID. 
Day 0 (randomization, 
initiation of 
stimulation) 
Scheduled study visit occurring 14 to 21 days after Implant Procedure during 
which subjects undergo the following study procedures in the order specified: 
• 
Day 0 assessments 
• 
Randomization 
• 
Initiation of stimulation 
Subjects must receive final surgical clearance with an approval to initiate study 
treatment before proceeding to the Day 0 visit. 
Device deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. Device deficiencies include malfunctions, use 
errors, and inadequate labeling. [BS EN ISO 14155] 
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Term 
Definition 
Device malfunction 
Failure of an investigational medical device to perform in accordance with its 
intended purpose when used in accordance with the instructions for use or 
clinical investigation protocol. [BS EN ISO 14155] 
DMC 
An independent data monitoring committee responsible for safeguarding the 
interests of study participants, assessing the safety and efficacy of the 
interventions during the study, and for monitoring the overall conduct of the 
clinical study. 
EGA 
A global assessment of the subject’s RA activity performed by an independent, 
blinded Joint Evaluator using NRS from 0 (inactive) to 10 (very active). 
EQ-5D-5L 
A standardized instrument for measuring general health status within the 
following 5 dimensions:  
• 
Mobility 
• 
Self-care 
• 
Usual activities 
• 
Pain/discomfort 
• 
Anxiety/depression 
Each dimension is scored on 5-point scale as:  
• 
No problems 
• 
Slight problems 
• 
Moderate problems 
• 
Severe problems 
• 
Extreme problems 
In addition, general health status is scored from 0 (the worst health) to 100 (the 
best health). 
Enrolled 
Subjects meeting all the inclusion and none of the exclusion criteria in whom the 
implant procedure is attempted. 
EULAR response 
criteria 
A means of measuring efficacy of treatment using DAS28-CRP, incorporating 
both an absolute measure of disease activity, and a measure of change in 
activity. 
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 
Flare 
Worsening of RA symptoms resulting in an increase between consecutive visits 
in DAS28 score ≥ 1.2, or an increase ≥ 0.6 if the first of the paired visits had 
DAS28 ≤ 3.2. 
HAQ-DI 
A questionnaire validated for RA self-assessment by subjects that contains 20 
questions in the following 8 functional areas: 
• 
Dressing and grooming 
• 
Arising 
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Term 
Definition 
• 
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 
A HAQ-DI score reduction by 0.22 represents the MCID. 
hsCRP 
Marker of systemic inflammation associated with disease activity in RA that is 
generally not detectable with routine CRP assays. 
ITT population 
Primary analysis population comprising all enrolled and randomized subjects.  
PTE population 
Subjects from ITT population who received the assigned treatment through 
Week 12, have no major procedural protocol deviations, and for whom follow-
up data are available. 
RA disease activity 
assessments  
A standardized set of RA assessments that should be performed in the following 
order:  
• 
HAQ-DI 
• 
SGA 
• 
Subject’s pain 
• 
TJC28 
• 
SJC28 
• 
EGA 
• 
hsCRP (mg/L) 
RAMRIS 
A standardized method for MRI acquisition of the hand and wrist, joint 
pathology definitions and a scoring system for semiquantitative evaluation of: 
• 
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 to 10, resulting in a 
total score from 0 to 250. Change by > 0.5 represents disease progression. 
• 
Osteitis.  25 bones each scored on a scale from 0 to 3, resulting in a total 
score from 0 to 75 
• 
CARLOS (cartilage loss).  25 joints each scored on a scale from 0 to 4, 
resulting in a total score from 0 to 100 
Randomization 
Process of randomly assigning subjects to a treatment or control group which 
occurs after completion of Day 0 assessments. 
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Term 
Definition 
Rescue treatment 
Additional or change in treatment to address worsening of RA symptoms or 
failure to achieve adequate clinical improvement prior to Week 12. Additional 
treatments considered as rescue include: 
• 
Addition of a biologic or targeted synthetic DMARD 
• 
Dose increase of the ongoing conventional synthetic DMARD background 
therapy or addition of another conventional synthetic DMARD 
• 
Addition or dose increase of a corticosteroid (equivalent to an average 
daily use > 10mg prednisone/day between study visits) 
• 
A corticosteroid injection within 30 days of a study visit 
Subjects initiating rescue treatment prior to Week 12 will be imputed as non-
responders in the analysis of primary and key secondary endpoints. 
SADE 
Adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event. Anticipated SADE is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
SAE 
Adverse events are considered “serious” if, in the view of either investigator or 
sponsor, they result in any of the following outcomes: 
• 
Death 
• 
A life-threatening illness or injury 
• 
Permanent impairment of a body structure or a body function 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, or  
• 
Fetal distress, fetal death, or a congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. [BS EN ISO 14155] 
Safety population 
All enrolled subjects.  
SF-36 
A survey of subject health with 36 questions in 8 domains: 
• 
Vitality 
• 
Physical functioning 
• 
Bodily pain 
• 
General health perceptions 
• 
Physical role functioning 
• 
Emotional role functioning 
• 
Social role functioning 
• 
Mental health 
The instrument's scores are norm-based: 
• 
0 Maximum disability  
• 
50 Average health status 
• 
100 No disability 
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Term 
Definition 
In addition, 2 global measures are derived:  
• 
PCS or physical component summary 
• 
MCS or mental component summary 
SGA 
Subject’s global assessment of their RA disease activity using a NRS from 0 
(inactive) to 10 (very active). 
Source data 
All information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for 
the reconstruction and evaluation of the trial.  
Source documents 
Original documents, data, and records. Printed, optical, or electronic documents 
containing source data.  
Stratification 
Allocation of subjects into treatment groups based on a characteristic that may 
affect trial outcome. 
Subject 
An individual who participates in a clinical investigation.  
Subject’s pain 
assessment 
Subject’s assessment of their RA-related pain using a NRS from 0 (no pain) to 
10 (worst pain imaginable). 
TJC28 & SJC28 
A standardized assessment examining a total of 28 joints for signs of swelling 
and tenderness or pain in the shoulder (2), elbow (2), wrist (2), knee (2), and 
fingers (2 in each finger and thumb knuckle and second finger joint, 10 per hand 
or 20 total). 
Treatment to Open 
Label (TOL) 
population 
Treatment subjects from ITT population who received active stimulation 
through Week 12, completed Week 12 assessments, continued to receive active 
stimulation during open-label follow-up, and for whom follow-up data are 
available. 
UADE 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application, or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects.  
[21 CFR 812] 
USADE 
Any serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis report. 
[BS EN ISO 14155] 
Use error 
Act or omission of an act that results in a different medical device response than 
intended by the manufacturer or expected by the user. Use error includes slips, 
lapses, and mistakes. An unexpected physiological response of the subject does 
not in itself constitute a use error. [BS EN ISO 14155] 
VNS 
A medical treatment that involves delivering electrical impulses to the vagus 
nerve. 
 
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4 
PROTOCOL SUMMARY 
Study Title 
Vagus Nerve Stimulation Using the SetPoint System for Moderate to Severe Rheumatoid 
Arthritis: The RESET-RA Study 
Objective 
To assess the safety and efficacy of the SetPoint System for the treatment of adult patients 
with active, moderate to severe rheumatoid arthritis (RA) who have had an inadequate 
response or intolerance to biologic or targeted synthetic Disease-Modifying Anti-
Rheumatic Drugs (DMARDs) 
Investigational 
Device 
The SetPoint System 
Phase 
Phase 3 Pivotal 
Study Design 
An operationally seamless, 2-stage, randomized, sham-controlled, double-blind, 
multicenter pivotal study enrolling at least 240 and up to 250 subjects at up to 45 study 
centers across the U.S.: 
• 
Stage 1 with approximately 60 randomized subjects at up to 25 study centers 
• 
Stage 2 with approximately 190 randomized subjects at up to 45 study centers, 
including centers from Stage 1 
There will be a pause in enrollment after enrollment in Stage 1 is completed. This pause 
in enrollment is intended to allow completion of Week 12 assessments by 60 enrolled and 
randomized subjects and review of interim analysis results by the independent Data 
Monitoring Committee (DMC) and the U.S. Food Drug Administration (FDA). The DMC 
and FDA will confirm whether the study can advance to enroll subjects in Stage 2.  
After completing primary endpoint assessments at Week 12, there will be a one-way 
crossover of control subjects to active stimulation and a 252-week open-label follow-up 
with all subjects (treatment and control) receiving active stimulation to evaluate long-term 
safety. Blinding will be maintained until the last enrolled and randomized subject in Stage 
2 completes Week 12 assessments, and the study dataset for primary analysis is locked. 
The initial, 12-week follow-up period will generate safety and efficacy data to support an 
application for Premarket Approval (PMA). The PMA application will also include 
supporting data on long-term safety for all subjects for whom long-term data are available 
at the time of application. 
Study Procedures 
• 
Enrollment.  Subjects meeting all the inclusion and none of the exclusion 
criteria are considered enrolled once Implant Procedure is attempted. 
• 
Implant Procedure.  Subjects meeting final eligibility will undergo placement 
of the SetPoint System in the neck, on the left cervical vagus nerve within the 
carotid sheath. The procedure will take place in an operating room under general 
anesthesia and be performed by surgeons trained and experienced in procedures 
involving implantation of vagus nerve stimulators.  
• 
Randomization.  Within 14-21 days after Implant Procedure and after 
completing Day 0 assessments, subjects will be assigned randomly in a 1:1 ratio 
into either a treatment or control group using an interactive response technology. 
Randomization will be stratified by inadequate response or loss of response to 
Janus kinase inhibitors (JAKi); inadequate response or loss of response to ≥4 
biological DMARDs (bDMARDs) with ≥ 2 mechanisms of action; and RA 
severity at Day 0. All subjects, investigators and site staff will remain blinded to 
the treatment assignment until the last subject in Stage 2 completes Week 12 
follow-up assessments and the dataset for primary analysis is locked.  
• 
Active & Non-active Stimulation.  Through Week 12, subjects assigned to the 
treatment group will receive active stimulation for 1 min once per day, and those 
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assigned to the control group will receive non-active (sham) stimulation for 1 
min once per day. After completion of Week 12 assessments, all subjects in the 
control group will crossover to active stimulation and all subjects (treatment and 
control) will receive active stimulation for 1 min once per day.  
Study Population 
Adults (22-75 years of age, inclusive) with active, moderate to severe RA despite ongoing 
treatment with a conventional synthetic DMARD who have had an inadequate response, 
loss of response or intolerance to 1 or more biologic or targeted synthetic DMARDs, 
including JAKi. 
Note: Subjects with an inadequate response or loss of response to JAKi will be limited 
to 6 subjects. 
Eligibility 
Criteria 
Key inclusion criteria: 
• 
22-75 years of age at informed consent 
• 
Moderate to severe RA, defined as at least 4/28 tender and 4/28 swollen joints 
• 
Demonstrated an inadequate response, loss of response, or intolerance to 1 or 
more biologic or targeted synthetic DMARDs, administered in accordance with 
their labels 
• 
Receiving treatment with at least 1 conventional synthetic DMARD for at least 
12 weeks and on a continuous non-changing dose and route of administration for 
at least 4 weeks prior to informed consent and able to continue the same stable 
dose through Week 12. Missing up to 2 doses due to COVID-19 vaccination is 
acceptable, except during the 4 weeks preceding informed consent.  
Key exclusion criteria: 
• 
Current, regular use of nicotine-containing products. Subject does not agree to 
abstain from using nicotine-containing products throughout study participation.  
• 
Untreated or poorly controlled psychiatric illness or history of substance abuse 
• 
Significant immunodeficiency due to underlying illness  
• 
History of stroke or transient ischemic attack, or diagnosis of cerebrovascular 
fibromuscular dysplasia  
• 
Clinically significant cardiovascular disease 
• 
Neurological syndromes, including multiple sclerosis, Alzheimer’s disease, or 
Parkinson’s disease 
• 
Uncontrolled fibromyalgia 
• 
History of left or right carotid surgery 
• 
History of unilateral or bilateral vagotomy, partial or complete splenectomy  
• 
Recurrent vasovagal syncope episodes 
• 
Hypersensitivity/allergy to MRI contrast agents and/or unable to perform MRI  
Primary Efficacy 
Endpoint 
Difference between treatment and control groups in the proportion of subjects who 
achieve the ACR20 response at Week 12 
Safety Evaluation  
All adverse events reported by subjects between informed consent and Week 264 (end of 
study) will be tabulated. 
Concomitant 
Medications 
• 
All subjects (treatment and control) will be required to continue background 
therapy with at least 1 conventional synthetic DMARD started at least 12 weeks 
prior and at a stable dose for at least 4 weeks prior to informed consent. Dosage 
and type must remain stable through Week 12. 
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• 
All subjects are allowed to use the following: 
Glucocorticoids at a stable dose equivalent to ≤ 10 mg/d of prednisone 
NSAIDs at a stable dose  
Mild oral opiates taken at a stable dose on a regular basis 
Mild oral opiates taken as needed, except 24 hours prior to assessments 
 
Note: For the above medications, dose changes are not allowed through completion of 
primary endpoint assessments at Week 12. These medications should not be started 
before completion of Week 12 assessments in subjects that are not taking them at time 
of informed consent.  
• 
All subjects (treatment and control) are not allowed to use biologic or targeted 
synthetic DMARDs from Implant Procedure through Week 12.  
• 
The application of rescue treatment is not allowed prior to completion of Week 
12 assessments to allow sufficient time to evaluate clinical response to the 
investigational treatment compared to background therapy alone. Additional RA 
treatment is allowed at any time after completion of Week 12 assessments if the 
subject experiences worsening of RA symptoms or does not experience adequate 
clinical improvement. The decision about the need, type and timing of rescue 
treatment is left to the discretion of the Co-PI Rheumatologist and the subject. 
Rescue treatment shall be consistent with standard of care. 
Follow-up 
Each subject will return for 6 follow-up visits through Week 12 (primary efficacy 
endpoint): 
• 
Week 1, 2 and 3 for dose titration  
• 
Week 4, 8 and 12 for assessments 
After Week 12, each subject will return for 24 follow-up visits through Week 264 (end of 
study): 
• 
Week 13, 14 and 15 for dose titration 
• 
Every 12 weeks from Week 24 through Week 264 for assessments  
Subjects may come in for unscheduled office visits, if necessary. Circumstances that may 
warrant additional visits include but are not limited to: RA-related adverse events 
requiring medical evaluation, device deficiency evaluation, device dose adjustment, 
suspending or resuming stimulation, or implant decommissioning.  
Site’s Roles and 
Responsibilities 
 
Rheumatology Site 
 
Surgery Site 
Co-Principal Investigator 
• 
Responsible for all aspects of 
the study conduct at a given 
site 
• 
IRB oversight 
• 
Informed consent process 
• 
Screening & follow-up 
assessments 
• 
Complete a blinding 
assessment 
• 
AE and device deficiency 
reporting 
 Co-Principal Investigator 
• 
Pre-surgical clearance 
• 
Surgical informed consent, if 
applicable 
• 
Implant procedure 
• 
Post-surgical clearance 
• 
AE and device deficiency 
reporting 
• 
Explant procedure, if applicable 
• 
 
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Research Coordinator 
• 
Data entry into eCRF & query 
resolution 
• 
Maintenance of regulatory & 
subject binders 
• 
Visit coordination 
• 
MRI coordination 
• 
IRB reporting 
• 
Subject IFU & Energizer 
training 
• 
Device check & programming 
(dose titration & adjustment) 
• 
Questionnaire administration 
• 
Blood draws  
• 
Transfer of applicable 
screening records for surgeon’s 
review  
• 
Device accountability 
 Research Coordinator  
• 
Coordination of pre- & post-
Surgical Clearance, Implant 
Procedure 
• 
Transferring source worksheets 
and hospital records to the paired 
rheumatology site 
• 
AE and device deficiency 
reporting to the paired 
rheumatology site 
• 
Device accountability, if stored 
at hospital 
Joint Evaluator 
 
 
• 
Perform joint & global 
assessments 
• 
Complete a blinding 
assessment 
 
 
Duration of Study 
Period  
For a given subject in Stage 1 and Stage 2, the maximum study duration is 1,899 days 
(about 5 years): 
• 
30 days from informed consent to Implant Procedure 
• 
21 days between Implant Procedure and randomization at Day 0 
• 
84 days (about 3 months) between initiation of stimulation at Day 0 and Week 12 
(primary endpoint) 
• 
1,764 days (about 4.5 years) between Week 12 and Week 264 
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5 
STUDY FLOW DIAGRAM 
5.1 
Informed Consent to Week 12 (Primary Endpoint) 
 
 
 
 
 
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5.2 
Long-Term Follow-up 
 
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6 
SCHEDULE OF ASSESSMENTS 
6.1 
Informed Consent to Week 12 (Primary Endpoint) 
Assessment 
Informed Consent 
& Screening 
(Baseline) 
Enrollment & 
Implant Procedure 
(≤ 30d post-
Informed Consent) 
Post-Surgical 
Clearance 
(14-21d post-
Implant Procedure) 
Day 0 
(Randomization & 
Initiation of 
Stimulation) 
(14-21d post-
Implant Procedure) 
Titration 1 
(7 ± 2d2) 
Titration 2 
(14 ± 2d2) 
Titration 3 
(21 ± 2d2) 
Week 4 
(28 ± 3d2) 
Week 8 
(56 ± 5d2) 
Week 12  
(Primary Endpoint 
& One-way 
Crossover) 
(84 ± 7d2) 
Informed consent 
X* 
 
 
 
 
 
 
 
 
 
Vital signs 
X* 
 
 
X 
 
 
 
 
 
X 
Physical exam and medical history 
X* 
 
 
 
 
 
 
 
 
 
Pregnancy test (childbearing female) 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RA disease activity assessments1 
X* 
 
 
X 
 
 
 
X 
X 
X 
RA prior and current medication 
X* 
 
 
 
 
 
 
 
 
 
Energizer fit test 
X* 
 
 
 
 
 
 
 
 
 
SF-36 & EQ-5D-5L questionnaires 
X 
 
 
X 
 
 
 
X 
X 
X 
Blood collection (RF, ACPA, eGFR) 
X 
 
 
 
 
 
 
 
 
 
Blood collection (CBC, biomarkers) 
X 
 
 
X 
 
 
 
X 
X 
X 
Hand MRI 
X 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
X-ray cervical spine 
X 
 
 
 
 
 
 
 
 
 
Surgical clearance 
X 
 
X 
 
 
 
 
 
 
 
Implant procedure in operating room 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
Subject training on the use of Energizer 
 
 
 
X 
 
 
 
 
 
 
Device check & dose titration 
 
 
 
X 
X 
X 
X 
 
 
X 3 
Device check & dose adjustment if needed 
 
 
 
 
 
 
 
X 
X 
 
Blinding assessment 4 
 
 
 
 
 
 
 
X 
 
X 
Treatment decision for long-term follow-up 
 
 
 
 
 
 
 
 
 
X 
Device deficiency reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ACPA, anti-citrullinated protein antibodies; CBC, complete blood count; d, day; EGA, evaluator’s global assessment; eGFR: estimated glomerular filtration rate; HAQ-DI, 
Health Assessment Questionnaire Disability Index; hsCRP, high-sensitivity C-reactive protein; MRI, magnetic resonance imaging; RA, rheumatoid arthritis; RF, rheumatoid factor; SGA, 
subject’s global assessment; SJC, swollen joint count; TJC, tender joint count 
* Screening assessments that must be conducted on the day of informed consent to determine subject’s initial eligibility and baseline values for the primary and key secondary efficacy endpoints. 
1 RA disease activity assessments include: HAQ-DI, SGA, subject’s pain assessment, TJC28, SJC28, EGA, and hsCRP. Subjects must have > 4TJC28 and > 4SJC28 at consent to be eligible.  
2 From Day 0 (randomization). 
3 Dose titration is not performed if subject and Co-PI Rheumatologist decide that subject should not receive active stimulation in open-label, long-term follow-up period. 
4 Blinding assessments are completed by the subject, Joint Evaluator and Co-PI Rheumatologist. 
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6.2 
Long-Term Follow-Up 
Assessment 
Titration 4 
(91 ± 2d2)  
Titration 5 
(98 ± 2d2)  
Titration 6 
(105 ± 2d2)  
Week 24 
(168 ± 7d2) 
Week 36 
(252 ± 14d2) 
Week 48 
(336 ± 14d2) 
Week 60 
(420 ± 14d2) 
Week 72 
(504 ± 14d2) 
Week 84 
(588 ± 14d2) 
Week 96 
(672 ± 14d2) 
Week 108 
(756 ± 14d2) 
Week 120 
(840 ± 14d2) 
Week 132 
(924 ± 14d2) 
Week 144 
(1,008 ± 14d2) 
Week 156 
(1,092 ± 14d2) 
Week 168 
(1,176 ± 14d2) 
Week 180 
(1,260 ± 14d2) 
Week 192 
(1,344 ± 14d2) 
Week 204 
(1,428 ± 14d2) 
Week 216 
(1,512 ± 14d2) 
Week 228 
(1,596 ± 14d2) 
Week 240 
(1,1680 ± 14d2) 
Week 252 
(1,764± 14d2) 
Week 264 
(1,848 ± 14d2) 
(End of Study) 
Vital signs 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (childbearing 
female) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RA disease activity 
assessments1 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36 & EQ-5D-5L 
questionnaires 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Satisfaction questionnaire 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection (CBC) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood collection (biomarkers) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hand MRI 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Device check & dose titration 
X3 
X3 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Device check & dose 
adjustment if needed 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Device deficiency reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: CBC, complete blood count; d, day; EGA, evaluator’s global assessment; HAQ-DI, Health Assessment Questionnaire Disability Index; hsCRP, high-sensitivity C-reactive protein; MRI, magnetic 
resonance imaging; RA, rheumatoid arthritis; SGA, subject’s global assessment; SJC, swollen joint count; TJC, tender joint count. 
 
1 RA disease activity assessments include: HAQ-DI, SGA, subject’s pain assessment, TJC28, SJC28, EGA, and hsCRP. Subjects must have > 4TJC28 and > 4SJC28 at consent to be eligible.  
2 From Day 0 (randomization). 
3 Dose titration is not performed if subject and Co-PI Rheumatologist decide that subject should not receive active stimulation in open-label, long-term follow-up period. 
 
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7 
BACKGROUND INFORMATION  
7.1 
Rheumatoid Arthritis, Treatment Options and Unmet Clinical Need 
Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with progressive joint 
damage, disability and systemic complications. RA has a prevalence of 0.5-1.0% of the population 
in developed countries. Reports of incidence range from 5 to 50 per 100,000 patient-years. The 
typical age of onset is between 40 and 50 years, and women are affected three times more 
commonly than men (Smolen 2016). 
RA is characterized by chronic joint inflammation that leads to permanent structural damage. 
Multiple joints are involved, typically in a symmetrical pattern. Systemic inflammation with 
elevated circulating levels of cytokines and other inflammatory mediators is accompanied by 
autoantibodies such as rheumatoid factor (RF), and anti-citrullinated peptide antibodies (ACPA). 
Chronic inflammation of the synovial lining of the joint leads to joint cartilage damage, formation 
of an inflammatory infiltrate termed a “pannus” and erosions of the peri-articular bone. With time, 
these processes result in physical deformity of the joint, loss of physical function, and eventual 
debility (McInnes 2010). 
In some patients, RA causes extra-articular inflammation of the pulmonary, dermatologic, 
nervous, and other organ systems that can be severe. The effect of systemic inflammation on the 
vascular system makes RA an independent risk factor for early and accelerated atherosclerosis, 
with elevated cardiovascular morbidity and mortality. This risk is further increased in patients 
whose disease remains active despite treatment (Nurmohamed 2015). Studies have suggested that 
RA patients with these extra-articular manifestations, as opposed to RA patients without them, 
have an increased mortality when compared with the general population (Turesson 2004, 
Turesson 2002). On average, the established RA patient has two or more comorbid conditions 
(Michaud 2007). Respiratory disease and cardiovascular disease mortality were both significantly 
elevated for women with RA.  
Many of the extra-articular manifestations of RA are associated with increased disease activity 
and with markers of inflammation, such as high levels of RF and C-reactive protein (CRP) 
(Baecklund 2006, Hannawi 2007, Jonsson 1995, Turesson 2007). This suggests that if RA is 
treated effectively, long term joint damage and disability might be avoided, and the comorbid 
impact of extra articular systemic inflammation might be attenuated. The risks of permanent 
disability and increased mortality support the need for novel therapies as options for patients who 
have not responded to or who are intolerant to currently available treatments.  
Current treatments of RA involve the early use of several older synthetic agents known as 
conventional synthetic Disease-Modifying Anti-Inflammatory Drugs (DMARDs). Over the past 
20 years, a number of newer, targeted protein therapeutic biologic DMARDs have been 
developed. In 2013 the first oral targeted synthetic DMARD, tofacitinib, was introduced. Biologic 
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or targeted synthetic DMARDs are typically begun once the patient has demonstrated an 
incomplete clinical response (IR) to one or more conventional synthetic DMARDs.  
Effectiveness of current treatment options often diminishes over time (Kalden 2017) and adverse 
events frequently emerge. As a result, a number of patients are unable to tolerate or fail to respond 
to available therapies for managing their disease. Failure to respond to targeted therapies is a 
complex process that involves both primary failure, secondary failure after loss of initial response 
and intolerance to the AE profile secondary to immunosuppression and infectious complications. 
Factors contributing to failure to respond include inadequate drug concentrations, presence of 
neutralizing anti-drug antibodies, AEs, and lack of compliance and persistence with drug therapy.  
The development of targeted therapies was a breakthrough that has resulted in substantial 
improvement in the care of RA and has greatly reduced long-term disability from the disease. 
However, aside from loss of effectiveness, these drugs are very costly and are associated with 
uncommon but severe and often life-threatening side effects (Chen 2018, Singh 2012). Thus, there 
clearly remains a significant unmet medical need in RA. 
Despite the availability of conventional synthetic DMARDs such as methotrexate, leflunomide 
and sulfasalazine and multiple biologic DMARDs such as TNF inhibitors (TNFi), up to 40% of 
RA patients fail to reach low disease activity and only about one-third of established RA patients 
meet the criteria for clinical remission (Haugeberg 2015). Adverse events associated with therapy, 
long-term non-compliance, and high cost are partially responsible for the low rates of response to 
treatment. Patients who have failed a particular mode of therapy, such as a TNFi, can switch to a 
mechanistically different mode, such as IL-6 inhibition, B-cell depletion or use of targeted 
synthetic DMARDs. However, despite switching to drugs with an alternative mode of action, only 
30% of patients achieve low disease activity or clinical remission after the treatment switch. 
Furthermore, use of biologic and targeted synthetic DMARDs may increase the rate of infection 
with viruses such as H zoster (shingles) and may predispose patients to rare and potentially fatal 
disorders, such as progressive multifocal leukoencephalopathy.  
Therefore, there is an unmet medical need for alternative therapies for patients who fail to respond 
to or are intolerant of approved targeted agents. A medical device may offer a useful, alternative 
solution to patients, caregivers and healthcare payers. 
7.2 
Investigational Device 
 
Intended Use 
The SetPoint System is indicated for the treatment of adult patients with active, moderate to severe 
RA who have had an inadequate response or intolerance to 1 or more biologic or targeted synthetic 
DMARDs. 
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Mechanism of Action 
The mechanism of action of the SetPoint System is based on electrical activation of the 
cholinergic anti-inflammatory pathway, or CAP (Figure 1) (Tracey 2002). Specifically, the 
SetPoint System activates the efferent arm of the inflammatory reflex, a highly conserved 
endogenous mechanism used by the central nervous system to detect infection and injury and 
coordinate the inflammatory response (Andersson 2012a, Andersson 2012b).  
The discovery that cholinergic neurons inhibit acute inflammation has expanded the 
understanding of how the nervous system modulates immune responses and represents a potential 
paradigm shifting approach to the management of RA. The SetPoint System has been designed to 
specifically modulate the CAP to treat autoimmune diseases using completely novel, application-
specific electrical pulse parameters delivered by an implantable neurostimulator with a unique 
physical form factor. 
 
Figure 1: Stimulation of the Cholinergic Anti-Inflammatory Pathway  
Since the feasibility of restricting systemic inflammation through electrical stimulation of the 
vagus nerve was first demonstrated 20 years ago (Borovikova 2000), several key findings about 
the neural and molecular specificities of this pathway have been elucidated by multiple 
researchers. In this reflex (Figure 1), cytokines are sensed in the periphery and cytokine-specific 
signals travel up the vagus nerve and enter the sensory nuclei in the brain stem (Steinberg 2016). 
Anti-inflammatory signals are then reflexively sent down the efferent vagus nerve, through the 
CAP (Tracey 2002), and this is the ideal intervention point for a neuromodulation-based therapy. 
Selective lesioning experiments in preclinical studies have demonstrated that the anatomical path 
of the CAP is hardwired through the subdiaphragmatic vagus nerve, across the celiac plexus, 
through the splenic nerve and into the spleen.  
The splenic nerve releases norepinephrine into the white pulp of the spleen, where it acts locally 
on β-adrenoceptors on the cell surface of a highly specialized subset of resident T cells that 
express choline acetyltransferase (ChAT+), the rate limiting enzyme in the production of 
acetylcholine (ACh). These T cells then produce and release ACh for at least 30 minutes (Rosas-
Afferent Arm: 
Increase in peripheral 
mediators is sensed
TNF
IL-6
IL-1
Celiac Plexus
Efferent Arm: 
“Cholinergic Anti-inflammatory Pathway”
Mediator production is decreased
1
2
3
4
5
6
7
SetPoint System 
intervention point
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Ballina 2011), a highly disparate timeframe from acetylcholine release within a typical nervous 
synapse. The ACh binds the α7 nicotinic ACh receptor (α7nAChR) expressed on the resident 
macrophages, leading to a reduced production of several key proinflammatory mediators. 
Fundamental to activating this pathway in treating RA, ACh released by ChAT+ T cells also act 
on resident B cells and circulating immune cells that traverse the spleen, leading to phenotypic 
changes in T cells, monocytes, and neutrophils, thereby decreasing inflammatory infiltrates at 
distant sites of inflammation such as the joints in RA (Huston 2009, Karimi 2010, Koopman 2016, 
Mina-Osorio 2012, Nizri 2009). Importantly, as the SetPoint System activates endogenous signal 
transduction pathways, key cytokines are reduced but not eliminated to a complete loss of 
bioavailability, allowing for competent immunosurveillance. Indeed, electrical stimulation of the 
vagus nerve increases levels of pre-resolving mediators that directly act on phagocytes to both 
reduce proinflammatory cytokines and to enhance microbial killing and clearance (Dalli 2017, 
Serhan 2018). 
 
Description of the SetPoint System 
The SetPoint System comprises 2 implantable parts (MicroRegulator, Positioning and Orientation 
Device or POD, Figure 2), and 2 external parts (Energizer, Prescription Pad).  
 
 
A) MicroRegulator, B) Positioning and Orientation Device (POD), C) 
MicroRegulator inside of POD and its placement on the left cervical vagus 
nerve  
Figure 2: SetPoint System Implantable Components 
MicroRegulator 
The surgically implanted MicroRegulator functions as a pulse generator with an integrated lead. 
The vagus nerve fits into a groove in the saddle-like base of the MicroRegulator, and the 
electrodes in the groove are thereby brought into close apposition to the nerve for efficient 
stimulation (Figure 2). An onboard microcontroller unit and an application-specific integrated 
circuit control MicroRegulator. MicroRegulator is powered by a rechargeable lithium-ion battery 
with Zero Volt™ technology. A ferrite core antenna mounted on the hybrid printed circuit board 
assembly provides links for telemetry and radio frequency-induced battery recharging. 
 
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MicroRegulator delivers symmetric, current-limited, charge-balanced bipolar pulses. It is 
approximately 2.5 cm in length and 2.6 g in weight. 
The MicroRegulator settings chosen for this study are based on extensive clinical experience with 
the VNS Therapy™ System (Cyberonics Inc., Houston, TX, USA [PMA P970003]), which is 
indicated for epilepsy and depression, clinical studies performed with the Cyberonics VNS 
Therapy System for treatment of RA (SPM-005 and SPM-006), and preclinical and RA clinical 
studies with the SetPoint System (SPM-008). Stimulation pulse parameters that modulate vagus 
nerve firing and elicit CAP response include output current, pulse frequency, pulse duration, and 
duty cycle (on time/off time). The protocol-specified settings for MicroRegulator are provided in 
Table 1.  
Table 1: Microregulator Stimulation Pulse Parameters 
Parameter 
Value 
Output current 
0 - 2.5 mA 
Pulse frequency 
10 Hz 
Pulse duration 
250 µs 
Duty cycle 
1 min once per day 
POD 
The surgically implanted POD is a flexible silicone enclosure that holds MicroRegulator and the 
vagus nerve together, maintaining the vagus nerve in a cradled position within the electrode 
groove on MicroRegulator. POD also electrically insulates MicroRegulator from surrounding 
tissues. 
Energizer 
Energizer is a non-implanted, externally worn collar powered by a lithium-ion battery. Integrated 
into Energizer is a coil running circumferentially, serving to transmit and receive telemetry 
information to and from MicroRegulator. Information transmitted includes the prescribed 
stimulation frequency, duration and intensity. Information received includes performance and 
compliance data. Energizer is also used to transmit radiofrequency energy to the MicroRegulator 
antenna for inductive battery charging. Energizer is positioned on the subject’s neck and secured 
with a magnetic closure. Energizer has a single outward facing visual indicator (a multi-color 
LED), an audio output (speaker), and an accelerometer (touch input) all of which serve as an 
interface for control of various Energizer and MicroRegulator functions. Energizer only needs to 
be worn for specific operations, i.e., programming MicroRegulator stimulation parameters, 
checking MicroRegulator performance and compliance, and recharging. Energizer is provided 
with a Wireless Charger used to charge Energizer whenever it is not in use. 
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Prescription Pad 
Prescription Pad is an Apple iPad application for SetPoint Medical’s proprietary user interface 
(UI) software with standard iOS touchpad controls. Prescription Pad communicates with 
Energizer through the onboard Apple Bluetooth hardware. Prescription Pad serves as the interface 
between the clinician and MicroRegulator and is used by clinicians only (not subjects) to adjust 
stimulation strength. It is also used to collect information on MicroRegulator performance and 
compliance.  
7.3 
Summary of Prior Clinical Experience 
 
Proof-of-concept studies using the VNS Therapy System  
SetPoint Medical conducted a proof-of-concept clinical study (SPM-005) with long-term follow-
up (SPM-006) using the VNS Therapy System, which was first approved in Europe in 1994 and 
in the U.S. in 1997 for medically refractory epilepsy. Unlike the implanted components of the 
SetPoint System which are configured as a single, self-contained unit that functions as a pulse 
generator with integrated leads, the VNS Therapy System consists of a separate pulse generator 
that is implanted in a subcutaneous, subclavicular pocket with a lead that runs from the generator 
to the neck where electrodes are applied to the vagus nerve (Figure 3). For the purpose of the 
proof-of-concept studies, the pulse characteristics of the VNS Therapy System were modified, 
and the device considered investigational because it was used outside the labeled indications. 
 
Figure 3: Cyberonics VNS Therapy System 
SPM-005 was a single-arm, open-label, pilot study in 18 adult patients with active, moderate to 
severe RA, who had experienced an insufficient response to methotrexate (Cohort I) or to 
methotrexate and at least 2 different types of biologic DMARD therapy (Cohort II). The study 
was conducted at 4 sites in Europe (1 in the Netherlands, 1 in Croatia, 2 in Bosnia) between 
August 2011 and May 2014. The objective was to evaluate the safety and efficacy of VNS for 
treatment of RA by using a modified version of the Cyberonics VNS Therapy System. The study 
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design is depicted in Figure 4. On the first treatment day (study Day 0), subjects received a single 
dose of stimulation lasting 60s with electric current pulses of 250 μs duration at 10 Hz and an 
output current between 0.25–2.0 mA, as tolerated. No further stimulation was delivered for 7 
days. On study Day 7, the output current was adjusted to the highest amperage tolerated, up to 2.0 
mA; and this level of current was subsequently delivered once daily for 60 s in 250 μs pulse 
widths at 10 Hz. Current escalation up to the highest tolerated amperage (up to 2.0 mA) was 
repeated weekly until Day 28. At that visit, the frequency of daily stimulation events was 
increased to 4 times daily in patients who had not achieved a moderate or good clinical response 
according to EULAR criteria. Daily stimulation was continued until the primary endpoint at Day 
42. Stimulation was discontinued for 14 days and then restarted from Day 56 to Day 84.  Subjects 
who completed SPM-005 were enrolled in SPM-006. 
 
Figure 4: SPM-005 Study Design 
Eighteen subjects were implanted, and 17 included into the efficacy analysis. All patients 
continued to use methotrexate (≤ 25 mg weekly). The mean age was 51 years (range 36-69), 78% 
were female, 94% were Caucasian, and mean RA duration was 11 years (SD 5.9). At Day 42, the 
mean DAS28-CRP score was reduced by 2.41 in Cohort I, 1.51 in Cohort II, and 1.91 overall 
from 5.99 (0.77) at baseline (Figure 5). Escalation to 4 times daily stimulation at Day 28 was 
necessary in 3 out of 8 subjects in Cohort I and in 6 out of 10 subjects in Cohort II.  
There were no deaths, serious AEs, withdrawals from the study because of AEs, opportunistic 
infections or implanted device infections observed in either cohort. In agreement with known 
risks of the procedure, 9 subjects experienced mild or moderate AEs associated with implanting 
the VNS on the left cervical vagus nerve. The reported AEs were typical to those seen with the 
implantation of the Cyberonics VNS Therapy system (Koopman 2016). 
 
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p < 0.05 vs. day -21, //p < 0.01 vs. day -21,+p < 0.001 vs. day -21, # p < 0.001 vs. day 42, ^p < 0.05 vs. day 42 
Figure 5: SPM-005 DAS28-CRP Change from Baseline 
The SPM-005 results demonstrated that the use of VNS was well tolerated and resulted in 
clinically meaningful improvement among multi-drug refractory RA patients. The ACR20 
response rate in the subset of subjects who had failed ≥ 4 biologic DMARDs with ≥ 2 mechanisms 
of action compares favorably with those reported in the JAKi trials (Figure 6) and represents a 
reasonable expectation that the VNS therapy could provide a valid alternative to JAKi patients. 
 
Figure 6: SPM-005 ACR20 Response in Subjects with ≥ 4 Prior bDMARDs Compared to JAKi Trials 
After completing SPM-005, all subjects were enrolled into SPM-006, an open-label, long-term 
observational study, and were followed until the final enrolled patient had completed 48 months 
in the study. In SPM-006, investigators were allowed to initiate biologic DMARDs at their 
discretion. SPM-006 also allowed the exploration of a variety of stimulation schedules, self-
administered by subjects, without any control over the number of stimulations sessions per day 
or the duration of each session. A review of site comments in the database showed that several 
patients did not fully comply with daily treatment. Of the 18 subjects enrolled, 4 subjects 
-3 .0
-2 .5
-2 .0
-1 .5
-1 .0
-0 .5
0 .0
-21 -14
0
7
14
28
42
56
84
21
S tu d y  V is it D a y
M e a n  C h a n g e  in  D A S 2 8 -C R P
C o h o rt I (N  =  8 )
C o h o rt II (N  =  1 0 )
C o m b in e d  (N  =  1 8 )
+
#
^
+
//
T re a tm e n t H ia tu s
P rim ary  E n d p o int
T re a tm e n t H ia tu s
Im p la n ta tio n  a n d
D ia g n o s tic  S tim u lu s
^
//
^
//
//
Stimulationin SPM005
-2
0
2
4
6
8
0
20
40
60
80
100
Study Week
ACR20 Response from Baseline
Implantation
Begin Daily 
stimulation
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discontinued prior to their Month 48, and 3 more discontinued after their month 48 but prior to 
the end of study. Two subjects discontinued from the study because of TEAEs (Medical Device 
Discomfort 2 years after stimulations began, and Whipple’s Disease 5 years after stimulations 
began). The other 5 withdrew for subject-defined reasons. 
All efficacy analyses were repeated for 2 subgroups: those who had biological treatment re-
introduced, and those who did not have biological treatment re-introduced (also called VNS 
monotherapy). The efficacy analysis was also repeated separately for Cohort I and Cohort II. The 
primary efficacy endpoint was the change in DAS28-CRP. However, analysis of the DAS28-CRP 
in the latter months of the study was hampered by sites not collecting CRP levels, which are 
needed to calculate the DAS28-CRP. Therefore, a post hoc analysis was added for the standard, 
validated metric known as the Clinical Disease Activity Index (CDAI), because the CDAI 
calculation does not include CRP.  
The primary efficacy endpoints were therefore the change in CDAI and DAS28-CRP from 
baseline 1 (Screening visit of base study SPM-005) and baseline 2 (Day 0 of SPM-006) to each 
follow-up visit. The time course of the average change in the DAS28-CRP is plotted in Figure 7. 
In this figure the MCID of -1.2 is indicated by the light blue dotted horizontal line. The average 
change in DAS28-CRP for the All Subjects group remained significantly reduced from baseline 
1 (shown as Study Visit Month -3.5) throughout 48 months of follow-up. The group that remained 
on VNS monotherapy had a larger reduction in DAS28-CRP from baseline 1 than the group that 
re-initiated biologic therapy. 
 
Figure 7: SPM-005/006 DAS28-CRP Change from Baseline 
The time course of the average change in the CDAI is plotted in Figure 8. The MCID of -12 is 
indicated by the light blue dotted horizontal line. The CDAI was significantly decreased from 
baseline 1 (shown as Month -3.5) at the start of SPM-006 and remained decreased throughout 48 
months of follow-up. 
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Figure 8: SPM-005/006 CDAI Change from Baseline  
Adverse events were recorded from the time of enrollment through end of study. There were no 
deaths in this study. Nine subjects experienced an SAE, but only 1 SAE was deemed to be device 
related. The device related TEAE was device pain and discomfort, which ranged from mild to 
moderate in severity. All 18 subjects reported at least 1 TEAE during the study. There were no 
significant findings based on review of vital signs, physical examination or other observations in 
this study. 
In conclusion, in this group of RA patients, VNS applied with the Cyberonics VNS Therapy 
System resulted in clinically important improvements in DAS28-CRP within several months of 
treatment initiation that was maintained over 48 months of follow-up. These improvements were 
observed for subjects that previously had an insufficient response to targeted biological therapies, 
as well those that had an insufficient response to conventional synthetic DMARDs. The addition 
of adjunctive therapy to biologic DMARD-refractory subjects with only partial response with 
VNS alone enabled several subjects to achieve low disease activity. Surprisingly, low disease was 
achieved in the 2 subjects who were prescribed the same biologic DMARD that they had 
previously failed as co-therapy to VNS, as if VNS had re-sensitized the patients to those drugs. 
The ability to add a biologic as an adjunctive therapy in patients that do not reach low disease is 
a unique and potentially very important aspect to VNS therapy. 
 
Pilot RCT using the SetPoint System 
Encouraged by the results generated in the proof-of-concept studies with the Cyberonics VNS 
System, SetPoint developed its own implantable VNS system to treat patients with drug-refractory 
RA. The SetPoint System is a miniaturized stimulator, with the electrodes and pulse generator 
integrated into a single component that is implanted directly on the nerve. The procedure to 
implant this device requires a single incision and is less invasive compared to the Cyberonics 
VNS System.  
SPM-008 was the first-in-human pilot study of the SetPoint System. The study enrolled 14 adult 
patients with active, moderate to severe RA and an incomplete response or intolerability to at least 
2 biologic and/or targeted synthetic DMARDs having at least 2 different mechanisms of action. 
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The study was conducted from March 2018 to December 2018 at 4 sites in the U.S. The objective 
was to evaluate the safety and efficacy of the SetPoint System for the treatment of RA. Subjects 
who completed SPM-008 were enrolled in a long-term extension study (SPM-011), which is 
currently ongoing. 
The study was conducted in 2 stages. Stage 1 (N = 3) was open-label, and Stage 2 (N = 11) was 
randomized, sham-controlled, blinded trial. All subjects in Stage 1 received a single dose of 
stimulation lasting 1 min, QD. Once all subjects in Stage 1 completed 1 week of VNS treatment, 
a Safety Review Team reviewed all available individual and aggregate safety data and 
recommended initiation of Stage 2 enrollment. The subjects in Stage 2 were randomized 1:1:1 
into 1 of 2 active device groups (1 min QD or 1 min QID) or a sham group (device is implanted 
but is not activated: 0 min QD). Three subjects were randomized to treatment QD, 4 subjects were 
randomized to treatment QID, and 4 subjects were randomized to sham. The study design is 
depicted in Figure 9. 
Screening clinical assessments of subjects were performed during the Week -6 Visit, and an 
inactive VNS system was implanted under general endotracheal anesthesia at the Week -2 Visit. 
The subjects then recovered from surgery for at least 14 days. At Day 0, after completing baseline 
assessments and randomization, subjects began daily stimulation (1 min QD, 1 min QID, or 0 min 
QD). Electric current pulses were 250 μs duration at 10 Hz with an output current between 0.25–
2.5 mA, which was increased up to the highest tolerated amperage, or upper comfort level (UCL, 
up to 2.5 mA) on a weekly basis until Week 5.  
 
Figure 9: SPM-008 Study Design 
Fourteen patients were implanted and continued to use a conventional synthetic DMARD 
throughout participation. The mean age was 51 years (range 26-73), and the majority of subjects 
were female (78%) and Caucasian (86%) with average RA duration of 14 years (SD 11.4). The 
DAS28-CRP score at baseline was 5.5 (SD 1.9). The primary efficacy endpoint was change in 
DAS28-CRP score from baseline to Week 12 (end of study) and is shown in Figure 10.  
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Figure 10: SPM-008 DAS28-CRP Change from Baseline 
The mean change in CDAI from Day 0 baseline is plotted in Figure 11. Both Stage 1 and 2 QD 
groups exceeded MCID in the CDAI metric at 12 weeks, based on the change from the Day 0 
baseline. In the sham group, 0 subjects exceeded the MCID in the CDAI metric at 12 weeks. 
 
Figure 11: SPM-008 CDAI Change from Baseline 
The subjects enrolled in SPM-008 had previously failed on average 5 different agents with nine 
(9) of 14 having failed a JAKi as well. It is well established that the more biologic agents that an 
RA patient had previously failed, the lower the expected clinical response rate will be for the next 
drug used to treat active disease. Fifty percent of these highly drug-refractory subjects receiving 
VNS with the SetPoint System showed clinically meaningful improvements within 12 weeks of 
stimulation. 
There were no deaths, device-related AEs, AE-related withdrawals, opportunistic infections or 
implanted device infections observed from the time of enrollment through Week 12. There were 
6 AEs related to the implantation procedure (Table 2), and included 1 Horner’s Syndrome, which 
resolved without permanent clinically significant sequelae prior to end of study, and 1 separate 
incident of postoperative left vocal cord paralysis. Vocal cord paralysis was ongoing at the time 
of study exit, however it resolved during participation in the long-term extension study without 
permanent clinically significant sequelae (Genovese 2020). 
0
4
8
12
-3
-2
-1
0
1
Study Week
Mean Change in DAS28-CRP
Stage 1 QD
Stage 2 QD
Stage 2 QID
Stage 2 Sham
1
0
4
8
12
-30
-20
-10
0
10
Study Week
Mean Change in CDAI
Stage 1 QD
Stage 2 QD
Stage 2 QID
Stage 2 Sham
1
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Table 2: SPM-008 Treatment Emergent AEs Related to the Implantation Procedure 
 
Stage 1  
Open-Label 
 
Stage 2  
RCT 
 
SYSTEM ORGAN CLASS 
Preferred Term 
QD  
(N = 3) 
QD 
(N = 3) 
QID 
(N = 4) 
Sham 
(N = 4) 
Subjects with events, n (%) 
1 (33.3) 
1 (33.3) 
2 (50.0) 
1 (25.0) 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
0 
1 (33.3) 
1 (25.0) 
0  
Post procedural inflammation 
0  
1 (33.3) 
0  
0  
Procedural pain 
0  
0  
1 (25.0) 
0  
NERVOUS SYSTEM DISORDERS 
0  
0  
1 (25.0) 
1 (25.0) 
Horner's syndrome 
0  
0  
0  
1 (25.0) 
Vocal cord paralysis 
0  
0  
1 (25.0) 
0  
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
2 (66.7) 
0  
0  
0  
Dermatitis contact 
1 (33.3) 
0  
0  
0  
Pruritus 
1 (33.3) 
0  
0  
0  
In conclusion, the pilot study results indicate that the SetPoint System was safe and well-tolerated 
in this group of RA patients. There were no device-related AEs, and surgical procedure-related 
AEs resolved without clinically significant sequelae. Several secondary and exploratory efficacy 
endpoints demonstrated meaningful clinical responses.  
All 14 SPM-008 subjects elected to enroll in SPM-011, a long-term extension study with 36-
month follow-up. In SPM-011, the subjects who received active stimulation in the base study 
SPM-008 remained in the same therapy group. The subjects from the QD sham stimulation were 
randomized at Day 0 in a 1:1 ratio to 1 min QD or 1 min QID dosing. Two (2) subjects were 
randomized to QD and 2 to QID. Just as in SPM-008, electric current pulses were 250 μs duration 
at 10 Hz with an output current between 0.25–2.5 mA, which was increased up to the highest 
tolerated amperage (up to 2.5 mA) on a weekly basis from Day 0 to Week 5. In SPM-011, subjects 
continued a background therapy of conventional synthetic DMARDs and had the option to add a 
biologic or targeted synthetic DMARD to the study therapy. As of the 24 Month interim update, 
8 of the 11 subjects still enrolled have added a biologic or targeted synthetic DMARD to their 
treatment. Two device-related AEs have been reported in SPM-011 to date. These occurred in the 
same subject and were described as sore throat and tenderness near implant site with mild and 
moderate severity, respectively. Both events resolved without sequelae upon reducing the 
stimulation strength. In conclusion, VNS stimulation using the SetPoint System for up to 24 
months was well tolerated and resulted in stabilization of RA disease activity in most subjects.  
8 
STUDY OBJECTIVE AND ENDPOINTS 
The overall objective of this study is to assess the safety and efficacy of the SetPoint System for 
the treatment of adult patients with active, moderate to severe RA who have had an inadequate 
response or intolerance to biologic or targeted synthetic DMARDs.  
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The study specific objectives and endpoints are defined in Table 3. 
Table 3: Study Objectives and Endpoints 
Objective 
Endpoint 
Justification of Endpoint 
Primary 
To assess the 
efficacy of the 
SetPoint System  
ACR20 response at Week 12 from baseline on 
the day of informed consent 
The ACR20 response is the most 
commonly used, RA-specific, 
clinically relevant, valid and 
reliable measure of therapeutic 
effect and clinical benefit of the 
investigational treatment on signs, 
symptoms and physical functions. 
Secondary 
Exploratory 
To provide 
further 
information on 
the therapeutic 
effect of the 
SetPoint System 
• 
Exploratory endpoints include, but are 
not limited to: 
• 
ACR20 response at Week 24, 48, 96, 
144 and 192 
• 
ACR50/70 response at Week 12, 24, 48, 
96, 144 and 192 
• 
20/50/70 response for ACR components 
(TJC28, SJC28, Subject Pain, SGA, 
HAQ-DI, EGA, hsCRP) based on 
change from baseline to Week 12, 24, 
48, 96, 144 and 192 
• 
DAS28-CRP score change from 
baseline, LDA/remission at Week 12, 
24, 48, 96, 144 and 192 
• 
DAS28-CRP response (MCID, 
good/moderate EULAR) at Week 24, 48, 
96, 144 and 192 
• 
CDAI score change from baseline, 
LDA/remission, response (MCID) at 
Week 12, 24, 48, 95, 144 and 192 
• 
EQ-5D-5L score change from baseline, 
response at Week 12, 24, 48, 96, 144 
and 192 
• 
SF-36/PCS/MCS score change from 
These are clinically relevant, and 
validated measures of the 
therapeutic effect on composite 
measures, patient-reported 
outcomes, inflammatory 
biomarkers and structural 
progression of disease. 
To further assess 
the efficacy of the 
SetPoint System in 
terms of clinically 
meaningful 
benefits 
Key secondary efficacy endpoints adjusted for 
multiplicity: 
• 
ACR20 response at Week 12 from Day 0 
• 
DAS28-CRP good/moderate EULAR 
response at Week 12 
• 
DAS28-CRP response (MCID -1.2) at 
Week 12  
• 
HAQ-DI response (MCID -0.22) at 
Week 12  
These are RA-specific, clinically 
relevant, valid and reliable 
measures of therapeutic effect of 
the investigational treatment on 
signs, symptoms and physical 
functions. 
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baseline to Week 12, 24, 48, 96, 144 and 
192 
• 
RAMRIS bone erosion, osteitis, 
synovitis, and CARLOS score change 
from baseline to Week 12 and 24 
• 
RAMRIS bone erosion progression (> 
0.5) rate from baseline to Week 12 and 
24  
• 
Change in plasma biomarker 
concentrations (e.g., IL-6, SAA, MMP3) 
Safety 
To evaluate the 
safety of the 
SetPoint System 
Incidence of AEs and SAEs from informed 
consent to Week 264 
Incidence of device malfunctions from Implant 
Procedure to Week 264 
The incidence of treatment 
emergent AEs and SAEs that are 
more common in the treatment 
group compared to control is a 
standard measure of the safety. 
The incidence of device 
malfunction informs about the 
device reliability. 
9 
STUDY DESIGN 
9.1 
Overall Design 
This is an operationally seamless, 2-stage randomized, sham-controlled, double-blind, 
multicenter pivotal study enrolling at least 240 and up to 250 randomized subjects at up to 45 
study centers across the U.S. Enrollment will be conducted in 2 consecutive stages: 
• 
Stage 1 with approximately 60 randomized subjects at up to 25 study centers; and 
• 
Stage 2 with approximately 190 randomized subjects at up to 45 study centers, including 
those from Stage 1. 
There will be a pause in enrollment for approximately 6 months after enrolling the last subject 
into Stage 1 to allow completion of Week 12 for all Stage 1 subjects and readout of comparative 
data (see Section 17.3). During the pause in enrollment, Stage 1 subjects will continue to be 
followed per protocol. 
Following primary endpoint assessment at Week 12, there will be a one-way crossover of control 
subjects to active stimulation and open-label follow-up with all subjects (treatment and control) 
receiving active stimulation through Week 264 for long-term safety. The initial, 12-week follow-
up period will support an application for PMA. Additional follow-up will evaluate long-term 
safety. Blinding will be maintained until all subjects have completed Week 12 assessments and 
the study dataset for primary analysis has been locked. A maximum of 20 subjects may be enrolled 
at a single study center. A schematic of the overall study design is provided in Figure 12: 
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Figure 12: SPM-020 Study Schematic 
9.2 
Rationale for Study Design  
The overall study design is well established to assess the efficacy of a novel treatment in subjects 
with active moderate to severe RA after failing prior biologic and/or targeted synthetic DMARD 
therapy and ongoing use of conventional synthetic DMARD.  
A key feature of the study is an interim analysis after Stage 1 to assess the initial treatment 
response, with a stopping rule for the trial if there is lack of efficacy. The Stage 1, 12-week data 
will be submitted to the DMC and FDA before moving to Stage 2. If the stopping rule is not met, 
there will be a seamless transition to Stage 2 after receiving DMC and FDA’s feedback to 
continue. This operationally seamless design allows both stages to be conducted under the same 
study protocol, Institutional Review Board (IRB) approvals, CTA and use of a single database, 
thereby increasing efficiency. 
A control group receiving non-active (sham) stimulation through Week 12 (primary endpoint) is 
included to measure the absolute effect of active VNS using the SetPoint System, allowing a 
robust determination of its clinical efficacy and safety profile. Following primary endpoint 
assessments at Week 12, there will be a one-way crossover of control subjects to active 
stimulation and open-label follow-up with all subjects (treatment and control) receiving active 
stimulation for 1 min once per day through Week 264 in order to assess long-term safety. All 
subjects must continue stable background therapy with at least 1 conventional synthetic DMARD 
started at least 12 weeks prior to informed consent to ensure that approved RA treatment is not 
withheld from control subjects and to ensure that all subjects remain blinded. In addition, the 
investigator can withdraw a subject from the study at any time as clinically indicated. Additional 
RA treatment may be provided at the discretion of the clinical investigator and subject at any time 
after completion of assessments at Week 12.  
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Follow-up visits are scheduled at least once every 12 weeks to ensure continuous oversight of the 
subject’s safety, collect laboratory samples to detect any abnormalities and determine RA disease 
activity. This timing is aligned with most drug studies and routine standard of care.  
10 
STUDY POPULATION 
The study population will consist of adults (22-75 years of age) with active, moderate to severe 
RA who have had an inadequate response, loss of response or intolerance to 1 or more biologic 
or targeted synthetic DMARDs, including JAKi.  
Subjects with inadequate response or loss of response to JAKi will be limited to 6 subjects. 
10.1 
Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following inclusion criteria: 
1. Male or female and 22-75 years of age, inclusive, at the time of informed consent 
2. Provided written informed consent by signing a form approved by the reviewing IRB 
3. Have active, moderate to severe RA, defined as at least 4/28 tender joints and 4/28 swollen 
joints 
4. Demonstrated an inadequate response, loss of response, or intolerance to 1 or more approved 
for RA biologic or targeted synthetic DMARDs, including JAKi 
5. Receiving treatment with at least 1 conventional synthetic DMARD for at least 12 weeks prior 
and on a continuous, non-changing dose for at least 4 weeks prior to informed consent and 
able to continue the same stable dose through Week 12. Missing up to 2 doses due to COVID-
19 vaccination is acceptable, except during the 4 weeks preceding informed consent. 
Permitted conventional synthetic DMARDs and their approved for RA dosage are: 
a. Hydroxychloroquine (200-400 mg/day) 
b. Leflunomide (10-20 mg/day) 
c. Methotrexate (10-25 mg/week)  
d. Sulfasalazine (1,000-3,000 mg/day) 
Higher stable doses are allowed if indicated by treating physician. Lower stable doses are 
allowed if dose limiting toxicity precludes using higher doses. Combinations are allowed 
provided all drugs comprising the combination meet stability requirements. 
6. Willing and able to comply with protocol requirements  
10.2 
Exclusion Criteria 
Subjects eligible for enrollment in the study must meet none of the following exclusion criteria: 
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1. Have taken biologic or targeted synthetic DMARDs within the minimum required number of 
washout days prior to Implant Procedure (see Appendix A) 
2. Demonstrated an inadequate response or loss of response to JAKi, once 6 subjects meeting 
this criterion have been enrolled. 
3. Have received an intra-articular corticosteroid injection within 30 days of Implant Procedure 
4. Are currently receiving glucocorticoids at doses greater than 10 mg QD of prednisone (or 
equivalent) or have been receiving an unstable dosing regimen within 14 days of informed 
consent 
5. Have started treatment with NSAIDs or have been receiving an unstable dosing regimen of 
NSAIDs within 14 days of informed consent. Over-the-counter use of NSAIDs is permissible 
(see Section 14.3) 
6. Regular use of or dependency on nicotine products within the past 2 years, including but not 
limited to cigarettes or other nicotine-containing products such as cigars, pipe tobacco, 
chewing tobacco, patches, gums, lozenges, or electronic cigarettes. Subject does not agree to 
abstain from using nicotine-containing products throughout study participation. 
7. Woman who is either pregnant or breast feeding  
8. Woman of childbearing potential who does not agree to use an effective method of 
contraception. If a woman becomes or decides she wants to become pregnant, the implant 
must be decommissioned and the subject followed for safety, per standard of care.  
9. Untreated or poorly controlled psychiatric illness or history of substance abuse 
10. Active infection requiring treatment with antibiotics or corticosteroids at Screening, unless 
cleared before Implant Procedure 
11. Significant immunodeficiency due to underlying illness (e.g., active, untreated HBV/HCV 
and HIV positive) 
12. History of CVA or transient ischemic attack, or diagnosis of cerebrovascular fibromuscular 
dysplasia  
13. Clinically significant cardiovascular disease, including cardiomyopathy with ejection fraction 
< 40%, myocardial infarction, unstable angina, or diagnosis of congestive heart failure 
(NYHA Class III or IV) in the preceding 12 months. Subjects with current, clinically 
significant cardiovascular disease must obtain clearance from a cardiologist prior to the 
implant procedure  
14. Neurological syndromes including multiple sclerosis, Alzheimer’s disease, or Parkinson’s 
disease 
15. Fibromyalgia that may confound outcome measures such as tender joint count, evaluator’s 
global assessment, subject’s global assessment, subject’s pain, HAQ-DI, SF-36, or EQ-5D-
5L 
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16. Known clinically significant cerebrovascular atherosclerotic disease including contralateral 
carotid artery disease (non-implanted side) 
17. History of or pre-surgical X-ray that shows cervical spine disorder or instability that, in the 
investigator’s opinion, would preclude safe endotracheal anesthesia or could be exacerbated 
by the implant procedure 
18. Estimated glomerular filtration rate (eGFR) less than or equal to 50 mL/min/1.73 m2 at 
Screening.  eGFR eligibility must be confirmed prior to Screening hand MRI 
19. History of left or right carotid surgery (e.g., carotid endarterectomy or stent) 
20. History of unilateral or bilateral vagotomy 
21. Partial or complete splenectomy 
22. Recurrent vasovagal syncope episodes 
23. Clinically significant cardiac rhythm disturbances, or ECG findings of atrioventricular block 
exceeding first degree, or cardiac conduction pathway abnormalities other than isolated right 
bundle branch block and/or isolated left anterior fascicle block on Screening ECG 
24. Cancer within last 3 years, except fully resected basal or squamous skin cancer, fully resected 
cervical carcinoma in situ, or fully treated mammary ductal carcinoma in situ that has been in 
clinical remission for at least 3 years 
25. Clinically significant esophageal dysfunction such as dysphagia, odynophagia, or esophagitis  
26. History of or current, clinically significant vocal cord dysfunction, vocal cord polyps, or 
thyroid nodules.  
27. Active and uncontrolled peptic ulcer disease 
28. Implanted active medical devices (e.g., cardiac pacemakers, automatic implantable 
cardioverter-defibrillators, drug pumps), or likely need for implantation of such devices within 
6 months  
29. Uncontrolled asthma, chronic obstructive pulmonary disease, sleep apnea, or any other 
pulmonary disease such as interstitial lung disease causing clinically significant dyspnea 
30. Limited life expectancy due to terminal disease 
31. Hypersensitivity/allergy to MRI contrast agents and/or unable to perform MRI (e.g., 
claustrophobia) 
32. Unable to use or wear Energizer 
33. Requires treatment by any of the prohibited interventions (see Section 14.4) 
34. Currently participating in another clinical research study with an investigational drug or 
medical device 
35. Have taken an investigational drug for RA within the defined time period prior to Implant 
Procedure:  
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a. Have taken an investigational drug consisting of biologic agents within 30 days prior 
to Implant Procedure 
b. Have taken an investigational drug consisting of small molecules within 30 days or 5 
times the pharmacokinetic half-life, whichever is longer, of Implant Procedure 
36. Uncontrolled hypertension 
37. Uncontrolled diabetes mellitus 
38. Any comorbidity or current status of subject’s physiological fitness that in the surgeon’s or 
anesthesiologist’s opinion represents safety concerns that make the subject medically unfit for 
the implant procedure or may prevent proper placement of MicroRegulator and POD 
39. A positive COVID-19 test between informed consent and Implant Procedure 
40. Works or resides in an environment where radio frequency (RF) exposure is higher than levels 
deemed safe for normal daily activity by the general public (e.g., near radio or television 
broadcasting antennas, radar systems, industrial heaters and sealers)  
41. Any condition that, in the investigator’s opinion, may preclude completion of screening, 
implant procedure, and post-surgical clearance over the course of 6-7 weeks or follow up 
assessments over the course of 192 weeks (e.g., a medical condition that may increase the risk 
associated with study participation or may interfere with interpretation of study results, 
inability to adhere to the visit schedule, or poor compliance with treatment regimen) 
42. History of thyroid surgery, parathyroid surgery, or other previous neck surgery that, in the 
opinion of the Co-PI Surgeon, puts the subject at increased risk of surgical complications 
43. BMI at screening   35 kg/m2 
44. Use of high potency opioids. Examples include (but are not limited to): morphine, 
hydromorphone, methadone (Dolophine), meperidine (Demerol), oxycodone (OxyContin, 
Percocet), oxymorphone, fentanyl (Sublimaze, Duragesic), levorphanol (Levo Dromoran), 
and buprenorphine (Subutex, Suboxone) 
Note: Use of high potency opioids is not permitted during participation except for analgesic care 
related to an AE. 
45. Inflammatory joint disease other than RA (including but not limited to gout, systemic lupus 
erythematosus, psoriatic arthritis, axial spondyloarthritis including ankylosing spondylitis and 
non-radiographic axial spondyloarthritis, reactive arthritis, overlap connective tissue diseases, 
scleroderma, polymyositis, dermatomyositis. Current diagnosis of secondary Sjogren's 
Syndrome is permitted 
 
10.3 
Subject Status 
Subjects will be classified as follows depending on their current status:  
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• Consented.  After signing an IRB-approved informed consent form 
• Screen failure.  Subject not meeting all inclusion or meeting any exclusion criteria 
• Enrolled.  Subject meeting all inclusion and none of exclusion criteria in whom the implant 
procedure is attempted 
• Implanted.  Subject in whom the implant procedure is successfully completed 
• Randomized.  After being randomly assigned to either treatment or control group 
• Withdrawn.  Meeting one of the withdrawal conditions listed in Section 10.4; or 
• Completed study.  After completing the study-required assessments at Week 264. 
10.4 
Subject Withdrawal  
Enrolled subjects may be withdrawn for any of the following reasons: 
• 
Subject death 
• 
Concomitant disease or any pre-existing disease or condition that precludes subject’s 
participation 
• 
Subject voluntarily chooses not to participate further in the study 
• 
Subject’s non-compliance with study procedures 
• Lost to follow-up, if a subject has missed a study visit, and 3 documented attempts to 
contact the subject have been unsuccessful. A subject who misses a study visit should be 
contacted by site personnel to determine the reason for the missed visit, which should be 
documented in the subject’s study records. A subject who misses a study visit but attends a 
subsequent visit will no longer be considered lost to follow-up 
• 
In the clinical investigator’s opinion, a significant safety concern arises that requires subject 
discontinuation 
• 
In the clinical investigator’s opinion, it is not in the best interest of the subject to continue 
study participation 
• 
In the study sponsor’s or IRB’s opinion, it is not in the best interest of subject to continue 
the study; or 
• 
Study is terminated. 
Clinical investigators should follow withdrawn subjects with ongoing AEs until resolution 
according to standard of care. Data collected up to the point of subject withdrawal or termination 
will be maintained in the study database and included in analyses as appropriate.  
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If, upon withdrawal, a subject wants or needs to have their implant permanently turned off and 
left in place, the implant will be decommissioned at the subject’s last scheduled visit, or an 
unscheduled visit, if necessary. Implant decommissioning is described in Section 11.9. 
If, upon withdrawal, a subject wants or needs to have their implant removed, an explant procedure 
will be scheduled according to protocol Section 11.10. 
All enrolled subjects, including those withdrawn, will be accounted for and documented. 
11 
SUBJECT TREATMENT AND STUDY PROCEDURES 
11.1 
Pre-screening 
During the pre-screening phase, clinical investigators or designees will perform an initial 
evaluation of potential candidates for study eligibility by reviewing their medical records to 
identify previously performed diagnostic measures, medical history, and labs in an effort to rule 
out subjects most likely ineligible for the study. Patients will be pre-screened as close to the date 
of consent and screening as is practicable. This will be included in the site training for the study. 
A log should be maintained to record limited details of those who were pre-screened, tracking the 
outcome of the screening (e.g., ineligible, potentially eligible but declined further study 
involvement, potentially eligible and attended a screening visit).  
11.2 
Informed Consent and Screening 
 
Informed consent  
If the patient appears to be a potential candidate for the study based upon existing information, a 
written informed consent will be obtained. Informed consent must be obtained prior to initiation 
of any clinical procedures that are performed solely for the purpose of determining eligibility for 
research, including withdrawal from medication. Patients who have completed or are in process 
of washout unrelated to this study may be considered for the study. When washout is done solely 
in anticipation of or in preparation for the research, it is part of the research and must be done 
after obtaining written consent.  
Clinical investigators or designees will approach the patient to obtain a written informed consent. 
The background of the proposed study, the implant procedure, the follow-up schedule and all 
potential risks and benefits will be carefully explained to each patient. The clinical investigator 
or designee obtaining informed consent shall: 
• 
Avoid any coercion of or undue influence of patients to participate, 
• 
Not waive or appear to waive patient’s legal rights, 
• 
Use language that is non-technical and understandable to the patient, and 
• 
Provide ample time for the patient to consider participation. 
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Each patient must sign and date the ICF approved by an appropriate IRB during an in-office visit. 
The original signed ICF will be placed in the study file, and a copy will be given to the subject.  
Subjects will be re-consented in situations where changes were made to the study protocol or new 
information about the risks, possible benefits or alternative treatments have been identified. The 
sponsor and IRB will notify clinical investigators in the event re-consent is necessary. In this case, 
subjects must sign and date the amended ICF during their next in-office visit. The original will be 
placed in the study file, and a copy will be given to the subject. 
 
Screening and baseline assessments 
During the same in-office visit that written informed consent is obtained, each subject will be 
assigned a unique identifying code and undergo the following screening assessments to confirm 
their initial eligibility and obtain baseline values for RA disease activity assessments from which 
the primary and the key secondary efficacy endpoints will be assessed: 
• 
Physical examination, including vital signs, height and weight 
Note: If a subject has an active infection that does not clear before Implant Procedure, the subject 
is considered as a screen failure. The subject can be consented and screened following treatment 
and full recovery.  
• 
Prior and current RA medications with detailed record of use of biologic, conventional and 
targeted synthetic DMARDs 
• 
Medical history 
• 
Female subjects of childbearing potential must confirm their nursing status, undergo 
pregnancy test, and confirm their birth control method(s) (see Section 12.1) 
• 
RA disease activity assessments (see Section 12.2) 
• 
Determining the need for washout from biologic or targeted synthetic DMARDs prior to 
Implant Procedure, depending on subject’s current usage:  
o Subjects in post-washout, requiring no further washout.  Subjects who stopped taking all 
biologic and targeted synthetic DMARDs for a period exceeding the required minimum 
washout period prior to Implant Procedure (see Appendix A) do not require further 
washout to qualify for the study. 
o Subjects during washout, requiring completion of washout.  Subjects who stopped taking 
any biologic and targeted synthetic DMARDs within less than the required minimum 
washout period prior to Implant Procedure (see Appendix A) must complete washout 
during the screening period, prior to Implant Procedure to qualify for the study.  
o Subjects in pre-washout, requiring washout.  Subjects who are currently taking any 
biologic and/or targeted synthetic DMARDs must stop taking them for the required 
minimum washout period during the screening period, prior to Implant Procedure 
(see Appendix A) to qualify for the study.  
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Note: If the required minimum washout period following informed consent exceeds 30 days for a 
given subject, this subject shall be considered screen failure without the possibility of 
reconsenting. This is because washout needs to be completed before Implant Procedure, which 
takes place within 30 days from the informed consent date. 
• 
Energizer fit test 
• 
Eligibility evaluation 
The remaining screening assessments can be completed on the day of informed consent or shortly 
after, depending on scheduling abilities: 
• 
Concomitant medications  
• 
SF-36 and EQ-5D-5L questionnaires 
• 
Blood collection for RF, ACPA, eGFR, CBC and biomarkers (see Section 12.3) 
Note: eGFR must be confirmed prior to screening hand MRI 
• 
Hand MRI (see Section 12.4) 
• 
Reporting of any AEs 
Pre-surgical clearance must be completed by the Co-PI Surgeon prior to the scheduled implant 
procedure and entails: 
• 
Review of the screening data collected by the rheumatologist investigator 
• 
12-lead ECG and any additional tests required for surgical or anesthesia clearance per 
hospital’s standard of care 
• 
Standard cervical spine X-ray, including anterior-posterior, lateral full flexion and 
extension, and odontoid views to ensure there are no degenerative or inflammatory changes 
observed in the cervical spine that would predict significant risk for atlanto-axial 
subluxation during neck extension required for endotracheal intubation prior to implantation 
(Krause and Matteson 2014). Cervical spine disorders or instability that would preclude safe 
endotracheal anesthesia will render the subject ineligible. The radiology report shall be filed 
with the subject’s source documentation. 
• 
An assessment of eligibility based on criteria associated with comorbidities or current status 
of physical fitness that would make the subject medically unfit for the implant procedure.  
Based on all screening assessments, Co-PI Rheumatologist conducts a final eligibility 
evaluation:  
• 
A subject must meet all the inclusion criteria and none of the exclusion criteria to be 
eligible. A subject not meeting all inclusion criteria or meeting any exclusion criterion will 
be classified as a screen failure and exited from the study. The reason(s) for screen failure 
will be documented.  
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11.3 
Enrollment and Implant Procedure 
Subjects meeting final eligibility criteria and in whom the implant procedure is attempted are 
considered enrolled. The implant procedure shall occur within 30 days from informed consent. 
The implant procedure is an outpatient procedure taking place in an operating room under general 
anesthesia. The implant (MicroRegulator) and POD will be placed on the left cervical vagus nerve 
within the carotid sheath by surgeons trained and experienced in procedures involving 
implantation of VNS devices. The implant procedure must be performed according to SetPoint 
System Instructions for Use Surgeon Manual. All surgeons performing the implant procedure 
must have documented training prior to performing the first case. Upon completing the implant 
procedure, any AEs, device deficiencies and changes in concomitant medications will be 
recorded. 
The pregnancy testing for female subjects of childbearing potential must be completed before 
initiation of the implant procedure (see Section 12.1). 
11.4 
Post-Surgical Clearance 
Subjects will undergo the following assessments within 14-21 days after Implant Procedure and 
prior to Day 0: 
• 
Pregnancy test for female subjects with childbearing potential and confirmation of birth 
control method (see Section 12.1) 
• 
Surgical clearance, which includes:  
o Post-operative surgical evaluation of wound healing by the Co-PI Surgeon or designee at 
the surgical site, with special attention to wound infections 
o Final surgical clearance with an approval to initiate study treatment 
• 
Reporting of any AEs, device deficiencies and change in concomitant medications 
11.5 
Day 0 Assessments, Randomization, and Initiation of Stimulation 
 
Day 0 assessments 
Subjects approved to initiate study treatment will undergo the following assessments within 14-
21 days after Implant Procedure and before randomization: 
• 
Collection of vital signs 
• 
Pregnancy test for female subjects of childbearing potential and confirmation of birth 
control method (see Section 12.1) 
• 
RA disease activity assessments (see Section 12.2) 
• 
SF-36 and EQ-5D-5L questionnaires 
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• 
Blood collection for CBC and inflammatory biomarkers (see Section 12.3) 
• 
Reporting of any AEs, device deficiencies and change in concomitant medications. 
 
Randomization 
Upon completion of all Day 0 assessments, subjects will be randomly assigned in a 1:1 ratio to 
either treatment or control group using an interactive response technology (IRT) system. Subjects 
assigned to the treatment group will receive active stimulation for 1 min once per day, and those 
assigned to the control group will receive sham (non-active) stimulation for 1 min once per day. 
Subjects and study staff will be kept blinded (see Section 18.3). 
For subjects assigned to the control group, their MicroRegulator will be registered to a 
prescription rule to deliver a sham stimulation, regardless of the setting assigned. The registration 
is performed by unblinded technicians at SetPoint Medical who have exclusive access to the 
subject’s treatment assignment. The prescription rule is written in the SetPoint Medical cloud and 
is received by the site’s Prescription Pad when connected to Wi-Fi and then applied to 
MicroRegulator via Energizer. The prescription rule is not visible to the site personnel to ensure 
they remain blinded to treatment assignment. 
 
Initiation of stimulation 
After randomization, all subjects (treatment and control) will undergo device check, dose titration 
and training on the use of Energizer. The device check and dose titration must be performed by a 
study staff member at the rheumatology site who has been delegated as the site’s device 
programmer and completed the required programming training. Both delegation and training must 
be documented in the appropriate forms.  
 
Device check and dose titration/adjustment 
Device check 
The research coordinator or designee delegated to perform device programming will first perform 
a device check and then dose titration while subjects are wearing their Energizer. The device 
check entails connecting Prescription Pad to the site’s WiFi and establishing the Bluetooth 
connection between Prescription Pad and the subject’s Energizer. Once Prescription Pad is 
connected to Energizer, and Energizer is connected to MicroRegulator, Prescription Pad will 
display the following information: 
• 
Current prescription settings (i.e., strength of stimulation) 
• 
Total number of doses delivered at current setting  
• 
Number of doses missed 
• 
MicroRegulator battery level 
• 
MicroRegulator impedance 
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Note: If a charge level of less than 75% is observed, the subject will be counseled on the 
importance of charging their implant on a weekly basis. Failure to charge the MicroRegulator 
for an extended period may result in a complete discharge of its battery. Once fully discharged, 
the battery cannot be recharged, and automatic delivery of stimulation will no longer occur. In 
this case, the MicroRegulator must be decommissioned (permanently turned off) and the subject 
must return all external equipment (Energizer and Wireless Charger) (see Section 11.9). 
Dose titration 
Dose titration entails an iterative procedure during which short test stimulations will be delivered 
and assessed by subject for tolerability. If tolerated, the stimulation strength will be incremented 
and assessed again. This will be repeated to the maximum level tolerated or to the maximum 
allowable current level specified for the visit, whichever comes first. Once the desired stimulation 
strength is determined or achieved, the subject’s MicroRegulator will be set to deliver stimulation 
at that dose for 1 minute per day. The device programmer will follow the same schedule and 
procedure for all subjects (treatment and control). Subjects, regardless of treatment assignment, 
should not be told or shown what their stimulation strength is set to. 
The titration visits occur at timepoints specified in Section 6. Titration visits will be short and 
consist of a device check and dose titration, as described above. No study required RA 
assessments will be performed during those visits. All AEs, device deficiencies and changes in 
concomitant medications will be recorded. Female subjects with childbearing potential will 
undergo a pregnancy test and confirmation of birth control method per Section 12.1. 
Dose adjustment 
If there is a need to change the stimulation strength, a dose adjustment may be performed. The 
reason for dose adjustment must be documented. Reasons include an AE such as subject side 
effect (see Section 16.2). The process for adjusting the stimulation strength is similar to that for 
dose titration and consists of short test stimulations that are assessed by subject for tolerability. If 
tolerated, the stimulation strength will be incremented and assessed again. This will be repeated 
to the maximum level tolerated. Once the desired stimulation strength is determined or achieved, 
the subject’s MicroRegulator will be set to deliver stimulation at that dose for 1 minute per day. 
11.6 
Follow-up 
The follow-up period begins immediately post-randomization and initiation of stimulation. Each 
subject will return for 6 follow-up visits between Day 0 and Week 12, and 24 follow-up visits in 
the open-label, long-term follow-up period, starting after Week 12 assessments and continuing 
through Week 264 (end of study). Visits must occur within specified windows from Day 0 as 
detailed in Schedule of Assessments (see Section 6). 
The protocol-required follow-up assessments are described in the following sections. 
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Follow-up through Week 12 
The protocol-required follow-up assessments at Week 4, 8 and 12 include the following and 
should be performed in the order specified prior to the device check and any dose adjustment: 
• 
Subject’s, Joint Evaluator’s and Co-PI Rheumatologist blinding assessment (Week 4 and 12) 
• 
Collection of vital signs (Week 12) 
• 
12-lead ECG (Week 12) 
• 
Pregnancy test for female subjects with childbearing potential and confirmation of birth 
control method (see Section 12.1)  
• 
RA disease activity assessments (see Section 12.2) 
• 
SF-36 and EQ-5D-5L questionnaires 
• 
Blood collection for CBC and inflammatory biomarkers (see Section 12.3) 
• 
Reporting of any AEs, device deficiencies and change in concomitant medications  
• 
Suspending therapy before the hand MRI (Week 12; see Section 11.8)  
• 
Hand MRI (Week 12; see Section 12.4) 
• 
Review of clinical outcomes and discussion of treatment options for continuation in the 
long-term follow-up period of the study (after completing assessments at Week 12). The Co-
PI Rheumatologist will review with the subject their clinical outcomes and determine which 
option is in the subject’s best interest. The Co-PI Rheumatologist and the subject are blinded 
to initial treatment assignment in making this decision. The option chosen will be recorded 
on the follow-up visit CRF and entered into EDC. Options include: 
o Receive active stimulation 
o Receive additional RA treatment with active stimulation (see Section 14.5)  
o Receive additional RA treatment without active stimulation (i.e., stimulation is suspended, 
see Section 11.8) with a possibility to receive active stimulation at a later time  
o Permanently turn off (decommission) the study implant (see Section 11.9) 
o Undergo an explant procedure to surgically remove the implant (see Section 11.10) 
• 
Re-registration of Microregulator following MRI at Week 12. Cross-over of the control 
group to active stimulation by updating the prescription rule to deliver active stimulation. 
The prescription rule for treatment subjects will remain the same, delivering active 
stimulation. Re-registration will be performed by unblinded technicians at SetPoint Medical. 
The blind for all study roles that are blinded will be maintained (see Section 18.3).  
• 
Device check and dose titration following MicroRegulator re-registration at Week 12, 
depending on the option chosen for long-term follow-up. 
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Open-label, long-term follow-up through Week 264 
Protocol-required follow-up assessments at Week 24 through Week 264 are detailed below and 
in Schedule of Assessments (see Section 6) and should be performed in the order specified prior 
to the device check and any dose adjustment: 
• 
Collection of vital signs 
• 
12-lead ECG (Week 24, 48, 96, 144, 192) 
• 
Pregnancy test for female subjects with childbearing potential and confirmation of birth 
control method (see Section 12.1) 
• 
RA disease activity assessments (see Section 12.2) 
• 
SF-36 and EQ-5D-5L questionnaires (Week 24, 48, 96, 144, 192) 
• 
Satisfaction Questionnaire (Week 24) 
• 
Blood collection for CBC (see Section 12.3) 
• 
Blood collection for inflammatory biomarkers (Week 24) (see Section 12.3)  
• 
Reporting of any AEs, device deficiencies and change in concomitant medications, 
including the need, timing and type of additional RA treatment 
• 
Suspending therapy before the hand MRI and resuming therapy afterwards (Week 24; see 
Section 11.8)  
• 
Hand MRI (Week 24; see Section 12.4) 
At Week 264, once all assessments are completed, every subject’s MicroRegulator must be 
decommissioned (see Section 11.9).   
11.7 
Unscheduled Visits  
Subjects may come for additional unscheduled office visits if necessary. Circumstances that may 
warrant additional visits include but are not limited to: 
• 
RA-related AEs requiring medical evaluation  
• 
Device deficiency evaluation; and/or 
• 
Device dose adjustment, suspending stimulation, resuming stimulation or implant 
decommissioning.  
Unscheduled visits are related to the study and not standard of care. Prescription refill visits are 
not considered unscheduled visits. Information gathered during an Unscheduled visit must be 
recorded and entered into the study database on the appropriate CRF. 
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11.8 
Suspending and Resuming Stimulation  
Stimulation must be suspended before an MRI, prior to an elective surgical procedure, or if there 
is a concern of subject’s safety.  
Additionally, stimulation may be suspended at any time after completion of Week 12 assessments 
at the discretion of the clinical investigator and the subject. The clinical investigator and subject 
may decide to suspend stimulation in the event the subject experiences worsening of RA 
symptoms or if the subject does not experience adequate clinical improvement and continuation 
of stimulation is deemed not in the best interest of the subject (e.g., subject experiences AE that 
is definitely or probably related to stimulation). RA disease activity is assessed and documented 
at all follow-up visits. Results from these assessments may be used to guide decision-making.  
MicroRegulator should be fully charged prior to suspending stimulation. Stimulation from 
MicroRegulator can be suspended by Prescription Pad as detailed under “Suspending Therapy” 
section of the SetPoint System IFU Prescriber Manual. Pink visual indicator on Energizer 
confirms therapy suspension. Stimulation will no longer be delivered until therapy is resumed. 
Subjects should continue to follow the regular visit schedule, adhere to all study procedures and 
be monitored for safety while therapy is suspended. 
If the clinical investigator and subject decide to resume stimulation (examples include, but are not 
limited to, following resolution of AE, after MRI, after elective procedure), stimulation from 
MicroRegulator can be resumed by Prescription Pad as detailed under “Resuming Therapy” 
section of the SetPoint System IFU Prescriber Manual. Green or orange visual indictor on 
Energizer confirms that therapy has been resumed. 
11.9 
Implant Decommissioning 
Implant battery charge level will be monitored by the designated research coordinator at every 
follow-up visit. If a charge level of less than 75% is observed, the subject will be counseled on 
the importance of charging their implant on a weekly basis and be reminded that their implant 
will be decommissioned in the event the subject does not comply. Once fully discharged, the 
battery cannot be recharged, and automatic delivery of stimulation will no longer occur. In this 
case, the MicroRegulator must be decommissioned (permanently turned off) and the subject must 
return all external equipment (Energizer and Wireless Charger). Contact SetPoint Medical to 
request placement of the MicroRegulator in decommission mode. If a subject wants or needs to 
have their implant permanently turned off and left in place at the end of the study or earlier, the 
implant will be decommissioned in accordance with the SetPoint System Instructions for Use 
Prescriber Manual. The subject would be required to return their Energizer and visit the site at 
least 24 hours following the initiation of decommissioning, to ensure that the decommissioning 
process occurred as expected.  
Subjects that have their implant decommissioned prior to Week 264 and remain in the study 
should continue to follow the regular visit schedule, adhere to all study procedures and be 
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monitored for safety. Subjects choosing to end participation after implant decommissioning will 
be asked to contact the clinical investigator in the event they experience any safety issue related 
to the investigational implant. 
If a device failure precludes decommissioning, the subject will be followed for safety for a period 
of 10 months, at which point the internal battery would be fully depleted. If the 10-month period 
has not elapsed at the point the subject exits the study, investigator agrees to follow subject under 
their standard of care. In this case, follow-up will constitute documented contact with the subject 
once every 2 months, along with documentation of any reported AEs. Subjects will be informed 
about the risks associated with attempting to recharge a device that has a completely depleted 
battery. 
11.10 
Explant Procedure  
If a subject wants or needs to have their implant removed at the end of the study or earlier, this 
must be communicated to the study sponsor prior to scheduling or performing the explant 
procedure. Before the explant procedure, MicroRegulator stimulation must be suspended (see 
Section 11.8). The surgical investigator will perform pre-surgical clearance testing per standard 
of care. The surgical investigator will remove the implant according to the explant procedure 
protocol outlined in SetPoint System Instructions for Use Surgeon Manual. In the event an implant 
cannot be explanted, it will be decommissioned. In the unlikely event that a failed implant cannot 
be explanted, and the nature of device failure precludes decommissioning, the subjects will be 
followed for safety for a period of 10 months, at which point the internal battery would be 
fully depleted. (see Section 11.9). 
The explanted MicroRegulator and POD shall be returned to SetPoint Medical according to the 
return shipping instructions provided or disposed according to investigator’s institutional 
procedures for disposal of blood contaminated medical devices. Following the explant procedure, 
subjects will be evaluated to assess for proper wound healing and post-op recovery per standard 
of care. Once the subject is cleared post-surgery, the subject will exit the study. Any AE resulting 
from the explant procedure should be followed to resolution. 
11.11 
Duration of Study Period  
The study duration is approximately 84 months (8 months for enrollment into Stage 1, 6 months 
for a pause in enrollment after Stage 1, 12 months for enrollment into Stage 2, and approximately 
58 months for completion of follow-up). 
For a given subject, the maximum study duration is 1,899 days (about 5 years, 3 months): 
• 
30 days from informed consent to Implant Procedure 
• 
21 days between Implant Procedure and randomization at Day 0 
• 
84 days (about 3 months) between initiation of stimulation at Day 0 to Week 12  
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• 
1,764 days (about 4 years, 10.5 months) between Week 12 and Week 264 
A timeline of the key study visits is provided in Figure 13. 
 
Figure 13: SPM-020 Study Timeline 
12 
STUDY PROCEDURES 
12.1 
Pregnancy Test and Birth Control Methods 
Female subjects of childbearing potential must undergo a pregnancy test and confirm birth control 
method on the day of informed consent, before initiation of the implant procedure, and at each 
follow-up visit in accordance with Schedule of Assessments (see Section 6). Female subjects that 
are post-menopausal or who have documented surgical history of hysterectomy or tubal ligation 
are not considered to be of childbearing potential. 
In case of a positive pregnancy test before Implant Procedure, the subject will be considered as a 
screen failure and will exit the study. 
In case of a positive pregnancy test after Implant Procedure, the pregnancy will be reported as an 
AE, the implant must be decommissioned (see Section 11.9) and the subject followed for safety, 
per standard of care. Data collected up to this point will be maintained in the EDC and included 
in the safety analysis. 
Risks associated with use of conventional synthetic DMARDs during pregnancy are identified in 
the labeling supplied with these drugs and should be reviewed with the subject. Leflunomide and 
Methotrexate should be stopped immediately in case of a positive pregnancy test, in accordance 
with the package labeling. 
Female subjects of childbearing potential will be required to use acceptable birth control 
method(s) during the entire duration of the study. Acceptable methods of contraception may 
include: 
• 
Established use of hormonal contraceptives (e.g., oral, injectables, vaginal ring, intra-uterine 
device, implant, transdermal patch); 
• 
Non-hormonal IUD 
• 
Double-barrier methods contraceptives (i.e., condom, diaphragm or cervical/vault caps used 
with spermicide (foam, gel, film, cream or suppository); 
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• 
Vasectomized male partner, if the sole partner for the subject; 
• 
Non-sexually active female; or 
• 
Same-sex partner. 
12.2 
RA Disease Activity Assessments 
RA disease activity assessments are listed below and shall be performed in the order indicated: 
• 
HAQ-DI 
• 
SGA 
• 
Subject’s pain assessment 
• 
TJC28 
• 
SJC28 
• 
EGA 
• 
hsCRP  
Refer to Section 3 for definitions of terms. 
 
HAQ-DI 
Subjects will complete the HAQ-DI questionnaire using a paper form. 
 
SGA 
Subjects will complete a global assessment of their RA disease activity using a paper form. 
Subjects must complete their assessments independently from Joint Evaluator’s assessment. 
 
Subject’s Pain Assessment  
Subjects will complete their assessment of the severity of their RA-related pain using a paper 
form. 
 
TJC28 and SJC28 
A total of 28 joints will be scored for presence or absence of tenderness or pain and swelling. All 
joint assessments will be performed by an independent, blinded Joint Evaluator with appropriate 
training and experience. Each subject should be assessed by the same Joint Evaluator throughout 
their participation in the study. The subject’s Joint Evaluator must be the same at Screening and 
Week 12. Joints that have been replaced or injected with intra-articular steroids during the study 
are considered unevaluable.  
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EGA 
After performing joint assessments, the same Joint Evaluator will conduct a global assessment of 
the subject’s RA activity using a paper form. Each subject should be assessed by the same Joint 
Evaluator throughout their participation in the study. The subject’s Joint Evaluator must be the 
same at Screening and Week 12. The Joint Evaluator must complete their assessments without 
knowledge of SGA. 
 
hsCRP 
Blood samples for hsCRP will be collected using sampling kits and shipped at room temperature 
to a central laboratory for analysis through Week 192 (see Section 12.3). Serum concentration of 
hsCRP (mg/L) will be determined by immunoturbidimetric assay. Blood samples for hsCRP will 
be analyzed locally from Week 204 through Week 264. 
12.3 
Clinical Laboratory Tests 
Blood samples will be collected at the site and sent to a central laboratory (ICON Laboratory 
Services) through Week 192. Analysis will include the following according to the schedule of 
assessments (see Section 6): 
• 
RF 
• 
ACPA 
• 
eGFR 
• 
CBC; and 
• 
Inflammatory biomarkers (e.g., IL-6, SAA, MMP3).  
The central laboratory will provide each site with sampling kits, shipping boxes and detailed 
instructions on blood sample collection, preparation and shipping. 
Blood samples collected at Week 204 through Week 264 will be analyzed locally. The following 
analytes will be tested: 
• Complete blood count (CBC), platelet count, differential count 
All laboratory reports shall be reviewed by the site investigator and filed in the subject binder. In 
the event of a clinically significant abnormality, an adverse event shall be reported and labs shall 
be repeated and monitored at the investigator’s discretion until resolved or considered medically 
stable.  
Samples collected for surgical clearance shall be in accordance with the site’s standard of care 
practices and analyzed locally. Testing may include: 
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• 
Platelet count, differential count 
• 
Serum sodium, potassium, bicarbonate, chloride, magnesium, calcium, BUN, serum 
creatinine 
• 
Urinalysis; and 
• 
PT, PTT, INR.  
12.4 
Hand MRI 
A contrast-enhanced MRI of one hand identified by the rheumatologist to be clinically most 
severe will be ordered by the rheumatology site and acquired at an MRI facility that has been 
selected and qualified to perform this procedure.  
The MRI images will be acquired before and after intravenous administration of gadolinium-
based contrast to maximize sensitivity and specificity for inflammation. Instructions on image 
acquisition will be provided in a separate manual from the MRI central laboratory. The same hand 
must be imaged using the same MRI scanner and coil at Screening, Week 12, and Week 24 for a 
given subject. Only 1.5T and 3.0T whole-body scanners and transmit-receive (Tx/Rx) coils, 
ideally knee coils, are acceptable for this study. In vitro testing of MicroRegulator and POD 
indicates that it passes standard testing for safe use in 1.5 T and 3.0 T MRI studies. Safe scanning 
parameters are provided in the SetPoint Medical Surgeon, Prescriber and Patient Manuals.   
The MRI images will be transmitted promptly to the MRI central laboratory for quality check, 
reading and quantification. If any of the images are rejected for inadequate quality, the subject 
shall be scheduled for a repeat MRI within 7 days from the first MRI date.  
13 
STUDY SUPPLIES AND DEVICE ACCOUNTABILITY 
The investigational study devices will be provided to each site upon study sponsor collection and 
approval of all required regulatory documentation. The device will be labeled “CAUTION: 
Investigational Device. Limited by United States Law to Investigational Use” and must be stored 
in a secure (locked) area under the appropriate storage conditions. Access should be limited to 
designated study staff only. Device accountability logs will be provided to the site. It is the site’s 
responsibility to document the receipt (maintain shipping records), disposition (per subject use), 
transfer (if applicable) and return of all study devices.  
All unused or expired investigational devices must be returned to SetPoint Medical in accordance 
with its Return Material Authorization procedures. Explanted Microregulator and POD can be 
returned or disposed according to investigator’s institutional procedures for disposal of blood 
contaminated medical devices. 
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14 
PRIOR AND CONCOMITANT MEDICATION 
14.1 
Prior RA Medication 
Prior use must start from date of RA diagnosis and include all approved for RA biologic and 
targeted synthetic DMARDs. At a minimum, the year of start and stop must be recorded. The 
subject’s medical record should substantiate the type, dose and duration of usage, as well as reason 
for stopping. 
14.2 
Required Background RA Therapy 
Each subject must continue a background therapy with at least 1 conventional synthetic DMARD 
started at least 12 weeks prior and at a stable dose since at least 4 weeks prior to informed consent 
and until Week 12. Missing up to 2 doses due to COVID-19 vaccination is acceptable, except 
during the 4 weeks preceding informed consent. 
Permitted conventional synthetic DMARDs and their approved for RA dosage are: 
• 
Hydroxychloroquine (200-400 mg/day) 
• 
Leflunomide (10-20 mg/day) 
• 
Methotrexate (10-25 mg/week) 
• 
Sulfasalazine (1,000-3,000 mg/day) 
Higher stable doses are allowed if indicated by treating physician. Lower stable doses are allowed 
if dose limiting toxicity precludes using higher doses. Combinations of oral conventional 
synthetic DMARDs such as methotrexate and hydroxychloroquine or sulfasalazine are acceptable 
provided all drugs comprising the combination meet stability requirements. Dose adjustments for 
management of toxicity of the above medications are allowed and should be documented, along 
with documentation of the AE which led to the change in the medication. 
Risks associated with conventional synthetic DMARDs are identified in the labeling supplied 
with these drugs and should be reviewed with the subject. 
Note: Temporary, perioperative changes in background RA therapy are allowed at the discretion 
of the Co-PI Rheumatologist and the Co-PI Surgeon to reduce the risk of potential bleeding, 
infection, or delayed wound healing related to the implant procedure. Such changes are 
considered standard of care. 
All changes in background therapy shall be noted on the Concomitant Medication Log. 
14.3 
Allowed Medications 
The following medications are allowed during study participation: 
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• 
Glucocorticoids at the equivalent of ≤ 10 mg prednisone daily may be continued at a dose 
documented to have been stable within 14 days prior to informed consent and until Week 
12. 
• 
NSAIDs: over the counter may be continued and those by prescription listed below at the 
approved dose for RA documented to have been stable within 14 days prior to informed 
consent and until Week 12:  
o Celecoxib (Celebrex) 
o Diclofenac (Voltaren, Cataflam) 
o Diflunisal (Dolobid) 
o Etodolac (Lodine) 
o Flurbiprofen (Ansaid) 
o Ibuprofen (Motrin) 
o Indomethacin (Indocin) 
o Ketoprofen (Orudis, Oruvail) 
o Ketorolac (Toradol) 
o Meloxicam (Mobic) 
o Nabumetone (Relafen) 
o Naproxen (Anaprox, Naprelan, Naprosyn) 
o Piroxicam (Feldene) 
• 
Mild oral opiates (i.e., acetaminophen-codeine [Tylenol 1, 2, 3], tramadol [Ultram], 
pentazocine [Talwin], hydrocodone [Vicodin, Lortab]) taken as needed to treat pain. Must 
not be taken 24 hours prior to RA disease activity assessments. 
Note: Mild oral opiates taken on a regular basis to treat pain may be continued at a dose 
documented to have been stable within 14 days prior to informed consent.  
Initiating or changing any of the above listed glucocorticoids, NSAIDs or oral opiates after study 
entry and until completion of Week 12 assessments is not allowed. Any change must be noted on 
the Concomitant Medication Log. 
Temporary, perioperative changes to any of the above listed medication is allowed at the 
discretion of the Co-PI Surgeon to reduce the risk of potential bleeding, infection, delayed wound 
healing, or post-operative pain related to the implant procedure. Such changes are considered 
standard of care and shall be noted on the Concomitant Medication Log.  
14.4 
Prohibited Medications and Interventions 
The following medication and interventions are prohibited: 
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• 
Steroid pulse therapy through completion of Week 12 assessments 
• 
Biologic or targeted synthetic DMARDs through completion of Week 12 assessments 
• 
Intra-articular corticosteroid injection through completion of Week 12 assessments 
• 
Ionic or nonionic linear chelated gadolinium-based contrast agents for MRI studies such as 
gadodiamide, gadoversematide, gadofosvest trisodium, gadoxetate disodium, gadopentate 
dimeglumine, and gadobenate dimeglumine  
The following interventions are prohibited for subjects with an implanted MicroRegulator: 
• 
External electrical stimulation devices (e.g., TENS units) on the neck 
• 
Electrically active implantable medical devices (e.g., cardiac pacemakers, automatic 
implantable cardioverter-defibrillators) 
• 
Extra-corporeal shock wave lithotripsy in the cervical spine region  
• 
Short-wave diathermy, microwave diathermy, or therapeutic ultrasound diathermy. 
Diagnostic ultrasound is not included in this contraindication 
• 
Electrosurgery (electrocautery or radio frequency ablation devices) in the cervical spine 
region 
• 
Monopolar electrocautery 
• 
Any investigational therapy 
• 
Therapeutic radiation 
In the event a subject requires any of the above interventions, MicroRegulator must be suspended 
(see Section 11.8), decommissioned (see Section 11.9) or explanted (see Section 11.10), as 
applicable. In the event therapy is suspended or decommissioned, subject should continue to 
follow the regular visit schedule and adhere to all study procedures and will be followed for safety. 
14.5 
Rescue Treatment 
Additional treatment for RA is only allowed after completion of Week 12 assessments in the event 
the subject experiences worsening of RA symptoms or if the subject does not experience adequate 
clinical improvement. If additional RA treatment must be provided prior to Week 12, this is 
considered rescue treatment and will be reported as a protocol deviation. Not allowing additional 
treatment until after Week 12 is consistent with contemporaneous drug studies and “FDA’s Draft 
Guidance for Industry Rheumatoid Arthritis: Developing Drug Products for Treatment (Draft 
Guidance May 2013)” because it ensures sufficient time for evaluation of clinical response to 
investigational treatment.  
After completion of Week 12 assessments, additional treatment for RA may be provided at any 
time. The decision about the need, type and timing of treatment is left to the discretion of the Co-
PI Rheumatologist and the subject. The Co-PI Rheumatologist will take into consideration in their 
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decision the available results from RA disease activity assessments, subject’s medical history and 
information in the labeling of the treatment being considered.  
IMPORTANT: The Co-PI Rheumatologist shall discuss with the subject risks associated with 
the treatment chosen, particularly any black box warnings included in the label for the 
prescribed treatment in the context of each subject’s medical history and comorbidities. If 
there are additional monitoring or testing required to help mitigate such risks, this shall also be 
discussed with the subject. The Co-PI Rheumatologist shall refer to the Medication Guide 
Database 
for 
current 
safety 
information 
related 
to 
the 
treatment 
chosen 
(https://www.fda.gov/drugs/drug-safety-and-availability/medication-guides). This information 
shall be reviewed with the subject and the subject shall be informed that the guide will be provided 
to them at the pharmacy when the drug is dispensed. 
Note: On September 1, 2021, FDA issued a drug safety communication specific to JAK inhibitors. 
It is important that the Co-PI Rheumatologist is aware of this information if considering a JAKi 
for the subject’s treatment. This information is provided in Appendix B and can also be located 
at the following website:  
https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-
risk-serious-heart-related-events-cancer-blood-clots-and-death 
This information shall be provided to the subject if a JAKi is chosen as treatment. 
Both the Co-PI Rheumatologist and subject will remain blinded to original treatment assignment 
when making this treatment decision. Blinding is maintained until the dataset for primary analysis 
is locked, and the study data are unblinded. 
Additional treatments considered as rescue are RA disease modifying drugs that may include, but 
are not limited to: 
• 
Addition of a biologic or targeted synthetic DMARD 
• 
Dose increase of the ongoing conventional synthetic DMARD background therapy or 
addition of another conventional synthetic DMARD  
• 
Addition or dose increase of a corticosteroid (equivalent to an average daily use  > 10 mg 
prednisone/day between study visits);  
• 
A corticosteroid injection within 30 days of a study visit. 
The need, timing, type and reason for rescue treatment are recorded on the follow-up visit and 
Concomitant Medication CRFs and entered into the EDC.  
Subjects initiating rescue treatment prior to Week 12 will be imputed as non-responders in the 
analysis of primary and key secondary efficacy endpoints. The initiation of these treatments with 
study treatment during open-label follow-up is considered “augmented therapy” since it is 
allowed at the discretion of the Co-PI Rheumatologist and the subject after Week 12.  Subjects 
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treated with augmented therapy will be evaluated as a subgroup for the purpose of exploratory 
efficacy analysis (see Section 17.7). 
Subjects that are rescued or receiving augmented therapy will continue to receive their assigned 
study treatment unless suspension of stimulation is judged necessary by the Co-PI Rheumatologist 
and the subject (see Section 11.8). 
Subjects that receive rescue treatment or augmented therapy are expected to continue adhering to 
the study follow-up visit schedule, complete the study procedures, and to be monitored for safety. 
15 
ASSESSMENT OF SAFETY 
15.1 
Specifications of Safety Parameters 
Adverse events (AEs) for each subject from the time the subject gives written informed consent 
through Week 264 (end of study) will be recorded in the EDC system and monitored. Each AE 
will be evaluated by clinical investigators in terms of seriousness, severity (i.e., mild, moderate, 
severe) and strength of relationship (i.e., not related, unlikely related, probably related, definitely 
related, indeterminate) to the implant device, implant procedure, explant procedure, Energizer 
and stimulation therapy. Each AE will be reviewed by sponsor in accordance with sponsor’s SOP. 
The study sponsor is responsible for ensuring that all AEs are appropriately recorded, adjudicated 
and, when applicable, reported to the government(s), ethics committee(s) and other study centers 
per applicable regulations. The sponsor will also appoint an independent Data Monitoring 
Committee (DMC) for ongoing monitoring of subject safety (see Section 18.2.5). Subjects with 
RA experience a persisting set of symptoms associated with the disease and may continue to 
present with a wide range of symptoms during the recovery process after the implant procedure. 
Subjects healing appropriately may suffer from acute infections and/or inflammatory 
exacerbations unrelated to the procedure due to the natural course of their RA. Therefore, clinical 
investigators will evaluate the occurrence of AEs, excluding usual post-operative recovery signs 
and symptoms experienced by study subjects, unless corroborated by objective findings and/or 
requiring specific medical or therapeutic interventions (e.g., antibiotics).  
15.2 
Classification of AEs 
 
AE severity 
All AEs will be reported from the time of consent through study exit. All AEs will be categorized 
in terms of their severity as: 
• 
Mild.  Event results in mild or transient discomfort, not requiring intervention or treatment; 
does not limit or interfere with daily activities  
• 
Moderate.  Event is sufficiently discomforting so as to limit or interfere with daily activities; 
may require interventional treatment  
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• 
Severe.  Event results in significant symptoms that prevents normal daily activities; may 
require hospitalization or invasive intervention  
 
AE causality 
The relationship of all AEs to the implant procedure, explant procedure, implant device, Energizer 
and stimulation will be evaluated by Co-PIs and categorized as:  
• 
Definitely related.  There is a clear temporal association, and no other possible cause. 
• 
Probably related.  There is a clear temporal association, and a potential alternative etiology 
is not apparent. 
• 
Unlikely related.  The AE does not follow a reasonable temporal association; or causal 
relationship with the device or procedure involved in the research is unlikely but cannot be 
completely ruled out. 
• 
Not related.  The AE is completely independent of the study investigational device, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the investigator.  
• 
Indeterminate. Information gathered about the AE is not sufficient to arrive at a definite 
conclusion about causal relationship. 
Any AE that is determined to be definitely related or probably related to the study investigational 
device or procedure will be categorized as device related. Once the study dataset is locked for 
primary analysis and the study is unblinded, if a subject was assigned to the control group but has 
an AE reported as related to stimulation, the AE relationship will be updated to “not related.” 
 
AE expectedness 
It is sponsor’s responsibility to evaluate expectedness of each device-related AE in accordance 
with sponsor’s standard operating procedure (SOP). Expectedness is categorized as either: 
• 
Expected.  AE is consistent with the risk information described in the ICF, IFU and clinical 
investigational protocol (see Section 16); or 
• 
Unanticipated or unexpected.  AE is considered UADE or USADE if it is not consistent 
with the risk information described in the ICF, IFU and clinical investigational protocol (see 
Section 16). 
15.3 
AE Adjudication 
AEs are reviewed by the sponsor on a regular, ongoing basis. Each AE will be reviewed by 
sponsor in accordance with the sponsor’s SOP. The study sponsor is responsible for ensuring that 
all AEs are appropriately recorded, adjudicated and, when applicable, reported to government(s), 
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ethics committee(s) and other study sites, per applicable regulations. The following is reviewed 
for each AE: 
• Need for clarification or additional information from the site 
• Appropriateness of classifications for severity, causality and expectedness 
• If the adverse event is unanticipated, determination as to whether it poses unreasonable risk 
of harm to study subjects if it were to reoccur; and 
• Requirements for reporting to the FDA and site IRB based on the nature of the event. 
Outputs of reviews are filed by sponsor, and action items are tracked to resolution. 
If the investigator and sponsor do not agree on the seriousness or causality of an event, the event 
will be reviewed by an independent adjudicator, who is a qualified medical expert. The 
adjudicator is blinded to treatment assignment and will have access to the following: 
• AE information reported in the EDC system  
• A list of potential risks associated with the implant device, implant procedure, explant 
procedure and stimulation therapy  
• Information provided by investigators, including clinical notes, laboratory results, 
concomitant medications, and medical/surgical history; and 
• Clinical outcome measures reported in the EDC system. 
The independent adjudicator may request further information if this is required to complete AE 
review. The adjudicator will confirm their determination of seriousness and causality of the event. 
The adjudicator’s decision is considered as final and is recorded in the EDC system and used in 
all analyses. 
In accordance with the DMC Charter, all AEs are reviewed by the DMC on an ongoing, regular 
basis, with ad-hoc reviews occurring within 5 working days of sponsor notification of any subject 
death or SAE related to the implant procedure, explant procedure, implant device, or stimulation. 
The DMC review meetings and recommendations will be documented in meeting minutes and 
filed in accordance with the DMC Charter. 
15.4 
Guidelines for Reporting of AEs 
All AEs, regardless of seriousness or relationship to the investigational device, will be recorded 
in the EDC system and will include event description, date of onset, investigator’s assessment of 
severity, relationship to investigational device, and date of resolution/stabilization of the event. 
All AEs will be followed through end of the study or through study exit of individual subject. 
Any pre-existing medical condition that is present at the time of Screening will not be reported as 
an AE, unless there is a worsening of that condition. The occurrence of diagnostic or elective 
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surgical procedures for a pre-existing condition will not be recorded as an AE, unless the condition 
becomes more severe or results in an AE. 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
investigator should specify the date of onset, severity, action taken with respect to the 
investigational device, corrective treatment/therapy given, additional investigations performed, 
outcome, and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the investigational device. 
The investigator should take appropriate measures to follow all AEs until resolution or until 
progression has been stabilized, or until study exit, to ensure the safety of the subjects. If the AE 
continues beyond the last planned visit per protocol and/or the subject withdraws from the study, 
clinical investigators should follow the subjects according to standard of care. 
All AEs must be reported to sponsor based on the following timeline:  
Type of AE 
Reporting Schedule to Sponsor 
Subject death 
Within 24 hours from becoming aware followed by a written report within 
2 working days 
SAE 
(SAE/SADE/UADE/USADE) 
Within 24 hours from becoming aware followed by a written report within 
4 working days 
Device-related AE 
Within 24-48 hours from becoming aware 
The investigator will report the above to the reviewing IRB per the IRB’s guidelines. The study 
sponsor is responsible for reporting safety events to the FDA as required per 21 CFR 812 and to 
IRB per the IRB’s guidelines. 
All SAEs (SAE/SADE/UADE/USADE) will be followed until satisfactory resolution, until the 
investigator deems the event to be chronic, or until the subject exits the study. Other supporting 
documentation of the event may be requested by the sponsor and should be provided as soon as 
possible.  
16 
RISK/BENEFIT ASSESSMENT 
16.1 
Assessment of Risks for the Proposed Investigation  
VNS therapy for the treatment of RA has risks associated with the surgical procedure required to 
implant the stimulation device and with the electrical stimulation itself. The risks are discussed in 
detail later in this section. These risks have been evaluated in animal studies, in the proof-of-
concept study in RA subjects implanted with the Cyberonics VNS Therapy System (SPM-005), 
and in the pilot study of the SetPoint System (SPM-008) (see Section 7.3). The risks are 
potentially severe, and the likelihood of AEs related to the device is only partially understood. 
Risk mitigation procedures include careful selection of eligible subjects, the use of specialized, 
highly experienced investigators, including neurosurgeons with previous surgical experience 
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using approved VNS devices and rheumatologists with extensive clinical trial experience. A 
formal training program will be required for all surgeons who participate in this study to ensure 
adequate experience. Device programmers will undergo formal training as well.  
The assessment of risk is informed by long-term follow-up studies of patients who have had FDA 
approved VNS devices implanted for treatment of drug refractory epilepsy or treatment resistant 
depression. These studies reveal complication rates of < 5%. Complications include post-
operative infections, device failure due to lead fracture, hoarseness, dysphasia, dysphonia, and 
vocal cord paralysis. In rare instances, the device had to be removed (Aalbers 2015). VNS devices 
were approved for use 20 years ago, and more than 100,000 VNS devices have been implanted in 
more than 80,000 patients (Revesz 2016). As such, there is an extensive safety record for VNS 
devices in non-immunosuppressed patients with seizure disorders or depression.  
It is possible that the likelihood of infection for an implanted VNS device will be higher in an RA 
patient population given the disease causes inflammation and that immunosuppressive drugs are 
routinely prescribed, such as methotrexate, steroids and TNF inhibitors.  
16.2 
Potential Risks with VNS Therapy  
Due to the novel application of the VNS therapy using the SetPoint System, risks are based on 
the FDA-approved VNS devices implanted for treatment of drug refractory epilepsy or treatment 
resistant depression. The most common side effects reported by patients implanted with a 
commercially available VNS device are: 
• 
Transient coughing during VNS stimulation   
• 
Neck pain 
• 
Hoarseness or other voice disturbances (dysphonia) during VNS stimulation  
• 
Shortness of breath (dyspnea) 
• 
Throat pain, a burning sensation, or inflammation of the back of the throat (pharyngitis)  
• 
Swallowing difficulties (dysphagia). Swallowing difficulties could lead to aspiration 
• 
Tingling, prickling or numbness near the implant site (paresthesia) 
• 
Nausea and indigestion 
In those patients, these symptoms generally occurred only during the time the device was 
delivering electrical stimulation. Flu-like symptoms and dizziness were also reported (Kahlow 
and Olivecrona 2013). Other uncommon side effects reported include: 
• 
Scarring or infections of the tissues around where the device is implanted.  
• 
Worsening of certain lung and breathing diseases such as asthma, and chronic obstructive 
pulmonary disease in patients who already had these diseases before the device 
was implanted  
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• 
Movement of the device from where it was placed by the surgeon and damage to the vagus 
nerve, other nerves, blood vessels, or other structures of the body  
• 
The device, or any of its parts, breaking and not delivering stimulation correctly  
• 
Worsening or new onset of sleep apnea  
• 
Prolonged hoarseness due to damage by the device to the nerve fibers supplying the 
muscles of the throat  
• 
Slowing or other alterations of the heart rate  
• 
Headaches 
• 
Flushing 
• 
Vomiting 
• 
Gagging 
• 
Eructation 
• 
Constipation 
• 
Syncope 
• 
Weight change (loss or gain) 
In the long-term extension of the SetPoint System pilot study (SPM-011), 1 subject experienced 
severe neutropenia. Although the event was classified as being related to the subject’s RA, the 
presentation and resolution coincided with changes in the subject’s stimulation regime. Because 
of this, investigational VNS could not be completely ruled out as a potential cause. 
16.3 
Potential Risks with Surgical Implantation  
Surgical placement of the implant device can cause damage to the vagus nerve. While the damage 
typically heals with time, in rare cases it can be permanent. The most significant symptoms from 
damage to the vagus nerve are hoarseness or other voice changes, breathing or swallowing 
changes. Swallowing difficulties could lead to aspiration.  These risks could occur because nerves 
that control some throat muscles and the vocal cords come from the vagus nerve.  
In rare cases, during the surgery for device placement, other muscles, nerves, blood vessels or 
tissues in the area can be damaged. Damage to sympathetic innervation to the orbit can result in 
Horner’s Syndrome which includes symptoms of ptosis, meiosis, and anhidrosis. Damage to the 
vocal cord can result in vocal cord paralysis. Symptoms of vocal cord paralysis include voice 
changes and difficult breathing, which generally resolve with surgical intervention and voice 
therapy. 
Other risks associated with surgical implantation of MicroRegulator include: 
• 
Complications related to general anesthesia with endotracheal intubation; 
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• 
Postoperative pain, redness, itching, swelling or seroma at the implant site; 
• 
Eructation, constipation, vomiting or gagging  
• 
Excessive bleeding due to unanticipated vessel injury; and 
• 
Scarring or infection of the tissues around where the device is placed. Infections usually 
treated with antibiotics, in rare cases requiring explantation. 
The risks associated with the explant procedure in the event the device requires removal needs to 
be factored into the overall risk assessment when evaluating participation in the clinical study. 
The safety and impact on vagus nerve function post-device explant is unknown. Preclinical 
studies in canines show no evidence of implantation site and device fibrosis and vagus nerve 
viability appears unaffected as assessed by morphologic and histopathologic examination 
including stains for myelin integrity. 
16.4 
Potential Risk Due to Concomitant Use of csDMARDs and/or Additional RA 
Treatment 
Risks associated with conventional synthetic DMARDs identified in Section 14.2 and/or 
additional RA treatment are identified in the labeling supplied with these drugs. It is unknown if 
these risks are increased by concomitant use with VNS therapy. 
IMPORTANT: The Co-PI Rheumatologist shall discuss with the subject risks associated with 
the treatment chosen, particularly any black box warnings included in the label for the 
prescribed treatment in the context of each subject’s medical history and comorbidities. If 
there are additional monitoring or testing required to help mitigate such risks, this shall also be 
discussed with the subject.  
16.5 
Potential Risk Due to Contrast Enhanced MRI 
The implanted MicroRegulator may exhibit force, torque, heating and vibration effects due to the 
static magnetic field, gradient magnetic and radio frequency fields in an MRI environment, which 
may be perceived as a slight tugging, vibration or heating sensation at the implant location while 
in or near an MRI scanner.  
There is a risk of nephrogenic systemic fibrosis from exposure to gadolinium-
based contrast agents used for enhanced MRI imaging of the hand, which is performed as part of 
the study assessments. Nephrogenic systemic fibrosis is a syndrome that occurs in patients with 
renal failure due to the decreased excretion of gadolinium ions and deposition of a gadolinium-
phosphate precipitate in organs, causing fibrosis (Olchowy 2017). The exclusion of subjects from 
the study having decreased eGFR is therefore mandated. Additionally, the deposition of 
gadolinium-based contrast agents (GBCA) in the brain has been observed even in patients with 
normal renal function, though the clinical significance is unknown (Murata 2016, Olchowy 2017). 
In several retrospective studies, those patients that had been exposed to linear open-chain chelated 
GBCAs had increases in MRI evidence of brain deposition of gadolinium, whereas those that had 
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been exposed to macrocyclic chelated GBCAs did not (Cao 2016, Kanda 2015, Radbruch 2015). 
Because of this, the subjects will not be allowed to receive linear open chain chelated GBCAs, 
and they must instead receive a macrocyclic chelated GBCA (see Section 14.4).  
16.6 
Risk Analysis of the SetPoint System 
For this pivotal study, a cross-functional team at SetPoint Medical performed a systematic risk 
analysis in accordance with BS EN ISO 14971:2012 to identify foreseeable sequences of events 
that could lead to hazardous situations when using the SetPoint System. These situations were 
then correlated to potential harms. Additional reasonably foreseeable harms beyond those 
identified above include: 
• 
Electrocution caused by malfunction or misuse of Energizer or Wireless Charger; 
• 
Critical tissue damage caused by a malfunction of Energizer that results in unsafe radio 
frequency exposure or a burn; 
• 
Critical tissue damage caused by a malfunction of Energizer that results in delivery of 
unsafe stimulation levels; 
• 
Critical tissue damage caused by damage to the implant; 
• 
Asphyxiation caused by misuse of Energizer; 
• 
Stroke caused by the implant migrating and obstructing a blood vessel; 
• 
Death due to radio frequency emissions interference between the SetPoint system and 
some other life-sustaining equipment; and 
• 
Catastrophic failure of the battery causing harm or severe injury, including death. 
16.7 
Benefit Assessment of the Proposed Investigation  
RA patients who have had inadequate responses or who are intolerant to biologic or targeted 
synthetic agents are the target study population for this pivotal study. These patients can be rotated 
on to other drugs with different mechanisms of action which may be effective in reducing disease 
activity, based on RCTs in patients who have failed at least 1 biologic or targeted synthetic 
DMARD. However, subjects who are prone to adverse side effects, such as infections, may not 
be able to tolerate other drugs with different mechanisms of action because they all impair host 
response to infection. For such subjects, VNS may be an appropriate and effective therapeutic 
choice. 
Initial data from the SPM-008 pilot study demonstrated clinically relevant reductions in RA 
disease activity in highly drug refractory patients when the investigational VNS device was 
activated. Reduction in clinical disease activity was documented in subjects who received active 
stimulation (Figure 14). Of note, 5 out of 10 subjects in the actively stimulated groups exceeded 
MCID in DAS28-CRP at 12 weeks and achieved EULAR good or moderate responses. Two 
subjects achieved DAS28 remission. Both had been diagnosed with RA 49 and 13 years prior to 
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enrollment and had incomplete responses to prior treatment with 4 different biologic or targeted 
synthetic DMARDs.  
 
Figure 14: SPM-008 Individual DAS28-CRP Score Change from Baseline to Week 12 
An improvement in the RAMRIS bone erosion scores correlated with a clinically meaningful 
response in DAS28-CRP (Figure 15), which is a particularly encouraging preliminary finding in 
this highly drug-refractory population. 
 
Dotted line at -1.2 represents the MCID of DAS28-CRP change 
Figure 15: SPM-008 Change in RAMRIS Bone Erosion Score by DAS28-CRP Response 
In addition, reduction in levels of proinflammatory cytokines and improvements in RA disease 
activity scores observed in the pilot study after 12 weeks of therapy, were similar with 
improvements observed in the European proof-of-concept study (SPM-005/006).  
Complete results from the initial study were filed in a final study report with FDA in April 2019 
(G170231/R002).   
16.8 
Consideration of Patient Preference 
Given the limited therapeutic treatment options for patients who failed or are intolerant to biologic 
DMARDs, patients are expected to have a high-risk tolerance for considering new therapeutic 
modalities like VNS. There are currently multiple biologic DMARDs which target TNF, IL-6, 
CTLA-4 cell signaling, IL-1, Janus Kinase and B-cell depletion. Patients who failed or are 
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intolerant to biologic DMARDs might choose to continue therapy with approved drugs with 
alternative molecular targets. All of these targeted agents carry a 1.5-2-fold higher risk of infection 
and require repetitive parenteral administration (infusion or SC injections), except JAKi that are 
taken orally (Listing 2013). These alternative drugs are expensive, and patient drug adherence is 
an issue given the parenteral route of administration for most of the therapeutic options. 
Other alternatives for therapy include oral glucocorticoids, which can increase the risk of infection 
and have a negative effect on bone and cartilage. Patients might prefer to volunteer to participate 
in RCTs of experimental agents to treat RA but must accept the fact that they could be randomized 
to the placebo arm during the conduct of the trial. Many drug refractory RA patients who do want 
to participate in clinical trials are excluded from participation because their acute phase ESR or 
CRP is below the minimum threshold for entry despite the presence of multiple swollen and tender 
joints on physical exam. These excluded patients might want to pursue alternative approaches to 
therapy with a VNS device. 
In addition, patients with RA are at increased risk for malignancies, including lymphoma, 
compared to the general population (Wilton and Matteson 2017). Factors associated with this 
increased risk of cancer include use of immunosuppressive drugs used to treat RA. Patients with 
the highest levels of disease activity appear to be at greatest risk for malignancy. Therefore, RA 
patients with poorly controlled disease need to decide what, if any, therapeutic option they want 
to choose given the association of disease activity with an increased risk of cancer. 
16.9 
Assessment of Uncertainty 
There is uncertainty with respect to the relative safety of the SetPoint System versus alternative 
approved therapies, as well as its anticipated degree of efficacy. While the preclinical and limited 
clinical data are encouraging, there is a clear need to study and document clinically meaningful 
responses in a controlled trial with longer term follow-up.  
17 
STATISTICAL CONSIDERATIONS 
Two detailed Statistical Analysis Plans (SAP) will be prepared for the primary analysis through 
Week 12 and the open-label, long-term follow-up prior to a formal interim analysis at the end of 
Stage 1. Following is a description of the study sampling plan and a summary of the intended 
analyses. 
17.1 
Randomization 
After completing Day 0 assessments, all enrolled subjects will be assigned in a 1:1 ratio to either 
the treatment or the control group. The randomization will be stratified to help ensure balanced 
distribution between treatment groups of subjects with: inadequate response or loss of response 
to JAKi; inadequate response or loss of response to ≥4 biological DMARDs (bDMARDs) with ≥ 
2 mechanisms of action; and those with < 4 TCJ28 or < 4 SJC28 at Day 0. The randomization 
scheme will be generated by the study biostatisticians and implemented centrally through an IRT.  
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17.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the difference between treatment and control groups in the 
proportion of subjects achieving the ACR20 response at Week 12 from baseline on the day of 
informed consent. The primary efficacy analysis will be performed on the ITT population (see 
Section 17.8) using pooled data from Stage 1 and 2. 
The hypothesis of interest is: 
H0: pt - pc = 0 
H1: pt - pc > 0 
where pt is the response rate in the treatment group and pc is the response rate in the control group. 
The study will test the null hypothesis (H0) that there is no difference between the treatment and 
control groups in the proportion of subjects achieving ACR20 response at Week 12 from baseline 
on the day of informed consent versus the alternative hypothesis (H1) that treatment group 
response rate exceeds the control group response rate. The study will be considered successful if 
there is a statistically significant improvement in the proportion of subjects with ACR20 response 
in favor of the SetPoint System. 
The sample size is calculated based on an estimated 60% response rate in the treatment group and 
30% response rate in the control group. A sample size of 250 subjects, 125 in each group, offers 
96% power to detect a difference of 30% at the one-sided alpha of 0.025. If the true response rates 
are 50% in the treatment and 30% in the control group, the sample size of 250 subjects has 77% 
power to detect a difference of 20% at the one-sided alpha of 0.025. Additional power calculations 
for 250 subjects using estimated response rates of 20 to 40% in control and 35-70% in treatment 
are provided in Table 4. Table 4 also shows power if enrollment ends at 240 subjects. The 
decrease in power is <1% for all scenarios and most often <0.5%. 
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Table 4: Power Calculations for ACR Response Based on Pooled Data from Stage 1 and 2  
Control (%) 
 
Treatment (%) 
Difference (%) 
 
Power  
N = 250 
Power  
N=240 
20 
50 
30 
0.967 
0.966 
20 
45 
25 
0.917 
0.916 
20 
40 
20 
0.812 
0.807 
20 
35 
15 
0.609 
0.601 
 
 
 
 
 
30 
60 
30 
0.959 
0.959 
30 
55 
25 
0.900 
0.898 
30 
50 
20 
0.773 
0.770 
30 
45 
15 
0.555 
0.549 
 
 
 
 
 
40 
70 
30 
0.959 
0.958 
40 
65 
25 
0.897 
0.893 
40 
60 
20 
0.762 
0.750 
Power based upon 1,000,000 simulations per scenario. 
17.3 
Interim Analysis 
One formal interim analysis is planned at the end of Stage 1 when the approximately 60 
randomized subjects enrolled in Stage 1 have reached their Week 12 endpoints. The interim 
analysis will be performed on the Stage 1 ITT population. The purpose of this interim analysis is 
to check for safety risks and a lack of efficacy prior to enrolling subjects in Stage 2. No early 
success stopping may possibly occur. Therefore, there is no alpha-spending as there is no 
possibility for early claim. As these data contribute to the overall device experience for the safety 
review, and no early success stopping is permissible, no Type I error inflation occurs with such 
interims. 
The DMC and FDA will review the 12-week unblinded data from Stage 1, including 
demographics, efficacy, safety, enrollment rates, and device implantation rates, and determine 
whether the following stopping rule is met:  
• 
The difference between treatment and control in the proportion of subjects achieving the 
ACR20 response at Week 12 from baseline on the day of informed consent is less than 
10%. 
This stopping rule in 60 subjects balances the need to stop a trial with a projected low probability 
of success with a need to avoid prematurely stopping a potentially successful trial after Stage 1, 
given the decision is based on a dichotomous endpoint in a relatively small number of subjects.  
For illustrative purposes, Table 5 provides stopping probabilities for 60 subjects and their effect 
on power in 250 subjects, using an estimated ACR20 response rate of 30% in the control group 
and a range of 35-60% in the treatment group. The proposed stopping rule has a 50% probability 
of stopping a study having < 30% power to meet the primary efficacy objective in 250 subjects. 
Type 1 error is maintained at 2.5% even without the futility stop. The last column in the table 
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shows power if enrollment ends at 240 subjects. Again, the power decreases by < 1% in all 
scenarios. 
Table 5: True Probability of Stopping after Stage 1 and Power of Study Success Based on Pooled Data 
Control (%) 
 
Treatment (%) 
Probability of 
Stopping 
N = 60 (Stage 1) 
Power  
N = 250 (Stage 1 + 2) 
Power  
N = 240 (Stage 1 + 2) 
30 
60 
0.040 
0.959 
0.959 
30 
55 
0.089 
0.900 
0.898 
30 
50 
0.173 
0.773 
0.770 
30 
45 
0.293 
0.555 
0.549 
30 
40 
0.444 
0.291 
0.282 
30 
35 
0.608 
0.096 
0.093 
Conversely, with this stopping rule, there is 17% probability of stopping a study having 77% 
power to detect a 20% difference, highlighting the need for a balanced approach on stopping rules 
based on a dichotomous endpoint with just 60 subjects. 
Based on their review, the DMC will convey their decision to terminate the study if the stopping 
rule is triggered or continue to Stage 2 as planned to the Chief Executive Officer (CEO) of 
SetPoint Medical or a designee. In the event the stopping rule is triggered, the CEO or designee 
will notify the FDA about the DMC’s decision and the study will be terminated. The study will 
be unblinded, and all Stage 1 data analyzed. The sponsor will submit to the FDA a report with the 
DMC’s decision together with the datasets, programs and program outputs as well as any 
proposals for further clinical research. If the stopping rule is not triggered, the sponsor will initiate 
an IDE Supplement to the FDA to request initiation of Stage 2 enrollment, and providing the 
name and contact information of the independent statistician from whom the FDA will request 
the Interim Report containing unblinded data. The unblinded data will be provided directly to the 
FDA upon request, maintaining blinding of the sponsor. The study will advance to Stage 2 only 
after receiving approval from the FDA. 
The DMC will continuously monitor subject safety throughout Stages 1 and 2 and can stop the 
study anytime if serious safety concerns arise, as detailed in the DMC Charter. 
17.4 
Analysis of Key Secondary Endpoints  
To support potential device labeling claims, a subset of secondary endpoints will be identified 
and analyzed using appropriate methods for controlling for family-wise type-1 error rate (FWER). 
This will be detailed in the SAP that will be submitted to the agency prior to the formal interim 
analysis.  
Operating characteristics calculated by simulating 1,000,000 trials per scenario using chi-square test. 
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17.5 
Analysis of Exploratory Endpoints 
To gather additional efficacy data and long-term safety. 
17.6 
Analysis of Safety Measures 
The incidence of AEs and SAEs from informed consent to Week 264 will be tabulated. Each AE 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and presented 
based on the system organ class and preferred term. 
17.7 
Handling of Rescue Treatment 
Subjects that initiate a rescue treatment prior to Week 12 (see Section 14.5) will be imputed as 
non-responders in the analysis of primary and key secondary efficacy endpoints (e.g., no ACR20 
response, no DAS28-CRP good/moderate EULAR response, no DAS28-CRP response, and no 
HAQ-DI response). Additional, exploratory, subgroup analysis will be presented for subjects 
combining additional RA treatment with VNS during open-label follow-up (i.e., augmented 
therapy).  
17.8 
Analysis Populations 
The interim and primary efficacy analyses at Week 12 will be conducted on the intent-to-treat 
(ITT) population. Exploratory analyses will be performed on the ITT and per-treatment-evaluable 
(PTE) populations through Week 12 and on the open-label and cross-over PTE populations during 
the open-label, long-term follow-up. The safety will be evaluated on the safety population. All 
analysis populations are defined below:  
• ITT population.  All enrolled and randomized subjects in Stage 1 and 2. 
• PTE population.  Subjects from ITT population who received the assigned treatment 
through Week 12, have no major procedural protocol deviations (see Section 18.2.2), and 
for whom follow-up data through Week 12 are available. 
• 
Treatment to Open Label (TOL) population. Treatment subjects from ITT population who 
received active stimulation through Week 12, completed Week 12 assessments, continued to 
receive active stimulation during open-label follow-up, and for whom follow-up data are 
available. 
• 
Control to Open Label (COL) population. Control subjects from ITT population who 
received non-active (sham) stimulation through Week 12, switched to active stimulation 
after completing Week 12 assessments, continued to receive active stimulation during open-
label follow-up, and for whom follow-up data are available. 
• 
Safety population.  All enrolled subjects.  
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18 
STUDY MANAGEMENT 
18.1 
Ethical Considerations 
The rights, safety and well-being of subjects shall be protected in accordance with the ethical 
principles based in the Declaration of Helsinki and consistent with ISO14155, 21 CFR Parts 11, 
50, 54, 56, and 812 Good Clinical Practice, all IRB requirements and all applicable local laws and 
requirements. All parties are responsible for ethical conduct of the study in accordance with their 
respective roles in the investigation. The sponsor and the investigators shall avoid improper 
influence or inducement of the study subject, monitor, the clinical investigator(s) or other parties 
participating in or contributing to the clinical investigation.  
18.2 
Sponsor Responsibilities 
SetPoint Medical, as the study sponsor, has the overall responsibility for the conduct of the study 
and will ensure that the study is conducted under the guidance of ICH Good Clinical Practice 
(E6), Clinical investigation of medical devices for human subjects – Good clinical practice 
(BS EN ISO 14155) and other applicable local and federal (e.g., 21 CFR Parts 11, 50, 54, 56, and 
812) regulations, including the archiving of essential documents. A list of the names, locations, 
and chairpersons of all IRBs (including actions taken by each IRB on the protocol) that have been 
or will be asked to review the protocol will be kept on file. Qualified personnel who participate 
in the conduct of this clinical trial will be qualified by education and/or experience and trained to 
perform their tasks. The sponsor will maintain a list of names and addresses of all investigational 
sites at which the investigation will be conducted and central labs providing study-related services 
under a separate cover. The study will not use, in any capacity, the services of any person debarred 
under section 306 of the Federal Food, Drug, and Cosmetic Act in connection with this clinical 
study.  
 
Training 
Sponsor personnel or designee will provide all clinical investigators with training on use of the 
SetPoint System prior to their participation in the clinical study. 
The study staff involved will undergo site initiation and training related to their delegated 
responsibilities, which will include:  
• 
Clinical investigational protocol SPM-020 
• 
SetPoint System 
• 
Concomitant medication 
• 
Central laboratory procedures 
• 
Safety and AE reporting 
• 
Device deficiency reporting 
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• 
Compliance reporting 
• 
Investigator responsibilities (GCP) 
• 
Device accountability 
• 
Authorization process 
• 
EDC and IRT systems 
• 
Study binders 
• 
Monitoring 
New members of the investigation site team may be added from time to time at new or existing 
sites. New personnel should only start their assignment after receiving adequate training in the 
clinical investigation requirements and this training shall be documented. The names, initials, 
signatures, functions, and designated authorizations of new site personnel shall be documented. 
 
Protocol deviation 
All efforts should be made to avoid any protocol deviation. Any deviation from the requirements 
outlined in this protocol will be considered a protocol deviation. Protocol deviations will be 
categorized as major procedural if a study subject: 
• 
Undergoes any study-related procedure before signing an IRB-approved informed consent 
form, or 
• 
Receives study treatment not consistent with the treatment assignment, or  
• 
Is no longer eligible but received study treatment. 
A protocol deviation that may affect the scientific soundness of the protocol or the rights, safety, 
or welfare of the patients should be reported to the sponsor and the IRB as required. Other 
deviations are those that occur in direct association with a specific study patient. These include, 
but are not limited to, deviations from the informed consent process, inclusion/exclusion criteria, 
protocol-specified procedures and assessments, and investigational device handling and usage. 
All protocol deviations and their reasons will be reported promptly to the study sponsor and 
documented in the study database.  
The following information shall be provided promptly to the sponsor and as per IRB guidelines: 
requests for deviations, and reports of deviations, if the deviation affects subject's rights, safety 
and well-being, or the scientific integrity of the clinical investigation. Under emergency 
circumstances, deviations from the protocol to protect the rights, safety and well-being of human 
subjects may proceed without prior approval of the sponsor and the IRB. Such deviations shall be 
documented and reported to the sponsor and the IRB as required. Unavoidable protocol 
modifications may be required due to COVID-19 illness and/or COVID-19 control measures (see 
Section 19). Efforts will be made to minimize impacts of protocol deviations on study integrity. 
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Device deficiency 
Any device deficiency related to the identity, quality, durability, reliability, safety or performance 
of an investigational medical device, including device malfunctions, use errors, and inadequate 
labelling shall be documented throughout the clinical investigation, investigated by the study 
sponsor, and reported to appropriate regulatory bodies and IRB as applicable. Also, all device 
deficiencies that do not lead to an AE but could have led to a medical condition if either suitable 
action had not been taken, intervention had not been made, or circumstances had been less 
fortunate shall be reported. 
 
Data monitoring 
Study site monitoring will be performed by trained and qualified CRAs from the study sponsor 
and contract CRAs who will be trained and qualified by sponsor. Study sites will be visited 
regularly to ensure that the study is conducted in compliance with 21 CFR Parts 11, 50, 54, 56, 
812, ISO 14155, the study protocol and other applicable regulations. Study monitors will also 
ensure that the data reported in the EDC system is consistent with the information found in the 
subject’s medical records and source documents (source data verification). Monitoring will 
include assessment of the site’s overall progress, including, but not limited to, the site’s ability to 
keep accurate records and to report study related data, including AEs, to the study sponsor in a 
timely fashion. A detailed monitoring plan will be developed and maintained by the sponsor.  
 
Data Monitoring Committee 
The sponsor will appoint an independent DMC to ensure compliance and proper clinical study 
monitoring. The DMC will be responsible for safeguarding the interests of study subject, 
assessing the safety and efficacy of the interventions during the trial, and for ongoing monitoring 
of the overall conduct of the study. During Stage 1 enrollment, the DMC will meet after 
enrollment of 15, 30, 45, and 60 subjects. During Stage 2 enrollment, the DMC will meet once 
every 3 months. Following completion of Stage 2 enrollment, the DMC will meet once every 6 
months.  
The DMC will provide recommendations about stopping or continuing the study based on their 
ongoing review of cumulative safety and efficacy data and at the end of Stage 1 based on a formal 
interim analysis of the Week 12 safety and efficacy data (see Section 17.3).  
Early termination considerations will generally apply only to emerging safety issues of major 
concern, or problems with trial conduct that suggest the trial could not be completed successfully 
with a reliable conclusion in a feasible time frame. To contribute to enhancing the integrity of the 
trial, the DMC may also formulate recommendations relating to improving adherence to protocol-
specified regimens and retention of participants, and the procedure for data management and 
quality control. The responsibilities of the DMC are further detailed in the DMC Charter.  
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Data management responsibilities 
Data management will be performed by the study sponsor. 
EDC System 
A validated and 21 CFR Part 11 compliant EDC system will be used as the study database. The 
system will undergo validation to confirm study-specific configuration and user acceptance 
testing (UAT) prior to release. The validation, testing and release documentation will be 
maintained on file by the study sponsor. Data entry will be performed by site personnel after 
completing an appropriate training. Modifications to the EDC will be made if deemed necessary 
by the study sponsor. 
IRT System 
A validated and 21 CFR Part 11 compliant IRT system will be used for randomization. The IRT 
system will be integrated with the EDC system and undergo validation to confirm study-specific 
configuration and UAT testing prior to release. The validation, testing and release documentation 
for the IRT system will be maintained on file by the study sponsor. Data entry will be performed 
by site personnel after completing an appropriate training. Modifications to the IRT system will 
be made if deemed necessary by the study sponsor. 
Data cleaning 
The database will be subject to initial inspection for omitted data, gross data inconsistencies, and 
deviations. Any deficiencies or deviations will be reviewed, and any necessary action determined 
(e.g., data query, communication with the study center).  
Intermittent data review will be performed, and any discovered errors will be reported to the study 
site using the electronic query process (as necessary). The study site will be expected to review 
and complete the query. The data cleaning cycle will be repeated until all data are considered 
clean. 
Data back-up, confidentiality and security 
Incremental data back-up will be performed on a regular basis by the EDC system vendor. 
All media will be stored in a secure location. Passwords will be issued to appropriate personnel 
to ensure confidentiality and protection of data.  
 
Investigational device accountability 
Sponsor will provide an appropriate number of the investigational devices to the study sites free 
of charge. The sites maintain the investigational devices in a locked, secure location. Only clinical 
investigators participating in the study will have access to the investigational device. Dispensing 
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of investigational device will be documented by authorized personnel. Each batch of the 
investigational device will be assigned a serial/lot number for tracking purposes.  
Investigational devices received by the clinical site will be logged in by the site personnel on 
inventory logs and/or the EDC system. Final reconciliation will be completed at each site before 
or during site closure. Any unused inventory of the investigational device will be returned to the 
sponsor at the direction of the sponsor or at the close of the study. At the end of the study, overall 
study final device reconciliation will be completed internally by the sponsor. 
18.3 
Blinding 
In order to avoid introduction of bias and maintain integrity of the study data, blinding to the 
randomized treatment assignment at Day 0 will be maintained until all subjects enrolled in Stage 
1 and 2 have completed Week 12 assessments, and the study dataset has been locked for the 
primary efficacy analysis. The blinding rules for each role involved are set up a priori (i.e., 
before enrollment of the first subject) and are detailed in Table 6.  
18.4 
Unblinding 
After locking the study dataset for the primary efficacy analysis, which will occur after the last 
subject enrolled in Stage 2 completes Week 12 assessments, treatment assignments will be made 
available to Co-PI Rheumatologists (Table 6). The Co-PI Rheumatologists may inform subjects 
about the treatment they were assigned at Day 0.  
Before locking the study dataset for the primary efficacy analysis, unblinding of subjects and Co-
PI Rheumatologists can occur only in exceptional circumstances when knowledge of the actual 
treatment is absolutely essential for further management of the subject. Investigators must discuss 
with the sponsor’s Chief Medical Officer (CMO) if he/she believes that unblinding is necessary. 
The CMO will determine whether or not unblinding is necessary. The decision and rationale to 
unblind or continue to blind will be documented and presented for review by the DMC to ensure 
concurrence with the recommendation. Any concerns or questions raised by the DMC are to be 
addressed and documented. If unblinding is recommended and the DMC concurs, the CMO will 
authorize the Co-PI Rheumatologist’s access to the subject’s treatment assignment in IRT.  The 
Co-PI Rheumatologist should not reveal the subject’s treatment assignment to the sponsor, subject 
or anyone else on the study staff. Unblinding should not necessarily be a reason for study 
treatment discontinuation. 
Table 6: Blinding Matrix 
Role 
Blinded for 
duration of 
clinical study  
Unblinded once 
last enrolled 
subject completes 
Week 12 
Blinding 
assessment at 
Week 4 and 12 
Subject 
Y 
Y 
Y 
Investigational Sites Staff 
 
 
 
  Co-PI Rheumatologist 
Y 
Y 
Y 
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  Co-PI Surgeon 
Y 
Y 
N 
  Joint Evaluator 
Y 
Y 
Y 
  Clinical Research Coordinators & Site Staff 
Y 
Y 
N 
Sponsor 
 
 
 
  Sponsor’s Representatives, except Unblinded 
Technician(s) 
Y 
Y 
-- 
  Unblinded Technician(s)  ¥ 
N 
Y 
-- 
  Study Biostatisticians 
Y 
Y 
-- 
DMC 
 
 
 
  Independent Biostatistician § 
N 
Y 
-- 
  DMC Chairperson and Members 
N 
Y 
-- 
Abbreviations: DMC, data monitoring committee; No, no; PI, principal investigator; Y, yes; --, not applicable. 
 ¥ Independent from the clinical operations. Has access to a password-protected database with the randomization scheme to be 
able to register each implanted MicroRegulator to a particular set of stimulation rules based on the subject’s treatment 
assignment. 
§ Non-voting statistician reporting to DMC. Responsible for receiving blinded data exports, accessing randomization 
assignments, conducting unblinded analyses and preparing outputs for review during DMC closed sessions. 
 
18.5 
Investigator Responsibilities 
 
General responsibilities 
• 
Co-PI Rheumatologists and Co-PI Surgeons are responsible for ensuring that an 
investigation is conducted per the signed investigator statement (Investigator 
Agreement/Commitment), the study protocol, and applicable regulations for protecting the 
rights, safety, and welfare of study subjects under the investigator’s care and for the 
control of devices under investigation.  
• 
Co-PI Rheumatologist assures the accuracy, completeness, legibility and timeliness of the 
data reported to the sponsor in the study EDC and all required reports.  
• 
Co-PI Rheumatologist obtains informed consent of each patient to whom the treatment is 
administered in accordance with provisions of 21 CFR Part 50 and ISO14155. In addition, 
Co-PI Surgeon shall obtain written surgical informed consent, if required by their 
institution. 
• 
All Co-PIs are responsible for complying with all applicable IRB requirements under 
21 CFR Part 56 and ISO14155. 
• 
All Co-PIs are responsible for disclosure of financial obligations/conflict of interest to the 
sponsor in accordance with provisions of 21 CFR Part 54. 
• 
All Co-PIs shall be trained on their responsibilities under 21 CFR 11, 50, 54, 56, 812 and 
ISO14155. 
• 
To ensure proper execution of the study protocol, each Co-PI will identify a research 
coordinator for this study. Working with and under the oversight of the Co-PI, the research 
coordinator ensures that all study requirements are fulfilled.  
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• 
Each Co-PI will allow monitoring and auditing of their clinical investigation procedure(s) 
by the sponsor or designee. 
• 
Each Co-PI will ensure timely acquisition and delivery of source documentation and 
redacted medical records required for adjudication and reporting of AEs by sponsor. 
 
Disposition of the investigational study device 
Co-PIs shall administer the investigational device only to subjects under the Co-PI’s personal 
supervision. The Co-PIs shall not supply the investigational device to any person not authorized 
to receive it. Co-PIs or designees are required to maintain adequate records of the disposition of 
the investigational devices, including dates, quantity, and use by subjects. All unopened unused 
devices must be returned to the sponsor. 
 
Maintenance of study records 
Co-PIs are required to prepare and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each subject participating in the 
investigational plan (including information maintained electronically such as digital imaging) per 
21 CFR 812. The investigator will also maintain original source documents from which study-
related data are derived, which may include, but are not limited to: 
• 
Clinic progress notes recording patient’s medical history and medications 
• 
Medical charts with operative reports and condition of patient upon discharge 
• 
Medical records regarding AEs, and investigational device malfunctions and deficiencies, 
use errors (as applicable) including treatment and clinical outcome  
• 
Results of diagnostic examinations 
• 
Imaging records such as X-rays, MRI or CT scans and associated reports (hard copy and 
digital copy of images, as applicable/available) 
• 
Printouts of source data generated by technical equipment (e.g., ECG, X-ray, MRI) must 
be filed with the subject’s records 
• 
Notes of phone calls and/or correspondence indicating study center’s attempts to follow 
study patients at the required follow-up visits until their participation in the study is 
complete or terminated 
• 
Records relating to subject deaths (e.g., death certificate, autopsy report) 
Co-PIs shall retain records required to be maintained for a period of 2 years following the date a 
marketing application is approved for the device for the indication for which it is being 
investigated. If no application is to be filed, records shall be retained for 2 years after the 
investigation is discontinued. To avoid error, the study site should contact the study sponsor prior 
to the destruction of study records to ensure that they no longer need to be retained. In addition, 
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the sponsor should be contacted if a Co-PI plans to leave the study center, so that arrangements 
can be made for the handling or transfer of study subjects study records, or if the records are 
moved to be under the oversight of a different sponsor-approved investigator or to an off-site 
location.  
 
Required documents from study sites 
The study site will provide to sponsor the following documents: 
• 
CV for the participating Co-PI Rheumatologists and Co-PI Surgeons, as well as Sub-Is, as 
applicable 
• 
Current medical license for the participating Co-PIs and Sub-Is 
• 
Investigator agreement/commitment for the Co-PIs and Sub-Is 
• 
Financial disclosure form for the participating Co-PIs and Sub-Is  
• 
Protocol acknowledgement form for Co-PIs 
• 
IRB study approval letter  
• 
IRB approved ICF  
• 
Fully executed CTA  
The study site will initiate enrollment of subjects after providing to sponsor the above listed 
documentation for Co-PI Rheumatologist and Co-PI Surgeon, completing a site initiation visit, 
and receiving from sponsor a written authorization to begin enrollment. 
18.6 
Protection of Subject Confidentiality 
In all clinical studies, confidentiality of protected health information may be breached due to 
study-related activities beyond those of routine clinical care. This risk will be minimized by not 
collecting personally identifying information on CRFs or other study related documentation to be 
provided to the study sponsor. It is the sponsor’s policy to redact any subject’s personally 
identifying information from any documentation sent to the sponsor that inadvertently contains 
it. 
At all times throughout the clinical investigation, confidentiality will be observed by all parties 
involved. All data shall be secured against unauthorized access. Privacy and confidentiality of 
information about each subject shall be preserved in the reports and in any publication. Each 
subject participating in this study will be assigned a unique identifier. All database forms and 
source documents sent to the sponsor will be tracked, evaluated, and stored using only this unique 
identifier. 
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Co-PI Rheumatologists will maintain confidential study subject lists identifying all enrolled 
subjects. The Co-PI Rheumatologists bear responsibility for keeping these lists current and 
confidential. These lists will not be provided to the study sponsor. 
Monitors and auditors will have access to the study screening and enrollment logs and other 
personally identifying information of study subjects to ensure that data reported in the EDC 
corresponds to the person who signed the ICF and the information contained in the original source 
documents. Such personal identifying information may include, the subject’s name, address, date 
of birth, gender, race, and medical record number.  
The subject’s name, medical record number or address will not be recorded in the monitor’s visit 
report or the database. Demographic data that will be recorded include age, race, and gender.  
Any source documents copied for monitoring purposes by the sponsor will be identified by using 
the assigned subject’s unique identifier in an effort to protect subject confidentiality. All 
personally identifiable information will be redacted from source documents. 
18.7 
Study Suspension or Early Termination 
The study can be discontinued at the discretion of the DMC, Co-PIs or study sponsor for reasons 
including the following: 
• 
Occurrence of AE unknown to date in respect to their nature, severity, or duration, or the 
unexpected incidence of known AE; 
• 
Obtaining new scientific knowledge that shows that the study is no longer valid or 
necessary 
• 
Insufficient recruitment of subjects; 
• 
Investigational device presents an unreasonable and significant risk to subjects (the 
sponsor may terminate the study immediately); 
• 
Persistent non-compliance with the study protocol; 
• 
Persistent non-compliance with the applicable ethics committee or regulatory 
requirements; or 
• 
Sponsor decision to terminate the study. 
If the study is discontinued or suspended prematurely, the sponsor shall promptly inform all 
clinical investigators and study centers of the termination or suspension and the reason(s) for 
termination. IRB, regulatory authorities, and the subject’s physicians may also need to be 
informed, if deemed necessary. 
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18.8 
Site Closeout 
At the site close-out visit or before, the monitor ensures all outstanding study documents are 
reconciled, the Co-PI’s files are accurate and complete, reviews record retention requirements 
with the Co-PIs, makes a final accounting of all study supplies, and ensures that all applicable 
requirements are met for the study. Any specific observations and actions made at this visit shall 
be documented in the close-out visit report. 
18.9 
Quality Assurance and Supervision by Authorities 
All documents and data shall be produced and maintained in such a way to assure control of 
documents and data to protect the subject’s privacy as far as reasonably practicable. The sponsor 
and representatives of the FDA or other regulatory authorities are permitted to inspect the study 
documents (e.g., study protocol, CRFs, and original study-relevant medical records/files) as 
needed. All attempts will be made to preserve subject confidentiality. 
The study centers are subject to audit by study sponsor personnel or designee for protocol 
adherence, accuracy of CRFs and compliance with applicable regulations. The sponsor will 
communicate to the sites any patterns of non-compliance. The sponsor will work with the sites to 
determine any necessary corrective action, as applicable. The sponsor will continue to monitor 
sites until compliance has been secured. If the site continues to display non-compliance, more 
serious action may be taken by the sponsor. The study protocol, data-recording procedures, data 
handling and study reports are subject to an independent clinical Quality Assurance audit by 
sponsor, its designee, or health authorities. 
18.10 
IRB Approved ICF and Protection of Study Subjects 
An IRB must review and approve an ICF specific to this study. The sponsor will provide an 
example ICF. The site may modify this example ICF to meet specific requirements. However, the 
ICF must contain all of the elements required by sponsor and applicable regulations (21 CRF Part 
50 and BS EN ISO 14155 14155), which will be verified by sponsor. IRB approved ICF and 
renewed approvals as appropriate will be maintained by the site for the duration of the study. The 
original, signed and dated ICF for each subject should be maintained by the site for monitoring.  
Subjects will be informed both verbally and in writing using the ICF about the nature of the study, 
the anticipated risks and benefits involved and the discomfort to which they will be exposed. 
Subjects will be instructed about their right to discontinue their participation at any time without 
prejudice or jeopardy to future medical care. Each subject must sign the ICF prior to any screening 
procedures. A copy of the signed ICF will be provided to the subject. 
18.11 
IRB Approval 
An IRB approval of the study protocol and ICF is required prior to study commencement under 
21 CFR Part 56. Co-PI must also obtain renewal of IRB approvals throughout the duration of the 
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study. They are also responsible for fulfilling any conditions of approval imposed by the 
reviewing IRB, such as safety reporting. Co-PI will provide the study sponsor with copies of such 
approvals and reports. 
18.12 
Other Investigator Reports 
All Co-PIs are responsible for notifying the sponsor about the following within the specified 
timeline: 
Type of Notification 
Timeline 
Withdrawal of IRB approval 
Verbal report within 24 hours of becoming aware followed by a written 
report within 5 working days 
Informed consent not 
obtained 
Verbal or written report within 24 hours of becoming aware 
Notifications must identify subjects using the unique study identifier to protect subject’s 
confidentiality. 
18.13 
Final Clinical Study Report 
A final clinical study report (CSR) will be prepared by the study sponsor and provided to the FDA 
and reviewing IRBs, as needed.  
18.14 
Publication Policy 
At the completion of the study, an abstract reporting the results will be prepared and may be 
presented at scientific meeting(s). A manuscript may also be prepared for publication in a peer-
reviewed scientific journal. Co-authorship will be granted to the National Co-PIs and those site 
Co-PIs from the top enrolling sites. Consistent with “Recommendations for the Conduct, 
Reporting, and Publication of Scholarly Work in Medical Journals”, every author should meet the 
following for authorship: 
• 
Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; and 
• 
Drafting the work or revising it critically for important intellectual content; and 
• 
Final approval of the version to be published; and 
• 
Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
19 
COVID-19 CONTINGENCY MEASURES 
This section identifies contingency measures for the study procedures and various aspects of study 
management to address limitations to study site visits imposed by the COVID-19 pandemic in 
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accordance with “FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency” (March 2020, updated on September 21, 2020). 
19.1 
Study Procedures During COVID-19 
The implementation of contingency measures should be consistent with the protocol to the extent 
possible, and sponsor and clinical investigators should document the reason for any contingency 
measures implemented.  
• 
Informed consent and Screening.  The ICF may be sent to prospective subjects for review 
and discussed remotely via phone contact or virtual visit but it must be signed and dated 
during on-site visit prior to and on the same day as the protocol-required screening 
assessments to confirm initial eligibility and obtain baseline values (see Section 11.2.2).  
 
In the event that new information requires a subject be re-consented, the updated ICF may 
be sent to the subject electronically or via mail for review and discussed remotely via phone 
contact or virtual visit. The consent form can be signed, scanned and returned electronically 
to the site, returned by mail using a prepaid envelope provided by the site, or returned in 
person. 
 
COVID-19 screening procedures that may be mandated by the clinical sites do not need to 
be entered into EDC. If a potential subject tests positive for COVID-19, the subject is 
considered screen failure. This subject may be consented and screened following treatment 
and full recovery (see Section 11.2.2) 
• 
Follow-up through Week 12.  If COVID-19 restrictions or subject’s health status prevent 
the subject from attending a protocol-required on-site visit at Week 4 or 8, those visits can 
be conducted remotely (see sections below). Only one, not both, of those visits may occur 
remotely. The protocol-required Day 0 and Week 12 visits shall be conducted on-site to 
ensure in-person RA disease activity assessments needed for randomization and maintain 
data quality and integrity for the primary and key secondary efficacy endpoints. If a subject 
completes the Day 0 and Week 12 visits out of window because of COVID-19, this will be 
reported as a protocol deviation with COVID-19 as a reason. The data from these late visits 
can be leveraged based on scientifically based rationale and clinical judgement. 
• 
Follow-up after Week 12.  If COVID-19 restrictions or subject’s health status prevent the 
subject from attending any of the protocol-required on-site visits, those visits can be 
conducted remotely (see sections below). If a subject completes any of the visits out of 
window because of COVID-19, this will be reported as a protocol deviation with COVID-19 
as a reason. The data from these late visits can be leveraged based on scientifically based 
rationale and clinical judgement. 
• 
Remote RA disease activity assessments. The HAQ-DI, SGA and Subject’s pain 
questionnaires can be sent to the subject’s home and completed during a virtual visit with 
study staff. The subject will return the completed and initialed paper questionnaires using 
envelopes provided by the study site. The TJC28 and SJC28 can be conducted during the 
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same virtual visit. In this case, the Joint Evaluator will instruct the subject on how to 
perform a self-evaluation of each joint. The Joint Evaluator will complete the source 
document worksheet based on the subject’s self-assessment. The Joint Evaluator will 
complete the EGA based on the results of the joint assessment and interview of the subject 
conducted remotely via telemedicine. Blood collection for hsCRP will be set as missing if it 
cannot be performed either at subject’s home or designated facility using the study kits. The 
visit type will be recorded in the EDC. 
• 
Pregnancy test.  If the pregnancy test must be completed remotely, a test kit will be 
delivered to the subject’s home. Once completed, the subject is instructed to photograph the 
result and send it to the study staff. The photograph will be placed in the subject binder. 
• 
SF-36 and EQ-5D-5L and Subject Satisfaction Questionnaire.  The study staff can mail 
the paper questionnaires to the subject’s home for completion during a virtual study visit. 
The completed and initialed questionnaires can be returned to the site in person or using 
envelopes provided by the study site. The visit type will be recorded in the EDC. 
• 
Blood collection.  In the event the clinical site has COVID-19 provisions for offering home 
health services, blood collection for hsCRP, RF, ACPA, eGFR, CBC, hsCRP and 
inflammatory biomarkers may be performed at the subject’s home using the sponsor-
supplied sampling kits. Once collected, samples shall be prepared and shipped from the 
study site in accordance with the instruction manual from the central laboratory service 
provider. The blood collection for RF, ACPA, eGFR, CBC and hsCRP can be done at a 
local laboratory performing such tests routinely. The sites should inform the sponsor about 
such cases. If samples cannot be shipped to the central laboratory, analysis should be 
performed locally. The local analysis shall be documented as a protocol deviation due to 
COVID-19. Blood collection for inflammatory biomarker shall only be collected at the 
study site or at the subject’s home. If this cannot be done, a protocol deviation shall be 
reported for the missing assessment. 
• 
Post-surgical clearance.  Wound healing by the treating surgeon investigator or designee 
with special attention to wound infections can be completed during a virtual visit and 
documented on the corresponding source worksheet. 
• 
Blinding assessments.  The paper questionnaires can be sent to the subject, Joint Evaluator 
and Co-PI Rheumatologist’s homes and completed individually during a virtual visit with 
study staff. The completed and initialed questionnaires can be returned to the site in person 
or using envelopes provided by the study site. The visit type will be recorded in the EDC.  
• 
Reporting of any AEs, device deficiencies and change in concomitant medications can be 
completed during virtual visit and documented in the EDC.  
• 
Concomitant medication and background therapy.  The use and timing of vaccination 
and immunomodulatory therapies in relation to COVID-19 vaccination shall be 
administered in subjects per the ACR’s COVID-19 Vaccine Clinical Guidance Summary for 
Patients with Rheumatic and Musculoskeletal Diseases (March 4, 2021 or latest). 
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19.2 
Contingency Measures for Study Management 
• 
SIV training.  The required training (see Section 18.2.1) can be completed through web-
based self-training or in person through video conferencing. The training must be 
documented. 
• 
Data monitoring.  In the event an in-person study site visit is not permissible, CRAs will 
perform remote monitoring. Remote monitoring will include remote source data verification 
and collection of essential documents. Remote performance of source data verification will 
require the rheumatology site research coordinator to redact, scan and upload certified 
copies of source documents to a secure, cloud-based portal.  Redacted copies should be kept 
in the investigator's site master file with records of their communication to the monitor. 
Uploaded source documents will be accessed by site monitors for source verification with 
entries in EDC. Issues identified and their resolution will be tracked through annotations 
made in the same system. Discrepancies between source and EDC will be managed and 
documented through the EDC query resolution process. Once source data verification is 
complete, the CRA will securely destroy any copy made locally and provide a certificate of 
destruction to the trial site.  
• 
EMR.  Collection of essential documents may be completed using the same process. If local 
study site policies allow access to the site electronic medical record (EMR) system, the CRA 
should be provided with secure, read-only access, including all modules relevant for review. 
This access should be restricted to the records of only those patients who participate in the 
trial. A list of the monitors to whom remote access has been granted should be maintained. 
In order to prevent unauthorized access, access rights should be revoked once remote SDV 
tasks have been completed for the trial. The EMR system should have an audit trail and be 
able to log information on who accessed data and when. Remote access to the EMR should 
only be possible using a two-factor authentication. It should not be possible to make local 
copies of trial participants' health records. Users should be aware of the automatic creation 
of temporary files on their computer when reviewing trial participant data and should 
securely delete such files immediately after each source data verification session. Situations 
where CRAs were unable to access, or had delay monitoring of a clinical site shall be 
documented, including whether identification of deviations or GCP non-compliance was 
delayed due to postponed monitoring Findings and action items resulting from remote 
monitoring can be discussed with Co-PI and site coordinator via teleconference. Monitoring 
activities shall be documented per normal procedure. 
• 
Reporting of protocol deviations.  When a deviation is the result of a COVID-19 
limitation, the deviation report shall include the specific limitation imposed by COVID-19 
leading to the inability to comply with the protocol. 
• 
Investigational device dispensing and accountability.  Delivery of Energizer and/or 
Energizer charger from the study site to subject’s home is permitted. Items must be shipped 
in the original, sponsor-supplied packaging, and the site shall retain record of the shipment 
and its receipt with device accountability documentation. In the event a subject needs to 
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return Energizer and/or its charger, a sponsor-supplied return kit will be sent to the subject 
from the site with instructions and prepaid shipping. In all cases, requirements under FDA 
regulations for maintaining required investigational device storage conditions and 
investigational device accountability remain under rheumatology site. 
20 
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21 
APPENDICES 
Appendix A: Required Minimum Washout Period from Biologic and Targeted Synthetic DMARDs Prior to 
Implant Procedure  
Drug Generic (Brand) Name 
Dosing Interval & Route, If 
Several 
Minimum Washout Period Relative 
to Last Dose Administered (days) 
Abatacept (Orencia) 
Weekly SC 
14 
 
Monthly IV 
30 
Adalimumab (Humira) 
- 
21 
Anakinra (Kineret) 
- 
2 
Baricitinib (Olumiant) 
- 
2 
Certolizumab (Cimzia) 
Every 2 weeks 
21 
 
Every 4 weeks 
30 
Etanercept (Enbrel) 
- 
14 
Golimumab (Simponi) 
Every 4 weeks SQ 
30 
  
Every 8 weeks IV 
60 
Infliximab (Remicade) 
Every 4 weeks 
30 
 
Every 6 weeks 
40 
 
Every 8 weeks 
60 
Rituximab (Rituxan) 
- 
120 
Sarilumab (Kevzara) 
- 
28 
Tocilizumab (Actemra) 
IV 
30 
 
SC 
21 
Tofacitinib (Xeljanz XR) 
- 
2 
Upadacitinib (Rinvoq) 
- 
2 
Abbreviations: IV, intravenous; SC, subcutaneous. 
Sources: Goodman (2017), Kerrigan (2019), 3-5 x half-life per drug prescribing information. 
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Appendix B: FDA Drug Safety Communication (DSC) issued on 09/01/2021 about JAK inhibitor 
 
 
 
FDA requires warnings about increased risk of serious heart-related events, cancer, blood 
clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions 
Approved uses also being limited to certain patients 
 
This information is an update to the FDA Drug Safety Communication issued on February 4, 
2021.  FDA also previously communicated about the safety clinical trial with Xeljanz, Xeljanz 
XR (tofacitinib) in February 2019 and July 2019. 
 
X-XX-2021  FDA Drug Safety Communication   
 
What safety concern is FDA announcing? 
Based on a completed U.S. Food and Drug Administration (FDA) review of a large randomized 
safety clinical trial, we have concluded there is an increased risk of serious heart-related events 
such as heart attack or stroke, cancer, blood clots, and death with the arthritis and ulcerative 
colitis medicines Xeljanz and Xeljanz XR (tofacitinib).  This trial compared Xeljanz with 
another type of medicine used to treat arthritis called tumor necrosis factor (TNF) blockers in 
patients with rheumatoid arthritis.  The trial’s final results also showed an increased risk of blood 
clots and death with the lower dose of Xeljanz.  A prior DSC based upon earlier results from this 
trial, reported an increased risk of blood clots and death only seen at the higher dose. 
 
We are requiring new and updated warnings for two other arthritis medicines in the same drug 
class as Xeljanz, called Janus kinase (JAK) inhibitors, Olumiant (baricitinib) and Rinvoq 
(upadacitinib).  Olumiant and Rinvoq have not been studied in trials similar to the large safety 
clinical trial with Xeljanz, so the risks have not been adequately evaluated.  However, since they 
share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar 
risks as seen in the Xeljanz safety trial. 
 
Two other JAK inhibitors, Jakafi (ruxolitinib) and Inrebic (fedratinib), are not indicated for the 
treatment of arthritis and other inflammatory conditions and so are not a part of the updates being 
required to the prescribing information for Xeljanz, Xeljanz XR, Olumiant, and Rinvoq.  Jakafi 
and Inrebic are used to treat blood disorders and require different updates to their prescribing 
information.  If FDA becomes aware of any additional safety information or data that warrants 
updates to the prescribing information for these medicines, we may take further action and will 
alert the public. 
 
What is FDA doing? 
We are requiring revisions to the Boxed Warning, FDA’s most prominent warning, for 
Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to include information about the risks of serious 
heart-related events, cancer, blood clots, and death.  Recommendations for health care 
professionals will include consideration of the benefits and risks for the individual patient prior 
to initiating or continuing therapy.  In addition, to ensure the benefits of these three medicines 
outweigh the risks in patients who receive them, we are limiting all approved uses to certain 
patients who have not responded or cannot tolerate one or more TNF blockers.  Changes will 
also be made to several sections of the prescribing information and to the patient Medication 
Guide. 
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What are Xeljanz/Xeljanz XR, Olumiant, and Rinvoq and how can they help me? 
Xeljanz/Xeljanz XR, Olumiant, and Rinvoq are used to treat certain serious, chronic, and 
progressive inflammatory conditions.  Xeljanz was the first to be approved in 2012.  All three 
medicines are approved to be used alone or with other drugs to treat rheumatoid arthritis (RA), a 
condition in which the body attacks its own joints, causing pain, swelling, joint damage, and loss 
of function.  Xeljanz is also approved to treat psoriatic arthritis, a condition that causes joint pain 
and swelling; ulcerative colitis, which is a chronic, inflammatory disease affecting the colon; and 
polyarticular course juvenile idiopathic arthritis, a type of childhood arthritis.  Xeljanz/Xeljanz 
XR, Olumiant, and Rinvoq work by decreasing the activity of the immune system; an overactive 
immune system contributes to RA, psoriatic arthritis, ulcerative colitis, and polyarticular course 
juvenile idiopathic arthritis. 
 
What should patients do? 
Those taking Xeljanz/Xeljanz XR, Olumiant, or Rinvoq should tell your health care professional 
if you are a current or past smoker, or have had a heart attack, other heart problems, stroke, or 
blood clots in the past as these may put you at higher risk for serious problems with the 
medicines.  Patients starting these medicines should also tell your health care professional about 
these risk factors.  Seek emergency help right away if you have any symptoms that may signal a 
heart attack, stroke, or blood clot, including: 
o Discomfort in the center of your chest that lasts for more than a few minutes, or that 
goes away and comes back 
o Severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw 
o Unusual pain or discomfort in your arms, back, neck, jaw, or stomach 
o Shortness of breath with or without chest discomfort 
o Breaking out in a cold sweat 
o Nausea or vomiting 
o Feeling lightheaded 
o Weakness in one part or on one side of your body 
o Slurred speech 
o Drooping on one side of your mouth 
o Swelling of a leg or arm 
o Leg pain or tenderness, or red or discolored skin in the painful or swollen leg or arm 
 
Treatment with these medicines is associated with an increased risk of certain cancers including 
lymphoma and lung cancer, so inform your health care professional if you experience signs and 
symptoms such as swelling of lymph nodes in your neck, armpits, or groin; constantly feeling 
tired; fever; night sweats; persistent or worsening cough; difficulty breathing; hoarseness or 
wheezing; or unexplained weight loss.  Talk to your health care professional if you have any 
questions or concerns. 
 
What should health care professionals do? 
Health care professionals should consider the benefits and risks for the individual patient prior to 
initiating or continuing therapy with Xeljanz/Xeljanz XR, Olumiant, or Rinvoq.  This is 
particularly the case in patients who are current or past smokers, those with other cardiovascular 
risk factors, those who develop a malignancy, and those with a known malignancy other than a 
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successfully treated nonmelanoma skin cancer.  Reserve these medicines for patients who have 
had an inadequate response or intolerance to one or more TNF blockers.  Counsel patients about 
the benefits and risks of these medicines and advise them to seek emergency medical attention if 
they experience signs and symptoms of a heart attack, stroke, or blood clot. 
 
What did FDA find? 
When FDA first approved Xeljanz, we required the manufacturer, Pfizer, to conduct a safety 
clinical trial in patients with RA who were taking methotrexate to evaluate the risk of serious 
heart-related events, cancer, and infections.  The trial studied two doses of Xeljanz (5 mg twice 
daily, which is the approved dosage for RA, and a higher 10 mg twice daily dosage) in 
comparison to a TNF blocker also used to treat the condition.  Patients in the trial were required 
to be at least 50 years old and have at least one risk factor for heart disease.   
 
Our review of the final trial results showed a higher rate of serious heart-related events such as 
heart attack and stroke, cancer, blood clots, and death in patients treated with both doses of 
Xeljanz compared to those treated with TNF blockers.  Importantly, a higher rate of blood clots 
and death was seen with both doses of Xeljanz compared to TNF blockers, whereas previous 
interim results showed the risk only with the higher dose.  For cancers, a higher rate of 
lymphomas was observed in patients treated with Xeljanz compared to those treated with TNF 
blockers.  A higher rate of lung cancers was observed in current or past smokers treated with 
Xeljanz compared to those treated with TNF blockers.  Current or past smokers had an additional 
increased risk of overall cancers (See Data Summary). 
 
Other JAK inhibitors have not been studied in similar large safety clinical trials, so the risk with 
these medicines has not been evaluated.  However, since they share mechanisms of action with 
Xeljanz, FDA considers that these medicines may have similar risks as seen in the safety trial 
with Xeljanz. 
 
What is my risk? 
All medicines have side effects even when used correctly as prescribed, but in general the 
benefits of taking a medicine outweigh these risks.  It is important to know that people respond 
differently to all medicines depending on their health, other medicines they are taking, the 
diseases they have, genetic factors, and many other factors.  As a result, we cannot determine 
how likely it is that someone will experience these side effects when taking Xeljanz/Xeljanz XR, 
Olumiant, or Rinvoq.  
 
However, if you are a current or past smoker, or have had a heart attack, other heart problems, 
stroke, or blood clots in the past, you should tell your health care professional as these may put 
you at higher risk for serious problems with these medicines.   
 
How do I report side effects from Xeljanz, Olumiant, or Rinvoq? 
To help FDA track safety issues with medicines, we urge patients and health care professionals 
to report side effects involving Xeljanz/Xeljanz XR, Olumiant, Rinvoq, or other medicines to the 
FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the 
page. 
 
How can I get new safety information on medicines I’m prescribing or taking? 
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Cli nical I n vesti gati o nal Pr ot oc ol S P M -0 2 0 ( T he R E S E T -R A St u d y)  
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C O N FI D E N TI A L  
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Y o u c a n s i gn u p f or  e mail a lerts ab o ut D ru g S afety C o m m u ni catio n s o n medi ci nes or medi cal 
s pecialties of i nterest t o y o u. 
 
F a cts  ab o ut  Xelj anz/ Xe lj anz  XR (t o f aciti ni b), Ol u mi a nt ( b ar iciti ni b), an d  Ri nv o q 
( up a d ac iti ni b) 
 
•  T hese m e dici nes are p art of a cl ass calle d Ja n us ki nase (J A K ) i n hi bit ors a nd ar e us ed t o tre at 
certain seri o us, c hr o ni c , an d pr o gr essive i nfla m mat or y c o n d itio ns.  
•  All t hre e me d ici nes are a p pr ove d t o  be use d al one  or wit h ot her me dici nes t o treat 
r he umat oi d  art hritis.  Xe ljanz is also a p p r ove d t o treat ps oriatic art hritis, ulce rati ve co litis, 
an d p ol ya rticul ar c our se ju ve ni le i di opa t hic art hritis. 
•  T hese m e dici nes w or k by  decreasi ng t h e  acti vit y of t h e i m m une  sys tem. 
•  T hese m e dici nes are avai lab le t o be gi ve n orall y as i m m e diate-release t a b lets, e xte nde d-
release t a blets t hat release t he medi cine i nt o the b o d y o ve r ti me, a n d s oluti o n.  
•  C o m m o n si de eff ects of t hese me dici nes i nclu de  u p per res pira t or y tract i n fecti ons s uc h as t he 
co m m o n c ol d a n d s in us i nf ectio ns, br o nc hi tis, heada che, c o u g h, i ncrease d  c h olester ol l e vels, 
hi g h bl o o d p ressur e, i ncreased m us cle e nz y me leve ls, ras h, n a usea, diarr hea, ac ne,  c ol d s ores,  
an d s hi n gl es. 
 
A d d iti on a l I nf orm a ti on f o r  Pa tien ts  
 
•  F D A  is req ui rin g n e w a n d u p dated w arni n gs a b o ut a n i nc reased r isk o f serio us he art-relate d 
eve nt s suc h a s heart attac k  or str o ke , ca ncer , bl o o d c lot s, a n d death wit h t he  medi cine s 
X elja nz/ Xelja nz XR (t ofac iti ni b), Ol umia nt ( b a riciti ni b), an d R in v o q (u pa da citi ni b) us ed t o 
treat certai n seri ous i nf la m mat or y c o n diti ons i ncl u d i ng r he u ma t oi d art hritis (R A)  an d 
u lcerati ve co litis. 
•  We ar e al s o li miti n g t he use of t hese m e dici nes t o cer tain  patie nts w h o ar e not  treate d 
effecti vel y or w h o e xp erie nce se vere si de effects wit h an ot he r t y pe of me dicine  use d t o tre at 
seri ous i nf la m mat or y c o n diti ons calle d t u m o r necr osis fact or ( T N F) bl oc kers. 
•  If y o u are taki n g X elja nz/Xe lja nz X R, Olu m iant, or  Rin v o q, tell y o ur h ealt h care pr ofessi ona l 
if y o u are a cur re nt or past sm o ke r, or ha ve ha d a he art attack, ot he r heart pr o bl e ms, stro ke, 
or bl o o d c lot s i n t he past as t hese ma y p ut y o u at hig he r risk f or  serio us pr o bl e ms  with t he  
m e dici nes.   B ef or e startin g the se medi cine s, also tell y o ur h ea lt h care pr ofessi onal a b o u t 
t hese ris k factor s.   
•  S ee k e mer genc y he lp rig ht a wa y i f y o u ha ve a n y s y m pt o ms t hat may  si gnal a heart a ttac k, 
stro ke, o r bl o o d clot, i nc lu di n g:  
o  D isc omf o rt i n t h e ce nter of y o ur c hest t h at lasts for m o re t ha n a fe w mi n utes, or t h at 
g oes a w a y an d c o mes b a c k 
o  Se ve re tig ht ne ss, pain, p ressur e, or heavi ne ss in y o ur c he st, thr oa t, neck, or j a w 
o  Pai n or di sco m for t i n y o ur ar ms, back, ne ck, j a w, or sto m ac h 
o  S h or tne ss of breath w ith or w ith o ut  che st disco m for t 
o  Brea ki n g o u t i n a col d s weat 
o  Na us ea or v o mitin g  
o  Feeli n g l ig ht he ade d 
o  Wea k ne ss i n o ne part or o n o ne s ide  of y o ur b o d y 
o  Sl urr e d s peec h 
S eri al N u m b er: d 8 5 a c a 5 8- 2 4 9 5- 4 5 9 7- 9 7f a- a 9 7 2 9 5 3 0 4 5 1 0 a c c e s s e d b y M eli s s a E v a n g eli st a ( M E V A N G E LI S T A) o n T h u, 2 8 A u g 2 0 2 5 1 8: 1 8: 3 3 G M T.

Cli nical I n vesti gati o nal Pr ot oc ol S P M -0 2 0 ( T he R E S E T -R A St u d y)  
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C O N FI D E N TI A L  
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o  Dr o o pi n g o n o ne s ide of  y o ur m o ut h 
o  S we lli ng  of a le g or a r m 
o  Le g pa in or  ten de r ness, or red or d iscol or ed s ki n  i n t he painf ul or s w ol len l eg or a r m 
•  Als o i nf or m y o ur he alth care prof essio na ls if y o u ex pe rienc e sig ns a n d s y m pt o m s suc h a s: 
o  S welli n g of  ly m p h n o de s i n y o ur neck, a r m pits or gr oi n 
o  C o ns tan tl y feeli ng ti red 
o  F e ver 
o  Ni g ht s w eats 
o  Pe rsistent or w or seni n g c o u g h  
o  D ifficu lt y breat hi ng 
o  H o ar se ness or w h eezi n g 
o  U ne x pl aine d  weig ht l os s. 
•  R ea d  the p atie nt Me di catio n G ui de  eve ry t i me y o u receive a p rescript io n f or  Xelja nz/ Xelja nz 
X R,  Olu m iant, or R in v o q.  T he M e di catio n G ui de  will be u p dated w ith thi s new  or othe r 
i m por tant i n f or mati on  ab o u t y o u r me d ici ne.  It ex pl ains  the i m p or tant t hi n gs t ha t y o u need t o 
k n o w.  T hese i nclu de t he si de eff ects, wh at the m e dicine is us e d  for,  ho w  to  ta ke a n d st ore it 
pr o pe rly, a nd ot he r thi n g s t o watch o ut f or w he n y o u a re taki n g t he m e dicine . 
•  Tal k t o y o ur he alth care pr of essio na l if y o u ha ve an y q ue stio n s or c o ncer ns. 
•  T o  help  FD A  trac k  safety  iss ues wit h me dici nes, rep ort s i de effects fr om Xe ljanz,  Ol u mian t, 
Ri n v o q,  or ot he r me dici nes to t he  FD A  Med W atch pr o gr a m, usin g t he  inf or mati o n i n the  
" Co n tact F D A" b o x  at t h e bo tt om o f t his pa ge. 
•  Y o u c a n s i gn u p f or  e mail a lerts ab o ut D ru g S afet y C o m m u ni catio n s o n medi ci nes or 
me d ical s pecialties of i nterest t o yo u. 
 
A d d iti on a l I nf orm a ti on f o r He a lth  Care  Pr ofessi on a ls 
 
•  F D A is re q u iri ng n e w a n d u p da ted w arni n gs a b o ut a n i nc reased r isk o f major a d v erse 
cardi o v asc u lar e ve nts, mali g na nc y, thr o m b os is, a n d m o rtalit y wit h t he Ja nu s ki nase (J A K) 
in hi bi tor s Xeljanz,  Xe ljanz  XR (t o faciti ni b), O l u miant ( b a riciti ni b), an d R in v o q 
(u pa da citi nib) . 
•  R eser ve t h ese m e dicin es f or patie nts w h o  ha ve h a d  a n in a de qu ate r es po n se or int ol era nce t o 
o ne or m or e T N F bl oc kers. 
•  C o ns i der t he be nefits an d ris ks f or t h e i n di vi dual pa tient pr i or t o i nitiati ng  or c o nti nu i ng 
the r ap y w it h Xeljanz /Xe lja nz X R, Olu m ia nt, or Rin v o q, pa rticul arly i n pa tient s w h o are 
c urrent or p ast s m o ke rs, t h ose with ot he r cardi o va scul ar risk factor s, th os e wh o de ve lo p a  
mali g na nc y,  a n d t h ose with a k n o w n m alig na nc y ot he r t ha n a s uccessf ul l y treated 
n o n m ela no m a s ki n ca ncer . 
•  I nf or m p atient s a b o ut the s y m pt o m s of serio us c ardi o va sc ular eve nt s a n d t o see k e merg e nc y 
me d ical a tten ti on  if t h e y occ ur. 
•  E n c our a g e patie nts t o read  th e Me dicati o n G ui de  t he y receiv e wit h eac h  prescr i pti o n, w hic h 
e x plai ns t he  safet y ris ks an d p r ov i des ot her i m p ortan t i nf or mati on. 
•  T o  help  FD A  trac k  safety  iss ues wit h me dici nes, rep o rt ad ve rse eve nt s in v ol vi n g  
X elja nz/Xe lja nz X R, Olu m ia nt, Rin v o q,  or o t her me dici nes t o the F D A Me d Watc h  pr o gra m, 
us in g t he  inf or mati o n i n the " C o nt act Us" b o x at t he b ott o m of t his page. 
•  Y o u c a n s i gn u p f or  e mail a lerts ab o ut D ru g S afet y C o m m u ni catio n s o n medi ci nes or 
m e dical s p ecialties of i nterest t o yo u. 
S eri al N u m b er: d 8 5 a c a 5 8- 2 4 9 5- 4 5 9 7- 9 7f a- a 9 7 2 9 5 3 0 4 5 1 0 a c c e s s e d b y M eli s s a E v a n g eli st a ( M E V A N G E LI S T A) o n T h u, 2 8 A u g 2 0 2 5 1 8: 1 8: 3 3 G M T.

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Data Summary 
 
When FDA first approved Xeljanz (tofacitinib), we required the manufacturer, Pfizer, to conduct 
a randomized safety clinical trial in patients with rheumatoid arthritis (RA) who were taking 
methotrexate to evaluate the risk of cardiovascular events, malignancy, and infections.  It was a 
multicenter, randomized, open-label trial to evaluate two doses of Xeljanz (5 mg twice daily 
(N=1455), which is the approved dosage for RA, and a higher 10 mg twice daily dosage 
(N=1456)) in comparison to treatment with a tumor necrosis factor (TNF) blocker (N=1451).  
Patients in the trial were required to be 50 years of age or older and have at least one 
cardiovascular risk factor.  The co-primary endpoints were major adverse cardiovascular events 
(MACE), defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; 
and malignancy, excluding nonmelanoma skin cancer (NMSC).  The trial was designed to 
exclude a prespecified risk margin of 1.8 for the hazard ratio of combined Xeljanz regimens 
when compared to the TNF blocker control for each co-primary endpoint.  The median on-study 
follow-up time was 4 years. 
 
The mean age of the population was 61 years and the median age was 60 (range 50-88 years).  
Most patients were female (78 percent) and Caucasian (77 percent).  The noninferiority criterion 
was not met for the comparison of the combined Xeljanz regimens to TNF blockers for the 
endpoints of MACE and malignancies since the upper limit of the 95% confidence intervals (CI) 
for these hazard ratios exceeded the prespecified noninferiority criterion of 1.8.  For MACE, the 
estimated hazard ratio and 95% CI associated with the combined Xeljanz regimens relative to 
TNF blockers were 1.33 (0.91, 1.94).  For malignancies excluding NMSC, the estimated hazard 
ratio and 95% CI associated with the combined Xeljanz regimens relative to TNF blockers were 
1.48 (1.04, 2.09).   
 
There was an increased risk of death, MACE, malignancies, and thrombosis associated with both 
regimens of Xeljanz.  The data showed evidence of a dose-dependent increased risk for MACE, 
all-cause mortality, and thrombosis at both doses of Xeljanz when compared to treatment with 
TNF blockers.  Additionally, the data showed evidence of a non-dose-dependent increased risk 
for malignancy excluding NMSC at both doses of Xeljanz when compared to TNF blockers.  
Lymphomas and lung cancers were observed at a higher rate in patients treated at both doses of 
Xeljanz compared to those treated with TNF blockers.  In particular, a higher rate of lung cancers 
was observed in current or past smokers treated with Xeljanz.  Current or past smokers had an 
additional increased risk of overall cancers. 
 
Other JAK inhibitors have not been studied in similar large safety clinical trials, so the risk with 
these medicines has not been evaluated.  However, since they share mechanisms of action with 
Xeljanz, FDA considers that these medicines may have similar risks as seen in the safety clinical 
trial with Xeljanz. 
 
Related Information 
 
National Institute of Arthritis and Musculoskeletal and Skin Diseases: Rheumatoid Arthritis 
 
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National Institute of Arthritis and Musculoskeletal and Skin Diseases: Psoriatic Arthritis 
 
National Institute of Diabetes and Digestive and Kidney Diseases: Ulcerative Colitis 
 
Genetic and Rare Diseases Information Center: Polyarticular onset juvenile idiopathic arthritis 
 
National Heart, Lung, and Blood Institute: Heart Attack 
 
National Heart, Lung, and Blood Institute: Stroke 
 
National Heart, Lung, and Blood Institute: Venous Thromboembolism 
 
National Cancer Institute 
 
FDA: Information on Tumor Necrosis Factor (TNF) Blockers 
 
The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective   
  
Think It Through: Managing the Benefits and Risks of Medicines 
 
 
 
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