SetPoint System

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION Device Generic Name: Vagus nerve stimulator for rheumatoid arthritis Device Trade Name: SetPoint System Device Product Code: SFJ Applicant's Name and Address: SetPoint Medical 25101 Rye Canyon Loop Valencia, CA 91355 U.S.A. Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P240039 Date(s) of the FDA Notice of Approval: July 30, 2025 ### Breakthrough Device: Granted breakthrough device status on March 15, 2024, because the device (1) could provide for more effective treatment of moderate to severe rheumatoid arthritis, a life-threatening or irreversibly debilitating human disease, and (2A) represents breakthrough technology that (2C) offers significant advantages over existing approved or cleared alternatives, and (2D) device availability is in the best interest of patients. ## II. INDICATIONS FOR USE The SetPoint System is indicated for use in the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response, loss of response, or intolerance to one or more biological or targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs). ## III. CONTRAINDICATIONS There are certain situations in which the SetPoint System should not be used because the risk(s) are greater than the potential benefit(s). The SetPoint System should not be used: - • If the patient has had certain health procedures that would interfere with how the device works, for example, - ○ If they have had surgery to remove the vagus nerve (vagotomy). - ○ If they had their spleen removed (splenectomy). - • If the patient's doctor determines that it might not be safe for them to have the surgery, for example, - ○ If the patient has spine disease in their neck that makes it risky to place a breathing tube (intubate). - ○ If the patient cannot be safely given anesthesia for surgery. - • If the patient cannot safely use the SetPoint Charger, for example, - ○ If their neck is too large to wear SetPoint Charger. - ○ If they have a pacemaker or a defibrillator implanted. PMA P240039: FDA Summary of Safety and Effectiveness Data 1 of 52 {1} #### IV. **WARNINGS AND PRECAUTIONS** The warnings and precautions can be found in the SetPoint System labeling. #### V. **DEVICE DESCRIPTION** The SetPoint System includes: - The Implant (A) which is placed within a Pod (B) and implanted on the left vagus nerve in the neck (C) - A Charger (D) with Docking Station (F) - A Programmer (E)  Figure 1: SetPoint System and Components #### Implant and Pod  Figure 2: Implant The Implant is an integrated neurostimulation device. It is used to electrically stimulate the vagus nerve for 1 minute, once daily. It is about 1 in (2.5 cm) long and weighs about 0.1 oz (3 g). A surgeon implants it next to the vagus nerve on the left side of the neck. The Implant is placed inside a Pod, which is a flexible cover made of silicone. The Pod PMA P240039: FDA Summary of Safety and Effectiveness Data 2 of 52 {2} holds the Implant in place, such that the nerve is held in the Pod's groove, and the Pod is closed with a suture using the suture holes on either side of the Pod Opening.  Figure 3: Pod Charger  Figure 4: Charger The Charger is a device worn around the patient's neck. It is used for charging the Implant at home and for programming the Implant at the clinic. It is recommended to be worn once a week for about 10 minutes to charge the Implant. The Charger is about 24 in (61 cm) long and 1.5 in (3.8 cm) wide, when unlatched and laid flat, and weighs about 9 oz (270 g). The Charger does not have any buttons or switches, but it does have a light-emitting diode (LED) and a speaker. The Charger only comes in one size that is meant to fit most people, forming a circular ring about 21 in (53 cm) in circumference when latched. Before the implant procedure, it PMA P240039: FDA Summary of Safety and Effectiveness Data 3 of 52 {3} is necessary to perform a fit and tolerability test on the patient to make sure it fits comfortably around their neck and that the magnetic latch closes. ### Docking Station  **Figure 5: The Docking Station** The Docking Station is provided with the Charger. The Docking Station is for charging and storing the Charger. Only the Docking Station provided in the Carrying Case should be used to charge the Charger. The Docking Station is about 4.5 in (11.4 cm) wide, 3 in (7.6 cm) deep, and 2 in (5.0 cm) tall, and weighs about 10 oz (290 g). The Docking Station does not have any buttons or switches, but it does have an LED. The Docking Station has a cradle in which the Charger is placed, and a power cord that must be plugged into an electrical outlet.  **Figure 6: Carrying Case Inside Sealed Product Box** ### Programmer The Programmer is an app installed on an Apple iPad® that is only used by an authorized healthcare professional. It is used with the Charger to program the Implant or to turn off or resume stimulation, if necessary. Additionally, it gives healthcare professionals PMA P240039: FDA Summary of Safety and Effectiveness Data 4 of 52 {4} information about the use of the Implant and Charger, such as how many stimulation doses have been delivered or missed, and Implant battery charge levels. # Strength, Mode of Administration The SetPoint System automatically delivers stimulation once per day, for a duration of 1 minute. Strength of stimulation is titrated to the maximum strength tolerated, with a maximum allowed amplitude of 2500μA and pulse width of 250 μs equivalent to 6.05 μC/cm² charge density) at 10 Hz. # Patient Identification (ID) Card The Patient ID Card is included in the Implant packaging. The Patient ID Card is filled out and provided to the patient after the surgery, and before they leave the hospital. Additionally, the QR code on the card provides access to critical information regarding the Implant, which is necessary to ensure that any diagnostic procedures and other medical treatments are compatible with the SetPoint System. The Patient ID Card identifies the Implant and Pod as magnetic resonance (MR) conditional, which means the Implant and Pod were demonstrated to be safe in the MR environment within defined conditions, including conditions for the static magnetic field, the time-varying gradient magnetic fields, and the radiofrequency fields. Patients are instructed by their surgeon to always have their Patient ID card on hand to present to healthcare professionals (such as physicians, dentists, imaging technicians (e.g., MRI, X-ray), estheticians, or beauty-care specialists), before pursuing any additional medical imaging or treatments, and during security screenings, such as at airports. Neglecting to inform these professionals about the Implant may result in injury to the patient, cause harm to the SetPoint System, and/or may lead to complications with the procedure or treatment. If the patient changes doctors, or loses their card, they should contact SetPoint Medical for a replacement card. # Therapy Parameters Card The SetPoint System provides stimulation to the patient for one minute each day, occurring at the same time each day. Although patients may be safely scanned using MRI anywhere in the body two weeks after implantation, MRI scans must never overlap with the time of stimulation of the implant, even after this two-week post-implantation window. To avoid this, patients are provided with a Therapy Parameters Card that documents the time of stimulation for their device and instructed to always present this card to healthcare professionals prior to scheduling an MR procedure. The card instructs healthcare providers to schedule MRI imaging such that the MRI will not occur within ±1 hour from the time documented on the patient's Therapy Parameters Card. However, if the implant is suspended or expired, this restriction is unnecessary. # VI. ALTERNATIVE PRACTICE AND PROCEDURES Currently, there are no FDA approved devices marketed for the treatment of RA. There are multiple approved pharmaceutical alternatives for the treatment of RA. Standard of care treatment options (SOC) for patients with moderate to severe RA include several FDA approved disease-modifying anti-rheumatic drugs (DMARDs) such as conventional synthetic DMARDs (csDMARDs), biological DMARDs (bDMARDs), and target synthetic DMARDs (tsDMARDs), which include Janus Kinase inhibitors (JAKi) (see Table 1).¹ Each alternative has its own advantages and disadvantages. A patient PMA P240039: FDA Summary of Safety and Effectiveness Data 5 of 52 {5} should fully discuss these alternatives with his/her physician to select the treatment that best meets their expectations and lifestyle. **Table 1: Disease-Modifying Anti-Rheumatic Drugs (DMARDs) for Rheumatoid Arthritis** | Category | Use of DMARD | Examples | | --- | --- | --- | | conventional-synthetic DMARD (csDMARD) | Typically, the initial DMARD prescribed. Only DMARD that may be used in combination with another DMARD. Typically taken orally or subcutaneously. | methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine | | biological DMARD (bDMARD) | Used after an inadequate response or intolerance to a csDMARD. Administered by subcutaneous injection (Sub-Q) or intravenous infusion (IV). | TNF inhibitors (e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab pegol), T-cell costimulatory inhibitor (abatacept), IL-6 receptor inhibitors (tocilizumab, sarilumab), anti-CD20 antibody (rituximab) and approved bio similar bDMARDs | | targeted-synthetic DMARD (tsDMARD) | Used after inadequate or intolerant response to one or more bDMARDs (referred to as bDMARD-IR). Most recently approved drug class for RA. Taken by oral administration. | tofacitinib, baricitinib, upadacitinib (collectively referred to as JAK inhibitors) | ## VII. MARKETING HISTORY The SetPoint System has not been marketed in the United States or any foreign country. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications, side effects) associated with the use of the device: ### Implantation and Explantation Surgery Potential risks with surgical placement or removal of the Implant and Pod, as well as other devices that stimulate the left vagus nerve, include: - • Complications related to general anesthesia with intubation. - • Damage such as stretching, pinching or cutting of the vagus nerve. The most common symptoms are caused by an injury to a branch of the vagus nerve that innervates a muscle in the throat, resulting in hoarseness or other voice change, or a change in breathing or swallowing. If the vagus nerve is damaged during surgery, unilateral vocal cord dysfunction (paresis) or paralysis may occur. Swallowing difficulties can lead to aspiration and pneumonia. Recovery of vocal cord function may require voice therapy and/or vocal cord augmentation filler injections in order to accelerate return to normal functioning. While these symptoms typically resolve over time (weeks to months), in rare cases, they can be permanent. - • Damage due to compression of the cervical sympathetic chain that goes to the left eye can result in Horner's Syndrome, a contracted (smaller) pupil (miosis), a droopy upper eyelid (ptosis), and/or inability to sweat on the left side of the face (anhidrosis). - • Damage to other muscles, nerves, blood vessels or tissues around the surgical area. - • Excessive bleeding or stroke due to blood vessel injury or blockage. - • Postoperative pain, redness, soreness, inflammation, fluid build-up under the skin, PMA P240039: FDA Summary of Safety and Effectiveness Data 6 of 52 {6} itching or swelling at the implant site. - Scarring or infection of tissue around the area of device placement or removal. Infections can usually be treated with antibiotics but may require that the device be surgically removed. - Belching (eructation), constipation, vomiting or gagging. - Removal of the Implant and Pod is associated with a higher occurrence of the risks above because of possible scarring around the Implant. There is also the possibility that surgical removal is attempted, but during the procedure, the surgeon decides the Implant and Pod cannot safely be removed. ### **Stimulation** Common side effects reported for the SetPoint System and other similar devices that stimulate the vagus nerve to treat different diseases are: - Coughing - Neck or facial pain - Hoarseness or other voice disturbances (dysphonia) - Shortness of breath (dyspnea) - Throat pain, a burning sensation, or inflammation of the back of the throat (pharyngitis) - Swallowing difficulties (dysphagia) that could lead to aspiration. - Tingling, prickling or numbness sensations near the implant site (paresthesias) - Nausea and indigestion - Constipation - Belching (eructation) - Flu-like symptoms - Dizziness These symptoms may occur during the time the Implant is delivering electrical stimulation. However, these symptoms may not occur in people who are less sensitive to stimulation than others. ### **Uncommon Side Effects Include:** - Worsening of pre-existing pulmonary diseases, such as asthma and chronic obstructive pulmonary disease - The Implant may move slightly from its original location, and this might cause damage to the vagus nerve, other nerves, blood vessels, or other surrounding tissue in the body - The Implant, or any of its parts, can break, in which case the stimulation may not be delivered correctly - Worsening or new onset of sleep apnea - Change in heart rate or rhythm (the heart may beat too fast, too slowly, too early, or irregularly) - Headaches - Flushing - Vomiting - Gagging PMA P240039: FDA Summary of Safety and Effectiveness Data 7 of 52 {7} - Weight change (loss or gain) - A decrease in blood pressure that could result in fainting (syncope) - Sleep disturbance - Dental pain - Dysgeusia For the specific adverse events that occurred in the clinical studies, please see Section X below. # IX. SUMMARY OF NONCLINICAL STUDIES # A. Laboratory Studies # Implantable Components (Implant and Pod) Key testing on the Implantable Components of the SetPoint System, the Implant and Pod, is summarized in Table 2, including the test, purpose, acceptance criteria, and results for each test. Table 2: Implantable Components Testing Summary | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Software / Firmware Verification and Validation Testing | To verify that software and firmware meet user needs and perform as intended, in accordance with the FDA guidance, “Content of Premarket Submissions for Device Software Functions,” issued on June 14, 2023, and demonstrate compliance to the ANSI/AAMI/IEC 62304:2006 Medical device software - Software life-cycle processes industry standard. | The software system shall meet the SetPoint System requirements and function as intended. | PASS | | Cybersecurity Testing | To verify that the SetPoint System complies with cybersecurity controls in accordance with FDA’s cybersecurity guidance, “Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions.” | The software system prevents unauthorized access, modification, misuse or denial of use of a medical device, or the unauthorized use of information that is stored, accessed, or transferred from a medical device to an external recipient. | PASS | | Engineering/ Bench Testing | To verify accuracy of device output specifications for stimulation parameters, battery life and communication with the external components. | The Implantable Components meet all the identified operational requirements. | PASS | | Mechanical Testing | To verify that the SetPoint System meets appropriate standards for mechanical shock, vibration and environmental conditions of temperature and pressure. | The SetPoint System shall meet the mechanical safety requirements identified in ISO 14708-1. | PASS | PMA P240039: FDA Summary of Safety and Effectiveness Data 8 of 52 {8} | Electrical Safety and EMC Testing | To verify that the SetPoint System meets appropriate standards for electrical safety. | The SetPoint System shall meet the electrical safety and EMC requirements identified in ISO 14708-3. | PASS | | --- | --- | --- | --- | | Thermal Testing | To verify the thermal safety of the Implantable Components of the System. | The SetPoint System shall meet the thermal safety requirements identified in ISO 14708-3. | PASS | | Sterilization Testing | To demonstrate that the process complies with ISO 11135:2014/ AMD 1: 2018 and meets acceptance criteria. | The sterilization process shall provide a minimum sterility assurance level (SAL) of 10^{-6}. | PASS | | Packaging and Shelf-Life Verification Testing | To verify the integrity of the primary and secondary packaging per ISO 11607-1:2019 as directed by ISO 14708-1. To validate the labeled shelf-life of 12 months. | The packaging of the Implantable Components shall meet the requirements of ISO 11607-1 and ISO 14708-1. | PASS | | Ultrasound Compatibility Testing | To verify the implantable components can withstand exposures typical during a diagnostic ultrasound examination. | The implantable components pass visual and functional testing after exposure to diagnostic levels of ultrasound energy. | PASS | | MRI Compatibility Testing | To verify the MRI compatibility of the implantable components in the MRI environment. | The implantable components (Implant and Pod) are considered MRI conditional (1.5 T- 3.0 T) for its intended use. | PASS | ### External Components (Charger and Docking Station) Key testing on the External Components of the SetPoint System, the Charger and Docking Station, is summarized in **Table 3**, including the test, purpose, acceptance criteria, and results for each test. **Table 3: External Components Testing Summary** | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Software / Firmware Verification and Validation Testing | To verify that software and firmware meets user needs and performs as intended, in accordance with the FDA guidance titled 'Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices' and demonstrate compliance to the ANSI/AAMI/IEC 62304:2006 Medical device software - Software life cycle processes industry standard. | The software system shall meet the SetPoint System requirements and function as intended. | PASS | | Cybersecurity Testing | To verify that the SetPoint System complies with cybersecurity controls in accordance with FDA's cybersecurity guidance, 'Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions.' | The software system prevents unauthorized access, modification, misuse or denial of use of a medical device, or | PASS | PMA P240039: FDA Summary of Safety and Effectiveness Data 9 of 52 {9} | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | | | the unauthorized use of information that is stored, accessed, or transferred from a medical device to an external recipient. | | | Engineering/ Bench Testing | To verify accuracy of device operations, battery life, and communication with the implantable components. | The external components meet all the identified operational requirements. | PASS | | Mechanical Testing | To verify that the SetPoint System meets appropriate standards for mechanical shock, vibration and environmental conditions of temperature and pressure. | The external components of the SetPoint System shall meet the mechanical safety requirements identified for basic safety and use in the home healthcare environment in IEC 60601-1 and IEC 60601-1-11. | PASS | | Electrical Safety and EMC Testing | To verify that the SetPoint System meets appropriate standards for electrical safety. | The SetPoint System shall meet the electrical safety and EMC requirements identified in IEC 60601-1. | PASS | | Thermal Testing | To verify the thermal safety of the external components of the SetPoint System. | The SetPoint System shall meet the thermal safety requirements identified for basic safety in IEC 60601-1. | PASS | | Packaging Testing | To verify the integrity of the primary and secondary packaging when exposed to shipping exposures. | The packaging of the external components shall meet the requirements of ASTM D4169-22 and associated standards for performance testing of shipping containers. | PASS | | Federal Communication Commission (FCC) Testing | To verify the safety of Radiofrequency (RF) electromagnetic radiation exposure driven by 47 CFR 2.1093. | The Specific Absorption Rate (SAR) values do not exceed the limits for local or whole body SAR per FCC regulations. | PASS | PMA P240039: FDA Summary of Safety and Effectiveness Data 10 of 52 {10} ## B. Biocompatibility Biocompatibility testing was performed for the patient-contacting components of the SetPoint System (i.e., the implant and pod) in accordance with ISO 10993-1 and the FDA Guidance Document, “Use of International Standard ISO 10993-1, “Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process” and in compliance with Good Laboratory Practices (GLP), 21 CFR Part 58. The biocompatibility endpoints listed in Table 4 were assessed. The results of testing demonstrate that the components of the SetPoint System are biocompatible for its intended use. Table 4: Summary of Biocompatibility Testing | Biological Effect (Applicable Standard) | Test Method | Results | | --- | --- | --- | | **Long-Term, Intact Skin Contacting Component: Charger** | | | | Cytotoxicity (ISO 10993-5) | MEM Elution | Non-cytotoxic | | Irritation, Intracutaneous Reactivity (ISO 10993-23) | Intracutaneous Reactivity Test | Non-irritant | | Sensitization, Maximization Sensitization (ISO 10993-10) | Guinea Pig Maximization Sensitization Test | Non-sensitizing | | **Permanent, Long-Term (>30 days) Components in Contact with Neural Tissue/Bone: Implant and Pod** | | | | Cytotoxicity (ISO 10993-5) | MEM Elution | Non-cytotoxic | | Irritation, Intracutaneous Reactivity (ISO 10993-23) | Intracutaneous Reactivity Test | Non-irritant | | Sensitization, Maximization Sensitization (ISO 10993-10) | Guinea Pig Maximization Sensitization Test | Non-sensitizing | | Systemic Toxicity (Acute (ISO 10993-11) | Acute Systemic Injection | No acute systemic toxicity | | Systemic Toxicity (Subacute, Subchronic, Chronic (ISO 10993-11) | Chronic Animal Study | Acceptable systemic toxicity risks | | | Analytical Chemical Characterization and Toxicological Risk Assessment | | | Materials Mediated Rabbit Pyrogenicity (ISO 10993-11) | Materials-Mediated Rabbit Pyrogen Test | Non-pyrogenic | | Genotoxicity (ISO 10993-3 and ISO 10993-33) | Bacterial Reverse Mutagenicity Test | Non-genotoxic | | | In Vitro Mouse Lymphoma Assay with Extended Treatment | | PMA P240039: FDA Summary of Safety and Effectiveness Data 11 of 52 {11} | Biological Effect (Applicable Standard) | Test Method | Results | | --- | --- | --- | | Local Effects after Implantation (ISO 10993-6) | Twelve canines with equal number of each sex were implanted with the device on the left vagus nerve, with sham procedures completed on the right vagus nerve. After 14 days of healing, the Implant was stimulated with the animals survived as follows: · Cohort 1 (N=6): Day 15-Day 42 · Cohort 2 (N=6): Day 15-Day 180 Pathological assessment and the changes noted on histological examination did not generate concerns for tissue safety; findings were attributed to the presence of a device around the implanted nerve for the in-life duration and were considered to be non-significant compared to sham control. Devices were then put in standby mode, perform device explants and necropsies. | Acceptable implantation risks | | Carcinogenicity (ISO 10993-3) | Analytical Chemical Characterization and Toxicological Risk Assessment | Non-carcinogenic | ### C. Human Factors and Usability Surgeon, Prescriber, and Patient usability studies were conducted per IEC 62366-1, Medical devices – Part 1: Application of usability engineering to medical devices, FDA guidance document, “Applying Human Factors and Usability Engineering to Medical Devices,” issued on February 3, 2016. Usability testing was conducted to evaluate whether three user groups - Surgeons (N=15), Prescribers (N=16), and Patients (N=16) - can safely and effectively perform all critical tasks associated with their respective use of the SetPoint System. Additionally, the studies were conducted to confirm that use-related risks associated with Surgeon, Prescriber, and Patient use of the SetPoint System were appropriately captured and assessed in the Use-Related Risk Analysis, and to uncover any unforeseen use errors. The testing was designed to test the unique aspects of the device for usability, not standard practice tasks and standard-of-care medical care tasks performed in the same manner regardless of the surgical procedure or specific VNS manufacturer. Usability testing was completed successfully in simulated intended use environments for the Surgeon, Prescriber, and Patient user groups. Based on both objective and subjective input across the Surgeon, Prescriber, and Patient usability validation studies, use-related risks have been eliminated or have residual risk that is considered acceptable. Use-related risks associated with use of the SetPoint System were appropriately captured in the Use-Related Risk Analysis and no previously unforeseen use errors were uncovered in the study. As the final device design was evaluated in usability testing but not in subjects enrolled in the pivotal study, SetPoint Medical is required per Conditions of Approval to provide real-world PMA P240039: FDA Summary of Safety and Effectiveness Data 12 of 52 {12} data via a Post-Approval Study (“SetPoint System Safety and Performance Post-Approval Study”). The study is intended to further support a reasonable assurance that the final finished SetPoint System, with its approved labeling, is safe when used as intended. Per the Conditions of Approval, SetPoint Medical will also provide information to FDA regarding the non-clinical training and training materials for the SetPoint System, including materials provided to surgeons and supporting surgical/operative staff, prescribers and patients. On-site SetPoint Medical representatives will be present for each surgeon’s first five implantation procedures. Specifically, the conditions require SetPoint Medical to submit: A. The training and training material provided to: i. The on-site SetPoint Medical representatives that will be present for each surgeon’s first five (5) implantation procedures; ii. Surgeons and supporting surgical/operative staff; iii. Patients and prescribers regarding charging procedures and identifying when the device is functioning properly; B. If any involved person is trained without any written materials, a description of the manner in which this training will occur in a real-world context. C. Documentation of training that includes the date, purpose, method(s), and the name, professional experience and qualifications of SPM representatives and surgical attendees, and performance (e.g., Pass/Fail, Complete/Incomplete) of surgical attendees. # D. Animal Studies SetPoint performed a GLP animal study to confirm device readiness for first clinical use. In addition, two other GLP animal studies were conducted to assess the performance of different stimulation configurations and evaluate the local tissue responses following electrocautery. # Animal study to support the first clinical use This preclinical study was conducted in 16 canines over a 6-month period. The primary objective of this study was to evaluate the safety of the SetPoint System in a chronic canine model. The secondary objective was to evaluate the safety of explanting the device in a chronic canine model. See Table 5 below. Table 5: GLP Preclinical Study (111-20) of the Device Design, Conducted to Support First Clinical Use | Study # | Animal Model (N) | Stimulation Parameters Evaluated | Study Duration* | Summary of Goals | Key Findings | | --- | --- | --- | --- | --- | --- | | Study 111-20 | Canines (N=16) | Output current based on OCE (output current escalation) procedure; Pulse width; Pulse frequency | Cohort A: 4 weeks; Cohort B: 12 weeks; Cohort C: 24 weeks; | • Evaluate the safety of the System in a chronic canine model; and • Evaluate the safety of the surgical explant procedure | • This study successfully evaluated the safety of the SetPoint System and the safety of explanting the Implant in a chronic canine model. • There were no adverse events, abnormal gross | PMA P240039: FDA Summary of Safety and Effectiveness Data 13 of 52 {13} | Study # | Animal Model (N) | Stimulation Parameters Evaluated | Study Duration* | Summary of Goals | Key Findings | | --- | --- | --- | --- | --- | --- | | | | | Cohort D: 12 weeks** | | pathology, arrhythmias, or histopathological adverse reactions attributed to the device or stimulation of the vagus nerve. | * Day 0 = First day of stimulation, after approximately 2 weeks of healing following the implantation procedure. ** After 6 weeks of active stimulation, the animals underwent a survival explantation procedure. Per protocol, animals in Cohort D were to be survived for a minimum of 4 additional weeks of post-explant healing. The animals were survived for 5 additional weeks of post-explant healing and then euthanized. This study successfully evaluated the safety of the SetPoint System and the safety of explanting the Implant in a chronic model. There were no adverse events, abnormal gross pathology, arrhythmias, or histopathological adverse reactions attributed to the test article. ### Animal study to assess the performance of stimulation This acute GLP canine study was to compare the neurophysiological and cardiac effects of vagus nerve stimulation via the Pod-secured Implant by measuring evoked compound action potentials in the vagus nerve distally, laryngeal muscle activation, and heart rate. Three canines, two females and one male, were included in the study. Results of this study supported the insulation effect of the Pod and demonstrated that switching polarity of stimulation between two electrodes did not affect the nerve activation. ### Animal study to evaluate electrocautery This GLP animal study assessed the performance and local tissue response to the Implant following exposure to electrocautery in 8 healthy canines. Four (2 males and 2 females) were treated with monopolar electrocautery (30 W, 3 times, at 1 cm from the implant) and the other four animals were treated with bipolar electrocautery (25 W, 3 times for 0.5 to 1 second at approximately 1 cm from the implant). Animals were euthanized for histology at 42 days post implantation. Compared to animals with implantation but without electrocautery, more severe fibrosis and neovascularization in the perineural connective tissue were observed. No significant findings were noted involving the nerve fiber other than slightly higher loss of axonal density. Based on the animal testing result that showed more substantial fibrosis and neovascularization in the perineural connective tissue when electrocautery was used within 1 cm of the implant and nerve, the device labeling indicates a minimum allowable distance of 2 cm between electrocautery and the implant to mitigate the risk of damage to both the implant and the nerve. ### X. SUMMARY OF PRIMARY CLINICAL STUDIES A total of two clinical studies were conducted to assess the safety, feasibility, and efficacy of the SetPoint System, an implantable vagus nerve stimulation (VNS) device for patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response, loss of response, or intolerance to one or more biological or targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs). Data from these clinical studies were the basis for the PMA approval decision. The Feasibility Clinical Study (SPM-008/SPM-011) was a first-in-human clinical study with the SetPoint System. In SPM-008, 14 patients with highly drug refractory RA were PMA P240039: FDA Summary of Safety and Effectiveness Data 14 of 52 {14} implanted with the SetPoint System (IDE G170231). SPM-008 was a randomized, blinded, sham-controlled clinical study and was conducted at four sites in the U.S. Patient selection for this study was limited to patients who had insufficient responses to at least two biological and/or targeted synthetic (JAKi) disease modifying antirheumatic drugs (bDMARD; tsDMARD), with multiple mechanisms of action (See Table 6 – Key Patient Selection Criteria, below), for whom there were limited or no other therapeutics options. Additionally, SetPoint performed a clinical study in the U.S. under IDE # G170231 to establish a reasonable assurance of safety and effectiveness of the SetPoint System for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response, loss of response, or intolerance to one or more biological or targeted synthetic disease modifying antirheumatic drugs (b/tsDMARDs). Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical studies is presented in Table 6. Table 6: Summary of Clinical Studies | | SPM-008 | SPM-011 | SPM-020 (RESET-RA) | | --- | --- | --- | --- | | Study | SPM-008: A Randomized Controlled Study of the Safety and Efficacy of Neurostimulation Using a Vagus Nerve Stimulation Device in Patients with Rheumatoid Arthritis | SPM-011: Long Term Extension Study of the Safety and Efficacy of Neurostimulation Using a Vagus Nerve Stimulation Device in Patients with Rheumatoid Arthritis | An operationally seamless, 2-stage, randomized, sham controlled, double-blind, multicenter, pivotal study with a 12-week follow-up for the primary effectiveness endpoint, followed by one-way crossover of the control group and a 252-week open-label follow-up of all patients on active stimulation for long-term safety. | | Key Patient Selection Criteria | • Adult-onset RA as defined by the 2010 ACR/EULAR (European League Against Rheumatism) classification criteria (Aletaha, 2010); • ≥ 4/28 tender and swollen joints and CDAI (Clinical Disease Activity Score) score > 10; and • Failed ≥ 2 bDMARDs and/or new tsDMARDs (JAKi) for ≥ 3 months with insufficient or loss of efficacy or intolerance of treatment. | | • 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 | | Device | SetPoint NCAP System (also referred to as the SetPoint System) | | SetPoint System | | Study Site Locations (Number of Sites, N) | United States (N=4) | | United States (N=41) | | Number of Patients (N) | 14 All patients from SPM-008 opted to participate in the long-term extension study SPM-011. | | 242 | | Follow-Up Length | 12 weeks | 93 months | 264 weeks | | Key Results | Results of this first-in-human Feasibility Study in highly drug refractory RA patients with active | | The study met its primary effectiveness endpoint of a | PMA P240039: FDA Summary of Safety and Effectiveness Data 15 of 52 {15} | | SPM-008 | SPM-011 | SPM-020 (RESET-RA) | | --- | --- | --- | --- | | | moderate to severe disease established the safety of implantation of the SetPoint Implant and active stimulation. Because this was the first clinical use of the SetPoint System, at FDA's request, SetPoint limited patient recruitment in this study to only highly drug refractory patients who had insufficient responses to multiple biologic and/or JAK inhibiting agents, representing multiple mechanisms of action, for whom there were no other therapeutics options. 50% of these highly drug refractory patients receiving VNS with the SetPoint System showed clinically meaningful improvements within 12 weeks of starting stimulation therapy. Long-term safety, device performance, and clinical improvements have been maintained throughout SPM-011, through 60 months. Follow-up is ongoing. Publication: Genovese MC, Gaylis NB, Sikes D, et al. Safety and efficacy of neurostimulation with a miniaturized vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study. Lancet Rheumatol. 2020;2(9):e527-e538. | | statistically significant difference between treatment and control groups in the proportion of patients achieving an American College of Rheumatology 20% response (ACR20) at Week 12 from baseline on the day of informed consent. Effectiveness was demonstrated by a 35% ACR20 response rate at Week 12 in the treatment arm vs. a 24% response in the control arm (p-value = 0.0209). Effectiveness observed during the blinded evaluation phase was observed to improved further between Week 12 and Week 24 and remained stable and consistent through Week 48. Across all pre-specified endpoints, the 12 Week and longer-term data demonstrated that patients have reduction in disease activity and improved functional disability. The device-related serious adverse event (SAE) rate was 1.6% for events associated with the implantation or explantation procedure (i.e., there were no serious adverse device effects (SADEs) after Week 12 attributed to stimulation or the device. The data support that the SetPoint System for the treatment of moderate-to-severe RA provides probable safety and effectiveness and the benefits outweigh the risks. | ### RESET-RA Pivotal Clinical Study (SPM-020) #### A. Study Design Patients were treated between 27 January 2021 (first patient implanted with the device) and 2 February 2024 (last patient implanted with the device). Dates of first randomization and last Week 12 visit are shown below. | First Randomization Day 0, about 14-21 days after Implant Procedure | Last Week 12 visit primary/secondary endpoints | Last Week 48 visit open-label outcomes | | --- | --- | --- | | 22 February 2021 | 16 May 2024 | 03 February 2025 | The database for this PMA reflected data collected through 10 March 2025 and included 242 patients in the Intent-to-Treat (ITT) population. There were 41 investigational sites. PMA P240039: FDA Summary of Safety and Effectiveness Data 16 of 52 {16} The RESET-RA Study was a prospective, multicenter, randomized, double-blinded, sham-controlled, pivotal clinical study comparing the active stimulation with SetPoint System (treatment) to sham (control, no stimulation) to evaluate safety and effectiveness. The study consisted of two stages, with Stage 1 enrolling 60 randomized subjects at up to 25 study centers, and Stage 2 increasing enrollment up to 190 randomized subjects at up to 45 study centers (including those from Stage 1). Enrollment was paused for 6 months after enrolling the last subject into Stage 1 to allow completion of Week 12 data collection and comparative data readouts for Stage 1 subjects. Blinding was maintained until all patients completed Week 12 assessments, and the dataset for primary analysis was locked. The Week 12 assessments were followed by one-way crossover of the control group and a 252-week open-label follow-up of all patients on active stimulation for long-term safety. The primary effectiveness endpoint was the difference between treatment and control groups in the proportion of patients achieving the ACR20 response at Week 12 from baseline on the day of informed consent. The primary effectiveness analysis was performed on the ITT population using pooled data from Stage 1 and 2. The hypothesis of interest was: $$H_0: p_t - p_c <= 0$$ $$H_1: p_t - p_c > 0$$ where $p_t$ is the response rate in treatment group and $p_c$ is the response rate in control group. The study tested the null hypothesis ($H_0$) that the treatment group response rate is less than or equal to the control group response rate in the proportion of patients achieving ACR20 response at Week 12 from baseline on the day of informed consent versus the alternative hypothesis ($H_1$) that treatment group response rate exceeds the control group response rate. The study was considered successful if there is a statistically significant improvement in the proportion of patients with ACR20 response in favor of the SetPoint System at a one-sided alpha of 0.025. To support labeling claims, a subset of secondary endpoints was identified and analyzed using appropriate methods for controlling for family-wise type-1 error rate (FWER). ### Sample Size Calculation The sample size was calculated based on an estimated 60% response rate at Week 12 in the treatment group and 30% response rate at Week 12 in the control group. A sample size of 250 randomized patients, 125 in each group, offered 96% power to detect a difference of 30% at the one-sided alpha of 0.025. If the true response rates were 50% in the treatment and 30% in the control group, the sample size of 250 patients would have 77% power to detect a difference of 20% at the one-sided alpha of 0.025. Power calculations were also considered for the scenario in which enrollment ended at 240 patients. The decrease in power was < 1% for all scenarios and most often < 0.5%. ### Core Labs and Independent Evaluators PMA P240039: FDA Summary of Safety and Effectiveness Data 17 of 52 {17} Two core labs provided independent, blinded evaluations of Magnetic Resonance Imaging (MRI) assessments and central lab service. Vendors are shown below. | Spire Sciences Inc 5314 Boca Marina Circle North Boca Raton, FL 33487 | MRI Evaluator | | --- | --- | | ICON plc 123 Smith Street Farmingdale, NY 11735 | Central Lab Services | ### *Data Monitoring Committee* An independent Data Monitoring Committee (DMC) was assembled to ensure safety, compliance, and proper clinical study monitoring. The DMC was responsible for safeguarding the interests of study patients, assessing the safety and effectiveness of the interventions during the trial, and for ongoing monitoring of the overall conduct of the study. The DMC met on a regular basis and was responsible for making recommendations about stopping or continuing the study based on their ongoing review of cumulative safety and effectiveness data. To date the DMC has consistently recommended that the study continue as planned without any significant alterations, changes, or interruptions. The DMC was comprised of a DMC Chair (Rheumatologist), DMC Biostatistician, DMC Clinician – Neurosurgeon, DMC Clinician – Otolaryngologist and Head & Neck Surgeon, Independent Biostatistician (non-voting). ### *Treatment and Control Groups* Starting with consent and screening, the implant procedure was completed within 30 days for all patients, followed by randomization (Day 0) about 2-3 weeks after implant to allow for healing of the incision site. Randomization was 1:1 to either active stimulation (treatment) or non-active stimulation (control or sham). Following the Week 12 assessments, all patients were offered to have their Implants turned on to receive active stimulation (treatment). Blinding was maintained until the last patient enrolled completed the Week 12 assessment. #### 1. Clinical Inclusion and Exclusion Criteria Patients enrolled in the RESET-RA clinical study were adults (22-75 years of age, inclusive) with moderately to severely active RA, despite ongoing treatment with a conventional synthetic DMARD (csDMARD), who had an inadequate response, loss of response, or intolerance to 1 or more biologic or targeted synthetic DMARDs (b/tsDMARDs). Enrollment was limited to patients who met the following 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 inadequate response, loss of response, or intolerance to 1 or more b/tsDMARDs - 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 PMA P240039: FDA Summary of Safety and Effectiveness Data 18 of 52 {18} stable dose through Week 12. Missing up to 2 doses due to COVID-19 vaccination was acceptable, except during the 4 weeks preceding informed consent. Patients were not permitted to enroll in the RESET-RA clinical study if they met any of the following key exclusion criteria: - Current, regular use of nicotine-containing products, and lack of agreement 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 or allergy to MRI contrast agents and/or unable to perform MRI 2. Follow-up Schedule Preoperatively, the Informed Consent and Screening (Baseline) assessments listed in Table 7 were performed up to 30 days prior to the implant procedure. Postoperatively, the objective parameters measured during the study included all assessments shown in Table 7 and Table 8 below. After completing Week 12, all patients had their devices re-registered and set to "active stimulation" and titration repeated (done to maintain blind of the original treatment assignments). This action marked crossover and start of open label with long-term follow-up planned up to Week 264 (Table 8). Adverse events and complications were recorded at all visits. The key timepoints are shown below in the tables summarizing safety and effectiveness. Table 7: Schedule of Assessments, 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) | Week 4 (28 ± 3d) | Week 8 (56 ± 5d) | Week 12 (Primary Endpoint & One-way Crossover) (84 ± 7d) | | --- | --- | --- | --- | --- | --- | --- | --- | | 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 | | RA disease activity assessments^{1} | X* | | | X | X | X | X | | RA prior and current medication | X* | | | | | | | PMA P240039: FDA Summary of Safety and Effectiveness Data 19 of 52 {19} | 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) | Week 4 (28 ± 3d^{2}) | Week 8 (56 ± 5d^{2}) | Week 12 (Primary Endpoint & One-way Crossover) (84 ± 7d^{2}) | | --- | --- | --- | --- | --- | --- | --- | --- | | Energizer [Charger] 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 | | | | | Patient training on the use of Energizer [Charger] | | | | X | | | | | Device check & dose titration | | | | X | | | X^{3} | | Device check & dose adjustment if needed | | | | | X | X | | | Blinding assessment^{4} | | | | | 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, patient'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 patient's initial eligibility and baseline values for the primary and key secondary efficacy endpoints. $^{1}$ RA disease activity assessments include: HAQ-DI, SGA, patient's pain assessment, TJC28, SJC28, EGA, and hsCRP. Patients must have ≥ 4TJC28 and ≥ 4SJC28 at consent to be eligible. $^{2}$ From Day 0 (randomization). $^{3}$ Dose titration is not performed if patient and Co-PI Rheumatologist decide that patient should not receive active stimulation in open-label, long-term follow-up period. $^{4}$ Blinding assessments are completed by the patient, Joint Evaluator and Co-PI Rheumatologist. Table 8: Schedule of Assessments, Long-Term Follow-Up | Assessment | Week 24 | Week 36 | Week 48 | Week 60 | Week 72 | Week 84 | Week 96 | Week 108 | Week 120 | Week 132 | Week 144 | Week 156 | Week 168 | Week 180 | Week 192 | Week 204 thru 264 (visits every) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Vital signs | 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 | | RA disease activity assessments | 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 | | Blood collection (biomarkers) | X | | | | | | | | | | | | | | | | | Hand MRI | X | | | | | | | | | | | | | | | | | 12-lead ECG | X | | X | | | | X | | | | X | | | | X | | | Device check & dose titration | | | | | | | | | | | | | | | | | | Device check & dose adjustment if needed | 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 | | Adverse event reporting | 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 | PMA P240039: FDA Summary of Safety and Effectiveness Data 20 of 52 {20} # 1. Clinical Endpoints With regard to safety, the risks of the device were based on nonclinical laboratory data as well as data collected in the RESET-RA clinical study. Safety of the SetPoint System was reported based on adverse events observed during the RESET-RA study. Adverse events were reported by the study doctor as related to either the implantation or explantation procedure, the device, stimulation therapy, or Charger associated with the SetPoint System. Additionally, adverse events were assessed by the study doctor as serious or non-serious as well as anticipated or unanticipated. With regard to effectiveness, the difference between treatment and control groups in the proportion of patients who achieved the American College of Rheumatology 20% response (ACR20) at Week 12 was the primary effectiveness endpoint.¹ The primary endpoint was further supported by additional efficacy measurements as secondary endpoints and exploratory endpoints. # Primary Endpoint The ACR20 is a common primary endpoint in randomized controlled trials (RCTs) to evaluate treatment in RA. ACR20 is a dichotomous composite endpoint indicating the proportion of patients with at least 20 percent improvement in the number of tender and swollen joints, and in three out of the remaining five ACR core-set measures: patient pain, patient global assessment of disease, evaluator global assessment of disease, physical functioning assessment (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and acute phase reactants (i.e., hsCRP).¹,² The core set of measures included in the ACR response criteria was established through a consensus process of clinical experts. Individual criteria were selected based on their construct validity, face validity, content validity, criterion validity, and discriminant validity. When considering the ability of an outcome measure to detect change, pain assessments, global assessments, tender and swollen joint counts, and HAQ scores all had strong discriminant validity.² The core-set of measures are briefly described below: - Tender Joint Count 28 (TJC280 and Swollen Joint Count 28 (SJC28): A total of 28 joints were scored for presence or absence of tenderness or pain and swelling 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). All joint assessments were performed by an independent, blinded Joint Evaluator with appropriate training and experience. Each patient was assessed by the same Joint Evaluator throughout their participation in the study. Joints that were replaced or injected with intra-articular steroids during the study are considered unevaluable. - Patient's Pain Assessment: Patient completed an assessment of the severity of their RA-related pain by marking a numerical rating scale on a paper form. The scale ranged from 0 (no pain) to 10 (worst pain imaginable). - Patient's Global Assessment (PGA): Patient completed a global assessment of their RA disease activity by marking a PMA P240039: FDA Summary of Safety and Effectiveness Data 21 of 52 {21} numerical rating scale on a paper form. The scale ranged from 0 (inactive) to 10 (very active). This assessment was completed independently from Joint Evaluator's assessment. - Evaluator's Global Assessment (EGA): After performing joint assessments, the same Joint Evaluator conducted a global assessment of the patient's RA activity by marking a numerical rating scale on a paper form. The scale ranged from 0 (inactive) to 10 (very active). Each patient was assessed by the same Joint Evaluator throughout their participation in the study. The Joint Evaluator completed their assessments without knowledge of SGA. - High-sensitivity C-reactive protein (hsCRP): Blood samples for hsCRP were collected using sampling kits and shipped at room temperature to a central laboratory for analysis, Serum concentration of hsCRP (mg/L) were determined by immunoturbidimetric assay. - Health Assessment Questionnaire Disability Index (HAQ-DI): A self-reported questionnaire that assesses functional ability in individuals. It evaluates the difficulty a patient experiences in performing activities of daily living across eight categories: dressing, arising, eating walking, hygiene, reach, grip, and common activities. The HAQ-Disability Index (HAQ-DI) is a comprehensive measure of the patient's perception of functional status and has been widely validated in RA.³,⁴ Patients completed the HAQ-DI questionnaire using a validated paper form in their language (English or Spanish). There are 20 questions in eight categories to assess a patient's physical functional status. For each question, there is a 4-level response set that is scored from 0 (without any difficulty) to 3 (unable to do). The eight category scores are averaged into an overall HAQ-DI score on a scale from zero (no disability) to three (completely disabled). Observational studies and RCTs have demonstrated that the HAQ-DI demonstrates face validity, content validity, construct validity, predictive validity, and discriminant validity.³,⁴ ### Secondary Endpoints # ACR20 response from Day 0 A patient achieved ACR20 response when this patient experienced a ≥ 20% improvement at Week 12 from the post-surgical baseline at Day 0 in TJC28 and SJC28 and 3 out of 5 ACR core measures and follows the same general and statistical analyses as for ACR20 response at Week 12 from baseline on the day of informed consent (primary endpoint). # DAS28-CRP response (MCID) The DAS28-CRP (28-joint Disease Activity Score using C-reactive protein) is a validated measure for assessing disease activity in RA.⁵ The DAS28-CRP score is a composite index providing a measure of disease activity, comprising TJC28 (tender joint count for 28 joints), SJC28 (swollen joint count for PMA P240039: FDA Summary of Safety and Effectiveness Data 22 of 52 {22} 28 joints), SGA (subjective global assessment), and hsCRP (high-sensitivity C-reactive protein in mg/L). A total score ranges from 0 to 10 and is computed as follows: $$DAS28-CRP = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.36 * ln(CRP+1) + 0.014 * SGA + 0.96$$ A DAS28-CRP score reduction by at least 1.2 from baseline on the day of inform consent to Week 12 represented the MCID response. ### DAS28-CRP good/moderate EULAR response The European League Against Rheumatism (EULAR) recommended that the clinical implications of the DAS28 score (such as good response, moderate response, or no response) be determined based on the baseline DAS28 scores.⁶ DAS28-CRP EULAR response at Week 12 was defined based on the combination of the current DAS28-CRP score and its improvement relative to baseline on the day of inform consent as illustrated in Table 9. Table 9: EULAR Response Criteria | DAS28-CRP Score Week 12 | DAS28-CRP Score Decrease from Baseline Value | | | | --- | --- | --- | --- | | | > 1.2 | > 0.6 to ≤ 1.2 | ≤ 0.6 | | ≤ 3.2 | Good response | Moderate response | No response | | > 3.2 to ≤ 5.1 | Moderate response | Moderate response | No response | | > 5.1 | Moderate response | No response | No response | A patient was considered having a moderate treatment response at Week 12 if: - DAS28-CRP score decreased from baseline to Week 12 by > 0.6 and ≤ 1.2, and the DAS28-CRP score at Week 12 was ≤ 5.1; or - DAS28-CRP score decreased from baseline to Week 12 by > 1.2, and the DAS28-CRP score at Week 12 was > 3.2. A patient was considered having a good treatment response at Week 12 if: - DAS28-CRP score decreased from baseline to Week 12 by > 1.2 and the DAS28-CRP score at Week 12 was ≤ 3.2. If the post-baseline DAS28-CRP score was missing, then the corresponding EULAR category was missing. ### HAQ-DI response (MCID) The HAQ–Disability Index (HAQ-DI) is a comprehensive measure of the patient's perception of functional status and has been widely validated in RA.⁴,⁵ Patients completed the HAQ-DI questionnaire using a validated paper form in their language (English or Spanish). There are 20 questions in eight categories to assess a patient's physical functional status: dressing, arising, eating, walking, hygiene, reach, grip, and common activities. Each functional area contains at least 2 questions. For each question, there is a 4-level response set that is scored from 0 (without any difficulty) PMA P240039: FDA Summary of Safety and Effectiveness Data 23 of 52 {23} to 3 (unable to do). If aids or devices or physical assistance are used for a specific functional area, and the maximum response of this functional area is 0 or 1, the according value is increased to a score of 2. The highest response within each functional area determines the score of that specific functional area. If no questions within a given functional area were answered, no score was provided for that category (even if answers on aids or equipment are available). The eight category scores are averaged into an overall HAQ-DI score on a scale from zero (no disability) to three (completely disabled). HAQ-DI score was only calculated if there were at least 6 functional area scores available. Observational studies and RCTs have demonstrated that the HAQ-DI demonstrates face validity, content validity, construct validity, predictive validity, and discriminant validity.⁵ The minimal clinically important difference (MCID) in HAQ-DI reflecting a meaningful improvement in physical function is a decrease in score of 0.22, derived from correlations with global assessments of disease activity in multiple randomized controlled trials and longitudinal case series.³ ### Exploratory Endpoints CDAI low disease activity or remission The Clinical Disease Activity Index (CDAI) is a validated composite measure that is widely used in clinical practice to assess disease activity level in rheumatoid arthritis in patients. The score is based on 4 items: - TJC28 - SJC28 - 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 DAS-28 CRP low disease activity or remission The DAS28-CRP score corresponds to the current RA activity as follows: - 0 to < 2.6 Remission - 2.6 to < 3.2 LDA - 3.2 to ≤ 5.1 Moderate activity - > 5.1 High activity Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS)⁷⁻¹¹ A contrast-enhanced MRI of one hand identified by the rheumatologist to be clinically most severe was ordered by the rheumatology site and acquired at an MRI facility that was selected and qualified to perform this procedure. The MRI images PMA P240039: FDA Summary of Safety and Effectiveness Data 24 of 52 {24} were acquired before and after intravenous administration of gadolinium-based contrast to maximize sensitivity and specificity for inflammation. RAMRIS was evaluated at baseline, Week 12, and then Week 24 (after one-way crossover) as an exploratory endpoint. RAMRIS is a standardized method for MRI acquisition of the hand and wrist to assess joint pathology by definitions and a scoring system for semiquantitative evaluation per: - 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. RAMRIS synovitis, bone erosion, and osteitis score changes from baseline, Week 12 and Week 24 were evaluated as an exploratory endpoint. The percentage of patients exhibiting a progression in bone erosions (increase in erosion score of > 0.5 compared to baseline) was also prespecified. Subgroup analysis was performed on patients that had only failed one prior b/tsDMARD and those with an erosive phenotype. Patients meeting the subgroup criteria for having an erosive phenotype had a baseline synovitis score of 2 or more on any joint; or, if none of the joints score greater than 2, had at least 4 joints with a score of 1 at baseline; or had any joint with osteitis (score of 1 or more) at baseline. The same hand was imaged using the same MRI scanner and coil at Screening, Week 12, and Week 24 for a given patient. Only 1.5 and 3.0 Tesla (1.5T and 3.0T) whole-body scanners and transmit-receive (Tx/Rx) coils, ideally knee coils, were acceptable for this study. In vitro testing of Implant and Pod passed standard testing for safe use in 1.5T and 3.0T MRI studies. Safe scanning parameters are provided in the SetPoint Medical Surgeon, Prescriber and Patient Manuals. MRI images were transmitted to the MRI central laboratory for quality check, reading and quantification. Images were scored centrally by two independent radiologists blinded to treatment allocation, clinical information and the order (study assessment) in which the images were acquired. Scores for each bone/joint were calculated as the average of the score provided by each of the two readers. The smallest detectable change (SDC) was calculated for each of the joint pathologies to assess whether a patient experienced a change beyond measurement error.10 Changes below the smallest detectable change (-SDC) reflect improvement in RAMRIS subscores; changes above the smallest detectable change (+SDC) reflect worsening. # Therapy Persistence Therapy persistence refers to the length of time a study patient continued to use the study therapy. Persistence was assessed in several ways: - Use of the SetPoint System without addition of a b/tsDMARD, additional csDMARD and/or steroid PMA P240039: FDA Summary of Safety and Effectiveness Data 25 of 52 {25} - Use of the SetPoint System with the addition of a b/tsDMARD - Use of the Setpoint System with an additional csDMARD or steroid # Patient Satisfaction Patient satisfaction with the SetPoint System for treatment of RA was assessed at Week 24 (after all participants had received at least 12 weeks of study therapy) using five-point Likert rating scale: - Very dissatisfied - Somewhat dissatisfied - Neither satisfied nor dissatisfied - Somewhat satisfied - Very satisfied Additionally, patients were asked a question about whether they would recommend the SetPoint System to family and friends. # B. Accountability of PMA Cohort At the time of database lock, 242 patients were implanted in the RESET-RA clinical study at 41 sites, all in the United States, with 240 (99.2%) of patients available for analysis at primary endpoint analysis at Week 12 after randomization. Patient accountability is shown in Figure 7 below. PMA P240039: FDA Summary of Safety and Effectiveness Data 26 of 52 {26}  Figure 7: Patient Accountability ### C. Study Population Demographics and Baseline Parameters Enrollment in the RESET-RA clinical study was entirely from study sites in the U.S. (i.e., no study sites outside the U.S. participated in RESET-RA), Therefore, the demographics for the study population are typical for what would be expected in an RA study performed in the U.S. and representative of a U.S. patient population with RA. The prevalence of RA is 3 times higher in women than men, the incidence is 4-5 times higher below the age of 50, but above 60-70 years the female/male ratio is only about 2.¹² PMA P240039: FDA Summary of Safety and Effectiveness Data 27 of 52 {27} Demographics for the ITT cohort are reported in **Table 10** below. The ITT population was predominately female (86%), with a higher proportion of males in the treatment group (19.7% treatment vs. control 8.3%). Mean age was 55.7 years at time of consent. By race and ethnicity, most patients were White (80.6%), and representation by Hispanic or Latino was 18.6%. On average, patients were overweight with mean BMI 30.3 kg/m$^{2}$. In general, demographics and baseline characteristics were balanced between the treatment and control group, with no differences identified that would have an unexpectedly material impact on clinical results. **Table 10: Demographics (ITT Population)** | | Treatment (N=122) | Control (N=120) | All (N=242) | | --- | --- | --- | --- | | **Age (years)** | | | | | I. Mean (SD) | 55.8 (10.28) | 55.5 (10.49) | 55.7 (10.36) | | II. Median | 57.0 | 56.5 | 57.0 | | III. Min, Max | 25, 75 | 30, 75 | 25, 75 | | **Sex** | | | | | IV. Male | 24 (19.7%) | 10 (8.3%) | 34 (14.0%) | | V. Female | 98 (80.3%) | 110 (91.7%) | 208 (86.0%) | | **Ethnicity** | | | | | VI. Hispanic or Latino | 23 (18.9%) | 22 (18.3%) | 45 (18.6%) | | VII. Not Hispanic or Latino | 98 (80.3%) | 95 (79.2%) | 193 (79.8%) | | VIII. Not disclosed | 1 (0.8%) | 3 (2.5%) | 4 (1.7%) | | **Race [1]** | | | | | IX. American Indian or Alaska Native | 1 (0.8%) | 0 | 1 (0.4%) | | X. Asian | 4 (3.3%) | 5 (4.2%) | 9 (3.7%) | | XI. Black or African American | 10 (8.2%) | 12 (10.0%) | 22 (9.1%) | | XII. Native Hawaiian or other Pacific Islander | 0 | 1 (0.8%) | 1 (0.4%) | | XIII. White | 102 (83.6%) | 93 (77.5%) | 195 (80.6%) | | XIV. Other | 5 (4.1%) | 9 (7.5%) | 14 (5.8%) | | **Body Mass Index (kg/m^{2})** | | | | | XV. Mean (SD) | 30.7 (7.25) | 29.8 (6.71) | 30.3 (6.98) | | XVI. Median | 29.6 | 28.7 | 29.2 | | XVII. Min, Max | 18.9, 56.7 | 17.9, 54.1 | 17.9, 56.7 | | [1] Race reported as 'Other' if more than 1 race is selected | | | | Baseline RA duration, disease activity, and serology are shown in **Table 11**. PMA P240039: FDA Summary of Safety and Effectiveness Data 28 of 52 {28} **Table 11: Baseline RA Duration, Disease Activity, Serology (ITT Population)** | | Treatment (N=122) | Control (N=120) | All (N=242) | | --- | --- | --- | --- | | **RA duration (years)** | | | | | I. Mean (SD) | 13.0 (10.59) | 11.8 (10.45) | 12.4 (10.52) | | II. Median | 10.0 | 8.5 | 9.2 | | III. Min, Max | 0.1, 55.5 | 0.7, 51.8 | 0.1, 55.5 | | **CDAI score** | | | | | IV. Mean (SD) | 36.1 (12.60) | 38.2 (12.75) | 37.1 (12.69) | | V. Median | 33.8 | 37.1 | 35.1 | | VI. Min, Max | 13.5, 73.5 | 16.5, 74.0 | 13.5, 74.0 | | **DAS28-CRP score** | | | | | VII. Mean (SD) | 5.3 (0.91) | 5.4 (0.96) | 5.3 (0.93) | | VIII. Median | 5.2 | 5.3 | 5.3 | | IX. Min, Max | 3.4, 7.6 | 3.0, 7.9 | 3.0, 7.9 | | **RF** | | | | | X. Negative | 73 (59.8%) | 64 (53.3%) | 137 (56.6%) | | XI. Positive | 49 (40.2%) | 56 (46.7%) | 105 (43.4%) | | XII. NA | 0 | 0 | 0 | | **ACPA** | | | | | XIII. Negative | 57 (46.7%) | 61 (50.8%) | 118 (48.8%) | | XIV. Positive | 61 (50.0%) | 59 (49.2%) | 120 (49.6%) | | XV. NA | 4 (3.3%) | 0 | 4 (1.7%) | | **Serology** | | | | | XVI. Negative | 56 (45.9%) | 54 (45.0%) | 110 (45.5%) | | XVII. Positive | 62 (50.8%) | 66 (55.0%) | 128 (52.9%) | | XVIII. NA | 4 (3.3%) | 0 | 4 (1.7%) | | *Abbreviations: RA, rheumatoid arthritis; ACPA, anti-citrullinated protein antibodies; CDAI, Clinical Disease Activity Index; DAS28-CRP, Disease Activity Score 28 using C-reactive protein; ITT, intent to treat; RF, Rheumatoid factor; SD, standard deviation* | | | | ACR components measured at baseline (day of consent) were comparable between treatment and control for tender and swollen joint counts, HAQ-DI score, pain score, subject global assessment, evaluator global assessment, and hsCRP (high-sensitivity CRP). ACR components at baseline are provided in **Table 12**. **Table 12: Baseline ACR Components (ITT Population)** | | Treatment (N=122) | Control (N=120) | All (N=242) | | --- | --- | --- | --- | | **TJC (out of 28 joints)** | | | | | I. Mean (SD) | 14.1 (6.94) | 15.0 (7.26) | 14.6 (7.10) | | II. Median | 12.4 | 14.0 | 14.0 | PMA P240039: FDA Summary of Safety and Effectiveness Data 29 of 52 {29} | | Treatment (N=122) | Control (N=120) | All (N=242) | | --- | --- | --- | --- | | III. Min, Max | 4.0, 28.0 | 4.0, 28.0 | 4.0, 28.0 | | **SJC (out of 28 joints)** | | | | | IV. Mean (SD) | 9.6 (5.46) | 10.5 (4.98) | 10.0 (5.23) | | V. Median | 7.8 | 9.2 | 9.0 | | VI. Min, Max | 4.0, 28.0 | 4.0, 28.0 | 4.0, 28.0 | | **HAQ-DI score** | | | | | VII. Mean (SD) | 1.4 (0.59) | 1.3 (0.61) | 1.4 (0.60) | | VIII. Median | 1.4 | 1.4 | 1.4 | | IX. Min, Max | 0.1, 2.8 | 0.0, 2.9 | 0.0, 2.9 | | **Pain (per subject)** | | | | | X. Mean (SD) | 5.5 (2.00) | 5.7 (2.23) | 5.6 (2.12) | | XI. Median | 5.5 | 6.0 | 6.0 | | XII. Min, Max | 1.0, 10.0 | 1.0, 10.0 | 1.0, 10.0 | | **SGA** | | | | | XIII. Mean (SD) | 6.2 (2.07) | 6.0 (2.25) | 6.1 (2.16) | | XIV. Median | 6.0 | 6.0 | 6.0 | | XV. Min, Max | 2.0, 10.0 | 1.0, 10.0 | 1.0, 10.0 | | **EGA** | | | | | XVI. Mean (SD) | 6.3 (1.88) | 6.7 (1.72) | 6.5 (1.80) | | XVII. Median | 6.3 | 7.0 | 7.0 | | XVIII. Min, Max | 1.5, 10.0 | 2.0, 10.0 | 1.5, 10.0 | | **hsCRP (mg/L)** | | | | | XIX. Mean (SD) | 8.41 (12.338) | 8.01 (12.762) | 8.21 (12.526) | | XX. Median | 3.87 | 2.63 | 3.08 | | XXI. Min, Max | 0.15, 69.76 | 0.09, 85.48 | 0.09, 85.48 | | *Abbreviations: TJC28, tender joint count; SJC, swollen joint count; HAQ-DI, health assessment questionnaire-disability index; SGA, subject global assessment; EGA, evaluator global assessment; hsCRP, high-sensitivity C-reactive protein* | | | | Medical history of prior biological and targeted synthetic DMARDs (b/tsDMARDs) is presented in **Table 13**. 43% of the study population met the EULAR criteria for difficult-to-treat (D2T) with available drug therapies.$^{6}$ **Table 13: Number of Prior b/tsDMARDs (ITT Population)** | | Treatment (N=122) | Control (N=120) | All (N=242) | | --- | --- | --- | --- | | **Prior b/ts DMARDs** | | | | | I. Mean (SD) | 2.5 (1.98) | 2.7 (1.87) | 2.6 (1.92) | | II. Median | 2.0 | 2.0 | 2.0 | | III. Min, Max | 1.0, 12.0 | 1.0, 10.0 | 1.0, 12.0 | | **Number of prior b/tsDMARDs** | | | | PMA P240039: FDA Summary of Safety and Effectiveness Data 30 of 52 {30} | | | Treatment (N=122) | Control (N=120) | All (N=242) | | --- | --- | --- | --- | --- | | IV. | 0 | 0 | 0 | 0 | | V. | 1 | 52 (42.6%) | 42 (35.0%) | 94 (38.8%) | | VI. | 2 | 25 (20.5%) | 28 (23.3%) | 53 (21.9%) | | VII. | 3 | 15 (12.3%) | 16 (13.3%) | 31 (12.8%) | | VIII. | 4 | 15 (12.3%) | 15 (12.5%) | 30 (12.4%) | | IX. | 5 | 7 (5.7%) | 8 (6.7%) | 15 (6.2%) | | X. | 6 | 2 (1.6%) | 5 (4.2%) | 7 (2.9%) | | XI. | 7 | 2 (1.6%) | 4 (3.3%) | 6 (2.5%) | | XII. | 8 | 2 (1.6%) | 1 (0.8%) | 3 (1.2%) | | XIII. | 9 | 0 | 0 | 0 | | XIV. | 10+ | 2 (1.6%) | 1 (0.8%) | 3 (1.2%) | | Prior b/tsDMARD by Classification [1] | | | | | | XV. | Anti-IL-1 agents | 0 | 4 (3.3%) | 4 (1.7%) | | XVI. | Anti-IL-6 agents | 27 (22.1%) | 28 (23.3%) | 55 (22.7%) | | XVII. | Anti-TNF agents | 116 (95.1%) | 109 (90.8%) | 225 (93.0%) | | XVIII. | B-cell depleting agents | 13 (10.7%) | 21 (17.5%) | 34 (14.0%) | | XIX. | JAKi | 25 (20.5%) | 24 (20.0%) | 49 (20.2%) | | XX. | CTLA4-Ig | 32 (26.2%) | 36 (30.0%) | 68 (28.1%) | | Abbreviations: ACPA, anti-citrullinated protein antibodies; b/tsDMARD, biologic or targeted synthetic disease-modifying antirheumatic drug; CTLA4-Ig, cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin; IL, interleukin; ITT, intent to treat; JAKi, Janus kinase inhibitor; RA, rheumatoid arthritis; SD, standard deviation; TNF, tumor necrosis factor | | | | | | [1] Patients could be counted in more than 1 category. | | | | | ### D. Safety and Effectiveness Results #### 1. Safety Results The analysis of safety was based on the safety cohort of 243 patients consented. The key safety outcomes for this study are presented below in Table 14 and Table 17. Adverse effects are reported in Table 14 to Table 17. ##### Adverse Events that occurred in the PMA Clinical Study Determination of safety for the SetPoint System is based on adverse events observed during the RESET-RA study. Adverse events were reported by the study doctor as related to either the implantation procedure, explantation procedure (if applicable), device, stimulation or Charger associated with the SetPoint System. Overall, no patients during the study experienced a life-threatening complication related to the SetPoint System, and no deaths were reported for any cause. ##### Summary of Adverse Events (AEs) through Primary Endpoint at Week 12 PMA P240039: FDA Summary of Safety and Effectiveness Data 31 of 52 {31} During the period from Screening through Week 12, non-serious AEs occurred in 13.9% of treatment and 18.3% of control patients (overall, 16% of patients). Most AEs were related to the implantation procedure. No events resulted in discontinuation of a patient during this period. There were no Unanticipated Adverse Device Effects (UADEs) and no deaths from Screening to Week 12. A total of 4 patients (1.6%) experienced a serious adverse event (SAE) related to the implantation or explantation procedure of the SetPoint System during the period from implantation procedure to Week 12 as summarized in **Table 14**. All (100%) SAEs resolved. **Table 14: Related, Serious AEs from Implantation to Week 12** | MedDRA Preferred Term | Treatment (N=122) n (%) | Control (N=120) n (%) | All (N=243) n (%) | | --- | --- | --- | --- | | Patient with AE | 3 (2.5%) | 1 (0.8%) | 4 (1.6%) | | XVIII. Incision site swelling [1] | 1 (0.8%) | 0 | 1 (0.4%) | | XIX. Vocal cord paresis [1] | 1 (0.8%) | 0 | 1 (0.4%) | | XX. Dysphonia [1] | 0 | 1 (0.8%) | 1 (0.4%) | | XXI. Pharyngeal perforation [2] | 1 (0.8%) | 0 | 1 (0.4%) | | Given in the table are number of patients, with percentage, experiencing events for each AE category. At each level of summation, patients are counted only once. | | | | | [1] Procedure-related, onset prior to randomization: incision site swelling hospitalized for evaluation that ruled out infection (resolved); vocal cord paresis with dysphagia that led to hospitalization (resolved); dysphonia deemed by investigator significant enough to impair daily activities (resolved, mild sequelae). | | | | | [2] Occurred during explant procedure, repaired intraoperatively, no hospitalization required (resolved). | | | | Non-serious AEs related to the implantation procedure and/or Implant are summarized in **Table 15**. These AEs were generally mild to moderate in severity and anticipated based on the nature of the surgical intervention. **Table 15: Non-Serious AEs Related to Implantation Procedure and/or Implant** | MedDRA Preferred Term | Treatment (N=122) n (%) | Control (N=120) n (%) | | --- | --- | --- | | **Patient with AE** | 17 (13.9%) | 22 (18.3%) | | I. Vocal cord paresis | 5 (4.1%) | 6 (5%) | | II. Dysphonia | 4 (3.3%) | 3 (2.5%) | | III. Cough | 1 (0.8%) | 0 | | IV. Diarrhea | 1 (0.8%) | 0 | | V. Dysphagia | 1 (0.8%) | 2 (1.7%) | | VI. Dyspnea | 1 (0.8%) | 0 | | VII. Gastrointestinal complication | 1 (0.8%) | 0 | | VIII. Implant site hypoesthesia | 1 (0.8%) | 1 (0.8%) | PMA P240039: FDA Summary of Safety and Effectiveness Data 32 of 52 {32} | MedDRA Preferred Term | | Treatment (N=122) n (%) | Control (N=120) n (%) | | --- | --- | --- | --- | | IX. | Implant site inflammation | 1 (0.8%) | 1 (0.8%) | | X. | Implant site swelling | 1 (0.8%) | 2 (1.7%) | | XI. | Medical device site swelling | 1 (0.8%) | 0 | | XII. | Migraine | 1 (0.8%) | 0 | | XIII. | Postoperative wound infection | 1 (0.8%) | 0 | | XIV. | Rash | 1 (0.8%) | 1 (0.8%) | | XV. | Scar pain | 1 (0.8%) | 0 | | XVI. | Stitch abscess | 1 (0.8%) | 0 | | XVII. | Swelling | 1 (0.8%) | 0 | | XVIII. | Swelling of eyelid | 1 (0.8%) | 1 (0.8%) | | XIX. | Application site rash | 0 | 2 (1.7%) | | XX. | Eyelid ptosis | 0 | 1 (0.8%) | | XXI. | Headache | 0 | 1 (0.8%) | | XXII. | Implant site erythema | 0 | 1 (0.8%) | | XXIII. | Implant site pain | 0 | 2 (1.7%) | | XXI…