Axium Neurostimulator System

P150004 · ABBOTT MEDICAL · PMP · Feb 11, 2016 · Neurology

Device Facts

• Record ID: P150004
• Device Name: Axium Neurostimulator System
• Applicant: ABBOTT MEDICAL
• Product Code: PMP · Neurology
• Decision Date: Feb 11, 2016
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The Axium Neurostimulator System is indicated for spinal column stimulation via epidural and intra-spinal lead access to the dorsal root ganglion as an aid in the management of moderate to severe chronic intractable pain of the lower limbs in adult patients with Complex Regional Pain Syndrome (CRPS) types I and II.

Device Story

The Axium Neurostimulator System is a totally implanted device for chronic intractable pain of the lower limbs. It delivers electrical stimulation to the dorsal root ganglion (DRG) via percutaneous leads. The system includes an Implantable Neurostimulator (INS), leads, a clinician programmer, and a patient programmer. The clinician uses the programmer to set stimulation parameters; the patient uses a handheld programmer to adjust stimulation intensity within physician-prescribed limits. The device uses a biphasic, voltage-regulated pulsed waveform. It is used in a clinical setting for implantation and at home for patient-controlled therapy. By stimulating the DRG, the device aims to provide pain relief, potentially reducing the need for oral medications and improving quality of life. The system is intended for patients who have failed conservative therapies.

Clinical Evidence

The ACCURATE study was a prospective, randomized, controlled, unblinded, multi-center clinical trial (n=152) comparing the Axium system to a legally marketed SCS system. The primary endpoint was a composite of safety (no stimulation-induced neurological deficit) and effectiveness (≥50% pain relief) at 3 months. Axium demonstrated 81.2% success vs. 55.7% for control (p<0.0001 non-inferiority; p=0.0004 superiority). No stimulation-induced neurological deficits occurred. Procedure-related adverse events were higher in the Axium group (46.1% vs 26.3%, p=0.0177), attributed to the number of leads implanted.

Technological Characteristics

The system consists of an INS (titanium case, 3.3V Lithium Carbon Monofluoride battery), percutaneous leads (1mm diameter, 4 electrodes, 80/20 or 90/10 Platinum/Iridium), and programmers. Stimulation is voltage-regulated, biphasic, rectangular pulses (4-80 Hz, 40-1000 μs). Connectivity is wireless between programmers and the INS. Sterilization is via 100% ethylene oxide. Complies with ISO 14708-1, ISO 14708-3, IEC 60601-1, and IEC 60601-1-2.

Indications for Use

Indicated for adult patients (22-75 years) with moderate to severe chronic intractable lower limb pain diagnosed with CRPS types I and II who have failed at least 2 prior pharmacologic treatments from 2 different drug classes. Contraindicated for patients unable to operate the system, poor surgical risks, or those failing trial stimulation.

Regulatory Classification

Identification

Stimulation of the dorsal root ganglion for the treatment of chronic, intractable pain of the lower limbs.

Reference Devices

• RestoreSensor (Medtronic, Inc.)
• RestoreUltra (Medtronic, Inc.)

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Dorsal root ganglion stimulator for pain relief

Device Trade Name: Axium Neurostimulator System

Device Procode: PMP

Applicant’s Name and Address: Michele Chin-Purcell
Spinal Modulation
1135 O’Brien Dr.
Menlo Park, CA 94025

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P150004

Date of FDA Notice of Approval: February 11, 2016

II. INDICATIONS FOR USE

The Axium Neurostimulator System is indicated for spinal column stimulation via epidural and intra-spinal lead access to the dorsal root ganglion as an aid in the management of moderate to severe chronic intractable* pain of the lower limbs in adult patients with Complex Regional Pain Syndrome (CRPS) types I and II**.

* Study subjects from the ACCURATE clinical study had failed to achieve adequate pain relief from at least 2 prior pharmacologic treatments from at least 2 different drug classes and continued their pharmacologic therapy during the clinical study.

** Please note that in 1994, a consensus group of pain medicine experts gathered by the International Association for the Study of Pain (IASP) reviewed diagnostic criteria and agreed to rename reflex sympathetic dystrophy (RSD) and causalgia, as complex regional pain syndrome (CRPS) types I and II, respectively.

III. CONTRAINDICATIONS

Patients contraindicated for the Axium Neurostimulator System are those who:

- Are unable to operate the system
- Are poor surgical risks
- Patients who fail to receive effective pain relief during trial stimulation.

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# IV. WARNINGS AND PRECAUTIONS

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

# V. DEVICE DESCRIPTION

The Axium Neurostimulator System is a totally implanted device that delivers electrical stimulation to the dorsal root ganglion for the treatment of chronic intractable pain of the trunk and/or limbs. The Axium Neurostimulator System is shown in Figure 1 below:

(a)

(b)

(c)
(d)
Figure 1: Axium Neurostimulator System (a) Implantable Neurostimulator (INS) (b) Clinical Programmer (c) Patient Programmer (d) Lead

# 1. Implanted Components

The implanted components of the Axium Neurostimulator System include the following:

- Implantable Neurostimulator (INS) (MN10200): The Axium INS is a non-rechargeable implanted device that can connect to up to 4-leads. It uses microelectronic circuitry, powered by a hermetically sealed battery (3.3 V Lithium Carbon Monofluoride), to generate a pulsed waveform to stimulate the dorsal root ganglion (DRG). The electronic circuitry and battery are housed in a hermetically sealed titanium case. The stimulation output parameters are listed in Table 1 below:

Table 1: Stimulation Output Parameters

| Number of Channels | 4† |
| --- | --- |
| Waveform | Biphasic |
| Pulse Shape | Rectangular |
| Current or Voltage Regulated | Voltage |
| Maximum Current Amplitude | 6000 μA at 500 Ω 6000 μA at 766 Ω‡ 4600 μA at 1000 Ω |

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| Maximum Output Voltage | 4.6 V |
| --- | --- |
| Pulse Width | 40 - 1000 μs |
| Frequency | 4-80 Hz |
| Current Path Options | Bipolar or Multipolar |

† Four lead connections with each lead having an independent control.
‡ Max amplitude is limited when 4.6 V is reached starting at 766 Ω

- Percutaneous Leads:
The leads are designed for percutaneous introduction into the epidural space near the DRG. Up to 4 leads can be placed using a special needle and a set of custom delivery tools provided in their respective kits. Each lead has four cylindrical electrodes spaced at equal intervals, which are intended to provide stimulation at the DRG. Lead models include the following: standard Trial Lead (MN10350-50, -90), SlimTip Trial Lead (MN10350-50A, -90A), standard Implant Lead (MN10450-50, -90), and implant SlimTip Lead (MN10450-50A, -90A). There is no difference in the design of the Trial and Implant leads. The lead specifications for the standard and SlimTip leads are the same except for the shape of the lead tip. Specifications are depicted in Table 2 below:

Table 2: Percutaneous Lead Specifications

| Lead Length | 50 cm or 90 cm |
| --- | --- |
| Lead Diameter | 1 mm |
| Number of Electrodes | 4 |
| Electrode Material | 80% Platinum/20% Iridium and 90% Platinum/10% Iridium |
| Electrode Spacing (edge-to-edge) | 5 mm |
| Electrode Span | 20 mm |
| Electrode Surface Area | 4.05 mm² |
| Impedance | < 20 Ω (50 cm)
< 35 Ω (90 cm) |
| Ball Tip Diameter | 1mm for Slim Tip
1.5mm for standard lead |

- Lead Extension (MN10550-50): A 50 cm long lead extension is available for scenarios when additional length is needed to accommodate a patient's anatomy.
- Soft Tissue Anchor: To anchor the lead in the subcutaneous soft tissue or on the skin surface proximal to the distal contacts of the lead.

2. External Components

The external components of the Axium Neurostimulator System include the following:

- Clinician Programmer (MN 10700): Used by the clinician to wirelessly program output stimulation parameters for the INS and Trial Neurostimulator (TNS). It is portable, hand-held devices powered by internal rechargeable batteries and

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contains an internal magnet to initiate communication with the INS and TNS devices.

- Patient Programmer (MN10600-02): A handheld battery operated unit able to communicate wirelessly with the INS or TNS. It allows the patient to adjust the stimulation strength within limits preset by the physician. It also allows the patient to select pre-programmed alternate groups of stimulation settings and turn stimulation off, if necessary.
- Trial Neurostimulator (TNS) (MN10100): Patients who are indicated for the Axium INS System will first undergo a temporary trial period using an external TNS connected to implanted leads. The TNS provides stimulation by emulating the INS during the intraoperative test and during the stimulation trial. The TNS stimulation parameters are the same as the INS.
- Connector Cable (MN11350): Connects the Leads or Lead Extension to the external TNS.

## 3. Accessories:

The following accessories are also available for use with the Axium Neurostimulator System:

- Small / Big Curve Delivery Sheath: To allow passage of the lead percutaneously into the epidural space.
- Axium Small / Big Curve Delivery Sheath: To allow passage of leads percutaneously into the epidural space. Axium sheaths are internally reinforced with thin stainless steel braiding.
- Complex Curve / Straight Stylet: To assist in steering and positioning the lead within the epidural space.
- 14G Delivery Needles: To access the epidural space, providing a conduit for lead, guidewire and delivery sheath placement. It is available as a straight needle or a curved needle.
- Guidewire: To verify that the needle is in the epidural space after using a loss of resistance technique. It also provides stability to the sheath before frontloading the SlimTip lead.
- Tunneling Tool: To provide a conduit for the Trial Lead, Implant Lead, or Lead Extension to the INS or away from the midline of the spine. It is packaged with 2 exchangeable tips: a blunt pencil tip and a sharp trocar tip.
- INS Sizer: Allows the physician to properly size the INS pocket.

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- Port Plugs: To fill unused ports in the INS.
- Sterile Magnet Sleeve: The magnet is placed in the sterile sleeve to allow it to be used during the implantation of the INS.
- Auxiliary Magnet: Allows the user to turn the NS off or activates Radio-Frequency (RF) to allow the user to communicate with the NS.
- Hex Key: Allows the user to release a set screw in the INS header or Lead Extension header that has been unscrewed too far.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of chronic, intractable pain of the lower limbs in adult patients with Complex Regional Pain Syndrome (CRPS) types I and II.

1. Non-surgical treatment options:
- Oral medication
- Rehabilitative therapy
- Transcutaneous electrical nerve stimulation (TENS)
- Behavior modification
- Neurolysis (i.e., Therapeutic nerve block, Cryoanalgesia, RF Lesioning)

2. Surgical treatment options:
- Sympathectomy- severing the sympathetic nerve pathway
- Implantable intrathecal drug delivery systems
- Partially implanted spinal cord stimulation (SCS) Systems – RF implantable spinal cord stimulators (the power source in this system is external)
- Commercially available fully implanted SCS Systems

Each alternative has its own advantages and disadvantages. A patient should discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

The Axium Neurostimulator System for the treatment of chronic intractable pain has been approved for commercial distribution in Europe since 2011. In addition, the Axium Neurostimulator System for the treatment of chronic, intractable pain of the trunk and/or limbs has been approved for commercial distribution in Australia since 2013. In 2014, communications and manual updates were sent to the European and Australian regulators and physicians with regard to appropriate lead removal. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness.

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# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device:

- 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 system placement procedures: pain at the implant site, swelling; infection, cerebrospinal fluid (CSF) leakage, CSF fistula, epidural hemorrhage, bacterial meningitis, seroma, weakness, hematoma, tissue damage, nerve damage, sensory loss, spinal cord compression; and paralysis. 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 the system: lead migration; INS migration; 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 INS and/or lead site, extension, or lead site; radicular chest wall stimulation; disturbed urination; dysesthesia; decubitus; headache; allodynia; hyperesthesia; premature battery depletion; loss of pain relief over time; escalating pain; clumsiness; numbness; temporary muscle activation; and uncomfortable stimulation or ineffective pain control caused by random failure of the system components or battery, changes in electrode position, loose electrical connections, lead or extension insulation breaches or fractures, lead retention, and inability to achieve the desired pain relief results.

Additional risks to the patients, as a result of the placement and stimulation of the lead in the area of the DRG, include pain due to setting the stimulation parameters too high.

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

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# IX. SUMMARY OF PRECLINICAL STUDIES

# A. Laboratory Studies

# 1. Implantable Neurostimulator (INS)

Testing was conducted on the Model MN10200 INS, including: mechanical design verification (including testing on devices subjected to accelerated aging), electrical/firmware design verification testing, electromagnetic compatibility testing, and medical procedure compatibility testing. Key testing on the INS is summarized in Table 3 below. Testing demonstrated the INS operated according to specifications after exposure to the tested conditions (i.e., passed testing).

Table 3: Summary of key testing performed and passed on the Axium Neurostimulator System INS

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Measurement of Output Pulses | Verify proper output (amplitude, pulse width, frequency, etc.) of the INS function are within specified tolerances. The characteristics of the output pulses shall be measured as described in International Standards Organization (ISO) 14708-3 clause 6.101. | Amplitude, Pulse width, Frequency, Etc. are within output specifications. |
| Dimensional Requirements | To demonstrate INS meet shape and profile requirements. | INS samples must meet size specifications for INS width, height, thickness, volume, mass, and radius. |
| DC Leakage Current | Verify the leakage current is in an acceptable range. | The maximum leakage current < 1 μA |
| Atmospheric Pressure Exposure | To expose each INS to pressure extremes the device may encounter. | Testing per ISO 14708-1, 25. (Exposure to 70 kPa and 150 kPa (50 feet underwater)). |
| Storage Temperature | To expose each INS to pressure extremes the device may encounter during storage and distribution. | Testing per ISO 14708-1, 26.2. (Exposure to low (-10±3°C) and high temperatures (55°±2C)). |
| Operating Temperature | To demonstrate the INS remains mechanically intact and capable of normal operation during exposure to low and high temperatures. | Exposure to low (-5°C) and high temperatures (45°C). |
| Mechanical Forces - Vibration | The implantable parts of the neurostimulator shall be constructed to withstand the mechanical forces that can occur during normal conditions of use. | INS meets specifications after testing per ISO14708-3, 23.2. |
| Mechanical Forces - Connections | The connector joining the INS to the permanent implantable Leads or Lead Extensions shall be identified and its hold force declared in the instructions for use per ISO-14708-1 Section 23.6. | 10 N max |
| Hermetic Leak Test | To demonstrate that the INS maintains hermeticity after exposure to environmental testing. | The INS enclosure shall be capable of passing an inert gas (20% HE, 80% Ar) leak test. The allowable helium leak rate shall be ≤ 2.5X10-9 cc-atm/sec. Test per MIL-STD-202G, Method 112E, Condition C. |
| Header Adhesion Testing | To demonstrate the header meets fatigue requirements. | The header shall not be damaged by a force test of a minimum of 30 lbf applied both in tension and shear directions. |

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| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Lead Insertion | To demonstrate that the INS, port plug, and lead meet specified interface requirements for insertion force. | The Lead shall be able to be inserted easily into the header with a gloved hand without damage to the Lead. Lead insertion force must be < 1.1 lbf. |
| Particulate matter | Verify there is no unacceptable release of particulate matter when the device is used as intended. | ISO-14708-3, 14.2 (The excess average count of particles from the test specimen compared to a reference sample shall not exceed 100 counts/ml greater than 5.0 μm and shall not exceed 5 counts/ml greater than 25 μm.) |
| Temperature | Verify the protection of patients from damage caused from heat. | 14708-3, 17 (No outer surface of the INS shall be greater than 2°C above the normal surrounding body temperature in normal operation or single-fault condition). |
| Battery | Electrical, Visual, Dimensional, Hermeticity, Short Circuit Testing, Environmental, and Forced Discharge Tests | Meets specifications. |

# 2. Percutaneous Lead Testing

The percutaneous underwent numerous tests for dimensional verification, electrical safety, environmental, and mechanical conditions. Key testing on the leads is summarized in Table 4 below. Testing demonstrated the percutaneous leads operated according to specifications after exposure to the tested conditions (i.e., passed testing).

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

| Test | Purpose | Acceptance Criteria |
| --- | --- | --- |
| Dimensional | To ensure the leads meet dimensional requirements for Overall Lead Length Lead Body Diameter, Distal Electrode Dimensions, Lead Tip Length, Connector Dimensions. | Meets dimensional specifications. |
| Stylet Interactions – Insertion/Removal | To demonstrate the force required to fully insert or remove each stylet into the lead. | The lead shall allow internal passage of a 0.254 mm (0.010”) diameter (maximum) removable stylet during insertion with sufficient clearance for 5 repeated insertion/removal cycles during the implantation process with exposure to blood or blood analog fluid. The proximal end of the lead shall allow easy insertion of the stylet into the stylet lumen in the lead. |
| Insertion Needle Insertion/Withdrawal | Demonstrate lead compatibility with Touhy Needle. | The distal ball of the lead (largest part of the lead) shall fit inside a 14 Ga thin wall delivery needle, as well as allowing the needle to be removed over the proximal end of the lead |
| Tensile Strength | Demonstrate the lead remains mechanically intact after a tensile load. | The lead's distal end shall withstand a minimum tensile pull of 6.7 N (1.5 lbf) and the lead or lead extension's proximal end shall withstand a minimum tensile pull of 5 N (1.1 lbf) without fracture of any conductor or cracking of either any functional electrical insulation or of the body of the lead. |
| Lead and Lead Extension Insertion Force | Demonstrate the lead shall be able to be inserted easily into the header with a gloved hand without damage to the lead. | Lead insertion force must be < 1.1 lbf. |

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| Test | Purpose | Acceptance Criteria |
| --- | --- | --- |
| Lead Body and Anchor Flexural Fatigue | Demonstrate that the leads do not fatigue after flexural stressors. | Verify no breakages, wears, tears or cracks are observed in any of the Implantable Leads or Proximal Soft Tissue Anchors (PSTA) after 3.5 million cycles of flexural fatigue. The maximum resistance of each post-fatigued Lead should remain < 20 Ω (50 cm lead) and <35 Ω (90 cm lead). |
| Proximal Connector End Flex Fatigue | Demonstrate that the lead proximal connector does not fatigue after flexural stressors. | No breakages, severe wear or tears in any of Lead proximal connectors (flexural region) after 110,000 cycles of flexural fatigue. The maximum resistance of each post-fatigued Lead should be < 20 Ω (50 cm lead) and <35 Ω (90 cm lead). |
| Lead & Lead Extension Insertion into INS | Demonstrate the Leads & Lead Extension can be inserted and removed from the IPG during expected use without damaging the INS or the Lead. | The Leads & Lead Extension shall be insert-able and removable from the INS 5 times, without damaging the INS or the Lead. |
| Maximum Resistance of Lead and Extension | Demonstrate the lead resistance is according to specification | The resistance of the Lead Extension shall be less than 60 ohms (when used with the lead) and the resistance of the Lead shall be less than 20 Ω.(50 cm lead) and <35 Ω (90 cm lead) |

3. Programmers

The software associated with the Clinical Programmer and Patient Programmer were documented and tested in accordance with the FDA guidance document entitled, "Guidance for the Content of Pre-market Submission for Software Contained in Medical Devices" (May 11, 2005) and all requirements were met. Electrical and mechanical verification and environmental testing were also performed per the following standards and all testing met specifications:

- ISO 14708-1: Implants for Surgery – Active implantable medical device, Part 1: General requirements for safety, marking and information to be provided by the manufacturer
- ISO 14708-3: Implants for Surgery – Active implantable medical devices, Part 3: Implantable neurostimulators
- IEC 60601-1: Medical electrical equipment Part 1 General requirements for basic safety and essential performance
- IEC 60601-1-11: Medical electrical equipment – part 1-11: General requirements for basic safety and essential performance – Collateral Standard: Requirements for medical electrical equipment and medical electrical systems used in the home healthcare environment
- IEC 60601-1-6: Medical electrical equipment Part 1-6: General requirements for safety - Collateral Standard: Usability
- IEC 60601-1-2: Medical electrical equipment, Part 1-2: General requirements for basic Safety and essential performance Collateral standard: Electromagnetic compatibility – Requirements and tests.

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4. Trial Neurostimulator (TNS)
Testing was conducted on the TNS, including: mechanical design verification, electrical/firmware design verification testing, electromagnetic compatibility testing, and firmware testing. The standards listed below were used in the testing. Testing demonstrated the TNS operated according to specifications after exposure to laboratory conditions (i.e., passed testing).

- IEC 60601-1: Medical electrical equipment, Part 1: General requirements for basic safety and essential performance.
- IEC 60601-1-11: Medical electrical equipment Part 1 General requirements for basic safety and essential performance Collateral Standard: Requirements for medical electrical equipment and medical electrical systems used in the home healthcare environment.
- ISO 14708-3: Implants for Surgery – Active implantable medical devices, Part 3 Implantable neurostimulators.
- IEC 60601-1: Medical electrical equipment Part 1 General requirements for basic safety and essential performance.
- IEC 60601-1-2: Medical electrical equipment, Part 1-2: General requirements for basic Safety and essential performance Collateral standard: Electromagnetic compatibility – Requirements and tests.

5. Electromagnetic Compatibility (EMC) and Wireless Technology
EMC and wireless technology (including quality of service (QOS), coexistence, and security of wireless transmissions testing) was performed in accordance with the relevant clauses of the following standards and 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" (appropriate essential performance criteria were used)
- ISO 14708-3:2008(E): Implants for surgery – Active implantable medical devices – Part 3: Implantable neurostimulators", Part 27
- FCC Part 95 Federal Communications Commission PART 95 MedRadio

Testing to address compatibility with Radio-frequency Identification (RFID) and Electronic Article Surveillance systems was also provided.

6. System Testing
Testing to verify that system-level design requirements were met for interactions between Axium Neurostimulator System components was performed. All test articles met defined acceptance criteria for the system

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integration tests conducted. System validation testing demonstrated that the system operated as expected and has been validated for safe and effective use.

## B. Biocompatibility

Biocompatibility testing was performed on the finished, sterilized devices for all patient-contacting components of the Axium Neurostimulator System in accordance with ISO 10993-1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process. All biocompatibility studies were conducted in compliance with Good Laboratory Practices (GLP), 21 CFR Part 58. The implanted components of the Axium Neurostimulator System are considered permanent (&gt; 30 days) implants in contact with tissue/bone. The Axium Neurostimulator System also contains external communicating components with limited (≤ 24 hours) tissue/bone contact and skin-contacting component with prolonged (&gt; 24 hours – 30 days) contact. The biocompatibility test data are summarized in Table 5 below. All pre-specified test acceptance criteria were met and all tests passed.

Table 5: Biocompatibility Test Data on the Implantable, External Communicating, and Skin-Contacting Components of the Axium®Neurostimulator System *

| Biological Effect (Applicable Standard) | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Implanted^{a}, External Communicating^{b}, and Skin-contacting^{c} Components: | | | |
| Cytotoxicity (ISO 10993-5) | ISO MEM Elution Assay | Reactivity grade is not greater than mild reactivity (Grade 2). | PASS |
| Sensitization (ISO 10993-10) | ISO Guinea Pig Maximization Sensitization Test | Grades of <1 in the test group provided grades of < 1 are observed on the control animals. (If grades of ≥ 1 are noted on the control animals, then the reactions of the test animals which exceed most severe control reaction are presumed to be due to sensitization). | PASS |
| Intracutaneous Reactivity (ISO 10993-10) | ISO Intracutaneous Reactivity Test | The difference between the test article and the control mean score is ≤ 1.0. | PASS |
| Implanted^{a} and External Communicating^{b} Components | | | |
| Systemic Toxicity (ISO 10993-11) | ISO Acute Systemic Toxicity Test | None of the test animals show a significantly greater biological reaction than the animals treated with vehicle control. | PASS |
| | Materials Mediated Rabbit Pyrogen Test* | No rabbit shows an individual rise in temperature of 0.5°C or more above the baseline temperature. | PASS |
| Implanted^{a} Components | | | |
| Genotoxicity (ISO 10993-3) | Bacterial Reverse Mutation Assay (Ames Test) | There is less than 2-fold increase in the number of revertants when compared to the solvent controls in strains TA98, TA100, and WP2uvrA and less than 3-fold increase in the number of revertants when compared to the solvent control in strains TA1535 and TA1537. | PASS |
| | In Vitro Mouse Lymphoma | There is less than 2-fold increase in mutant | PASS |

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| Biological Effect (Applicable Standard) | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| | Assay | frequency over the negative control. | |
| | In Vivo Mouse Peripheral Blood Micronucleus Assay | There is no statistically significant increase in the frequency of micronucleated reticulocytes (% MN-RET) in the test group as compared to the concurrent negative control. | PASS |
| Implantation (ISO 10993-6), Subchronic and Chronic Toxicity (ISO 10993-11) | ISO Subcutaneous Implantation Study in Rabbits – 2 weeks and 6 Weeks | The test results are considered acceptable based on an overall interpretation of the degree of biocompatibility exhibited by the test article based on the macroscopic and microscopic analysis of the implantation sites comparing test to control article (USP high density polyethylene reference standard), as well as clinical observations. | PASS |
| | Systemic Toxicity Study in Rats following Subcutaneous Implantation – 13 weeks and 26 weeks | The test results are considered acceptable based on an overall interpretation of the degree of biocompatibility exhibited by the test article based on the clinical observations, body weights, necropsy results, organ weights and organ/body weight percentages, microscopic evaluation of organs, hematology and clinical chemistry values, and gross and microscopic evaluation of the implantation sites comparing the test article to the control article (USP high density polyethylene). | PASS |
| | 6-month Implantation Study in Sheep model | A 6-month implantation study was conducted in sheep model to assess the local tissue response as well as long-term safety of the device. The leads were implanted in the sheep within its neural foramen at the dorsal root ganglion (DRG). There were two groups in the sheep study – a 45-day group and a 180-day group. The effect of stimulation of DRG was assessed in the 45-day group with active leads. In the 180-day group, the long-term biocompatibility of the leads at the DRG site was assessed with a non-stimulating device. Safety was determined in the study by evaluating adverse events related to the use of the device including neurological evaluation of the animals, general health of the animals, hematology and clinical chemistry, gross necropsy and histology findings of the animals. No device-related adverse reactions were noted in the study. | |
| Carcinogenicity (ISO 10993-3) | An adequate carcinogenicity risk assessment was provided. | | |

a Components tested: INS, Leads, and Soft Tissue Anchor (Lead Extension and Port Plug were not tested as they are identical in processing and materials to the Lead and the INS (header assembly))
b Components tested: Stylets, Delivery Needles, Delivery Sheaths, Tunneling Tools, and INS Sizer
* Among the external communicating device components, following components were tested in the rabbit pyrogen test - Delivery Sheaths, Delivery Needles, and Guidewire
c Component tested: Connector Cable

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C. Sterility and Packaging

The sterile components of the Spinal Modulation Axium Neurostimulator system are terminally sterilized using a 100% ethylene oxide (EO) sterilization process to provide a minimum sterility assurance level (SAL) of 10⁻⁶. Validation of the sterilization process is in compliance 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.

The bacterial endotoxin levels on the sterile components of the Spinal Modulation Axium Neurostimulator system are determined using Limulus Amebocyte Lysate (LAL) testing and demonstrated to be in compliance with the bacterial endotoxin limits specified in the USP Chapter &lt;161&gt; Transfusion and Infusion Assemblies and Similar Medical Devices and FDA’s Guidance for Industry - Pyrogen and Endotoxins Testing: Questions and Answers (June 2012).

Packaging and shelf- life validation tests were completed in compliance with ISO 11607-1:2009 Packaging for Terminally Sterilized Medical Devices. Part 1: Requirements for materials, sterile barrier systems and packaging systems. Shelf life for the sterile system components has been established as two (2) years from the date of manufacturing.

X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study (ACCURATE) to establish a reasonable assurance of safety and effectiveness of stimulation of the DRG with the Axium Neurostimulator System as an aid in the management of severe chronic intractable pain of the lower limbs in adult patients with Complex Regional Pain Syndrome (CRPS) types I and II under IDE # G110186. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

A. Study Design

Patients in the ACCURATE study were enrolled and randomized between August 23, 2013 and July 28, 2014. The database for this PMA reflected data collected through October 2, 2015 and included 152 patients. There were 22 investigational sites.

The study was a prospective, randomized, controlled, unblinded, multi-centered clinical study comparing the Axium Neurostimulator System (Axium group) to a legally marketed spinal cord stimulation (SCS) system from a single manufacturer (Control group) (i.e., the RestoreSensor or RestoreUltra SCS devices manufactured by Medtronic, Inc.). Note that the Control device is approved for use in the treatment of chronic, intractable pain of the trunk and limbs. Note also that the Axium Neurostimulator System group received electrical stimulation at the DRG while the Control group received electrical stimulation at the dorsal column of the spinal cord.

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Additionally, programming features were selected in the Control devices in order to be as comparable as possible to the Axium Neurostimulator System. For purposes of ensuring comparable features to assess this endpoint, the RestoreSensor Control device had an accelerometer feature that can adjust stimulation based on the patient's needs and preferences in different body positions (including stimulation to maintain paresthesia) deactivated. The Restore Ultra device did not have the feature.

Subjects were not blinded as to their device assignment. Subjects were randomized in a 1:1 ratio to the Axium and Control arms. The primary objective of the study was to demonstrate that a composite endpoint of safety and effectiveness of the Axium Neurostimulator System as compared to (i.e., non-inferior or superior) the legally-marketed SCS comparator for the treatment of chronic intractable pain associated with Complex Regional Pain Syndrome (CRPS) and Peripheral Causalgia. Note that although the ACCURATE study enrolled subjects with CRPS and peripheral causalgia, the indications for use utilized the updated terms of CRPS I and CRPS II. Since the study protocol uses the terms CRPS and peripheral causalgia and not CRPS I and CRPS II, the study summary in this document will use the terms CRPS and peripheral causalgia.

The study included a "Trial Neurostimulator Phase" (Subject received between 3 to 30 days of temporary trial neurostimulation, or TNS Phase), an "Implantable Neurostimulator Phase" (implantable neurostimulator, or INS Phase), and a "Follow-up Phase". Only subjects who had a ≥ 50% reduction in pain during TNS phase and expressed a desire to have an INS implant moved on to the INS phase. The initial planned sample size was 152 subjects (76 Axium and 76 Controls). An unblinded sample size re-estimation (SSR) based on the "Promising Zone" methods of Mehta and Pocock (2010) was conducted by an independent statistician when 50% of the expected primary endpoint information was available. The SSR found that no sample size increase was needed.

A Data Safety Monitoring Board (DSMB) monitored the study.

1. Clinical Inclusion and Exclusion Criteria

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

- Subject is male or female between the ages of 22 and 75 years.
- Subject is able and willing to comply with the follow-up schedule and protocol.
- Subject has chronic, intractable pain of the lower limb(s) for at least 6 months.
- Subjects are diagnosed with complex regional pain syndrome (CRPS) and/or peripheral causalgia.
- Subjects have a minimum VAS ≥ 60 mm in the area of greatest pain in the lower limb(s).
- Subject has failed to achieve adequate pain relief from at least 2 prior pharmacologic treatments from at least 2 different drugs classes.

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- Subject has had stable neurologic function in the past 30 days.
- In the opinion of the Investigator, the subject is psychologically appropriate for the implantation of an active implantable medical device.
- Subject is able to provide written informed consent.

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

- Back pain is the greatest region of pain as measured on the baseline VAS.
- Female subject of childbearing potential is pregnant/nursing, plans to become pregnant or is unwilling to use approved birth control.
- Subject has exhibited escalating or changing pain condition within the past 30 days as evidenced by Investigator examination.
- Subject is currently involved in medically related litigation, including workers compensation.
- Subject has had corticosteroid therapy at an intended site of stimulation within the past 30 days.
- Subject’s pain medication(s) dosage(s) are not stable for at least 30 days.
- Subject has had radiofrequency treatment of an intended target DRG within the past 3 months.
- Subject has previously failed spinal cord stimulation therapy.
- Subject currently has an active implantable device including ICD, pacemaker, spinal cord stimulator or intrathecal drug pump or subject requires magnetic resonance imaging (MRIs) or diathermy.
- Subject has pain only within a cervical or thoracic distribution.
- Subject has cognitive, physical or sensory impairment that, in the opinion of the Investigator, may limit their ability to operate the device.
- Subject currently has an indwelling device that may pose an increased risk of infection.
- Subject currently has an active systemic infection.
- Subject has, in the opinion of the Investigator, a medical comorbidity that contraindicates placement of an active medical device.
- Subject has participated in another clinical investigation within 30 days.
- Subject has a coagulation disorder or uses anticoagulants that, in the opinion of the Investigator, precludes participation.
- Subject has been diagnosed with cancer in the past 2 years.
- Imaging (MRI, CT, x-ray) findings within the last 12 months that, in the Investigator’s opinion, contraindicates lead placement.
- Subject is a prisoner.

2. Follow-up Schedule

All subjects had a temporary trial neurostimulator (TNS) for a period of three to 30 days, similar to that used in current clinical practice. If the subject was a treatment success at the end of TNS (i.e. had a ≥50% reduction in pain as measured by a 100 mm visual analogue scale and expressed a desire to have a

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permanent implant), they were scheduled for the fully implantable neurostimulator (INS) procedure.

Post INS placement, subjects were seen for device programming as needed to customize their stimulation parameters. Approximately one week following the INS implant the subjects had a wound check visit. Regularly scheduled study follow-up visits were required at 1-, 3-, 6-, 9-, 12 months, and annually until the study is closed. Primary and secondary endpoints were assessed through the 3 month follow-up visit. Postoperatively, the objective parameters measured during the study included the assessments listed in Table 6 and Table 7 below. Adverse events and complications were recorded at all visits.

The key time-points are shown below in the tables summarizing safety and effectiveness.

Table 6: ACCURATE Study Visit Schedule (Baseline to 1 Month Post-Implant)

| | Screening/Baseline | TNS | Post-TNS Placement | End of TNS | INS Implant | Post-INS Placement | 1 Month ± 14 days |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | TNS Phase^{1} | | | INS Phase^{1} | | |
| Informed Consent | X | | | | | | |
| Inclusion/Exclusion MRI/CT/X-ray | X | | | | | | |
| Baseline Pregnancy Test Medical History/ Physical Exam Neurological Exam Medications (all) | X | | | | | | |
| Subject Questionnaire Form A: Pain Distribution, Pain (VAS), SF-36, BPI, POMS | X | | | | | | X |
| Pain Diary | X | | | | | | X |
| Procedure Evaluation X-rays/Fluoroscopy | | X | | | X | | |
| Subject Questionnaire Form B: Pain Distribution, Pain (VAS) | | | | X | | | |
| Physical and Neurological Exam | | | | X | | | X |
| Paresthesia Assessment | | | X^{2} | X | | X^{2} | X |
| Programming | | | X^{3} | X | | X^{3} | X |
| Subject Satisfaction | | | | X | | | |
| Pain Medications | | | | X | | | X |

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Table 7: ACCURATE Study Visit Schedule (3 Months to Study End)

| | 3 Months ± 14 days | 6 months ± 28 days | 9 months ± 28 days | 12 months ± 28 days | 24 – 60 months ± 90 days | Unscheduled Visits^{1} | Revision/Replace Procedure |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Physical/Neurological Exam | X | X | X | X | X | | X^{3} |
| Pain Medications | X | X | X | X | X | | |
| Subject Questionnaire Form A: Pain Distribution, Pain (VAS), SF-36, BPI, POMS | X | X | X | X | X | | |
| Subject Questionnaire Form B: Pain Distribution, Pain (VAS) | | | | | | X^{1} | |
| Pain Diary | X | X | X | X | | | |
| Telephone Follow-up (prior to visit) | X | X | X | X | | | |
| Paresthesia Assessment | X | X | X | X | X | | |
| Programming | X | X | X | X | X | X | X^{3} |
| Subject Satisfaction | X | X | | X | | | |
| Revision/Replacement Procedure: X-rays/Fluoro | | | | | | | X^{3} |
| Explant Procedure: X-rays/Fluoro | | | | | | | |
| Study Exit | | | | | X^{2} | | |
| Adverse Events & Protocol Deviations (if needed) | X | X | X | X | X | X | X |

1 The post- TNS and post-INS phases do not require unscheduled visits (e.g. Subject Questionnaire B) unless it is determined that more assessments are warranted based on the subjects condition. Only those unscheduled visits that occur after the 1-month visit will be subject to the unscheduled visit requirements. There may be programming forms in the unscheduled interval that are really post-revision/replacement or required to assess an AE in which are not true unscheduled visits (e.g. do not require Subject Questionnaire B).

2 The Study Exit form is required at the time of study exit or 60 months as appropriate.

3 Replacement procedures that include external components (TNS, patient programmer, connector cable) do not require pre/post X-rays, physical or neurological exam, or programming. In addition, pre-x-rays were not always attainable (e.g., TNS leads pulled out at subject's home) and were not considered deviations

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3. Clinical Endpoints

The primary endpoint was a composite safety and efficacy endpoint, assessed through three months post-implant (including the Trial Stimulation (TNS) and the Implant (INS) phases). Safety and efficacy were determined by the percentage of subjects that were free from a stimulation-induced neurological deficit and achieved at least 50% pain relief in the lower limbs, in the region of greatest baseline pain, in both the TNS and INS phases of the trial. Subjects were required to remain on stable pain medications; as seen in Table 28, changes in pain medication were minimal.

A stimulation induced neurological deficit was defined as a measureable motor or sensory deficit on the neurological examination, within the appropriate concordant anatomy, that is induced by stimulation and does not persist in the absence of stimulation within a 24-hour timeframe. Changes in motor and sensory scales were classified into three categories: Change ≤ -2 points (worsening), -1 ≤ Change ≤ +1 (no clinically meaningful change, and Change ≥ +2 (improvement). Subjects' pain intensity was measured via a 100 mm visual analogue scale (VAS) with 100 mm representing the "Worst Imaginable Pain" and 0 mm representing "No Pain".

The Statistical Analysis Plan specified the use of the modified-intention-to-treat (MITT) analysis dataset for analyses of primary and secondary endpoints. The MITT analysis data set includes all subjects that were randomized and received a trial neurostimulator. The primary composite endpoint data was also analyzed using the intention-to-treat subjects (ITT) (i.e., all subjects who met the enrollment criteria and received a randomization assignment.) and per-protocol subjects (PP) (i.e., all randomized subjects who have valid data at baseline and the 3-month follow-up, and have no major protocol deviations that would potentially affect study outcomes).

Individual Subject Success

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

- Experienced at least 50% lower limb pain relief (VAS Score Reduction) in their primary area of pain at the end of the trial phase (TNS), and expressed a desire to go on to INS implant, and
- Received at least 50% lower limb pain relief (VAS Score reduction) in their primary area of pain at the 3-Month visit post implant (INS), and
- Did not experience a stimulation-induced neurological deficit through three months as adjudicated by the Data Safety Monitoring Board (DSMB).

A subject was considered a primary composite endpoint failure if the subject:

- Did not receive at least 50% lower limb pain relief (VAS Score reduction) in their primary area of pain at the end of the trial phase (TNS), or

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- Did not receive at least 50% lower limb pain relief (VAS Score reduction) in their primary area of pain at the 3-Month visit post implant (INS), or
- Did receive at least 50% lower limb pain relief (VAS Score reduction) in their primary area of pain at the end of the trial phase (TNS), but chose not to receive the implantable neurostimulator (INS), or
- Experienced a stimulation-induced neurological deficit through three months as adjudicated by the DSMB, or
- Exited the study due to a device- or procedure-related adverse event through three months as adjudicated by the DSMB, or
- Exited the study due to the need for a revision, replacement or explant procedure.

A subject was considered missing for the primary composite endpoint analysis if the subject:

- Exited the study after the initiation of the TNS procedure but prior to INS implant for any reason other than,
- achieved less than 50% improvement in VAS scores at the End of TNS visit (i.e. primary-endpoint failure), or
- achieved at least 50% improvement in VAS scores but chose not to move on to INS procedure (i.e. primary-endpoint failure), or
- had a device- or procedure-related adverse event as adjudicated by the DSMB (i.e. primary-endpoint failure).

- Exited the study after the INS implant for any reason other than a device- or procedure-related adverse event through three months as adjudicated by the DSMB.

## Study Success

Study success was defined as the percentage of subjects who met each success criteria in the Axium group and the Control group, using a 10% non-inferiority margin. If non-inferiority was achieved at a one-sided alpha of 0.05, a one-sided superiority test was performed at the significance level of 0.025.

## Secondary Endpoint – Non-powered

Subjects reported whether or not they felt paresthesia when stimulation was on as a non-powered secondary endpoint. At the 3- month study visit subjects responded "Yes" or "No" to the question "During the past month, did you feel paresthesia in your lower limbs when stimulation was on?" Subjects were categorized into two groups based on their response: Group 1 - Subjects with paresthesia and Group 2 - Subjects without Paresthesia.

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At the time of the trial and implant procedures, all subjects were asked to confirm that they were feeling stimulation (i.e. sensation of paresthesia) in the targeted area of pain in order to confirm placement of the implanted leads. Post-procedure, stimulation settings were then programmed based upon physician judgment to optimize the appropriate therapy for each study subject. In addition, all study subjects were able to adjust the intensity level of the therapy, within a physician-prescribed range, with their patient programmers.

Note that the clinical relevance of this result is unknown. The instructions for use for the Control device instructed that subjects be programmed to receive paresthesia. In addition, the number of subjects that did not have paresthesia is very small and this endpoint was not adequately powered to detect the difference in pain relief for subjects who reported feeling versus not feeling paresthesia. A placebo controlled trial would be necessary to rule out the possibility that the effect is greater than placebo.

## Tertiary Endpoints

The following are the study Tertiary endpoints:

- SF-36 Quality of Life Questionnaire at 3, 6, and 12-months
- Profile of Mood States (POMS) at 3, 6, and 12-months
- Brief Pain Inventory (BPI) at 3, 6, and 12-months
- Subject Satisfaction at 3, 6, and 12-months:
- Subjects completed a satisfaction scale at the End of TNS visit, and at three, six, and 12-months. The first three items were evaluated on an 11-point numeric scale with 0 indicating “Not Satisfied/Not Likely” and 10 indicating “Very Satisfied/Very Likely”. The last item was measured on a 7-point scale from “Much Worse” to “Much Better.”
- Please rate your satisfaction with the pain relief provided by the stimulation.
- Please rate your satisfaction with the therapy in general.
- Please rate how likely you would be to undergo this therapy again based on your experience thus far.
- Please rate the change in your pain compared to before the device was implanted.

- Stimulation Specificity at 3-months:
The baseline pain diagrams completed by the subjects were compared to the subjects’ paresthesia maps completed at the end of the follow-up visit. The pain and paresthesia diagram forms had identical diagrams of the human body on which subjects marked where they felt pain and paresthesia coverage. The stimulation specificity endpoint was evaluated at all scheduled visits by determining whether a subject felt paresthesia in anatomical regions that were reported as having no pain at baseline.

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B. Accountability of PMA Cohort

The ACCURATE study enrolled and randomized 152 subjects (76 Axium subjects and 76 Control subjects) at 22 investigational sites. As of October 2, 2015, when the database was locked for this report, the average months implanted for subjects that received an INS was 12.6 (± 3.5) months in the Axium group, and 12.0 (± 2.3) months in the Control group. The cumulative INS months of implanted experience for subjects that received an INS device in the Axium group was 768 months (64 cumulative years), and in the Control group was 649.2 months (54.1 cumulative years).

The Statistical Analysis Plan (SAP) specified the use of the modified-intention-to-treat (MITT) analysis dataset for analyses of primary and secondary endpoints. Missing data sensitivity analyses, Intention-to-treat (ITT) and per-protocol (PP), were conducted to assess the robustness of the primary endpoint analysis.

The MITT analysis data set includes all 146 subjects (73 Axium, 73 Control) that were randomized and received a trial neurostimulator. Six subjects in the ITT analysis data set (3 in the Axium group and 3 in the Control group) were randomized, did not go on to have a TNS procedure, withdrew from the study prior to the TNS procedure, and are not included in the MITT analysis set. One Control subject in the MITT analysis data set had a TNS procedure but withdrew from the study prior to undergoing the end of TNS study visit. Since the subject withdrew due to a device-related adverse event, the subject is counted as a treatment failure. One Axium subject in the MITT data set had an INS procedure but withdrew from the study prior to the 3-month study visit. Since the subject withdrew due to a device-related adverse event, the subject is counted as a treatment failure. Another Axium subject in the MITT data set exited the study prior to their INS procedure due to a device-related adverse event post-TNS procedure. Since this subject withdrew due to a device related adverse event, the subject is counted as a treatment failure.

Seven subjects (four in the Axium group and three in the Control group) in the MITT analysis data set have no evaluable data for the study endpoints and are counted as missing because they withdrew from the study prior to the 3-month study visit, and did not meet any prospectively defined criteria for treatment failure/success at the time of study withdrawal.

The ITT population includes all 152 randomized subjects, 76 subjects in each group. The Per Protocol (PP) analysis set includes all randomized subjects who have valid data at baseline and the 3-month follow-up, and have no major protocol deviations that would potentially affect study outcomes. Major protocol deviations were defined prior to database lock.

The Control group had 16 major protocol deviations in 15 subjects. Twelve deviations were due to noncompliant programming, three deviations were due to performing the neurological examination without stimulation turned on, and one

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deviation was due to the neurological examination not being done at a follow-up visit. The Axium group had 1 subject with one major protocol deviation due to an incomplete neurological exam at a follow-up visit. These deviations did not change the conclusions drawn from the primary composite endpoint.

See Figure 2 below for a flow chart describing the subject accountability. Note in Figure 2, there are three subjects with missing visits at 12 months. One subject moved to another state. The site is in communication with the individual and the subject plans to return to the site for another visit at a time that is convenient and has not exited the study. One subject is lost to follow-up. The site has attempted to contact the subject and has sent a certified letter. There has been no response from the subject. One subject missed the 12-month visit but still is enrolled in the study and will be seen at the site as soon as a visit can be scheduled out of window for the 12-month assessment.

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Figure 2: Subject Accountability

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# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a study of this type performed in the US. Table 8 presents information on key subject characteristics. No statistically significant differences were found among the baseline characteristics between the Axium group and the Control group. The average age of the subjects in the Axium and Control groups was 52.4 years and 52.5 years, respectively. The distribution of female gender in the Axium and Control groups was $51.3\%$ and $51.3\%$ respectively. Race was predominately white (94.7% and $92.1\%$ Axium and Control, respectively). On average, subjects had an average BMI of 30.5 (Axium) and 28.9 (Control).

The distribution of Complex Regional Pain Syndrome (CRPS) (Axium $57.9\%$ and Control $56.6\%$ ) and Peripheral Causalgia (Axium $42.1\%$ and Control $43.4\%$ ) was similar between the groups. Subjects' medical history and prior surgeries were comparable for both groups, with average duration of lower extremity pain at 7.5 years (Axium) and 6.8 years (Control).

Table 8: Baseline Demographics and Characteristics

| Baseline Characteristics | Axium N = 76 | Control N = 76 | p-value |
| --- | --- | --- | --- |
| Gender (% Female) | 39/76 (51.3%) | 39/76 (51.3%) | 1.0000†† |
| Age in Years ± SD (Min., Max.) | 52.4 + 12.7 (23.9, 75.8) | 52.5 ± 11.5 (25.4, 75.9) | 0.9363* |
| BMI (kg/m2) ± SD (Min., Max.) | 30.5 ± 7.2 (16.9, 54.0) | 28.9 ± 6.0 17.4, 44.6) | 0.1266* |
| Duration of Lower Limb Pain in years ± SD (Min., Max.) | 7.5 ± 7.5 (1.0, 39.0) | 6.8 ± 7.6 (0.7, 51.0) | 0.5571** |
| Primary Diagnosis (n/N (%)) | | | |
| Complex Regional Pain Syndrome | 44/76 (57.9%) | 43/76 (56.6%) | 0.8698†† |
| Peripheral Causalgia | 32/76 (42.1%) | 33/76 (43.4%) | |

$^{*}T$ -test, $^{**}$ Wilcoxon test, Fisher exact test, Chi-square test

# Baseline Lower Limb Pain Medications

Subjects' baseline lower limb pain medications were comparable between the Axium and Control groups (see Table 9). Opioids, anticonvulsants and nonsteroidal anti-inflammatory drugs (NSAIDS) were the most frequent medication classes taken by the subjects at the baseline visit. Opioids were taken by $60.5\%$ (Axium) and $67.1\%$ (Control) of subjects. Anticonvulsant medications were taken by $47.4\%$ (Axium) and $46.1\%$ (Control) of subjects. NSAIDS were taken by $48.7\%$ (Axium) and $31.6\%$ (Control) of subjects. There were no statistically significant differences in the use of lower limb pain medications, with the exception of NSAIDS.

Table 9: Baseline Pain Medication Usage for Lower Limb Pain by Medication Class

| | Axium n/N (%) | Control n/N (%) | p-value |
| --- | --- | --- | --- |
| Analgesics | 5/76 (6.6) | 5/76 (6.6) | 1.0000†† |
| Anticonvulsants | 36/76 (47.4) | 35/76 (46.1) | 0.8709†† |

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| | Axium n/N (%) | Control n/N (%) | p-value |
| --- | --- | --- | --- |
| Antidepressant | 10/76 (13.2) | 11/76 (14.5) | 0.8142†† |
| Anxiolytics | 2/76 (2.6) | 1/76 (1.3) | 1.0000† |
| Hypnotics | 0/76 (0.0) | 0/76 (0.0) | N/A |
| Muscle Relaxant | 6/76 (7.9) | 5/76 (6.6) | 0.7542†† |
| NSAIDs (OTC & prescription) | 37/76 (48.7) | 24/76 (31.6) | 0.0315†† |
| Opioids (incl. synthetic and semisynthetic derivatives) | 46/76 (60.5) | 51/76 (67.1) | 0.3987†† |
| Sedative | 2/76 (2.6) | 0/76 (0.0) | 0.4967† |
| Local Anesthetic | 10/76 (13.2) | 8/76 (10.5) | 0.6156†† |
| Other | 2/76 (2.6) | 3/76 (3.9) | 1.0000† |

†Fisher exact test, ††Chi-square test

## Lower Limb Pain History

The subjects' lower limb pain history is summarized in Table 10. The distribution of Complex Regional Pain Syndrome (CRPS) (Axium 57.9% and Control 56.6%) and Peripheral Causalgia (Axium 42.1% and Control 43.4%) was similar between the groups. All subjects' diagnoses were confirmed by the Medical Monitor during his review.

The diagnostic criteria required for a diagnosis of CRPS were taken from the 1994 consensus statement from the International Association for the Study of Pain (IASP) (van Eijs et al., 2010). The CRPS diagnostic criteria were met when the following were present:

- Continuing pain that is disproportionate to any inciting event.
- At least 1 symptom reported in at least 3 of the following categories:
- Sensory: Hyperesthesia or allodynia.
- Vasomotor: Temperature asymmetry, skin color changes, skin color asymmetry.
- Sudomotor/edema: Edema, sweating changes, or sweating asymmetry.
- Motor/trophic: Decreased range of motion, motor dysfunction (e.g., weakness, tremor, dystonia), or trophic changes (e.g., hair, nail, skin).
- At least 1 sign at time of evaluation in at least 2 of the following categories.
- Sensory: Evidence of hyperalgesia (to pinprick), allodynia (to light touch, temperature sensation, deep somatic pressure, or joint movement).
- Vasomotor: Evidence of temperature asymmetry (&gt;1°C), skin color changes or asymmetry.
- Sudomotor/edema: Evidence of edema, sweating changes, or sweating symmetry.
- Motor/trophic: Evidence of decreased range of motion, motor dysfunction (e.g., weakness, tremor, dystonia), or trophic changes (e.g., hair, nail, skin).

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- No other diagnosis better explaining the signs and symptoms.

For peripheral causalgia, the diagnosis required that the subjects' chronic pain was due to damage to a nerve (Fishman et al., 2010). The pain was required to be in an anatomical area consistent with the innervation pattern of the damaged nerve (or nerves), and generally, in a hyperalgesic state. In some cases, the nerve damage progressed with secondary changes manifesting themselves. However, this was not a diagnostic requirement. Nerve damage typically resulted from blunt trauma (injury) or other types of injury such as post-surgical nerve cutting or lesioning.

Subjects' average duration of lower extremity pain is 7.5 years (Axium) and 6.8 years (Control). Subjects reported previous attempts to relieve lower extremity pain. Physical therapy, massage therapy, surgery, and injections (epidural steroid injections, sacroiliac joint injections and selective nerve blocks) were most frequently reported.

A primary region of pain targeted for treatment was identified by the investigators for each subject based on their baseline VAS pain assessment. The region with the highest VAS score consistent with the subjects' diagnoses was selected as the primary region of pain. Nine anatomical regions of the lower extremity were defined and subjects rated their pain intensity for each region on the 100mm VAS scale at baseline and at each scheduled visit. The distribution of primary regions of pain was comparable for the Axium and Control groups.

No statistically significant differences were observed in Lower Extremity Pain History indicating similar baseline characteristics; the two groups are balanced based on the randomization scheme.

Table 10: Lower Limb Pain History

| Pain History Parameter | Axium N=76 | Control N=76 |
| --- | --- | --- |
| Primary Diagnosis (n/N (%)) | | |
| Complex Regional Pain Syndrome | 44/76 (57.9) | 43/76 (56.6) |
| Peripheral Causalgia | 32/76 (42.1) | 33/76 (43.4) |
| P-value | 0.8698†† | |
| Duration of CRPS Diagnosis (years) | | |
| N | 43 | 43 |
| Mean (SD) | 1.8 (4.1) | 1.1 (2.1) |
| Median | 0.4 | 0.2 |
| Min. Max. | -0.0, 22.1 | 0.0, 9.9 |
| P-value | 0.5416** | |
| Duration of PC Diagnosis (years) | | |
| N | 32 | 33 |
| Mean (SD) | 1.6 (5.1) | 0.8 (2.7) |
| Median | 0.0 | 0.0 |
| Min. Max. | -0.0, 24.8 | -0.0, 11.6 |
| P-value | 0.5401** | |
| Duration of Lower Limb Pain (years) | | |
| N | 76 | 76 |

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| Pain History Parameter | Axium N=76 | Control N=76 |
| --- | --- | --- |
| Mean (SD) | 7.5 (7.5) | 6.8 (7.6) |
| Median | 5.0 | 4.5 |
| Min. Max. | 1.0, 39.0 | 0.7, 51.0 |
| P-value | 0.5571** | |
| Primary Region of Pain (n/N (%)) | | |
| Region 2 (right groin) | 4/76 (5.3) | 2/76 (2.6) |
| Region 3 (left groin) | 4/76 (5.3) | 7/76 (9.2) |
| Region 4 (right buttock) | 1/76 (1.3) | 2/76 (2.6) |
| Region 5 (left buttock) | 2/76 (2.6) | 2/76 (2.6) |
| Region 6 (right leg) | 14/76 (18.4) | 16/76 (21.1) |
| Region 7 (left leg) | 8/76 (10.5) | 11/76 (14.5) |
| Region 8 (right foot) | 21/76 (27.6) | 19/76 (25.0) |
| Region 9 (left foot) | 22/76 (28.9) | 17/76 (22.4) |
| P-value (Regions 2-5 vs. Regions 6/7 vs. Regions 8/9) | 0.5228†† | |
| Previous Attempts to Relieve Lower Limb Pain (not mutually exclusive n/N (%)) | | |
| Massage therapy | 39/76 (51.3) | 33/76 (43.4) |
| Occupational therapy | 18/76 (23.7) | 13/76 (17.1) |
| Physical therapy | 68/76 (89.5) | 63/76 (82.9) |
| Lumbar sympathetic blocks | 33/76 (43.4) | 24/76 (31.6) |
| Facet blocks | 6/76 (7.9) | 5/76 (6.6) |
| Surgery for lower limb pain | 40/76 (52.6) | 40/76 (52.6) |
| Local anesthetic injection | 33/76 (43.4) | 26/76 (34.2) |
| Intradiscal electrothermal therapy (IDET) | 1/76 (1.3) | 1/76 (1.3) |
| Intrathecal injection | 0/76 (0.0) | 3/76 (3.9) |
| Drug pumps (e.g. intrathecal for chronic pain) | 1/76 (1.3) | 0/76 (0.0) |
| TENS unit | 31/76 (40.8) | 31/76 (40.8) |
| Sacroiliac joint injection | 7/76 (9.2) | 9/76 (11.8) |
| Epidural steroid injection | 27/76 (35.5) | 30/76 (39.5) |
| Pulsed or constant radiofrequency near the target DRG | 4/76 (5.3) | 5/76 (6.6) |
| Selective nerve blocks | 27/76 (35.5) | 23/76 (30.3) |
| Other | 38/76 (50.0) | 30/76 (39.5) |

**Wilcoxon test, †Chi-square test

## Implant Characteristics

The following four subgroups were defined: CRPS Type I - Unilateral, CRPS Type I - Bilateral, peripheral causalgia (aka CRPS II) - Unilateral, peripheral causalgia - Bilateral. Table 11 presents the number of Axium subjects in each subgroup, the number of leads implanted per subject in each sub-group, and the number of subjects in each sub-group with permanent leads at each spinal level. Table 12 presents the number of Control subjects in each subgroup, the number of leads implanted per subject in each sub-group, and the number of subjects in each sub-group with permanent leads at each spinal level.

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Table 11: Leads Implanted in the Axium Group by Primary Diagnosis and Unilateral/Bilateral Pain - Axium

| | Unilateral CRPS n/N (%) | Bilateral CRPS n/N (%) | Unilateral PC n/N (%) | Bilateral PC n/N (%) |
| --- | --- | --- | --- | --- |
| Number of Subjects Implanted at INS | 23/61 (37.7) | 11/61 (18.0) | 17/61 (27.9) | 10/61 (16.4) |
| Number of Leads Implanted per Subject | | | | |
| 1 lead | 7/23 (30.4) | 0/11 (0.0) | 6/17 (35.3) | 0/10 (0.0) |
| 2 leads | 15/23 (65.2) | 8/11 (72.7) | 7/17 (41.2) | 8/10 (80.0) |
| 3 leads | 1/23 (4.3) | 1/11 (9.1) | 3/17 (17.6) | 0/10 (0.0) |
| 4 leads | 0/23 (0.0) | 2/11 (18.2) | 1/17 (5.9) | 2/10 (20.0) |
| Level of Lead(s) Implanted Per Subject (not mutually exclusive)* | | | | |
| T10 | 0/23 (0.0) | 0/11 (0.0) | 0/17 (0.0) | 0/10 (0.0) |
| T11 | 1/23 (4.3) | 0/11 (0.0) | 0/17 (0.0) | 0/10 (0.0) |
| T12 | 0/23 (0.0) | 0/11 (0.0) | 3/17 (17.6) | 0/10 (0.0) |
| L1 | 4/23 (17.4) | 2/11 (18.2) | 5/17 (29.4) | 0/10 (0.0) |
| L2 | 4/23 (17.4) | 2/11 (18.2) | 6/17 (35.3) | 3/10 (30.0) |
| L3 | 7/23 (30.4) | 2/11 (18.2) | 3/17 (17.6) | 1/10 (10.0) |
| L4 | 12/23 (52.2) | 5/11 (45.5) | 8/17 (47.1) | 3/10 (30.0) |
| L5 | 12/23 (52.2) | 7/11 (63.6) | 7/17 (41.2) | 6/10 (60.0) |
| S1 | 0/23 (0.0) | 0/11 (0.0) | 1/17 (5.9) | 0/10 (0.0) |
| S2 | 0/23 (0.0) | 0/11 (0.0) | 0/17 (0.0) | 0/10 (0.0) |

* "Not mutually exclusive" refers to the fact that subjects may have up to 4 leads implanted in the Axium group. Subjects may have one or more leads implanted at one level or at multiple lead levels and are counted in multiple lead level categories. One lead may be implanted per DRG.

Table 12: Leads Implanted in the Control Group by Primary Diagnosis and Unilateral/Bilateral Pain

| | Bilateral CRPS n/N (%) | Bilateral PC n/N (%) | Unilateral CRPS n/N (%) | Unilateral PC n/N (%) |
| --- | --- | --- | --- | --- |
| Number of Subjects Implanted at INS | 22/54 (40.7) | 12/54 (22.2) | 11/54 (20.4) | 9/54 (16.7) |
| Number of Leads Implanted per Subject | | | | |
| 1 lead | 1/22 (4.5) | 0/12 (0.0) | 2/11 (18.2) | 1/9 (11.1) |
| 2 leads | 21/22 (95.5) | 12/12 (100.0) | 9/11 (81.8) | 8/9 (88.9) |
| Level of Lead(s) Implanted Per Subject (not mutually exclusive)* | | | | |
| T1 | 0/22 (0.0) | 0/12 (0.0) | 0/11 (0.0) | 0/9 (0.0) |
| T2 | 0/22 (0.0) | 0/12 (0.0) | 0/11 (0.0) | 0/9 (0.0) |
| T3 | 0/22 (0.0) | 0/12 (0.0) | 0/11 (0.0) | 0/9 (0.0) |
| T4 | 0/22 (0.0) | 0/12 (0.0) | 0/11 (0.0) | 0/9 (0.0) |

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| | Bilateral CRPS n/N (%) | Bilateral PC n/N (%) | Unilateral CRPS n/N (%) | Unilateral PC n/N (%) |
| --- | --- | --- | --- | --- |
| T5 | 0/22 (0.0) | 0/12 (0.0) | 0/11 (0.0) | 0/9 (0.0) |
| T6 | 0/22 (0.0) | 0/12 (0.0) | 0/11 (0.0) | 0/9 (0.0) |
| T7 | 0/22 (0.0) | 0/12 (0.0) | 0/11 (0.0) | 1/9 (11.1) |
| T8 | 0/22 (0.0) | 2/12 (16.7) | 2/11 (18.2) | 0/9 (0.0) |
| T9 | 2/22 (9.1) | 2/12 (16.7) | 3/11 (27.3) | 3/9 (33.3) |
| T10 | 7/22 (31.8) | 3/12 (25.0) | 4/11 (36.4) | 1/9 (11.1) |
| T11 | 8/22 (36.4) | 2/12 (16.7) | 1/11 (9.1) | 1/9 (11.1) |
| T12 | 6/22 (27.3) | 5/12 (41.7) | 4/11 (36.4) | 5/9 (55.6) |

* "Not mutually exclusive" refers to the fact that subjects may have up to 2 leads implanted in the Control group. Subjects may have one or more leads implanted at one level or at multiple lead levels and are counted in multiple lead level categories.

## Axium Programming Parameters

Table 13 presents a summary of the average amplitude, frequency and pulse width programmed settings for all Axium subjects over time. The median frequency was 20 Hz at all-time points; the median pulse width was 300μs at all time points except 12 months when it was 255μs. The median amplitude varied from 575μA to 687.5μA at the different time points. The median impedance ranged from 1225.5Ω to 1355.0Ω at the different time points.

Table 13: Summary of Axium Programmed Settings Based on Active Leads

| | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month |
| --- | --- | --- | --- | --- | --- |
| Number of Subjects | 61 | 59 | 59 | 55 | 55 |
| Number of Active Leads | 124 | 118 | 117 | 107 | 110 |
| Frequency/Rate Range (Hz) | | | | | |
| N | 123 | 118 | 117 | 107 | 110 |
| Mean | 22.5 | 20.8 | 20.0 | 19.0 | 19.0 |
| SD | 6.4 | 7.1 | 6.8 | 5.5 | 5.1 |
| Median | 20 | 20 | 20 | 20 | 20 |
| Minimum | 10 | 10 | 10 | 8 | 10 |
| Maximum | 40 | 48 | 48 | 40 | 36 |
| Pulse Width (μs) | | | | | |
| N | 124 | 118 | 117 | 107 | 110 |
| Mean | 312.4 | 308.9 | 315.4 | 295.6 | 289.8 |
| SD | 148.6 | 145.9 | 166.0 | 140.7 | 133.8 |
| Median | 300 | 300 | 300 | 300 | 255 |
| Minimum | 100 | 100 | 60 | 90 | 90 |
| Maximum | 1000 | 1000 | 1000 | 1000 | 1000 |

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| | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month |
| --- | --- | --- | --- | --- | --- |
| Amplitude (μA) | | | | | |
| N | 122 | 118 | 116 | 107 | 107 |
| Mean | 892.3 | 915.4 | 836.4 | 764.6 | 827.4 |
| SD | 703.9 | 822 | 721.9 | 630.9 | 657.1 |
| Median | 687.5 | 675 | 650 | 575 | 650 |
| Minimum | 150 | 75 | 100 | 100 | 75 |
| Maximum | 4400 | 6000 | 4600 | 3950 | 4000 |
| Impedance (Ω) | | | | | |
| N | 116 | 116 | 114 | 107 | 110 |
| Mean | 1321.2 | 1431.7 | 1504.7 | 1583.9 | 1458.9 |
| SD | 527.9 | 571.4 | 700.4 | 792.8 | 714.5 |
| Median | 1225.5 | 1329.5 | 1324.5 | 1355.0 | 1256.5 |
| Minimum | 645 | 589 | 586 | 572 | 547 |
| Maximum | 5000 | 4795 | 5000 | 5000 | 4962 |

## D. Safety and Effectiveness Results

### 1. Safety Results

As pre-specified in the Statistical Analysis Plan, the study primary composite endpoint data was analyzed using a modified intention to treat (MITT) analysis which included all subjects that were randomized and received a trial neurostimulator. The analysis of safety in the composite endpoint was based on 146 (73 Axium and 73 Control) evaluable subjects at the 3-month time point. The analysis of safety also included the intent-to-treat (ITT) population of 152 subjects (76 Axium and 76 Control) available for the 3 month evaluation and 105 subjects (55 Axium and 50 Control) available at 12 months. None of the study subjects experienced a primary composite endpoint safety event (stimulation induced neurological deficit) through 12 months and up to the date of the database lock.

The overall motor examination results indicate that most of the subjects in both groups experienced no change in their motor examination at three months (96.6% Axium and 100% Control had no change). None of the subjects in the Axium or Control groups experienced a worsening of motor scores. Improvement in the overall motor score occurred in three subjects in the Axium group and none of the subjects in the Control group.

The overall sensory examination results indicate that most of the subjects in both groups experienced no change in their sensory examination at three months (98.3% Axium and 98.1% Control had no change). None of the subjects in the Axium or Control group experienced a worsening of sensory scores. Improvement in sensory scores occurred in one subject in the Axium group, and two subjects in the Control group.

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# Serious Adverse Events

A total of 21 serious adverse events occurred in 19 subjects, four events in four subjects (Axium 1, Control 3) during the TNS phase, and 17 events in 15 subjects (Axium 7, Control 8) in the INS phase. The overall difference in the rate of SAEs between the groups was not statistically different (Axium $10.5\%$ , Control $14.5\%$ , $p = 0.6248$ ); the rate during the TNS phase (Axium $1.3\%$ , Control $3.9\%$ , $p = 0.62$ ), and INS phase (Axium $9.2\%$ , Control $10.5\%$ , $p = 1.0$ ) also were not statistically different. See Table 14 below. There were no unanticipated AEs or deaths in the study.

Table 14: Percent of Subjects with SAEs

| | Axium N=76 | Control N=76 | P-value |
| --- | --- | --- | --- |
| SAE during TNS Phase | (1/76) 1.3% | (3/76) 3.9% | 0.6200 |
| SAE during INS Phase | (7/76) 9.2% | (8/76) 10.5% | 1.0000 |
| Total | (8/76)10.5% | (11/76) 14.5% | 0.6248 |

Fourteen of the serious adverse events resolved (6 with and 8 without sequelae). In the Control group, there were five unrelated SAEs and one device/procedure related SAE still ongoing at the time of the database lock on Oct. 2, 2015. In the Axium group there was one unrelated SAE still ongoing.

Eighteen of the 21 SAEs were unrelated to the implant procedure, device or stimulation therapy. Two of the SAEs in the Control group were definitely related to the implant procedure and/or device:

- One Control subject had an infection following the TNS procedure that required explantation of the system.
- A second Control subject had an infection following the INS procedure that required explantation of the system.

One Axium subject experienced an episode of atrial fibrillation in the recovery room following the INS implant that was adjudicated as possibly related to a pre-existing condition, the implant procedure or the device.

Table 15 and Table 16 present the serious adverse events (SAEs) reported for subjects in both the Axium and Control groups through the TNS and INS phases. The total rate of SAEs in the Axium group was not significantly different than the Control group.

Table 15: Distribution of Serious Adverse Events through the TNS Phase

| | Axium N=76 | | Control N=76 | |
| --- | --- | --- | --- | --- |
| Subsystem Code/Preferred Code | Events N | Subjects n (%) | Events N | Subject n (%) |
| Total Serious Adverse Events (based on ITT) | 1 | 1 (1.3) | 3 | 3 (3.9) |
| Total Serious Adverse Events (based on At | 1 | 1 (1.3) | 3 | 3 (3.9) |
| Total Serious Adverse Events (based on At | 1 | 1 (1.3) | 3 | 3 (3.9) |
| Total Serious Adverse Events (based on At | 1 | 1 (1.3) | 3 | 3 (3.9) |

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| | Axium N=76 | | Control N=76 | |
| --- | --- | --- | --- | --- |
| Subsystem Code/Preferred Code | Events N | Subjects n (%) | Events N | Subject n (%) |
| Risk)† | | | | |
| Blood Components / Abnormal Blood Chemistry | 1 | 1 (1.3) | 0 | 0 (0.0) |
| Lower Extremity / Bilateral Lower Leg Pain | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Substance Related Disorders / Overdose | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Wound Issue / Wound Infection | 0 | 0 (0.0) | 1 | 1 (1.3) |

† Subjects at risk means are all randomized subjects, n=76 in each group

Table 16: Distribution of Serious Adverse Events through the INS Phase

| | Axium N=76 | | Control N=76 | |
| --- | --- | --- | --- | --- |
| Subsystem Code/Preferred Code | Events N | Subjects n (%) | Events N | Subject n (%) |
| Total Serious Adverse Events (based on ITT) | 7 | 7 (9.2) | 10 | 8 (10.5) |
| Total Serious Adverse Events (based on At Risk)1 | 7 | 7 (11.5) | 10 | 8 (14.8) |
| Degenerative Joint Disease / Arthritis2 | 2 | 2 (2.6) | 0 | 0 (0.0) |
| Bone / Bone Infection3 | 1 | 1 (1.3) | 0 | 0 (0.0) |
| Cardiac / Arrhythmia and Irregularities | 1 | 1 (1.3) | 0 | 0 (0.0) |
| Injury / ADL4 | 1 | 1 (1.3) | 0 | 0 (0.0) |
| Intestinal / Nausea and/or Vomiting | 1 | 1 (1.3) | 0 | 0 (0.0) |
| Joint or Muscle / Surgery | 1 | 1 (1.3) | 0 | 0 (0.0) |
| Blood Pressure / Hypertension | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Dermatologic5 | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Eyes or Ears or Nose or Throat (EENT)6 | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Infection / Cellulitis | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Infection / Systemic Infection or General or Unknown | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Intestinal / Diverticulitis | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Liver / Cirrhosis or Fatty Liver | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Substance Related Disorders / Substance Dependence or Withdrawal | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Trunk or Ribs / Trunk or Rib Pain | 0 | 0 (0.0) | 1 | 1 (1.3) |
| Wound Issue / Wound Infection | 0 | 0 (0.0) | 1 | 1 (1.3) |

1. Subjects at risk means all subjects that underwent an INS procedure, (Axium n=61, Control n=54).
2. One subject reported worsening of left shoulder arthritis. The subject was treated with left shoulder hemiarthroplasty for arthritis, cuff tear and biceps tendonitis. During the surgery a degenerative osteocartilagenous cyst was removed. A second subject had baseline ongoing condition of neck pain with previous cervical radiofrequency thermocoagulation. Three months post INS implant, the subject reported having surgery (ACF and discectomy at C4-5 and C5-6) due to cervical spondylosis with radiculitis.
3. Subject reported osteomyelitis of right great toe. The subject's right toe was run over by a cart while working and the right toe started to become red/black. The subject then went to the hospital and was admitted. The subject presented to the hospital with worsening swelling with a $\frac{1}{2}$ cm diameter deep ulceration and discharge of the right great toe. The subject was started on IV antibiotics (vancomycin) and underwent a great right toe amputation at the MTPJ level.
4. The subject reported a chainsaw cutting incident in which he broke his left leg (tibia bone near the knee).
5. The subject was noted to have an ulcer of the left plantar foot (neuropathic foot ulcer sub left 1st metatarsal heal with a dry neurotic base and large periwound keratosis). The subject has a medical history

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of diabetes. The subject was treated with an excisional debridement of the ulcer and application of a Aquacel AG dressing.

6. The subject reported loss of vision in the right eye. The subject did not receive any treatment from the investigator but it was noted that the subject was being evaluated and treated by an ophthalmologist.

# Adverse Events by Relatedness to Implant Procedure, Device or Stimulation Therapy

Adverse events were classified by the DSMB as device-, procedure-, and/or stimulation-related. Note that the categories of device related, procedure related and stimulation related are not mutually exclusive. For some events the DSMB adjudicated an event as related to multiple categories such as device and procedure related, or device and stimulation related, etc.

As seen in Table 17, which represents the ITT population, the rates of device- and stimulation-related events were not statistically different between the groups. However, procedure-related AEs were more frequent in the Axium group (52 even…