← Product Code LGW · P190002

# Saluda Medical Evoke SCS System (P190002)

_Saluda Medical Pty, Ltd. · LGW · Feb 28, 2022 · Neurology · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P190002

## Device Facts

- **Applicant:** Saluda Medical Pty, Ltd.
- **Product Code:** LGW
- **Decision Date:** Feb 28, 2022
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Neurology
- **Attributes:** Therapeutic

## Indications for Use

The Saluda Medical Evoke SCS System is indicated as an aid in the management of chronic intractable pain of the trunk and/or limbs, including unilateral or bilateral pain associated with the following: failed back surgery syndrome, intractable low back pain and leg pain.

## Device Story

The Evoke SCS System is a fully implantable, rechargeable spinal cord stimulation (SCS) system for chronic intractable pain. It delivers electrical stimulation to the spinal cord via percutaneous leads. The system uniquely measures electrically evoked compound action potentials (ECAPs)—the neural response to stimulation—in real-time. It operates in two modes: open-loop (fixed-output) or ECAP-controlled closed-loop. In closed-loop mode, the device uses the measured ECAP amplitude as feedback to automatically adjust stimulation current for every pulse, maintaining spinal cord activation near a clinician-set target. This minimizes fluctuations in stimulation intensity caused by patient movement or posture changes. The system includes an implantable pulse generator (CLS), percutaneous leads, a patient-operated pocket console, and a clinician interface for programming. By maintaining consistent spinal cord activation, the device aims to provide more stable pain relief and improve patient outcomes compared to traditional open-loop systems. It is used in clinical settings for programming and by patients at home for daily stimulation management.

## Clinical Evidence

Pivotal prospective, multicenter, randomized, double-blind study (n=134) compared closed-loop to open-loop SCS. Primary endpoint: composite of ≥50% reduction in overall trunk/limb pain VAS at 3 months with no increase in baseline pain medications. Closed-loop demonstrated non-inferiority (p<0.001) and superiority (p=0.005) to open-loop at 3 months, with 82.3% vs 60.3% success rates. Superiority maintained at 12 months (p=0.006). Secondary endpoints (leg/back pain reduction) also favored closed-loop. Safety profile consistent with existing SCS systems; no UADEs reported.

## Technological Characteristics

Rechargeable 25-channel implantable pulse generator (CLS) with lithium-ion battery. Leads: 12-contact percutaneous, platinum/iridium electrodes, 4mm spacing. Stimulation: charge-balanced biphasic/triphasic, current-regulated (0-12.5 mA/output, max 50 mA total). Connectivity: wireless communication between stimulator and external interface. Sterilization: ethylene oxide (EO). Software: proprietary Saluda Medical programming/data viewer. Standards: ISO 14708-1, ISO 14708-3, IEC 62304, IEC 60601-1.

## Reference Devices

- PRECISION Spinal Cord Stimulator (SCS) System ([P030017](/device/P030017.md))
- Senza Spinal Cord Stimulation (SCS) System ([P130022](/device/P130022.md))
- Proclaim Implantable Pulse Generator ([P150002](/device/P150002.md))

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Stimulator, Spinal-Cord, Totally Implanted for Pain Relief

Device Trade Name: Saluda Medical Evoke® SCS System

Device Product Code: LGW

Applicant's Name and Address: Saluda Medical Pty Ltd.
407 Pacific Highway Level 1
Artarmon, New South Wales 2064
Australia

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P190002

Date of FDA Notice of Approval: February 28, 2022

II. INDICATIONS FOR USE

The Saluda Medical Evoke SCS System is indicated as an aid in the management of chronic intractable pain of the trunk and/or limbs, including unilateral or bilateral pain associated with the following: failed back surgery syndrome, intractable low back pain and leg pain.

III. CONTRAINDICATIONS

The Evoke SCS System should not be used in patients who:
- Do not receive effective pain relief during trial stimulation
- Are unable to operate the Evoke SCS System
- Are unsuitable surgical candidates

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Evoke System labeling.

V. DEVICE DESCRIPTION

The Saluda Medical Evoke Spinal Cord Stimulation (SCS) System (Evoke System) is a rechargeable, upgradeable, totally implantable spinal cord stimulation system that delivers electrical stimulation to the spinal cord for the treatment of chronic intractable pain of the trunk and/or limbs.

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SCS consists of applying an electrical stimulus to the spinal cord which causes the activated fibers (e.g., Aβ-fibers) to generate action potentials. Aβ-fibers are the low-threshold sensory fibers in the dorsal column that contribute to inhibition of pain signals in the dorsal horn (1). The action potentials summed together form the electrically evoked compound action potential (ECAP). Therefore, ECAPs are a direct measure of spinal cord fiber activation that generates pain inhibition for an individual.

The Evoke System is designed to operate in either of two modes: ECAP-controlled closed-loop stimulation mode, or open-loop (fixed-output) stimulation mode. The open-loop stimulation mode is equivalent to other commercially available SCS systems but has an additional feature to measure ECAPs. The Evoke System has the ability to measure ECAPs following every stimulation pulse from two electrodes not involved in stimulation. The recorded ECAP signal is sampled by the stimulator and processed to allow measurement of the ECAP amplitude. ECAP measurement may be performed in either stimulation mode. Additionally, the Evoke System can use ECAPs in a feedback mechanism to deliver closed-loop stimulation. The feedback mechanism minimizes the difference between the measured ECAP amplitude and the ECAP amplitude target (set by the clinician and adjusted by the patient using the pocket console) by automatically adjusting the stimulation current for every stimulus. In doing so, it maintains spinal cord activation near the target level (Figure 1).

![img-0.jpeg](img-0.jpeg)
Figure 1. ECAP-controlled, Closed-Loop Stimulation

## A. Implanted Components

The implanted components of the Evoke System include the following:

- Closed Loop Stimulator (CLS): A rechargeable, 25-channel implantable pulse generator (IPG or stimulator) which generates an electrical stimulus and measures and records the nerve fibers' response to stimulus (i.e., ECAPs). It has a lithium ion rechargeable battery and connects to two 12-contact leads. Although named "Closed Loop Stimulator", this stimulator delivers both open-loop and closed-

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loop stimulation modes. The CLS has a single current source with four scaled outputs that can deliver controlled current to each of the active stimulation electrodes. In addition, the CLS can be programmed with up to four stimulation programs and up to four stimulation sets per program that may be interleaved using up to 25 independently programmable channels (lead(s) plus CLS case for recording ECAPs only). The stimulation output parameters are listed in Table 1.

Table 1. Stimulation Output Parameters

|  Number of Programs | 1 to 4  |
| --- | --- |
|  Number of Channels | 25; 24 epidural electrodes and the CLS case (case may be used for recording ECAPs only)  |
|  Waveform | Charge Balanced Biphasic or Triphasic  |
|  Pulse Shape | Symmetrical, Rectangular Biphasic or Rectangular Triphasic  |
|  Current or Voltage Regulated | Current  |
|  Maximum Current Amplitude | 0-12.5 mA per current source output (maximum 50 mA and a total of 20 mA at 750 Ω)  |
|  Maximum Output Voltage | 7.5 – 15 V  |
|  Pulse Width | 20 – 1000 μs  |
|  Frequency | 10 – 1500 Hz (Open-loop) 10 – 250 Hz (Closed-loop)  |
|  Current Path Options | Bipolar or Multipolar  |

- Percutaneous Leads: Electrical current is delivered to the spinal cord via the electrodes on leads that are introduced into the epidural space through an epidural needle and connected to the stimulator. ECAPs are measured using the non-stimulating contacts of the leads. The lead specifications are listed in Table 2.

Table 2. Percutaneous Lead Specifications

|  Lead Length (cm) | 60, 90 cm  |
| --- | --- |
|  Lead Diameter (mm) | 1.32 mm  |
|  Number of Electrodes | 12  |
|  Electrode Material | Platinum/Iridium  |
|  Electrode Spacing (edge-to-edge) (mm) | 4 mm  |
|  Electrode Span (mm) | 80 mm  |
|  Electrode Surface Area (mm2) | 12.44 mm2  |
|  Impedance (Ω) | <16 Ω  |

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- Lead Extension: Used to provide additional length if needed to connect the implanted lead to the CLS or external closed loop stimulator (eCLS).
- Suture Anchors and Active Anchors: Used to anchor the lead to the supraspinous ligament or deep fascia.
- CLS Port Plug: Used to block unused ports in the CLS header.

B. External Components

- Accessory Belt: Aids the patient in holding the external charging coil and eCLS in place during use.
- Clinical Interface (CI): Used by the clinician to program output stimulation parameters and measure and record ECAP signals. It is an off-the-shelf tablet computer installed with proprietary Saluda Medical software to allow programming of the CLS, eCLS, as well as data collection and analysis.
- Clinical System Transceiver (CST): Connects to the CI via a USB port to provide wireless communication between the CI and the stimulator (CLS and eCLS).
- Pocket Console (EPC): A handheld battery-operated unit that allows patients to adjust stimulation within clinician prescribed program limits stored on the stimulator (CLS or eCLS). Adjustments include starting and stopping stimulation, increasing and decreasing stimulation intensity, and toggling between stimulation programs. The EPC batteries are disposable and non-rechargeable.
- Chargers: A battery-operated unit used to inductively charge the CLS transcutaneously. The Charger battery is non-removable and rechargeable.
- External Closed Loop Stimulator (eCLS): Provides stimulation by emulating the CLS during the intraoperative test and during the stimulation trial. The eCLS stimulation parameters are the same as the CLS.
- Intraoperative Cables: Used during intraoperative testing to connect the eCLS to the implanted lead(s).
- Lead Adapter: Used during the stimulation trial to connect the eCLS to the implanted lead(s).

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- Surgical Accessories:
- Epidural Needle: Consists of a cannula and stylet assembly that is used to introduce the percutaneous lead into the epidural space.
- Stylets: Used to steer the lead in the epidural space to the desired location. Available in two tip shapes: straight and bent.
- Tunneling Tool: Consists of the tool and passing straw assembly that is used to create a subcutaneous path from the CLS pocket to the lead incision site. It may also be used to create a path to an intermediate incision point or lead extension point when needed.
- Torque Wrench: Used to tighten and loosen set screw connector systems that lock the lead into the active anchor, lead extension, and CLS header.

VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of chronic intractable pain of the trunk and/or limbs. Patients are typically treated on a treatment continuum with less invasive therapies prescribed first. Established non-surgical treatment options include, but are not limited to, oral medications, massage therapy, physical/occupational/exercise therapy, psychological therapies (e.g., behavior modification, hypnosis), transcutaneous electrical nerve stimulation (TENS), acupuncture, sympathetic nerve blocks, epidural blocks, intrathecal blocks, and facet joint blocks. The surgical treatment options for these patients include sympathectomy, implantable intrathecal drug delivery (IDD) systems, partially implanted SCS systems (power source is external) and commercially available fully implantable SCS systems. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

VII. MARKETING HISTORY

The Evoke System has not been marketed in the United States. The Evoke System has been approved for commercial distribution in Europe. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness.

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of potential adverse effects (e.g., complications) associated with the use of SCS systems. The adverse effects include: (1) those associated with any surgical procedure, (2) those associated with the SCS system placement procedures, and (3) those associated with having an implanted SCS system to treat pain, including the Evoke System. In addition to the risks listed below, there is the risk that the SCS therapy may not be effective in relieving symptoms, or may cause worsening of symptoms. Additional intervention may be required to correct some of the adverse effects.

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- Risks associated with any surgical procedure: abscess; cellulitis; excessive fibrotic tissue; wound dehiscence; wound, local or systemic infection; wound necrosis; edema; inflammation; foreign body reaction; hematoma; seroma; thrombosis; ischemia; embolism; thromboembolism; hemorrhage; thrombophlebitis; adverse reactions to anesthesia; hypertension; pulmonary complications; organ, nerve or muscular damage; gastrointestinal or genitourinary compromise; seizure, convulsion, or changes to mental status; complications of pregnancy including miscarriage and fetal birth defects; inability to resume activities of daily living; and death.

- Risks associated with SCS system placement procedures: temporary pain at the implant site, infection, cerebrospinal fluid (CSF) leakage, CSF fistula, epidural hemorrhage, bacterial meningitis, seroma, hematoma, paralysis, skin irritation, inadequate wound healing or wound dehiscence, spinal cord compression; nerve, nerve root, or spinal cord injury. Patient use of anticoagulation therapies may increase the risk of procedure-related complications such as hematomas, which could produce paralysis.

- Risks associated with the use of a SCS system: lead/IPG migration or suboptimal placement; allergic response or tissue reaction to the implanted system material; hematoma or seroma at the implant site; skin erosion at the implant site; persistent pain at the implant site; dysesthesia; decubitus; premature battery depletion; loss of pain relief over time; uncomfortable stimulation; unwanted stimulation (e.g., radicular chest wall stimulation, gastrointestinal symptoms, bladder symptoms); increased pain; weakness, clumsiness, numbness or pain below the level of lead implantation; and failure or malfunction resulting in ineffective pain control or other undesirable changes in stimulation, and possibly requiring explant and re-implantation.

For specific adverse events that occurred in the clinical study, please see Section X.D.1 below.

IX. SUMMARY OF NONCLINICAL STUDIES

A. Laboratory Studies

1. Closed Loop Stimulator (CLS)

Testing was conducted on the Evoke CLS, including: mechanical design verification (including testing on devices subjected to accelerated aging), standards compliance testing, electrical basic safety testing, and medical procedure compatibility testing. Key testing on the CLS is summarized in Table 3. Testing demonstrated that the CLS operated according to specifications after exposure to the test conditions and thus passed all testing.

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Table 3. Summary of Key Testing Performed and Passed on the Evoke System CLS

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Dimensional Requirements | Confirms CLS meets volume requirements | Meets specification for total volume ≤ 45cc  |
|  Lead Insertion and Withdrawal Forces | Confirms lead can be inserted and withdrawn from the CLS lead port without excessive force. | Insertion and withdrawal force ≤ 14N  |
|  DC Leakage Current | Confirms CLS meets requirements of ISO 14708-1:2014 §16.2 | DC Leakage currents to patient shall be less than 0.75μA/mm2  |
|  Protection from External Defibrillators | Confirms CLS meets requirements of ISO 14708-1:2014 §20.2 | CLS meets functional requirements and maximum current requirements after exposure.  |
|  Mechanical Stress | Confirms CLS is able to function within specification after exposure to random vibration, shock, pressure and temperature conditions set out in ISO 14708-1. | Passes final production functional test.  |
|  Hermetic Leak Test | Confirms CLS battery area is maintained under a hermetic seal | Helium leak shall not exceed 6.6 x 10-8std/cc/s.  |
|  Particulate Matter | Confirms CLS meets requirements for particulate per ISO 14708-1:2014 | (Particulate size, acceptable number/volume) ≥ 5μm, ≤100 particles/ ml ≥ 25μm, ≤5 particles/ ml  |
|  Battery | Confirms Battery Charge/Discharge Cycle Verification (Longevity) | Acceptable for intended use.  |
|   | Electrical, Visual, Dimensional, Hermeticity, Short Circuit Testing, Environmental, and Forced Discharge Tests | Meets acceptance criteria  |
|  Header Bond Strength | Confirms the CLS header is able to withstand applied mechanical forces and remain functional | Passes visual inspection with no sign of header delamination and passes final electronic control test  |

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|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Temperature | Confirms ability of CLS charging system to disable charging if CLS temperature reaches a maximum temperature limit. | Verified to disable charging at 41°C.  |
|  Stimulation Verification | Confirms that stimulation parameters programmed produce appropriate stimulation | Meets acceptance criteria  |
|  Feedback Mechanism | Confirms ECAP measurement, stimulation adjustment and stimulation monitoring function per requirements. | Meets acceptance criteria  |

# 2. Percutaneous Lead Testing

The percutaneous leads underwent testing for dimensional verification, electrical safety, environmental, and mechanical conditions. Key testing on the leads is summarized in Table 4. Testing was performed on pre-conditioned leads and demonstrated that they operated according to specifications after exposure to the test conditions and thus passed all testing.

Table 4. Summary of Key Testing Performed on the Percutaneous Leads

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Dimensional | Confirm lead overall and electrode dimensions | As per specifications  |
|  Stylet Insertion/Removal | Confirm ability to fully insert / remove straight and bent stylets from lead lumen without penetrating lead lumen or distal end of lead | Full insertion / removal without damage or change to electrical property with insertion force of 15N. Distal end of lumen not penetrated after applying 5N of force with stylet.  |
|  Lead/ Needle Interaction – Insertion/Removal | Confirm lead remains electrically and mechanically undamaged after 5 insertions/removals from needle | Lead meets DC resistance criteria and lead body is free of damage to insulation or conductors  |
|  Lead Retention in CLS | Confirm ability of lead to be retained in the CLS lead port | Lead shall not be removed with a force less than 14N.  |
|  DC Resistance | Confirm electrical continuity after mechanical bending along body, at header, at anchor and with acute bends and torque | Lead meets DC resistance criteria and lead is free of damage to insulation or conductors  |

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|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Dielectric Strength | Confirms Lead meets requirements of ISO 14708-1:2014 §16.3 | Leakage current between any two Lead conductors, as well as between any Lead conductor and a reference electrode, shall not exceed 480uA in RMS magnitude  |
|  Lead Body Flex Fatigue | Confirm ability of lead body to withstand mechanical bending simulating actual use | Lead meets DC resistance criteria and lead body is free of damage to insulation or conductors after 47,000 cycles of flexural fatigue  |
|  Connector End Flex Fatigue | Confirm ability of lead connectors to withstand mechanical bending simulating actual use | Lead meets DC resistance criteria and lead body is free of damage to insulation or conductors after 82,000 cycles of flexural fatigue  |

3. External Closed Loop Stimulator, Clinical Interface, and Evoke Pocket Console

The software associated with the External Closed Loop Stimulator, Clinical Interface and Patient Console was developed and tested in accordance with IEC 62304:2015, Edition 1.1 - Medical device software – Software life cycle processes, and all requirements were met. Software information provided is based on guidance from the FDA document “Guidance for the Content of Pre-market Submission for Software Contained in Medical Devices” (May 11, 2005). Electrical, mechanical and environmental testing for the devices was also performed and all testing met specifications.

- External Closed Loop Stimulator (eCLS, Trial Stimulator)

The External Closed Loop Stimulator was subjected to the following types of testing: electrical/firmware design verification, mechanical, shipping, environmental (storage and operational), product safety testing (per IEC 60601-1, Type BF safety classification, and IEC 60601-1-11), drop testing (per IEC 60601-1, 3rd edition), EMC testing (per IEC 60601-1-2). All test articles met defined acceptance criteria for the defined verification tests.

- Clinical Interface (CI)

The Clinical Interface is an off-the-shelf Microsoft Surface Pro and has been subjected to testing applicable for its general use. The CI has been validated for use with Saluda Medical programming and data viewer

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software through System Validation testing.

- Evoke Pocket Console (EPC)

The Evoke Pocket Console was subjected to the following types of testing: functional verification, mechanical, environmental (storage and operational), product safety testing (per IEC 60601-1, 3rd edition, Type BF, and IEC 60601-1-11), including ingress, protection against electric shock (internally powered equipment), and drop testing. All test articles met defined acceptance criteria for the defined verification tests.

4. Electromagnetic Compatibility Testing and Wireless Technology

EMC and wireless technology (including quality of service (QOS), coexistence, and security of wireless transmissions testing) was performed using appropriate essential performance criteria in accordance with relevant clauses of the following standards. All components met specified acceptance criteria:

- IEC 60601-1-2: 2007, Medical electrical equipment - Part 1-2: General requirements for basic safety and essential performance - Collateral standard: Electromagnetic compatibility - Requirements and tests
- ISO 14708-3:2017(E): Implants for surgery – Active implantable medical devices – Part 3: Implantable neurostimulators, Part 27

5. System Testing

Testing to verify that system-level design requirements were met for interactions between Evoke System components was performed. All test articles met defined acceptance criteria for the system integration tests conducted. System validation testing consisting of the following was conducted on the Evoke system components: evaluating the compatibility, interaction and functional operation of the system components when used together as a system. All validation steps passed. System validation testing demonstrated that the system operated as expected and has been validated for safe and effective use.

6. CLS Medical Compatibility Testing

The Evoke CLS was tested for compatibility with external defibrillation, high power electric fields and diagnostic ultrasound (see Table 5). The implanted SCS system (CLS and leads) was evaluated for effects on its function and programming by exposure to the medical therapies that may occur on a patient during or after implantation of an Evoke System. Functional testing was

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performed on each CLS before exposure to confirm that it meets all of its performance requirements, and where appropriate, each was monitored during exposure. Functional testing was then performed post exposure to confirm that the CLS still met all functional requirements, and that the exposure to medical therapy had no effect on device performance, program, or stored calibrations. All samples met all functional requirements of the testing after exposure to medical therapy conditions, verifying that the CLS meets requirements for compatibility with these therapies.

Table 5. Summary of Key CLS Medical Compatibility Testing

|  Test | Acceptance Criteria  |
| --- | --- |
|  External Defibrillator Test | System meets functional electrical test requirements after exposure to external defibrillation per ISO 14708-1, clause 20.2  |
|  High Power Electrical Fields Test | System meets requirements of ISO 14708-1, clause 21  |
|  Diagnostic Ultrasound Test | System meets requirements of ISO 14708-1, clause 22.1  |

B. Animal Studies

1. Recording and Measurement of Evoked Spinal Cord Potentials in Ovine: An Acute Study – First Sheep Study

This study was approved by the animal ethics committee at the University of Melbourne (Melbourne, Victoria, Australia). The purpose of this study was to determine if an evoked response can be measured from the spinal cord. A total of 6 sheep were evaluated in this study. Electrodes were connected to a TDT (Tucker-Davis Technologies, Fl. USA) RZ5 amplifier and bio-processor system and a WPI (World Precision Instruments, Fl. USA) A385 current source. The evoked response was measured after directly stimulating the electrodes in the spinal canal or after stimulating the periphery either electrically or mechanically. Clear evoked responses were measured after stimulating the spinal cord. This study demonstrated that it was possible to record ECAP signals directly from the lead being used to apply the stimulation and characterized neurophysiological properties of nerve fibres activated during SCS in sheep.

2. Recording and Measurement of Evoked Spinal Cord Potentials in Ovine: An Acute Study – MCS Sheep Study

The study was approved by the ethics committee (ACEC) at the Royal North Shore Hospital (Sydney, New South Wales, Australia). The purpose of this study was to further characterize the neurophysiological properties of dorsal column fibres and to evaluate a custom stimulator and recording system (NICTA Multi-

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channel stimulation and recording system (MCS); NICTA Implant Systems/Saluda Medical, Sydney Australia). Experiments aimed at understanding properties of the dorsal columns included measuring conduction velocities, rheobase, chronaxie, and refractory periods. Preliminary testing of feedback control was also performed. Twenty-seven sheep were evaluated acutely under this protocol. This study demonstrated the ability to measure ECAPs with the NICTA system in sheep and characterized the neurophysiological properties of nerve fibres activated during SCS in sheep. The results of this study are published in Parker et al. (2013) (2).

# C. Biocompatibility

Biocompatibility was evaluated for all user- and patient-contacting components of the Evoke SCS System in accordance with ISO 10993-1 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process. FDA's 2016 Biocompatibility Guidance "Use of International Standard ISO 10993-1, 'Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process' was also followed. Testing was conducted in compliance with Good Laboratory Practices (GLP), 21 CFR Part 58, on finished, sterilized devices or representative samples reflecting all materials and manufacturing processes. The implanted components of the Evoke SCS System are considered long-term ( $&gt;30$  days) implants in contact with tissue/bone. The Evoke SCS System also contains external communicating components with limited ( $\leq 24$  hours) tissue/bone contact and skin-contacting component with limited to long-term ( $\leq 24$  hours to over 30 days) contact. The biocompatibility test data are summarized in Table 6 below.

Table 6. Biocompatibility Test Data on the Implantable, External Communicating, and Skin-Contacting Components of the Evoke SCS System

|  Biological Effect (Applicable Standard) | Test Method | Results  |
| --- | --- | --- |
|  Implanted (long-term)a, External Communicating (limited)b, and Skin-contacting (limited to long-term)c Components:  |   |   |
|  Cytotoxicity (ISO 10993-5) | MEM Elution Cytotoxicity Assay (implant & external communicating components, and skin-contacting component with long-term contact*) | Non - cytotoxic  |
|   |  Agar Overlay Cytotoxicity Assay (skin-contacting components) | Non-cytotoxic**  |
|  Sensitization (ISO 10993-10) | Guinea Pig Maximization Test (implant & external communicating components, and skin-contacting component with long-term contact*) | Non-sensitizing  |
|   |  Closed-Patch (Buehler) Test (skin-contacting components)  |   |

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|  Irritation or Intracutaneous Reactivity (ISO 10993-10) | Intracutaneous Reactivity Test (implant & external communicating components, and skin-contacting component with long-term contact*) | Non-irritant  |
| --- | --- | --- |
|   |  Skin Irritation Test (skin-contacting components)  |   |
|  Implanted (Long-term)a and External Communicating (limited)b Components  |   |   |
|  Systemic Toxicity (ISO 10993-11) Material-Mediated Pyrogenicity USP <151> | Material-Mediated Pyrogenicity Test | Non-pyrogenic  |
|  Systemic Toxicity (ISO 10993-11) Acute | Acute Systemic Toxicity Test | No acute systemic toxicity  |
|  Implanted (long-term)c Components  |   |   |
|  Systemic Toxicity (ISO 10993-11) Subacute Subchronic, Chronic | 13-week Rabbit Subcutaneous Implantation / Systemic Toxicity Study | Acceptable systemic toxicity risks  |
|   |  Chemical characterization and toxicological Risk Assessment  |   |
|  Genotoxicity (ISO 10993-3) | Bacterial Reverse Mutation Assay (Ames Test) | Non-genotoxic  |
|   |  In Vitro Mouse Lymphoma Assay  |   |
|   |  |   |
|   |  Chemical characterization and toxicological risk assessment  |   |
|  Local Effects after Implantation (ISO 10993-6) | 4-week Rabbit Subcutaneous Implantation Study | Acceptable implantation risks  |
|   |  13-week Rabbit Subcutaneous Implantation Study  |   |
|   |  90-day Ovine Implantation Study  |   |
|  Carcinogenicity (ISO 10993-3) | Chemical characterization and toxicological risk assessment | Non-carcinogenetic  |

a Components tested: Evoke Closed Loop Stimulator, Lead, Lead Extension, Port Plug, Lead Anchor
b Components tested: Tunneling Tool, Epidural Needle, Torque Wrench
c Component tested: Evoke Charger, Pocket Console, Case, Belt Strap, Belt Pouch
* Evoke Pocket Console is an intact skin-contacting component with prolonged (&gt;24 hours, &lt; 30 days) contact
** For assessment of cytotoxicity risk from the Belt Strap, the testing data as well as use of the belt strap materials in US legally marketed devices were considered.

## D. Sterility and Packaging

The Evoke SCS System components that are provided sterile are terminally sterilized using a 100% ethylene oxide (EO) sterilization cycle. Validation of the sterilization process demonstrates a Sterility Assurance Level (SAL) of 10⁻⁶ and complies with ANSI/AAMI/ISO 11135-1:2007. Sterilization of health care products – Ethylene oxide – Part 1: Requirements for development, validation, and routine control of a sterilization process for medical devices.

Sterilant residuals conform to the maximum allowable limits of EO) and Ethylene Chlorohydrin (ECH) residuals specified in ISO 10993-7: 2008. Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide Sterilization Residuals.

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The product bacterial endotoxin limits were chosen based on FDA’s Guidance for Industry - Pyrogen and Endotoxins Testing: Questions and Answers (June 2012) and were verified using Limulus Amoebocyte Lysate (LAL) testing.

Packaging and shelf-life validation tests were completed in compliance with ISO 11607:2006 Packaging for Terminally Sterilized Medical Devices. A shelf-life of two years has been established for the CLS and one year has been established for the other sterile system components.

## E. Usability Testing

Patient and clinician usability testing were conducted per IEC 62366-1: 2015-02 Medical Devices – Part 1: Application of usability Engineering to medical devices to verify users’ ability to perform those tasks for which failure to properly perform them could lead to death or serious injury. Usability aspects of tasks required for the overall safe and effective use of the device, but not posing serious risk to the user was also performed by patients and health care providers. System usability testing was completed successfully with no critical user errors identified in any of the use environments.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the Evoke System for treatment of chronic, intractable pain of the trunk and/or limbs in the US under Investigational Device Exemption (IDE) #G150266. A summary of the clinical study is presented below.

Additionally, long-term safety and effectiveness of the Evoke System is supported by a clinical study performed in Australia (Avalon study) and is summarized in section XI.A.

## A. Study Design

The Evoke pivotal clinical study was a prospective, multicenter, randomized, double-blind, clinical trial. The study was designed to compare the use of ECAP-controlled, closed-loop stimulation to open-loop stimulation. The Evoke System open-loop stimulation mode is equivalent to other commercially available SCS systems. Because the Evoke System additionally features the ability to measure ECAPs in both open- and closed-loop stimulation modes, use of the Evoke System in both treatment groups allowed for a more direct comparison of spinal cord activation between groups. Thus, the study population was randomized to either the Evoke System closed-loop stimulation mode (Investigational group) or to open-loop stimulation (representative of treatment with commercially available SCS systems) using the Evoke System open-loop stimulation mode (Control group). Spinal cord activation was measured via ECAPs in both treatment groups.

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Subjects, Investigators, and investigational site staff were blinded to the treatment assignment (double-blind). Subjects were randomized in a 1:1 ratio to the treatment arms and a frequentist statistical analysis was performed. The primary objective of the study was to demonstrate that outcomes related to chronic intractable trunk and/or limb pain were at least as good (non-inferior) when using closed-loop SCS compared to open-loop SCS. Additionally, if non-inferiority was established, the study was designed to further assess the potential superiority of closed-loop SCS for treatment of chronic intractable trunk and/or limb pain compared to open-loop SCS. The required sample size was 120 subjects total (60 subjects in each treatment group). To account for potential drop-out, a total of up to 134 subjects (67 subjects in each treatment group) could be randomized.

An independent, blinded Clinical Events Committee (CEC) reviewed and adjudicated all adverse events occurring in the study. An independent, blinded Medical Monitor provided guidance on the study.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Evoke study was limited to patients who met the following inclusion criteria:

a. Subject is male or female between the ages of 18 and 80 years.
b. Have been diagnosed with chronic, intractable pain of the trunk and/or limbs, which has been refractory to conservative therapy for a minimum of 6 months.
c. VAS (visual analog scale) leg pain score ≥ 6 cm.
d. VAS back pain score ≥ 6 cm.
e. VAS overall trunk and limb pain score ≥ 6 cm.
f. Be an appropriate candidate for an SCS trial and the surgical procedures required in this study based on the clinical judgment of the Investigator.
g. Prescribed pain medications have been stable for at least 30 days prior to the baseline evaluation.
h. Owestry Disability Index (ODI) score of 41-80 (severely disabled or crippled) out of 100 at the baseline evaluation.

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i. Be willing and capable of giving informed consent and able to comply with study-related requirements, procedures, and visits.

j. The subject’s primary back pain is located such that lead placement will be in the thoracolumbar region.

Patients were not permitted to enroll in the Evoke study if they met any of the following exclusion criteria:

a. Have a medical condition or pain in other area(s), not intended to be treated with SCS, that could interfere with study procedures, accurate pain reporting, and/or confound evaluation of study endpoints, as determined by the Investigator.

b. Have evidence of an active disruptive psychological or psychiatric disorder or other known condition significant enough to impact perception of pain, compliance of intervention, and/or ability to evaluate treatment outcomes.

c. Are not a surgical candidate due to a diagnosis of an uncontrolled coagulation disorder, bleeding diathesis, progressive peripheral vascular disease, uncontrolled diabetes mellitus, or morbid obesity.

d. Have an existing drug pump and/or SCS system or another active implantable device such as a pacemaker, deep brain stimulator (DBS), or sacral nerve stimulator (SNS).

e. Have prior experience with SCS.

f. Have a condition currently requiring or likely to require the use of MRI or diathermy.

g. Have a life expectancy of less than 1 year.

h. Have an active systemic infection or local infection in the area of the surgical site.

i. Be allergic, or have shown hypersensitivity, to any materials of the neurostimulation system which come in contact with the body.

j. Be pregnant or nursing (if female and sexually active, subject must be using a reliable form of birth control, be surgically sterile, or be at least 2 years post-menopausal).

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k. Have a documented history of substance abuse (narcotics, alcohol, etc.) or substance dependency in the 6 months prior to the baseline evaluation.

l. Be concomitantly participating in another clinical study.

m. Be involved in an injury claim under current litigation or have pending/approved worker’s compensation claim.

n. Had surgery and/or interventional procedure to treat back and/or leg pain within 90 days (if surgery) and 30 days (if any other procedure) prior to the baseline evaluation.

o. Subject is a prisoner.

p. Being treated with electroconvulsive therapy (ECT) or transcranial magnetic stimulation (rTMS).

q. Subject is unwilling or unable to discontinue and remain off of any medication used to treat chronic pain that is not FDA approved for chronic pain.

r. Subject has pain due to peripheral vascular disease or angina.

s. Subject is on anticoagulation therapy that would preclude their ability to undergo the implant procedure.

2. Follow-up Schedule

All subjects first underwent a trial with the external trial stimulator to determine eligibility for the permanent implant. Randomization occurred following trial lead placement. Subjects who had at least a 50% reduction compared to baseline in overall trunk and limb pain as measured by a Visual Analog Scale (VAS) at the end of the trial were approved to receive a permanent implant. Other preoperative assessments are described in Table 7. All subjects were scheduled to return postoperatively at 1-, 3-, 6-, 9-, and 12-months after implantation and biannually thereafter for up to 3 years. Postoperative assessments are described in 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. Pre- and Intraoperative Visit Schedule (Baseline through Implant Procedure)

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|  Assessment | Screening/ Baseline | Trial Procedure | Trial End (≤30 days) | Implant Procedure (Day 0)  |
| --- | --- | --- | --- | --- |
|  Informed Consent | X |  |  |   |
|  Inclusion/Exclusion | X |  |  |   |
|  Baseline Evaluation (Demographics, Medical History, Physical Exam, Psychological Evaluation) | X |  |  |   |
|  Pain Medication/ Therapies | X | X | X | X  |
|  Procedure/X-rays |  | X | [X] | X  |
|  Programming |  | X |  | X  |
|  Pain Assessment (Visual Analog Scale (VAS) & Pain Map) | X |  | X |   |
|  Pain Diary | X |  |  |   |
|  Oswestry Disability Index (ODI) | X |  |  |   |
|  Short Form Health Survey (SF-12) | X |  |  |   |
|  EuroQoL (EQ-5D-5L) | X |  |  |   |
|  Profile of Mood States (POMS) | X |  |  |   |
|  Pittsburgh Sleep Quality Index (PSQI) | X |  |  |   |
|  Adverse Event Monitoring | X | X | X | X  |
|  Study Exit |  |  | X^{1} |   |
|  [X] = Optional
^{1}A Study Exit form was completed for all enrolled (i.e., randomized) subjects at the time of study exit (i.e., study completion or early withdrawal).  |   |   |   |   |

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Table 8. Postoperative Visit Schedule (Follow-up)

|  Assessment | 1 Month1 | 3 Month1 | 6 Month1 | 9 Month1 | 12 Month1 | 18, 24, 30, & 36 Month1  |
| --- | --- | --- | --- | --- | --- | --- |
|  Telephone Follow-up | X | X | X | X | X | X  |
|  Pain Medication/Therapies | X | X | X | X | X | X  |
|  Procedure/X-rays | [X] | [X] | [X] | [X] | [X] | [X]  |
|  Programming | [X] | [X] | [X] | [X] | [X] | [X]  |
|  Pain Assessment (Visual Analog Scale (VAS) & Pain Map) | X | X | X | X | X | X  |
|  Pain Diary | X | X | X |  | X | X  |
|  Oswestry Disability Index (ODI) | X | X | X |  | X | X  |
|  Short Form Health Survey (SF-12) | X | X | X |  | X | X  |
|  EQ-5D-5L | X | X | X |  | X | X  |
|  Profile of Mood States (POMS) | X | X | X |  | X | X  |
|  Pittsburgh Sleep Quality Index (PSQI) | X | X | X |  | X | X  |
|  Patient Global Impression of Change (PGIC) & Patient Satisfaction | X | X | X |  | X | X  |
|  Posture Change Assessment | X | X | X |  | X | X  |
|  Stimulation Characteristics |  | X |  |  | X | X  |
|  Blinding Assessments |  | X |  |  | X |   |
|  Adverse Event Monitoring | X | X | X | X | X | X  |
|  Study Exit |  |  |  |  |  | X²  |
|  [X] = Optional 1Visit Windows: 1-Month (30 days ± 14 days), 3-Month (90 days ± 14 days), 6-Month (180 days ± 30 days), 9-Month (270 days ± 30 days), 12-Month (365 days ± 30 days), 18-month (545±90 days), 24-month (730±90 days), 30-month (910±90 days), and 36-month (1095±90 days) 2A Study Exit form was completed for all enrolled (i.e., randomized) subjects at the time of study exit (i.e., study completion or early withdrawal).  |   |   |   |   |   |   |

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## 3. Clinical Endpoints

### Primary Effectiveness Endpoint

The primary endpoint was a composite of the percentage of subjects that experienced a 50% or greater reduction in average overall trunk and limb pain at the primary endpoint visit (3-month) and had no increase in baseline pain medications within 4 weeks of the primary endpoint visit.

The primary analysis was conducted at the 3-month follow-up and an additional pre-defined analysis was completed at the 12-month follow-up.

### Individual Subject Success

An individual subject was considered a primary composite endpoint success if the subject:

- Experienced at least 50% pain relief in average overall trunk and limb pain as measured by a 100 mm Visual Analogue Scale (VAS) at 3-month visit; and
- No increase in baseline pain medications within 4 weeks of the primary endpoint visit.

Subjects who increase their baseline pain medications under the following conditions were considered a failure for this component of the primary endpoint:

- An increase in morphine equivalent units (MEU) of a baseline opioid within 4 weeks of primary endpoint visit.
- Exceptions: temporary increase to treat post-procedure pain or an acute co-morbidity unrelated to the study indication that was not expected to respond to SCS.
- An increase from baseline in non-opiate pain medication used to treat their study indication pain for a duration of greater than 5 days that was not stopped within 4 weeks of primary endpoint visit.
- Exceptions: Tylenol/rescue medication was allowed up to two weeks prior to the primary endpoint visit.

### Study Success

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Study success was defined as the percentage of subjects who met the criteria for Individual Subject Success in the closed-loop (Investigational) group compared to the open-loop (Control) group, using a 10% non-inferiority margin. If non-inferiority was achieved at a one-sided alpha of 0.05, a two-sided superiority test was performed at the significance level of 0.05.

## Hierarchical Secondary Effectiveness Endpoints

If non-inferiority was met in the testing of the primary composite endpoint, the following secondary endpoints were successively evaluated (hierarchical test approach) in the order shown using a 10% non-inferiority margin with a 0.05 significance level until statistical significance was not achieved. All four secondary endpoints were initially tested at 3 months. If all four secondary endpoints passed non-inferiority at the 3-month analysis, hierarchical testing continued at 12 months in the same order specified below until a hypothesis test failed. All secondary endpoints that passed their non-inferiority test were tested for superiority, first at 3-months and then at 12-months. P-values adjusted for multiple comparisons (via the Hochberg method) are provided for the tests of superiority.

a. Comparison of percentage change from baseline in average leg pain (as assessed by VAS) between Investigational and Control groups at the primary endpoint visit.
b. Comparison of percentage change from baseline in average back pain (as assessed by VAS) between Investigational and Control groups at the primary endpoint visit.
c. Comparison of incidence of ≥80% reduction in average overall trunk and limb pain (as assessed by VAS) between Investigational and Control groups at the primary endpoint visit.
d. Comparison of incidence of ≥50% reduction in average back pain (as assessed by VAS) between Investigational and Control groups at the primary endpoint visit.

## Additional Secondary Endpoints

A number of additional secondary endpoints were also collected and assessed across study visits. These endpoints include the following:

a. Comprehensive summary of all Adverse Events (AEs)

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b. Change, percent change, incidence of ≥50% (“responders”) and ≥80% (“high responders”) reduction, and cumulative proportion of responders analysis in VAS pain scores

c. Pain Map

Data were collected by asking subjects to shade in the areas where they were experiencing pain on a body map drawing. These data were used to record the location of the pain being treated with the SCS system.

d. Pain Diary

Data on pain variability were collected through subject completion of a pain diary.

e. Oswestry Disability Index (ODI)

f. Short Form Health Survey (SF-12)

g. EQ-5D-5L

h. Profile of Mood States Brief (POMS)

i. Pittsburgh Sleep Quality Index (PSQI)

j. Patient Global Impression of Change (PGIC)

Data on patient global impression of change were collected as a single item measure of global improvement with treatment using a 7-point rating scale containing the options “very much improved”, “much improved”, “minimally improved”, “no change”, “minimally worse”, “much worse”, and “very much worse”.

k. Patient Satisfaction

Data on subject satisfaction with the therapy and pain relief (“very satisfied,” “satisfied,” “neither satisfied nor unsatisfied,” “unsatisfied,” and “very unsatisfied”) along with likelihood of recommending the therapy (“strongly recommend,” “recommend,” “neutral,” “not recommend,” and “definitely not recommend”) were collected.

l. Posture Change Assessment

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Data on spinal cord (SC) activation (ECAP amplitude) and the subjects' perception of stimulation intensity (11-point numeric scale, from 0 representing "No Feeling" to 10 "Very Intense" based on a published paresthesia intensity rating scale (3)) were collected in different postures in-clinic to mimic activities of daily living (i.e., coughing, lying down, and sitting).

m. Stimulation Characteristics

Data on subjects' general stimulation sensation and experience, including usage, perception of paresthesia, stimulation management strategies, and interaction with the device, were collected.

n. Programming and Neurophysiologic Properties

Programming parameters collected for each program during programming sessions included:

- Frequency (Hz)
- Pulse Width (μs)
- Stimulation Current Amplitude (mA)
- Measured Sensitivity (i.e., rate of change of the ECAP amplitude per unit input current (μV/mA))

Neurophysiological properties collected during programming sessions included:

- ECAP waveform features: ECAP amplitude, width, slope, and shape.
- Conduction Velocity: the speed at which an ECAP propagates along a neural pathway (m/s).
- Rheobase: the minimum stimulus current needed for neural activation at an infinitely long pulse width (mA).
- Chronaxie: the minimum pulse width needed for neural activation at twice the rheobase current (μs).
- Late Responses: neural responses resulting from dorsal root activation.

The ECAP amplitude is representative of the number of spinal cord (SC) fibers activated by stimulation (4). The Evoke System produces an ECAP amplitude for each stimulus and stores the ECAP amplitudes as histogram data. The ECAP amplitude histograms are an objective measure of the SC activation in response to spinal cord stimulation over time. The ECAP amplitude histograms were characterized by some key statistics to elucidate any differences in SC activation between closed-loop (Investigational) and open-loop (Control) stimulation. These include:

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- Mode ECAP Amplitude: is a measure of the most frequent SC activation level for a given histogram period.
- Ratio of the Mode ECAP Amplitude to the Comfort Level ECAP Amplitude (mode/comfort level): is a measure of how close the most frequent SC activation level is to the comfort level. A value closer to 1 is indicative of SC activation near or at the comfort level.
- Ratio of the Interdecile ECAP Amplitude Range to the Median ECAP Amplitude ((90th percentile – 10th percentile)/median): is a measure of the spread of the ECAP amplitude histogram where lower values mean that the spread of the distribution is tighter around the median.

The therapeutic range of SC activation is defined by the ECAP amplitudes between patient perception threshold and maximum (i.e., therapeutic window).

- Patient Perception Threshold: the SC activation level the patient first feels a change in sensation (e.g., paresthesia, pain relief).
- Comfort Level: the SC activation level perceived as comfortable by the patient.
- Maximum Level: the SC activation level the patient can withstand (or tolerate) for approximately one minute.

The percent time the subjects’ SC activation was within the therapeutic window was calculated. Refer to Figure 2 for theoretical examples of ECAP amplitude represented as histogram data (normal and non-normal distribution) and how statistical measures from these histograms may be used to describe SC activation for a patient.

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![img-1.jpeg](img-1.jpeg)
Figure 2. Theoretical Examples of ECAP Amplitude Histogram Statistics

![img-2.jpeg](img-2.jpeg)

# Safety Endpoint

The incidence and characteristics of all adverse events were evaluated for the entire study population and also compared between treatment groups.

# Analysis Populations

The primary analysis population, as prespecified in the Statistical Analysis Plan (SAP) was the Intention-To-Treat (ITT) analysis dataset, which included all randomized subjects with known endpoint status or classified as a presumed non-responder.

Additionally, the SAP prespecified an additional analysis population to assess study outcomes. The Permanent Implant Subset (PIS), a subset of the ITT analysis dataset, included the subjects in the ITT population who received a permanent implant.

The following events eliciting missing data at 3 months caused a subject to be classified as a presumed non-responder:

- Failure of the trial stimulation phase (&lt;50% improvement in average overall trunk and limb pain VAS).
- Subject voluntary withdrawal due to an AE adjudicated as related to the device or stimulation.

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- Investigator withdrawal due to an AE adjudicated as related to the device or stimulation.

Additionally, a subject was considered a presumed non-responder after 3 months if they withdrew due to lack of efficacy.

Presumed non-responders were analyzed as failures for the primary endpoint, hierarchical secondary endpoint, and other secondary endpoint VAS incidence measures. For hierarchical secondary endpoint and other secondary endpoint in-clinic VAS continuous measures, subjects with missing data categorized as presumed non-responders utilized a last-value carried forward imputation methodology. Subjects that failed the medication component of the primary endpoint had a change from baseline value of “0” imputed for the hierarchical secondary endpoint calculations.

## B. Accountability of PMA Cohort

Patients were enrolled and randomized in the Evoke study between February 21, 2017 and February 20, 2018. The database for this PMA reflected data collected through April 1, 2019 and included 134 subjects (67 Investigational subjects, 67 Control subjects) from 13 investigational sites. All patients had passed through the 12-month window, and the study was in follow-up. The ITT population included 125 subjects (62 Investigational subjects, 63 Control subjects) at 3 months (timing of primary endpoint analysis) that were randomized and had known endpoint status (58 Investigational, 53 Control) or were classified as a presumed non-responder (4 Investigational, 10 Control), and 118 subjects at 12 months that were randomized and had known endpoint status (55 Investigational subjects, 48 Control subjects) or were classified as a presumed non-responder (4 Investigational subjects, 11 Control subjects).

Of the 125 subjects in the ITT population, 111 subjects (58 Investigational subjects, 53 Control subjects) received a permanent implant and were included in the PIS analysis set at 3 months. Fourteen randomized subjects failed the trial procedure (4 Investigational subjects, 10 Control subjects) and were therefore excluded from the PIS analysis dataset. At 12 months, there were 104 subjects (55 Investigational subjects, 49 Control subjects) in the PIS analysis dataset.

See Figure 3 for a flow diagram of subject accountability.

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![img-3.jpeg](img-3.jpeg)
Figure 3. Subject Accountability

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# C. Study Population Demographics and Baseline Parameters

Table 9 presents information on key baseline demographics and characteristics. There were no statistically significant differences in baseline demographics and characteristics between treatment groups, indicating that the randomization resulted in balanced groups, supporting the validity of comparisons between the groups. The demographics of the study population are typical for a study of this type performed in the US.

Table 9. Baseline Demographics and Characteristics - Randomized

|  Characteristic | Investigational N=67 Subjects | Control N=67 Subjects | P-value  |
| --- | --- | --- | --- |
|  Age (years) |  |  |   |
|  Mean (SD) | 54.6 (9.7) | 55.9 (11.6) | 0.490  |
|  Min., Max. | 28.7, 80.1 | 24.8, 80.8 |   |
|  Gender (n (%)) |  |  |   |
|  Male | 34 (50.7%) | 35 (52.2%) | 1.000  |
|  Female | 33 (49.3%) | 32 (47.8%) |   |
|  Race (not mutually exclusive) (n (%)) |  |  |   |
|  American Indian or Alaska Native | 1 (1.5%) | 2 (3.0%) |   |
|  Asian | 0 (0.0%) | 0 (0.0%) |   |
|  Black or African American | 2 (3.0%) | 6 (9.0%) |   |
|  Native Hawaiian or Other Pacific Islander | 0 (0.0%) | 0 (0.0%) |   |
|  White | 63 (94.0%) | 59 (88.1%) | 0.3651  |
|  Other2 | 0 (0.0%) | 2 (3.0%) |   |
|  Ethnicity (n (%)) |  |  |   |
|  Hispanic/Latino | 3 (4.5%) | 6 (9.0%) | 0.492  |
|  Non-Hispanic/Latino | 64 (95.5%) | 61 (91.0%) |   |
|  BMI (kg/m2) |  |  |   |
|  Mean (SD) | 31.3 (5.7) | 32.4 (6.8) | 0.335  |
|  Min., Max. | 18.3, 46.2 | 17.5, 48.5 |   |

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|  Characteristic | Investigational N=67 Subjects | Control N=67 Subjects | P-value  |
| --- | --- | --- | --- |
|  Duration of Pain (years) |  |  |   |
|  Mean (SD) | 13.6 (9.6) | 11.2 (9.9) | 0.151  |
|  Min., Max. | 0.5, 41.4 | 0.7, 46.0 |   |
|  Pain Location (n (%)) |  |  |   |
|  Chronic Intractable Back Pain | 67 (100%) | 67 (100%) |   |
|  Chronic Intractable Leg Pain | 67 (100%) | 67 (100%) |   |
|  Unilateral | 24 (35.8%) | 28 (41.8%) | 0.595^{3}  |
|  Bilateral | 43 (64.2%) | 39 (58.2%) |   |
|  Pain Etiology (not mutually exclusive) (n (%)) |  |  |   |
|  Arachnoiditis | 0 (0.0%) | 2 (3.0%) | 0.496  |
|  Complex Regional Pain Syndrome (CRPS) I | 0 (0.0%) | 1 (1.5%) | 1.000  |
|  Degenerative Disc Disease | 33 (49.3%) | 42 (62.7%) | 0.164  |
|  Failed Back Surgery Syndrome (FBSS) | 38 (56.7%) | 41 (61.2%) | 0.726  |
|  Internal Disc Disruption or Tear / Discogenic Pain | 7 (10.4%) | 10 (14.9%) | 0.605  |
|  Lumbar Facet-Mediated Pain | 8 (11.9%) | 8 (11.9%) | 1.000  |
|  Mild-Moderate Spinal Stenosis | 26 (38.8%) | 27 (40.3%) | 1.000  |
|  Neuropathic Pain | 1 (1.5%) | 1 (1.5%) | 1.000  |
|  Radiculopathy | 61 (91.0%) | 59 (88.1%) | 0.779  |
|  Sacroiliac Joint-Mediated Pain | 9 (13.4%) | 5 (7.5%) | 0.398  |
|  Spondylolisthesis | 6 (9.0%) | 5 (7.5%) | 1.000  |
|  Spondylosis with Myelopathy | 2 (3.0%) | 3 (4.5%) | 1.000  |
|  Spondylosis without Myelopathy | 26 (38.8%) | 24 (35.8%) | 0.858  |
|  Other Chronic Pain | 6 (9.0%) | 3 (4.5%) | 0.492  |
|  Baseline Pain Medication Usage | 63 (94.0%) | 59 (88.1%) | 0.365  |

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|  Characteristic | Investigational N=67 Subjects | Control N=67 Subjects | P-value  |
| --- | --- | --- | --- |
|  Opioids | 41 (61.2%) | 40 (59.7%) | 1.000  |
|  Non-opioids4 | 51 (76.1%) | 52 (77.6%) | 1.000  |
|  Previous Non-Invasive Therapies5 | 65 (97.0%) | 64 (95.5%) | 1.000  |
|  Previous Interventional Procedure6 | 63 (94.0%) | 62 (92.5%) | 1.000  |
|  Previous Back Surgery7 | 39 (58.2%) | 41 (61.2%) | 0.860  |
|  Two-sample t-test between treatment groups for continuous variables; Fisher's exact test between treatment groups for categorical variables. 1Comparison of white versus non-white races. 2The 'Other' races included Middle Eastern (1) and Latino (1). 3Comparison of unilateral versus bilateral leg pain. 4Non-opioid pain medication classes include: anticonvulsant, antidepressant, local anesthetic, muscle relaxant, and NSAIDs 5Non-invasive therapies include: acupuncture, aquatherapy, assistive device, biofeedback, chiropractic care, exercise therapy, massage therapy, psychotherapy, physical therapy, transcutaneous electro-nerve stimulator (TENS) 6Interventional procedures include: ankle surgery, benign cyst removal, block/injection – other, epidural steroid injection, facet joint injection, intradiscal procedure (e.g., Intradiscal Electrothermal Therapy (IDET)), lumbar rhizotomy, lumbar sympathetic block, medial branch block, radiofrequency denervation, sacroiliac joint injection, trigger point injection 7Back surgeries include: artificial disc replacement, discectomy or microdiscectomy, foraminotomy, kyphoplasty and vertebroplasty, laminectomy, nucleoplasty (e.g., disc decompression, laser surgery), spinal fusion, back surgery – not otherwise specified, back surgery – other  |   |   |   |

# 1. Study Execution

Aside from the difference in stimulation mode, subjects in both treatment groups received the same care, with the device, implant procedure, and programming process being the same for both groups. There were no statistically significant differences between groups in procedure duration or lead placement for the trial or permanent implant procedures. All programming parameters were chosen using the process outlined in the Evoke Clinical Manual. Programming in both groups utilized ECAP measurement in addition to subject feedback to optimize patient outcomes. The only difference in programming was enabling (Investigational) or disabling (Control) the feedback loop. There were no statistically significant differences between groups in the frequency of programming visits, programming duration, and programming parameters (Table 10). Both treatment groups used the device the majority of the time with no statistically significant differences in usage between groups.

Table 10. Summary of Programming Parameters - ITT

|  Parameter | Investigational | Control | P-value  |
| --- | --- | --- | --- |
|  Stimulation Frequency (Hz) |  |  |   |
|  Mean (SD) | 41.7 (16.6) | 42.3 (13.6) | 0.850  |

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|  Parameter | Investigational | Control | P-value  |
| --- | --- | --- | --- |
|  Min., Max. | 10.0, 180.0 | 10.0, 90.0 |   |
|  Pulse Width (μs) |  |  |   |
|  Mean (SD) | 308.9 (83.2) | 296.9 (76.8) | 0.660  |
|  Min., Max. | 80.0, 740.0 | 100.0, 800.0 |   |
|  Processing Offset (μs) |  |  |   |
|  Mean (SD) | 182.9 (117.9) | 176.7 (80.2) | 0.662  |
|  Min., Max. | 61.0, 2441.0 | 61.0, 610.0 |   |
|  Filter Frequency (Hz) |  |  |   |
|  Mean (SD) | 951.1 (135.9) | 970.9 (182.8) | 0.147  |
|  Min., Max. | 565.0, 1928.0 | 565.0, 1928.0 |   |
|  Patient Sensitivity* (μV/mA) |  |  |   |
|  Mean (SD) | 98.9 (111.5) | -- | --  |
|  Min., Max. | 6.0, 1000.0 | -- |   |
|  Target Amplitude† (μV) |  |  |   |
|  Mean (SD) | 49.5 (59.4) | -- | --  |
|  Min., Max. | 0.0, 348.1 | -- |   |
|  Repeated measures mixed model for difference between groups. *Patient Sensitivity is used to set up the loop for the closed-loop (Investigational) therapy; is not relevant to the open-loop (Control) therapy. *Target Amplitude is set to the preferred level using the EPC during daily use by the patient for closed-loop (Investigational) therapy; is not relevant to the open-loop (Control) therapy. It is represented here by the Mode of the ECAP amplitude histogram collected prior to the 12-month visit.  |   |   |   |

Furthermore, at 3 and 12 months the subjects' electrophysiological measurements in both groups were statistically equivalent, demonstrating the ability of stimulation to recruit nerve fibers and produce action potentials (ECAP amplitude and other features), activate the same fiber types (conduction velocity), and produce comparable axonal excitability (rheobase) and membrane time constant (chronaxie) (Table 11). These data indicate that the randomization generated directly comparable treatment groups with respect to neurophysiology. On average, the conduction velocity was approximately  $60~\mathrm{m / s}$  in both treatment groups, which is within the literature reported range for  $\mathrm{A}\beta$  sensory fibers (5).

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Table 11. Summary of Neurophysiological Property Measurements at 3 and 12 Months – ITT

|   | 3 Month |   |   | 12 Month  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   | Investigational | Control | P-value | Investigational | Control | P-value  |
|  Conduction Velocity (m/s) |  |  |  |  |  |   |
|  Median | 57.3 | 58.9 | 0.430 | 60.2 | 58.9 | 0.996  |
|  Min., Max. | 45.1, 93.2 | 42.0, 82.9 |  | 43.3, 84.2 | 45.2, 86.2 |   |
|  Chronaxie (μs) |  |  |  |  |  |   |
|  Median | 359.5 | 311.0 | 0.181 | 306.6 | 236.2 | 0.259  |
|  Min., Max. | 75.7, 684.0 | 78.0, 866.7 |  | 116.9, 609.0 | 89.4, 633.4 |   |
|  Rheobase (mA) |  |  |  |  |  |   |
|  Median | 2.8 | 2.9 | 0.676 | 2.9 | 2.8 | 0.725  |
|  Min., Max. | 0.7, 6.0 | 1.0, 9.9 |  | 1.1, 6.8 | 1.0, 6.9 |   |
|  Kruskal-Wallis test between treatment groups.  |   |   |   |   |   |   |

Lastly, the double-blind design was maintained with no deviations in blinding, reducing the potential of data being systematically distorted by knowledge of the treatment received. The extent to which the characteristics of the treatment arms are statistically comparable and the robustness with which the study was executed and operationalized supports the strength of the study conclusions.

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on all randomized subjects (134 subjects total; 67 Investigational subjects, 67 Control subjects), and included all adverse events reported and adjudicated as of database lock. On average, Investigational subjects had a permanent implant for $16.3 \pm 3.8$ months and Control subjects had a permanent implant for $16.2 \pm 4.8$ months (mean $\pm$ SD). The cumulative implant months of experience for subjects that received a permanent implant was 959.0 months (79.8 years) in the Investigational group and 874.9 months (72.8 years) in the Control group.

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Key safety outcomes are presented below in Error! Reference source not found. through Table 17.

As all subjects received the same investigational device, underwent the same trial and permanent implant procedures, and received active stimulation. The characteristics of the adverse events are presented by treatment group and treatment groups combined (total) (Error! Reference source not found.), and by treatment groups combined only for the incidence of adverse event types (Table 13 through Table 17). Adverse events are reported according to the CEC adjudication. An adverse event was classified as 'study-related' if it was possibly or definitely related to the procedure, device, or stimulation therapy. The Clinical Events Committee guidelines were used to determine if an adverse event was definitely related, possibly related, or unrelated to the study.

The characteristics of all adverse events occurring in the study are presented by treatment group and by treatment groups combined (total) in Error! Reference source not found.. The type, nature, and severity of adverse events were similar between groups. No unanticipated serious adverse device effects (UADEs) occurred in this study as of database lock. There has been one death (cardiac arrest), unrelated to the study.

Table 12. Characteristics of All Adverse Events – Randomized

|   | Investigational N=67 Subjects |   | Control N=67 Subjects |   | TOTAL N=134 Subjects  |   |
| --- | --- | --- | --- | --- | --- | --- |
|  Characteristic | Events n | Subjects n (%) | Events n | Subjects n (%) | Events n | Subjects n (%)  |
|  Total Adverse Events | 150 | 45 (67.2%) | 104 | 45 (67.2%) | 254 | 90 (67.2%)  |
|  Adverse Event (AE) | 134 | 42 (62.7%) | 93 | 43 (64.2%) | 227 | 85 (63.4%)  |
|  Study-related* | 22 | 12 (17.9%) | 9 | 9 (13.4%) | 31 | 21 (15.7%)  |
|  Serious Adverse Event (SAE) | 16 | 10 (14.9%) | 11 | 8 (11.9%) | 27 | 18 (13.4%)  |
|  Study-related* | 1 | 1 (1.5%) | 2 | 2 (3.0%) | 3 | 3 (2.2%)  |
|  Relation to Device |  |  |  |  |  |   |
|  Unrelated | 143 | 45 (67.2%) | 99 | 44 (65.7%) | 242 | 89 (66.4%)  |

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|   | Investigational N=67 Subjects |   | Control N=67 Subjects |   | TOTAL N=134 Subjects  |   |
| --- | --- | --- | --- | --- | --- | --- |
|  Characteristic | Events n | Subjects n (%) | Events n | Subjects n (%) | Events n | Subjects n (%)  |
|  Possible | 4 | 4 (6.0%) | 3 | 3 (4.5%) | 7 | 7 (5.2%)  |
|  Definite | 3 | 3 (4.5%) | 2 | 2 (3.0%) | 5 | 5 (3.7%)  |
|  Relation to Procedure |  |  |  |  |  |   |
|  Unrelated | 133 | 44 (65.7%) | 96 | 41 (61.2%) | 229 | 85 (63.4%)  |
|  Possible | 4 | 3 (4.5%) | 3 | 3 (4.5%) | 7 | 6 (4.5%)  |
|  Definite | 13 | 9 (13.4%) | 5 | 5 (7.5%) | 18 | 14 (10.4%)  |
|  Relation to Stimulation Therapy |  |  |  |  |  |   |
|  Unrelated | 145 | 44 (65.7%) | 101 | 43 (64.2%) | 246 | 87 (64.9%)  |
|  Possible | 4 | 3 (4.5%) | 2 | 2 (3.0%) | 6 | 5 (3.7%)  |
|  Definite | 1 | 1 (1.5%) | 1 | 1 (1.5%) | 2 | 2 (1.5%)  |
|  Severity |  |  |  |  |  |   |
|  Mild | 41 | 27 (40.3%) | 32 | 24 (35.8%) | 73 | 51 (38.1%)  |
|  Moderate | 87 | 37 (55.2%) | 59 | 34 (50.7%) | 146 | 71 (53.0%)  |
|  Severe | 22 | 14 (20.9%) | 13 | 9 (13.4%) | 35 | 23 (17.2%)  |
|  Phase at Onset |  |  |  |  |  |   |
|  Prior to Trial | 5 | 5 (7.5%) | 3 | 3 (4.5%) | 8 | 8 (6.0%)  |
|  Trial Period | 1 | 1 (1.5%) | 2 | 2 (3.0%) | 3 | 3 (2.2%)  |
|  End of Trial to Implant | 7 | 6 (9.0%) | 6 | 5 (7.5%) | 13 | 11 (8.2%)  |

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|   | Investigational N=67 Subjects |   | Control N=67 Subjects |   | TOTAL N=134 Subjects  |   |
| --- | --- | --- | --- | --- | --- | --- |
|  Characteristic | Events n | Subjects n (%) | Events n | Subjects n (%) | Events n | Subjects n (%)  |
|  Implant to 30 Days | 12 | 11 (16.4%) | 9 | 7 (10.4%) | 21 | 18 (13.4%)  |
|  >30 days to 90 Days | 26 | 17 (25.4%) | 20 | 19 (28.4%) | 46 | 36 (26.9%)  |
|  >90 Days to 365 Days | 68 | 33 (49.3%) | 51 | 29 (43.3%) | 119 | 62 (46.3%)  |
|  >365 Days | 31 | 16 (23.9%) | 13 | 11 (16.4%) | 44 | 27 (20.1%)  |
|  Outcome |  |  |  |  |  |   |
|  Ongoing | 36 | 22 (32.8%) | 28 | 21 (31.3%) | 64 | 43 (32.1%)  |
|  Resolved without sequelae | 99 | 35 (52.2%) | 62 | 33 (49.3%) | 161 | 68 (50.7%)  |
|  Resolved with sequelae | 15 | 10 (14.9%) | 14 | 9 (13.4%) | 29 | 19 (14.2%)  |
|  Unanticipated Adverse Device Effect (UADE)1 | 0 | 0 (0.0%) | 0 | 0 (0.0%) | 0 | 0 (0.0%)  |
|  1An unanticipated adverse device effect (UADE) was defined as 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. *An adverse event was classified as 'study-related' if it was possibly or definitely related to the procedure, device, or stimulation therapy.  |   |   |   |   |   |   |

## Serious Adverse Events

Table 13 presents the study-related serious adverse events by treatment groups combined (total). Three serious adverse events in three subjects (1 Investigational and 2 Control) were study-related (2.2%); none were stimulation related. All three serious study-related serious adverse events occurred within 30 days of the procedure. These events included wound infection, epidural abscess, and lead breakage/fracture.

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Table 13. Summary of Study-Related Serious Adverse Events – Randomized

|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Total Adverse Events | 3 | 3 (2.2%)  |
|  Epidural Abscess | 1 | 1 (0.7%)  |
|  Lead Breakage/Fracture | 1 | 1 (0.7%)  |
|  Wound Infection | 1 | 1 (0.7%)  |

Table 14 presents the serious adverse events by treatment groups combined (total). Among the 134 randomized subjects, a total of 27 serious adverse events (SAEs) in 18 subjects (13.4%) were reported (16 SAEs, 14.9% Investigational subjects; 11 SAEs, 11.9% Control subjects). Eighteen of the 27 (66.7%) serious adverse events were classified as severe. At the time of database lock three SAEs were still ongoing (3/27 = 11.1%).

Table 14. Summary of Serious Adverse Events – Randomized

|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Total Adverse Events | 27 | 18 (13.4%)  |
|  Cellulitis | 3 | 2 (1.5%)  |
|  Arrhythmia and Irregularities | 2 | 2 (1.5%)  |
|  Abdominal Pain | 1 | 1 (0.7%)  |
|  Anxiety Disorders | 1 | 1 (0.7%)  |
|  Arthritis | 1 | 1 (0.7%)  |
|  Benign Prostatic Hypertrophy | 1 | 1 (0.7%)  |
|  Cardiac Chest Pain | 1 | 1 (0.7%)  |
|  Cholecystitis | 1 | 1 (0.7%)  |
|  Coronary Artery or Heart Disease | 1 | 1 (0.7%)  |

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|   | Total
N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events
n | Subjects
n (%)  |
|  Dehydration | 1 | 1 (0.7%)  |
|  Diverticulitis | 1 | 1 (0.7%)  |
|  Epidural Abscess | 1 | 1 (0.7%)  |
|  Facet Cyst | 1 | 1 (0.7%)  |
|  Fall or Trip or Slip or Twist | 1 | 1 (0.7%)  |
|  Lead Breakage/Fracture | 1 | 1 (0.7%)  |
|  Liver Abscess | 1 | 1 (0.7%)  |
|  MRSA | 1 | 1 (0.7%)  |
|  Myocardial Infarct or Heart Attack | 1 | 1 (0.7%)  |
|  Peripheral Vascular Disease | 1 | 1 (0.7%)  |
|  Prostate Cancer | 1 | 1 (0.7%)  |
|  Renal Insufficiency | 1 | 1 (0.7%)  |
|  Suicidal Ideation or Attempt | 1 | 1 (0.7%)  |
|  Transient Ischemic Attack | 1 | 1 (0.7%)  |
|  Wound Infection | 1 | 1 (0.7%)  |

## All Adverse Events

Table 15 presents the study-related adverse events by treatment groups combined (total). There were no differences between treatment groups in study-related (device, procedure and/or stimulation therapy) adverse events. As both treatment groups received the same device and underwent the same procedure, as expected there were no differences between groups in device- and procedure-related adverse events. Importantly, there were no differences in stimulation therapy-related adverse events.

Among the 134 randomized subjects, a total of 34 study-related adverse events (AEs) in 24 subjects (17.9%) were reported. The Investigational group had 23 study-related adverse events in 13 subjects (19.4%; 95% CI: 10.8, 30.9) and the Control group had 11 study-related adverse events in 11 subjects (16.4%; 95% CI:

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8.5, 27.5). The most frequently reported study-related adverse events in both treatment groups were lead migrations (6.7%), IPG pocket pain (3.7%), and muscle spasm or cramp (2.2%). There were five stimulation therapy-related events in four Investigational subjects (6.0%; 95% CI: 1.7, 14.6) and three stimulation therapy-related events in three Control subjects (4.5%; 95% CI: 0.9, 12.5).

Table 15. Summary of Study-Related Adverse Events – Randomized

|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Total Adverse Events | 34 | 24 (17.9%)  |
|  Lead Migration | 10 | 9 (6.7%)  |
|  IPG Pocket Pain | 5 | 5 (3.7%)  |
|  Muscle Spasm or Muscle Cramp | 3 | 3 (2.2%)  |
|  Dural Puncture or Tear | 2 | 2 (1.5%)  |
|  IPG Malfunction due to Electrocautery | 2 | 2 (1.5%)  |
|  Unwanted Stimulation Location | 2 | 2 (1.5%)  |
|  Wound Infection | 2 | 2 (1.5%)  |
|  Dysesthesia - Lower Extremity | 1 | 1 (0.7%)  |
|  Epidural Abscess | 1 | 1 (0.7%)  |
|  Inadequate Lead Placement | 1 | 1 (0.7%)  |
|  Lead Breakage/Fracture | 1 | 1 (0.7%)  |
|  Low Back Pain | 1 | 1 (0.7%)  |
|  Nausea and/or vomiting | 1 | 1 (0.7%)  |
|  Skin Irritation or Redness | 1 | 1 (0.7%)  |
|  Wound Dehiscence | 1 | 1 (0.7%)  |

Table 16 presents all adverse events for treatment groups combined (total). Among the 134 randomized subjects, a total of 254 adverse events (AEs) in 90 subjects  $(67.2\%)$  were reported (150 AEs,  $67.2\%$  Investigational subjects; 104

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AEs,  $67.2\%$  Control subjects). The majority of all adverse events  $(219 / 254 = 86.2\%)$  were classified as mild or moderate in severity with only  $13.8\%$  (35/254) being considered severe for 23 subjects  $(17.2\%)$ . At the time of database lock, of the 254 adverse events, 64 were still ongoing  $(25.2\%)$ , and 190 AEs were resolved  $(74.8\%)$ .

Table 16. Summary of All Adverse Events – Randomized

|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Total Adverse Events | 254 | 90 (67.2%)  |
|  Fall or Trip or Slip or Twist | 22 | 18 (13.4%)  |
|  Upper Respiratory Symptoms or Upper Respiratory Tract Infection | 18 | 14 (10.4%)  |
|  Lead Migration | 10 | 9 (6.7%)  |
|  Bronchitis | 6 | 5 (3.7%)  |
|  IPG Pocket Pain | 5 | 5 (3.7%)  |
|  Bursitis | 5 | 4 (3.0%)  |
|  Cellulitis | 5 | 4 (3.0%)  |
|  Motor Vehicle Accident | 5 | 4 (3.0%)  |
|  Sinus Infection or Sinusitis | 5 | 4 (3.0%)  |
|  Anxiety Disorders | 4 | 4 (3.0%)  |
|  Ear Infection | 4 | 4 (3.0%)  |
|  Unilateral Leg Pain | 4 | 4 (3.0%)  |
|  Nausea and/or vomiting | 4 | 3 (2.2%)  |
|  Abdominal Pain | 3 | 3 (2.2%)  |
|  Arrhythmia and Irregularities | 3 | 3 (2.2%)  |
|  Arthritis | 3 | 3 (2.2%)  |
|  Hip Joint Pain | 3 | 3 (2.2%)  |
|  Muscle Spasm or Muscle Cramp | 3 | 3 (2.2%)  |

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|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Peripheral Neuropathy - Lower Extremity | 3 | 3 (2.2%)  |
|  Radiculopathy - Lower Extremity | 3 | 3 (2.2%)  |
|  Upper Extremity Pain | 3 | 3 (2.2%)  |
|  Activities of Daily Living (ADL) Injury | 3 | 2 (1.5%)  |
|  Knee Pain | 3 | 2 (1.5%)  |
|  Abnormal Blood Chemistry | 2 | 2 (1.5%)  |
|  Bladder Infection | 2 | 2 (1.5%)  |
|  Bone Fracture | 2 | 2 (1.5%)  |
|  Bone Spur | 2 | 2 (1.5%)  |
|  Cardiac Chest Pain | 2 | 2 (1.5%)  |
|  Dental Issues | 2 | 2 (1.5%)  |
|  Diarrhea | 2 | 2 (1.5%)  |
|  Disc Bulge or Protrusion | 2 | 2 (1.5%)  |
|  Dural Puncture or Tear | 2 | 2 (1.5%)  |
|  Dysesthesia - Lower Extremity | 2 | 2 (1.5%)  |
|  Facet joint deterioration | 2 | 2 (1.5%)  |
|  Foot Pain | 2 | 2 (1.5%)  |
|  Gastroenteritis | 2 | 2 (1.5%)  |
|  Headache | 2 | 2 (1.5%)  |
|  IPG Malfunction due to Electrocautery | 2 | 2 (1.5%)  |
|  Neck or Cervical Pain | 2 | 2 (1.5%)  |
|  Peripheral Vascular Disease | 2 | 2 (1.5%)  |
|  Prostate Cancer | 2 | 2 (1.5%)  |
|  Pulled or Strained Muscle | 2 | 2 (1.5%)  |

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|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Restless Leg Syndrome | 2 | 2 (1.5%)  |
|  SI Joint Pain | 2 | 2 (1.5%)  |
|  Sacroiliitis | 2 | 2 (1.5%)  |
|  Skin Infection | 2 | 2 (1.5%)  |
|  Skin Rash | 2 | 2 (1.5%)  |
|  Spinal Stenosis | 2 | 2 (1.5%)  |
|  Syncope or Fainting | 2 | 2 (1.5%)  |
|  Tremor - Upper Extremity | 2 | 2 (1.5%)  |
|  Trigger Finger or Stenosing Tenosynovitis | 2 | 2 (1.5%)  |
|  Unwanted Stimulation Location | 2 | 2 (1.5%)  |
|  Wound Infection | 2 | 2 (1.5%)  |
|  Back Pain and Bilateral Radiation into Legs | 2 | 1 (0.7%)  |
|  MRSA | 2 | 1 (0.7%)  |
|  Abnormal Uterine Bleeding | 1 | 1 (0.7%)  |
|  Acne | 1 | 1 (0.7%)  |
|  Adrenal Nodule | 1 | 1 (0.7%)  |
|  Alopecia | 1 | 1 (0.7%)  |
|  Ankylosing Spondylitis | 1 | 1 (0.7%)  |
|  Back Pain | 1 | 1 (0.7%)  |
|  Back and Upper Extremities Pain | 1 | 1 (0.7%)  |
|  Benign Prostatic Hypertrophy | 1 | 1 (0.7%)  |
|  COPD (Chronic Obstructive Pulmonary Disease) | 1 | 1 (0.7%)  |
|  Cholecystitis | 1 | 1 (0.7%)  |
|  Chronic Pain Syndrome | 1 | 1 (0.7%)  |

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|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Cirrhosis or Fatty Liver | 1 | 1 (0.7%)  |
|  Coccydynia | 1 | 1 (0.7%)  |
|  Coronary Artery or Heart Disease | 1 | 1 (0.7%)  |
|  Dehydration | 1 | 1 (0.7%)  |
|  Diverticulitis | 1 | 1 (0.7%)  |
|  Diverticulosis | 1 | 1 (0.7%)  |
|  Edema - Lower Extremities | 1 | 1 (0.7%)  |
|  Epidural Abscess | 1 | 1 (0.7%)  |
|  Erythema | 1 | 1 (0.7%)  |
|  Eye Infection | 1 | 1 (0.7%)  |
|  Eye Injury or Pain | 1 | 1 (0.7%)  |
|  Facet Cyst | 1 | 1 (0.7%)  |
|  Fibromyalgia | 1 | 1 (0.7%)  |
|  Forgetfulness or Memory Loss | 1 | 1 (0.7%)  |
|  Gastritis | 1 | 1 (0.7%)  |
|  Hypertension | 1 | 1 (0.7%)  |
|  Impaired Balance | 1 | 1 (0.7%)  |
|  Inadequate Lead Placement | 1 | 1 (0.7%)  |
|  Incontinence | 1 | 1 (0.7%)  |
|  Joint Disorders or Injury | 1 | 1 (0.7%)  |
|  Kidney Stone | 1 | 1 (0.7%)  |
|  Lead Breakage/Fracture | 1 | 1 (0.7%)  |
|  Leukemia | 1 | 1 (0.7%)  |
|  Liver Abscess | 1 | 1 (0.7%)  |

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|   | Total N=134 Subjects  |   |
| --- | --- | --- |
|  Preferred Term | Events n | Subjects n (%)  |
|  Low Back Pain | 1 | 1 (0.7%)  |
|  Lytic Lesion(s) | 1 | 1 (0.7%)  |
|  Macromastia | 1 | 1 (0.7%)  |
|  Migraine | 1 | 1 (0.7%)  |
|  Myocardial Infarct or Heart Attack | 1 | 1 (0.7%)  |
|  Myofascial Pain Syndrome | 1 | 1 (0.7%)  |
|  Osteoporosis | 1 | 1 (0.7%)  |
|  Overdose | 1 | 1 (0.7%)  |
|  Peripheral Neuropathy - Upper Extremity | 1 | 1 (0.7%)  |
|  Plantar fasciitis | 1 | 1 (0.7%)  |
|  Pneumonia | 1 | 1 (0.7%)  |
|  Radiculopathy - Upper Extremity | 1 | 1 (0.7%)  |
|  Renal Cyst | 1 | 1 (0.7%)  |
|  Renal Insufficiency | 1 | 1 (0.7%)  |
|  Shingles | 1 | 1 (0.7%)  |
|  Sinus Problems - Other | 1 | 1 (0.7%)  |
|  Skin Irritation or Redness | 1 | 1 (0.7%)  |
|  Strep Throat | 1 | 1 (0.7%)  |
|  Str…

---

**Source:** [https://fda.innolitics.com/device/P190002](https://fda.innolitics.com/device/P190002)

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