NEVRO SENZA SPINAL CORD STIMULATION (SCS) SYSTEM

P130022 · Nevro Corporation · LGW · May 8, 2015 · Neurology

Device Facts

• Record ID: P130022
• Device Name: NEVRO SENZA SPINAL CORD STIMULATION (SCS) SYSTEM
• Applicant: Nevro Corporation
• Product Code: LGW · Neurology
• Decision Date: May 8, 2015
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The Senza 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

Totally implanted spinal cord stimulation system; delivers electrical stimulation to dorsal column. Components: Implantable Pulse Generator (IPG), percutaneous leads, lead extensions, anchors, and external controllers (Clinician Programmer, Patient Remote). IPG (Model 1500) provides 16-channel stimulation; 10 kHz frequency (paresthesia-free) or 2-1200 Hz (paresthesia-based). Physician programs stimulation parameters via laptop software; patient uses remote to adjust settings. System treats chronic intractable pain; reduces pain intensity (VAS) and disability (ODI). Benefits include paresthesia-free therapy option, improved pain management, and reduced reliance on pain medications. Used in clinical settings for implantation; patient-operated at home.

Clinical Evidence

Prospective, randomized, multi-center non-inferiority trial (IDE #G110156) of 198 randomized subjects (101 Test, 97 Control). Primary endpoint: composite of ≥50% back pain VAS reduction at 3 months, no increase in pain meds, and no stimulation-related neurological deficit. Test group (10 kHz) met non-inferiority and superiority vs. control (2-1200 Hz). 75.0% Test vs 37.7% Control met primary endpoint (p<0.001). Secondary endpoints (leg pain, ODI) also showed superiority. Safety profile consistent with existing SCS systems; no stimulation-related neurological deficits reported.

Technological Characteristics

Totally implanted system. IPG: Titanium housing, 3.6V Li-Ion rechargeable battery, 16 output channels. Leads: 1.4mm diameter, 8-electrode (Pt/Ir), ETFE-insulated MP35N conductors, Pellethane 55D body. Stimulation: Biphasic, rectangular, current-regulated (0-15 mA), 2-10,000 Hz. Connectivity: RF communication between IPG, Patient Remote, and Programmer Wand. Sterilization: Ethylene Oxide (EO). Standards: ISO 14708-3, ISO 10993-1, IEC 60601-1-2.

Indications for Use

Indicated for patients 18+ with chronic intractable pain of trunk/limbs (failed back surgery syndrome, intractable low back/leg pain) refractory to conservative therapy for ≥3 months. Contraindicated for poor surgical candidates, those failing trial stimulation, or unable to operate the system.

Reference Devices

• Medtronic Synergy (referenced in clinical study)
• St. Jude Medical Lamitrode S8 (referenced in literature)
• EonC IPG (referenced in literature)
• Genesis XP IPG (referenced in literature)
• Medtronic Resume lead (referenced in literature)
• Itrel II IPG (referenced in literature)
• Boston Scientific Precision system (referenced in literature)

Submission Summary (Full Text)

{0}

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

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

Device Trade Name: Senza Spinal Cord Stimulation (SCS) System

Device Procode: LGW

Applicant’s Name and Address: Nevro Corp.
4040 Campbell Avenue, Suite 210
Menlo Park, CA 94025

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P130022

Date of FDA Notice of Approval:

II. INDICATIONS FOR USE

The Senza 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 Senza SCS System should not be used for those patients who:

- Are poor surgical candidates.
- Fail to receive effective pain relief during trial stimulation.
- Are unable to operate the SCS system.

IV. WARNINGS AND PRECAUTIONS

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

V. DEVICE DESCRIPTION

The Senza SCS System is a totally implanted device that delivers electrical stimulation to the dorsal column of the spinal cord for the treatment of chronic intractable pain of the trunk and/or limbs. The Senza SCS System is shown in Figure 1 below:

PMA P130022: FDA Summary of Safety and Effectiveness Data

{1}

Figure 1: Senza SCS System Implantable Pulse Generator (IPG) and Percutaneous Leads

# A. Implanted Components

The implanted components of the Senza SCS System include the following:

- Implanted Pulse Generator (IPG) (Model 1500): The IPG is a rechargeable implantable device with 16 output channels. Each of the 16 outputs can be programmed as a cathode or an anode. The IPG is powered by a $3.6\mathrm{V}$ nominal Li-Ion rechargeable battery (single cell). It is capable of stimulating the spinal cord nerves through the electrodes of the leads connected to any combination of the output terminals, using a single current source. The battery of the IPG can be transcutaneously recharged using a Nevro Charger. There are two versions of the IPG which vary slightly in the shape of the header. Approximate dimensions of the IPGs are $53.5\mathrm{mm}$ (height without header; with header $69\mathrm{mm}$ ), $47.5\mathrm{mm}$ (width) and $12.5\mathrm{mm}$ (thickness). The stimulation output parameters are listed in Table 1 below:

Table 1: Stimulation Output Parameters

| Number of Programs | 1 to 3 |
| --- | --- |
| Number of Channels | 16 |
| Waveform | Charged Balanced Biphasic |
| Pulse Shape | Rectangular |
| Current or Voltage Regulated | Current |
| Maximum Current Amplitude @ 500 Ω | 0 to 15 mA per channel |
| Maximum Output Voltage @ 500 Ω | 7.5 V |
| Pulse Width | 20 to 1000 μs |
| Frequency | 2 to 10,000 Hz |
| Current Path Options | Bipolar or Multipolar |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{2}

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 3

- Percutaneous Leads:
The lead specifications are depicted in Table 2 below:

Table 2: Percutaneous Lead Specifications

| | Percutaneous Leads |
| --- | --- |
| Lead Length (cm) | 30-90 in increments of 5 |
| Lead Diameter (mm) | 1.4 |
| Number of Electrodes | 8 |
| Electrode Material | Platinum/Iridium |
| Electrode Spacing (edge-to-edge) (mm) | 1-9 |
| Electrode Span (cm) | 3.1-8.7 |
| Electrode Surface Area (mm²) | 12.7 |
| Impedance (Ω) | < 18 |
| Conductor Material | Ethylene tetrafluoroethylene (ETFE) insulated MP35N cable with Silver core |
| Lead Body Insulation | Pellethane 55D – Dow Corning 2363 |

- Lead Extensions: Used when the implant site for the IPG is located too far from the stimulation site to directly connect to the Percutaneous Lead. The design, material and construction methods on the proximal end and lead body of the Lead Extension are identical to the Percutaneous Lead. They come in lengths of 15 to 60 cm in 5 cm increments.
- Lead anchors: Used to anchor the Percutaneous Lead to the fascia or supraspinous ligament (Asymmetrical Eyelets, N100, N200, and N300).
- Lead Adapters: The M8 and S8 Lead Adaptors allow a physician to connect an implanted Medtronic or St. Jude Medical lead, respectively, with the Nevro Lead Extension or IPG.

B. External Components

- Clinician Programmer (Model PG2000): Used by the clinician to program output stimulation parameters. It is an off-the-shelf laptop installed with proprietary Nevro software to allow the programming of the IPG or Trial Stimulator and Patient Remote via the Programmer Wand.
- Patient Remote (Models RC1000 and RC2000): A handheld battery operated unit able to communicate via radio frequency (RF) energy with the IPG or Trial Stimulator. There are two versions of the Patient Remote available. One version includes multiple controls and indicators that allow patients the ability to turn the Patient Remote on or off, turn off stimulation, select from three stimulation

{3}

programs, control and observe the stimulation level, and observe the status of the Trial Stimulator battery. The other version has a simpler user interface design and allows patients to select one of two stimulation programs.

- Trial Stimulator: Provides stimulation by emulating the IPG during the intraoperative test and during the stimulation trial. The Trial Stimulator stimulation parameters are the same as the IPG.
- IPG Charger: Used to transcutaneously recharge the IPG battery
- Operating Room Cables: Used during intraoperative testing and stimulation trial. One end of the cable is plugged into a connector which holds the leads proximal ends, and the other end of the cable is attached to the Trial Stimulator.
- Programmer Wand: The Programmer interface that allows the communication with an IPG or Trial Stimulator. The Programmer Wand connects to the Programmer laptop through a USB port and communicates via RF with the IPG or Trial Stimulator.)
- Mx Trial Adaptor: The Mx Trial Adaptor is intended to connect a Medtronic operating room (OR) cable to the Nevro Trial Stimulator.

- Surgical Accessories:
- Torque Wrench: Used to tighten the set screws that lock the lead into the IPG and/or lead extension.
- Insertion Needle: Used during implant surgery to introduce the Percutaneous Lead between the vertebrae into the epidural space.
- Coiled Lead Blank: Optionally used during surgery to clear a path for the introduction of the Percutaneous Lead into the epidural space.
- Stylets: Used to maneuver the Lead through the epidural space to the desired implant location.
- IPG Port Plug: Provided to seal the port of the IPG that is not in use when only one Lead is implanted.
- IPG Template: Acts as an optional aid for physicians in proper sizing of the IPG implant pocket.

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 4

{4}

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 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 Senza SCS System has been in commercial distribution in the European Union (EU) (approval in May 2010) and Australia (approval in June 2011). 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 Senza SCS 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.

- 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, and paralysis. Patient use of anticoagulation therapies may increase the risk of procedure-related complications such as hematomas, which could produce paralysis.

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 5

{5}

- Risks associated with the use of a SCS system: lead migration; IPG 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 IPG, extension, or lead site; radicular chest wall stimulation; disturbed urination; dysesthesia; decubitus; premature battery depletion; loss of pain relief over time; 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.

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

## IX. SUMMARY OF PRECLINICAL STUDIES

## A. Laboratory Studies

### 1. Implanted Pulse Generator (IPG)

Testing was conducted on the Model 1500 IPG, 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 IPGs is summarized in Table 3 below. Testing demonstrated the IPGs 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 Senza SCS System IPG

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Measurement of Output Pulses | The characteristics of the output pulses shall be measured as described in ISO 14708-3 clause 6.101. Verify proper output (amplitude, pulse width, frequency, etc.) of the IPG function are within specified tolerances | Amplitude, Pulse width, Frequency, and Inter pulse delay are within output specifications. |
| Dimensional Requirements | To demonstrate IPGs meet shape and profile requirements. | IPG samples must meet size specifications for IPG width, height, thickness, volume, mass, and radius. |
| DC Leakage Current | Verify the leakage current is in an acceptable range. Leakage current was measured with a 500 Ω load per the instructions in ISO 14708-3, clause 16.2. | The maximum leakage current < 1 μA |
| Environmental Conditions | Atmospheric Pressure Exposure: To expose each IPG to pressure extremes the device may encounter during storage and distribution. | Testing per ISO 14708-3, 25 |
| | Operating Temperature: To demonstrate the IPG remains mechanically intact and capable of normal operation during exposure to low and high temperatures. | Testing per ISO 14708-1, 26.2. The IPG shall remain mechanically intact and capable of normal operation during exposure to low (0°C) and high temperatures (45°C) for 3 |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{6}

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| | | hours. |
| | Mechanical Forces: Verify device conforms to functional requirements and is not damaged by mechanical forces that may occur during conditions of use | Testing per ISO 14708-1, 23 |
| Hermetic Leak Test | To demonstrate that the IPG (including feedthroughs) maintains hermeticity after exposure to environmental testing. | Must be hermetically- sealed titanium can, helium leak shall be < 1x10-8 std/cc/s |
| Header Adhesion Testing | To demonstrate the header meets fatigue requirements the IPG maintains isolation between channels and externally. | After a 10-day saline soak, the IPGs were subjected to a 50 N pull force applied in axial (to the IPG port), lateral and vertical directions. This stress conditions far exceeds worst case clinical scenarios. Visual and electronic do not reveal any damage and demonstrate that the header is securely bonded to the IPG. |
| Lead Insertion and withdrawal Forces | To demonstrate that the IPG, port plug, and lead meet specified interface requirements for insertion force and withdrawal force (without setscrew engaged) when the IPG and lead are in a dry and wet conditions. | - Port plug and lead retention force shall be more than 15N
- Port plug and Lead insertion force shall be < 8.9N (2.0 Lbf). |
| Particulate matter | Verify there is no unacceptable release of particulate matter when the device is used as intended. | 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 | Based on clinical data from IDE G110156 (88 subjects) and outside U.S. (1738 patients) (42°C for an average of approximately 23 minutes (approximate 90 minutes maximum) during recharge) |
| Battery | Battery Charge/Discharge Cycle Verification (Longevity). | For 12-hour therapy days the longevity of the batteries on a single charge shall > 4 days and for 24-hour therapy days and longevity of the batteries on a single charge > 10 days. |
| | Electrical, Visual, Dimensional, Hermeticity, Short Circuit Testing, Environmental, and Forced Discharge Tests | Meets specifications. |

2. Percutaneous Lead Testing

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

PMA P130022: FDA Summary of Safety and Effectiveness Data

{7}

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 |
| DC Resistance | Demonstrate protection from electricity. | DC resistance between electrodes and contact shall not exceed 10 Ohms. |
| Stylet Interactions – Insertion/Removal | To demonstrate the force required to fully insert or remove each stylet into the lead | Fully insert a 0.014” straight stylet into a 50cm length percutaneous lead. Apply 1.1 lb (5N) push force to the stylet for 30 seconds. The percutaneous lead shall not exhibit any signs of damage. |
| Insertion Needle Insertion/Withdrawal | Demonstrate lead compatibility with Touhy Needle. | The insertion and extraction force of the insertion needle shall be less than 1.5 pounds |
| Hipot | Demonstrate the safety of the electrical insulation. | The leakage current shall not exceed 50 microamps |
| Pull Test | Demonstrate the integrity of the lead body joints after the Percutaneous lead is stressed by a saline soak and wet pull. | - No lead bond separation, cracks, tears, permanent elongation in excess of 5% or lead resistance change > 10% after the tensile force is applied. - Lead leakage current ≤ 50 microamperes when a 100V is applied between any two conductor pairs or any conductor pair and reference electrode |
| Tensile Strength | Demonstrate the lead remains electrically and mechanically intact after a tensile load. | Apply a 8.8N (2 lbs) +10% -0% tensile force between the proximal and distal most section of the lead and hold this force a minimum of 1 minute. No conductor failure shall be observed during the testing. |
| Lead Body Flex Fatigue | Demonstrate that the leads do not fatigue after flexural stressors. | The resistance on any of the conductor shall not change by more than 25% after a minimum of 47,000 cycles (1X CENELEC) when compared to DC resistance prior to the testing |
| Connector End Flex Fatigue | Demonstrate that the lead connector ends do not fatigue after flexural stressors. | The DC resistance on any of the eight conductors on the samples shall not increase by more than 25% after a minimum of 82,000 cycles (1X CENELEC) when compared to DC resistance prior to the testing |
| Lead Anchor Testing | To verify the lead anchors slide into position and provide appropriate retention force for clinical usage and verify a tied suture material does not damage the underlying lead anchor or percutaneous lead. | - The maximum sliding force of the untied anchor tested dry is 0.30 lb. (1.3N). - The maximum sliding force of the untied anchor tested wet is 0.25 lb. (1.1N). - The minimum retention force of the tied anchor tested wet is 0.7 lb. (3.1N). - The lead body and anchor shall not exhibit any tears, rips or delamination. |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{8}

| Test | Purpose | Acceptance Criteria |
| --- | --- | --- |
| M8 and S8 Lead Adaptors | Verify the compatibility of specified leads | Programmed outputs should be at safe levels. Meet same criteria as Nevro leads for DC Resistance, Hipot, and Seal Integrity Connector is compatible Accurate Impedance measurements |

3. Programmers

The software associated with the Clinician Programmer, Patient Remote, Trial Stimulator, and Programmer Wand was 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 (per ISO 14708-3 and IEC 60068-2-14) were also performed and all testing met specifications.

4. Electromagnetic Compatibility (EMC) 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 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”
- ISO 14708-3:2008(E): Implants for surgery – Active implantable medical devices – Part 3: Implantable neurostimulators”, Part 27
- Wireless radio testing per United States FCC CFR Title 47 Parts 15 and 95 Subpart I

5. System Testing

Testing to verify that system-level design requirements were met for interactions between Senza SCS System components was performed. All test articles met defined acceptance criteria for the system integration tests conducted. System validation testing demonstrated that the system operated as expected and has been validated for safe and effective use.

6. IPG Medical Compatibility Testing

The Senza SCS System was tested for compatibility with external defibrillation, High Power Electric Fields, diagnostic ultrasound, and diagnostic x-ray exposure (see Table 5 below). All samples met all functional requirements of the testing after exposure to medical therapy conditions, verifying that the IPG meets requirements for compatibility with these therapies. The Senza SCS System was also tested for compatibility with magnetic resonance imaging (MRI) and was determined to be safe

PMA P130022: FDA Summary of Safety and Effectiveness Data

{9}

when the patient is scanned according to the Senza SCS System MR Conditional labeling.

Table 5: IPG Medical Compatibility Testing

| Test | Acceptance Criteria |
| --- | --- |
| External Defibrillator Test | Verify that the device meets functional electrical test requirements after exposure to external defibrillation per ISO 14708-3, clause 20.2 |
| High Power Electrical Fields Test | Verify protection from high power electrical fields according to standard ISO 14708-3, clause 21 |
| Diagnostic Ultrasound Test | Verify that the IPG withstands exposure to ultrasound specified in EN45502-1:1997 and ISO 14708-3, clause 22 |
| X-Ray Compatibility Test | Device remains functional after exposure to x-ray; radiographic marker is visible in x-ray; and minimal to no distortion of anatomical features adjacent to device |
| MRI Compatibility | Verify it is safe when scanned according to the Senza SCS System MR Conditional labeling. |

# B. Animal Studies

Safety of stimulation at $10\mathrm{kHz}$ was assessed in goats. Twelve goats were implanted (Day 0) with one Advanced Bionics $50\mathrm{cm}$ 8-contact trial linear lead placed at or near midline in the epidural space overlying (dorsal to) the L2 - L3 intervertebral space. In six animals, Nevro Therapy was applied to the Advanced Bionics $50\mathrm{cm}$ 8-contact trial linear lead 24 hours per day for $10 + / - 1$ day at a frequency of $10\mathrm{kHz}$ with a $100\%$ duty cycle using the Nevro Trial Stimulator (NTS). A duty cycle refers to the ratio of stimulation on time versus stimulation off time; a duty cycle of $100\%$ states that the stimulation is on all the time, with no stimulation off time. The stimulation amplitude was set below the animal's discomfort stimulation threshold and above the animal's perception stimulation threshold. The average stimulation amplitude ranged from 0.2 to $1.5\mathrm{mA}$ . The remaining six animals received the same implant as the therapy group and were fitted with a mock external NTS, but at no time was stimulation applied. There were no morphologic differences between the therapy and Mock (control) groups. All morphologic changes were interpreted to be due to the placement and/or presence of the implanted lead or to the inevitable manipulation of the spinal cord and adjacent tissues during such an implant procedure. The morphologic changes were interpreted to be non-adverse and to represent the consequence of the administration of a therapy via a device implanted into the epidural space.

# C. Biocompatibility

Biocompatibility testing was performed for all patient-contacting components of the Senza SCS System in accordance with ISO 10993-1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process, on the finished sterilized devices. All biocompatibility studies were conducted in compliance with Good Laboratory Practices (GLP), 21 CFR Part 58. The implanted components of the Senza SCS System are considered permanent (&gt;30 days) implants in contact with tissue/bone. The Senza SCS System also contains external communicating and

PMA P130022: FDA Summary of Safety and Effectiveness Data

{10}

skin-contacting components with both prolonged (&gt; 24 hours – 30 days) and limited (≤ 24 hours) tissue/bone contact. All pre-specified test acceptance criteria were met and all tests passed.

## D. Sterility and Packaging

The Senza SCS System components that are provided sterile 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 109937: 2008. Biological Evaluation of Medical Devices – Part 7: Ethylene Oxide Sterilization Residuals. The product bacterial endotoxin limits are based on FDA’s Guidance for Industry - Pyrogen and Endotoxins Testing: Questions and Answers (June 2012) and are verified using Limulus Amebocyte Lysate (LAL) testing

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 three (3) years from the date of manufacturing.

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of 10 kHz stimulation with the Senza SCS System for treatment of chronic, intractable pain of the trunk and/or limbs in the US under IDE #G110156. Data from this clinical study were the basis for the PMA approval decision for 10 kHz stimulation without paresthesia.

The safety and effectiveness of the Senza SCS System for stimulation parameters similar to commercially available SCS systems (i.e., output is between 2 and 1,200 Hz with paresthesia) for the treatment of chronic intractable pain of the trunk and/or limb was based on published literature.

A summary of the clinical study and literature review is presented below.

## A. Study Design

Patients were enrolled between June 7, 2012 and December 28, 2012. The database for this PMA reflected data collected through February 6, 2014 and included 241 patients. There were 11 investigational sites.

The study was a prospective, randomized, multi-center non-inferiority trial comparing the Senza SCS System to a legally marketed SCS system (control group). The

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 11

{11}

control group consisted of subjects treated with a legally marketed device from a single manufacturer which delivers stimulation in the 2 to 1,200 Hz frequency range. The legally marketed device has a similar indication for use.

Subjects were not blinded as to their device assignment. 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 a composite endpoint of safety and effectiveness of the Senza SCS System was non-inferior to the legally-marketed SCS comparator. The sample size required was estimated to be 77 subjects in each group (154 subjects total). In addition at least 60 subjects implanted with the Senza SCS System who were programmed to 10 kHz were required to have 12 month follow-up to assess safety. To account for potential drop-out, a total of up to 125 subjects per group (250 subjects total) were allowed to be randomized. The success rate was estimated to be 58% in the Senza SCS System group and 48% in the control group. The rate of stimulation-related neurological deficit was estimated to be 2% in both the test and control groups.

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

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Senza SCS System study was limited to patients who met the following inclusion criteria:

a. Have been diagnosed with chronic, intractable pain of the trunk and/or limbs which has been refractory to conservative therapy for a minimum of 3 months. Previous conservative therapy includes pain medications and physical therapy, and may include other treatment modalities such as nerve root blocks or facet joint blocks/denervations.

b. Considering daily activity and rest, have average back pain intensity of ≥ 5 out of 10 cm on the Visual Analog Scale (VAS) at enrollment.

c. Be severely disabled or crippled as defined by an Oswestry Disability Index score of 41-80 out of 100 at enrollment.

d. Be an appropriate candidate for the surgical procedures required in this study based on the clinical judgment of the implanting physician.

e. Be on stable pain medications, as determined by the Investigator, for at least 28 days prior to enrolling in this study.

f. Be 18 years of age or older at the time of enrollment

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

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 12

{12}

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 outcome, as determined by a psychologist.

c. Have a current diagnosis of a progressive neurological disease such as multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, rapidly progressive arachnoiditis, rapidly progressive diabetic peripheral neuropathy, brain or spinal cord tumor, or severe/critical spinal stenosis.

d. Have a current diagnosis of a coagulation disorder, bleeding diathesis, progressive peripheral vascular disease or uncontrolled diabetes mellitus.

e. Have a diagnosis of scoliosis that precludes lead placement.

f. Have mechanical spine instability detected by &gt;4 mm translational movement or excessive angular movement manifested by 20 degrees greater angular movement than in an adjacent segment based on flexion/extension films of lumbar spine (imaging is required for this determination and must have been done within the past 6 months).

g. Be benefitting within 30 days prior to enrollment from an interventional procedure and/or surgery to treat back and/or leg pain.

h. Have an existing drug pump and/or SCS system or another active implantable device such as a pacemaker.

i. Have prior experience with SCS.

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

k. Have metastatic malignant disease or active local malignant disease.

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

m. Have an active systemic or local infection.

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

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 13

{13}

o. Have within 6 months of enrollment a significant untreated addiction to dependency producing medications or have been a substance abuser (including alcohol and illicit drugs).
p. Be concomitantly participating in another clinical study.
q. Be involved in an injury claim under current litigation.
r. Have a pending or approved worker's compensation claim.

## 2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations during the trial phase and at 1, 3, 6, 9, and 12 months post-implantation. Subjects had the option of consenting to an additional year of follow-up with 18 and 24 month study visits to collect longer term data.

Preoperatively, subjects had a pregnancy test, flexion/extension imaging, a psychological exam and pain and disability assessments. Postoperatively, the objective parameters measured during the study included a pain assessment (using the visual analog scale (VAS) and Short-form McGill Pain Questionnaire), the Oswestry Disability Inventory, the Global Assessment of Functioning, Short Form-12, Quality of Life Assessment, Beck Depression Inventory, Pittsburg Sleep Quality Index, Patient Global Impression of Change, Clinician Global Impression of Change, Subject Satisfaction and Neurological Assessment. The key timepoints for each assessment are shown in Table 6 and Table 7 below. Adverse events and complications were recorded at all visits.

Table 6: Assessment Timepoints for Pre-Trial and Trial Study Phases

| Assessment | Pre-Trial | | Trial Phase | |
| --- | --- | --- | --- | --- |
| Visit | Enrollment | Enrollment
Baseline | Enrollment
Initial
Implant | Enrollment
End of Trial |
| Informed Consent | X | | | |
| Pregnancy Test | X^{1} | | | |
| Flexion/Extension Imaging | X | | | |
| Psychological Evaluation | X | | | |
| Pain Diary | X | | X | |
| Entry Criteria Evaluation | | X | | |
| Medical/Surgical History | | X | | |
| Visual Analog Scale (VAS) | X | X | | X |
| Short-form McGill Pain Questionnaire (SF-MPQ2) | | X | | |
| Percent Pain Relief (PPR) | | | | X |

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 14

{14}

| Assessment | Pre-Trial | | Trial Phase | |
| --- | --- | --- | --- | --- |
| Visit | Enrollment | Entry Criteria/ Baseline | Trial Implant | End of Trial |
| Oswestry Disability Inventory (ODI) | X | X | | |
| Medication Usage | | X | | |
| Global Assessment of Functioning (GAF) | | X | | |
| Short Form 12 Quality of Life Assessment (SF-12) | | X | | |
| Beck Depression Inventory (BDI-II) | | X | | |
| Pittsburg Sleep Quality Index (PSQI) | | X | | |
| AP and Lateral X-Rays | | | X | X |
| Paresthesia Questionnaire | | | | |
| Patient Global Impression of Change (PGIC) | | | | |
| Clinician Global Impression of Change (CGIC) | | | | |
| Subject Satisfaction | | | | |
| Neurological Assessment | | X | | X |
| Adverse Event Monitoring | | | X | X |
| Device Programming | | | X | |
| Device Follow-Up3 | | | | |
| Study Completion | | | | X2 |

1 Completed for females of child bearing potential
2 Completed for those subjects who do not pass the Trial Phase.
3 For subjects randomized to the Nevro arm only

Table 7: Assessment Timepoints for Permanent Implant Study Phase

| Assessment | Permanent Implant Phase | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Visit | Implant | Permanent | Device Activation | 1 Month Visit | 3 Month Visit | 6 Month Visit | 9 Month Visit |
| Informed Consent | | | | | | | |
| Pregnancy Test | | | | | | | |
| Flexion/Extension Imaging | | | | | | | |
| Psychological Evaluation | | | | | | | |
| Pain Diary | X | X | X | X | X | X | |
| Entry Criteria Evaluation | | | | | | | |
| Medical/Surgical History | | | | | | | |
| Visual Analog Scale (VAS) | | | X | X | X | X | X |
| Short-form McGill Pain Questionnaire (SF-MPQ2) | | | | X | X | | X |
| Percent Pain Relief (PPR) | | | X | X | X | X | X |
| Oswestry Disability Inventory (ODI) | | | | X | X | | X |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{15}

| Assessment | Permanent Implant Phase | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Visit | Implant | Permanent | Device Activation | 1 Month Visit | 3 Month Visit | 6 Month Visit | 9 Month Visit |
| Medication Usage | | | X | X | X | X | X |
| Global Assessment of Functioning (GAF) | | | | | X | X | X |
| Short Form 12 Quality of Life Assessment (SF-12) | | | | | X | X | X |
| Beck Depression Inventory (BDI-II) | | | | | X | X | X |
| Pittsburg Sleep Quality Index (PSQI) | | | | | X | X | X |
| AP and Lateral X-Rays | X | | | [X] | [X] | [X] | [X] |
| Paresthesia Questionnaire | | | | | X | | X |
| Patient Global Impression of Change (PGIC) | | | | | X | | X |
| Clinician Global Impression of Change (CGIC) | | | | | X | | X |
| Subject Satisfaction | | | | | X | | X |
| Neurological Assessment | | | X | X | X | X | X |
| Adverse Event Monitoring | X | X | X | X | X | X | X |
| Device Programming | | | X | [X] | [X] | [X] | [X] |
| Device Follow-Up1 | | | | | X | X | X |
| Study Completion | | | | | | | [X] |

[X] Optional.
For subjects randomized to the Nevro arm only

3. Clinical Endpoints

The primary endpoint was a composite of safety and effectiveness, specifically, the percentage of subjects who respond (referred to as "responders") to SCS therapy for back pain and do not have a stimulation-related neurological deficit at the primary endpoint assessment (non-inferiority analysis).

Individual Subject Success

Individual subject success was defined by the following:

a. Effectiveness Components:

- A decrease in back pain VAS by at least 50% at 3 months Post-Permanent Device Activation as compared with Baseline, and
- No increase in any pain medication two weeks prior to scheduled follow-up visits as compared to baseline, and
- No increase from Baseline in pain medication used to treat their back and/or leg pain for duration of greater than 5 days.

PMA P130022: FDA Summary of Safety and Effectiveness Data

{16}

b. Safety Component: No stimulation-related clinically meaningful neurological deficit at 3 months post-permanent device activation as compared with baseline neurological status. Neurological status includes motor, sensory and reflex functions.

## Study Success

Study success was defined as the percentage of subjects who met each success criteria in the test group and the control group, using a 10% non-inferiority margin.

## Secondary Endpoints

The following secondary endpoints were successively evaluated (hierarchical test approach) in the order shown with a 0.05 significance until statistical significance was not achieved. A 10% non-inferiority margin was used to evaluate all secondary endpoints.

a. Comparison of percentage change from baseline in back pain between test and control groups (as assessed by VAS) at the primary efficacy assessment (non-inferiority analysis).

b. Comparison of percentage change from baseline in leg pain between test and control groups (as assessed by VAS) at the primary efficacy assessment (non-inferiority analysis).

c. Comparison of change from baseline between the test and control groups in disability as measured by Oswestry Disability Index (ODI) at the primary efficacy assessment (non-inferiority analysis).

d. Comparison of percentage change from baseline in back pain between test and control groups (as assessed by VAS) at the 6-month secondary efficacy assessment (noninferiority analysis).

e. Comparison of percentage change from baseline in leg pain between test and control groups (as assessed by VAS) at the 6-month secondary efficacy assessment (noninferiority analysis).

f. Comparison of percentage change from baseline in back pain between test and control groups (as assessed by VAS) at the 12-month secondary efficacy assessment (noninferiority analysis).

g. Comparison of percentage change from baseline in leg pain between test and control groups (as assessed by VAS) at the 12-month secondary efficacy assessment (noninferiority analysis).

## B. Accountability of PMA Cohort

At the time of database lock, of 241 patients enrolled in the PMA study, 198 (82.2%) were randomized, 101 in the Senza SCS System (Test) group and 97 in the Control

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 17

{17}

group and this comprised the Intent-to-Treat (ITT) analysis population. The Per Protocol (PP) analysis population included 179 subjects (92 in the Test group and 87 in the Control group). A total of 171 randomized subjects received a permanent implant, defining a Permanent Implant Subset (PS) of 90 Test subjects and 81 Control subjects. One-hundred and fifty-five (155) subjects (86 in the Test group and 69 in the Control group) completed the 12 month follow-up visit. See Figure 2 below.

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 18

{18}

Figure 2: Accountability of PMA Cohort

PMA P130022: FDA Summary of Safety and Effectiveness Data

{19}

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a pain study performed in the US. See Table 8 below.

Table 8: Subject Demographics

| Characteristics | Test (N=92) | Control (N=87) | P-value |
| --- | --- | --- | --- |
| Gender - n (%) | | | |
| Female | 57 (62.0%) | 51 (58.6%) | 0.760a |
| Male | 35 (38.0%) | 36 (41.4%) | |
| Age (years) at enrollment | | | |
| Mean ± SD | 54.6 ± 12.4 | 55.2 ± 13.4 | 0.717b |
| Range | 32.8 to 82.2 | 19.2 to 82.3 | |
| Years since diagnosis | | | |
| Mean ± SD | 13.0 ± 10.4 | 14.2 ± 12.2 | 0.659b |
| Range | 1.0 to 52.0 | 1.0 to 62.0 | |
| Ethnicity - n (%) | | | |
| Non-Hispanic/Latino | 89 (96.7%) | 85 (97.7%) | 1.000a |
| Hispanic/Latino | 3 (3.3%) | 2 (2.3%) | |
| Race - n (%) | | | |
| White | 85 (92.4%) | 77 (88.5%) | 0.703a |
| Black/African American | 3 (3.3%) | 5 (5.7%) | |
| American Indian/Alaska Native | 2 (2.2%) | 3 (3.4%) | |
| Asian | 1 (1.1%) | 0 (0.0%) | |
| Other | 1 (1.1%) | 2 (2.3%) | |
| Diagnosisc - n (%) | | | |
| Chronic intractable back pain | 92 (100.0%) | 87 (100.0%) | 1.000a |
| Chronic intractable leg pain | 91 (98.9%) | 87 (100.0%) | |
| Leg pain - n (%) | | | |
| Bilateral | 49 (53.3%) | 54 (62.1%) | 0.290a |
| Unilateral | 43 (46.7%) | 33 (37.9%) | |
| Pain etiologyd - n (%) | | | |
| Failed back surgery syndrome | 73 (79.3%) | 65 (74.7%) | 482a |
| Radiculopathy | 61 (66.3%) | 53 (60.9%) | 534a |
| Degenerative disc disease | 57 (62.0%) | 49 (56.3%) | 452a |
| Spondylosis | 38 (41.3%) | 32 (36.8%) | 544a |
| Mild/moderate spinal stenosis | 21 (22.8%) | 17 (19.5%) | 715a |
| Sacroiliac dysfunction | 19 (20.7%) | 14 (16.1%) | 448a |
| Other neuropathic pain | 19 (20.7%) | 11 (12.6%) | 166a |
| Other chronic pain | 18 (19.6%) | 18 (20.7%) | 855a |
| Lumbar facet-mediated pain | 14 (15.2%) | 14 (16.1%) | 1.000a |
| Internal disc disruption/annular tear | 8 (8.7%) | 2 (2.3%) | 0.101a |
| Spondylolisthesis | 8 (8.7%) | 2 (2.3%) | 0.101a |
| Previous back surgery - n (%) | 80 (87.0%) | 75 (86.2%) | 1.000a |
| Baseline use of opioids - n (%) | 83 (90.2%) | 75 (86.2%) | 0.488a |
| Baseline VAS scores | | | |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{20}

| Characteristics | Test (N=92) | Control (N=87) | P-value |
| --- | --- | --- | --- |
| Back pain: | | | |
| Mean ± SD | 7.4 ± 1.2 | 7.8 ± 1.2 | 0.060^{b} |
| Range | 5.0 to 9.7 | 5.2 to 10.0 | |
| Leg pain | | | |
| Mean ± SD | 7.1 ± 1.5 | 7.6 ± 1.4 | 0.017^{b} |
| Range | 2.7 to 9.9 | 3.0 to 9.8 | |

Abbreviations: SD = standard deviation; VAS = visual analog scale
a P-value by Fisher's exact test or Fisher-Freeman-Halton test
b P-value by Wilcoxon rank sum test
c Subjects may have both diagnoses.
d Subjects may have more than one pain etiology. Pain etiology was reported by a study Investigator; no criteria were prespecified. Pain etiology information is provided for descriptive purposes and should not be interpreted as claims of effectiveness.

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the ITT population which included 171 subjects with permanent implants (90 Test and 81 Control subjects) with follow-up through 12 months. On average, Test subjects had a permanent implant for 50.4 weeks, while Control subjects had a permanent implant for 47.6 weeks, resulting in a total of 82.1 implant-years for Test subjects and 71.1 implant-years for Control subjects.

The key safety outcome for this study was the neurological assessment of motor, sensory and reflex functions. At baseline, the majority of subjects had normal motor, sensory, and reflex function but with some expected abnormalities typical of chronic pain patients. One Test subject at Month 3 and one Test subject at Month 12 had a neurological deficit that was determined by the Investigator to be unrelated to stimulation. All other assessments showed either "No Change" or "Improvement" in neurological function and the results in the categories were similar between treatment groups.

Among the 198 randomized subjects, 22 serious adverse events (SAEs) were reported in 15 Test subjects (15/101, 14.9%) and 23 SAEs were reported in 16 Control subjects (16/97, 16.5%). None of the SAEs were categorized as both unanticipated and device-related. A similar percentage of Test and Control subjects experienced a non-serious AE (67.3% and 69.1%, respectively). See Table 9 below.

PMA P130022: FDA Summary of Safety and Effectiveness Data

{21}

Table 9: Overall Summary of Adverse Events Intent-to-Treat Population

| | Test | | Control | |
| --- | --- | --- | --- | --- |
| | Number of AEs | Number (%) of Subjects with AE (N=101) | Number of AEs | Number (%) of Subjects with AE (N=97) |
| All adverse events | 312 | 71 (70.3%) | 293 | 71 (73.2%) |
| Serious adverse events | 22 | 15 (14.9%) | 23 | 16 (16.5%) |
| Study-related serious adverse events | 5 | 4 (4.0%) | 8 | 7 (7.2%) |
| Non-serious adverse events | 290 | 68 (67.3%) | 270 | 67 (69.1%) |
| Study-related non-serious adverse events | 39 | 28 (27.7%) | 48 | 32 (33.0%) |
| Unanticipated adverse device effects1 | 0 | 0 (0.0%) | 0 | 0 (0.0%) |

1 An unanticipated adverse device effect is defined as an event that is unanticipated in nature (e.g., is not pre-defined in the protocol), is device-related, and is serious.

## Serious Adverse Events

Table 10 lists study-related serious adverse events (SAEs) by treatment group.

Table 10: Study-Related Serious Adverse Events, Intent-to-Treat Population

| MedDRA Preferred Term | Test | | Control | | Total | |
| --- | --- | --- | --- | --- | --- | --- |
| | No. of SAEs | No. (%) of Subjects with SAE^{a} (N=101) | No. of SAEs | No. (%) of Subjects with SAE^{a} (N=97) | No. of SAEs | No. (%) of Subjects with SAE^{a} (N=198) |
| Total SAEs | 5 | 4 (4.0%) | 8 | 7 (7.2%) | 13 | 11 (5.6%) |
| Wound infection staphylococcal | 2 | 2 (2.0%) | 0 | 0 (0.0%) | 2 | 2 (1.0%) |
| Arrhythmia | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Cardiac arrest | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Extradural abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Impaired healing | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Intracranial hypotension | 0 | 0 (0.0%) | 1^{b} | 1 (1.0%) | 1 | 1 (0.5%) |
| Paresis | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Post lumbar puncture syndrome | 0 | 0 (0.0%) | 1^{c} | 1 (1.0%) | 1 | 1 (0.5%) |
| Postoperative wound infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Procedural pain | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Stitch abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Wound dehiscence | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |

Abbreviations: No., number; SAE, serious adverse event.
a Subjects may have experienced more than one event.
b Reported by the site as "fluid leak at lead insertion site".
c Reported by the site as "post dural puncture headache".

PMA P130022: FDA Summary of Safety and Effectiveness Data

{22}

Table 11 provides an overview of the SAEs by treatment group. Neither group had a stimulation-related SAE. The majority of SAEs in both treatment groups occurred in the Permanent Phase (21/22, 95.5% in the Treatment group and 19/23, 82.6% in the Control group). Thirty-six of the 45 (80.0%) total SAEs were categorized as severe with 91.1% of the events (41 of the 45 total events) resolved.

Table 11: Serious Adverse Events by Treatment Group

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of SAEs | No. (%) of Subjects with SAE (N=101) | No. of SAEs | No. (%) of Subjects with SAE (N=97) |
| Total SAEs1 | 22 | 15 (14.9%) | 23 | 16 (16.5%) |
| Arthralgia | 2 | 2 (2.0%) | 1 | 1 (1.0%) |
| Pneumonia | 2 | 2 (2.0%) | 1 | 1 (1.0%) |
| Intervertebral disc degeneration | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Wound infection staphylococcal | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Ankle fracture | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Aortic valve incompetence | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Aphasia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Arrhythmia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Benign prostatic hyperplasia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Bradycardia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Bronchitis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Cardiac arrest | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Cholelithiasis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Chronic obstructive pulmonary disease | 2 | 1 (1.0%) | 0 | 0 (0.0%) |
| Clostridial infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Concussion | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Convulsion | 2 | 1 (1.0%) | 0 | 0 (0.0%) |
| Dyspnoea | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Encephalopathy | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Extradural abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Gastroenteritis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Impaired healing | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Intestinal obstruction | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Intracranial hypotension2 | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Medical device complication3 | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Migraine | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Myocardial infarction | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Pain in extremity | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Paresis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 23

{23}

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of SAEs | No. (%) of Subjects with SAE (N=101) | No. of SAEs | No. (%) of Subjects with SAE (N=97) |
| Post lumbar puncture syndrome4 | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Postoperative wound infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Procedural pain | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Rib fracture | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Spinal compression fracture | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Stitch abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Upper respiratory tract infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Wound dehiscence | 1 | 1 (1.0%) | 0 | 0 (0.0%) |

Abbreviations: No., number; SAE, serious adverse event.
Subjects may have experienced more than one event.
2 Reported by the site as "fluid leak at lead insertion site".
3 Reported by the site as "fractured fusion hardware, lumbar spine".
4 Reported by the site as "post dural puncture headache".

## Deaths

There were 2 study subject deaths. One control subject died as a result of a myocardial infarction during the device implant procedure. One test subject was diagnosed with hepatic neoplasm malignant after their Month 12 visit and subsequently died.

## All Adverse Events

Table 12 provides a summary of all study-related adverse events (both serious and non-serious) by treatment group through one year. Among the 198 randomized subjects, a total of 44 study-related AEs were reported in 28 Test subjects (28/101, 27.7%) and a total of 56 study-related AEs were reported in 35 Control subjects (35/97, 36.1%). The most frequent study-related AEs were 1) implant site pain with 11 events occurring in 10 Test subjects (10/101, 9.9%) and 10 events occurring in 9 Control subjects (9/97, 9.3%), and 2) uncomfortable paresthesia with no occurrences in Test subjects and 11 events occurring in 11 Control subjects (11/97, 11.3%).

Table 12: Study-Related Adverse Events Ordered by Percent of Total Subjects with Event Intent-to-Treat Population

| MedDRA Preferred Term | Test | | Control | | Total | |
| --- | --- | --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) | No. of AEs | No. (%) of Subjects with AE (N=198) |
| Total AEs1 | 44 | 28 (27.7%) | 56 | 35 (36.1%) | 100 | 63 (31.8%) |
| Implant site pain | 11 | 10 (9.9%) | 10 | 9 (9.3%) | 21 | 19 (9.6%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{24}

| MedDRA Preferred Term | Test | | Control | | Total | |
| --- | --- | --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) | No. of AEs | No. (%) of Subjects with AE (N=198) |
| Paraesthesia2 | 0 | 0 (0.0%) | 11 | 11 (11.3%) | 11 | 11 (5.6%) |
| Device dislocation3 | 3 | 3 (3.0%) | 5 | 5 (5.2%) | 8 | 8 (4.0%) |
| Therapeutic product ineffective4 | 1 | 1 (1.0%) | 6 | 6 (6.2%) | 7 | 7 (3.5%) |
| Impaired healing | 3 | 3 (3.0%) | 0 | 0 (0.0%) | 3 | 3 (1.5%) |
| Implant site effusion | 2 | 2 (2.0%) | 1 | 1 (1.0%) | 3 | 3 (1.5%) |
| Intracranial hypotension5 | 1 | 1 (1.0%) | 2 | 2 (2.1%) | 3 | 3 (1.5%) |
| Rash | 3 | 1 (1.0%) | 2 | 2 (2.1%) | 5 | 3 (1.5%) |
| Dermatitis contact6 | 2 | 2 (2.0%) | 0 | 0 (0.0%) | 2 | 2 (1.0%) |
| Implant site haematoma | 0 | 0 (0.0%) | 2 | 2 (2.1%) | 2 | 2 (1.0%) |
| Implant site swelling | 2 | 2 (2.0%) | 0 | 0 (0.0%) | 2 | 2 (1.0%) |
| Muscle spasms | 0 | 0 (0.0%) | 2 | 2 (2.1%) | 2 | 2 (1.0%) |
| Pain in extremity | 2 | 2 (2.0%) | 0 | 0 (0.0%) | 2 | 2 (1.0%) |
| Wound infection staphylococcal | 2 | 2 (2.0%) | 0 | 0 (0.0%) | 2 | 2 (1.0%) |
| Anxiety | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Arrhythmia | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Cardiac arrest | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Cellulitis | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Device battery issue | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Device stimulation issue7 | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Extradural abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Implant site erythema | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Implant site irritation | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Implant site pruritus | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Implant site rash | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Incision site pain | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Limb discomfort | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Micturition urgency | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Motor dysfunction | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Paresis | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Post lumbar puncture syndrome8 | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{25}

| MedDRA Preferred Term | Test | | Control | | Total | |
| --- | --- | --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) | No. of AEs | No. (%) of Subjects with AE (N=198) |
| Postoperative wound infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Procedural pain | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Stitch abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Suture removal | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Tinnitus | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Urinary retention | 0 | 0 (0.0%) | 1 | 1 (1.0%) | 1 | 1 (0.5%) |
| Wound complication | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Wound dehiscence | 1 | 1 (1.0%) | 0 | 0 (0.0%) | 1 | 1 (0.5%) |
| Wound secretion | 2 | 1 (1.0%) | 0 | 0 (0.0%) | 2 | 1 (0.5%) |

Abbreviations: No., number; AE, adverse event. Subjects may have experienced more than one event.
2 Reported as uncomfortable paresthesia.
3 Reported as lead migration.
4 Reported as lack of pain relief.
Reported as CSF leak or possible CSF leak.
Reported as bandage allergy.
Reported as "stimulation that continues after IPG is turned off".
Reported as post dural puncture headache

Table 13 provides a summary of all adverse events (both serious and non-serious), through one year, by treatment group. Among the 198 randomized subjects, a total of 312 AEs were reported in 71 Test subjects (71/101, $70.3\%$ ) and a total of 293 AEs were reported in 71 Control subjects (71/97, $73.2\%$ ). Stimulation related AEs were reported in 3 (3/101, $3.0\%$ ) of Test subjects and 17 (17/97, $17.5\%$ ) $17.5\%$ of Control subjects. The majority of AEs in both treatment groups occurred in the Permanent Phase (287/312, $92.0\%$ of events in Test subjects and 256/293, $87.4\%$ of events in the Control subjects). Most events were categorized as mild or moderate (284/312, $91.0\%$ of events in the Test subjects and 269/293, $91.8\%$ of Control subjects) and the majority of the events had resolved as of the data cutoff for this report (62/101, $61.4\%$ and 61/97, $62.9\%$ of the events in Test and Control subjects, respectively). Most AEs were classified as mild or moderate.

Table 13: All Adverse Events - Intent-to-Treat Population

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) |
| Total AEs1 | 312 | 71 (70.3%) | 293 | 71 (73.2%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{26}

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) |
| Related to Stimulation | 5 | 3 (3%) | 20 | 17 (17.5%) |
| AEs by phase at onset | | | | |
| Before randomization | 3 | 3 (3.0%) | 4 | 3 (3.1%) |
| Between randomization and Trial Phase | 2 | 2 (2.0%) | 2 | 2 (2.1%) |
| Trial Phase | 12 | 10 (9.9%) | 15 | 11 (11.3%) |
| Between Trial and Permanent Implant | 8 | 5 (5.0%) | 16 | 10 (10.3%) |
| Permanent Implant Phase | 287 | 67 (66.3%) | 256 | 65 (67.0%) |
| Permanent implant to Month 3 | 94 | 41 (40.6%) | 104 | 49 (50.5%) |
| Month 3-6 | 86 | 39 (38.6%) | 61 | 29 (29.9%) |
| Month 6-12 | 107 | 46 (45.5%) | 91 | 38 (39.2%) |
| AEs by severity | | | | |
| Mild | 138 | 52 (51.5%) | 143 | 56 (57.7%) |
| Moderate | 146 | 48 (47.5%) | 126 | 45 (46.4%) |
| Severe | 28 | 19 (18.8%) | 24 | 15 (15.5%) |
| AEs by outcome | | | | |
| Resolved | 176 | 62 (61.4%) | 164 | 61 (62.9%) |
| Ongoing² | 136³ | 36 (35.6%) | 128⁴ | 33 (34.0%) |
| Death⁵ | 0 | 0 (0%) | 1 | 1 (1.0%) |
| Arthralgia | 22 | 16 (15.8%) | 23 | 15 (15.5%) |
| Back pain | 23 | 18 (17.8%) | 7 | 6 (6.2%) |
| Implant site pain | 13 | 12 (11.9%) | 11 | 10 (10.3%) |
| Pain in extremity | 13 | 10 (9.9%) | 8 | 7 (7.2%) |
| Paraesthesia | 1 | 1 (1.0%) | 14 | 13 (13.4%) |
| Bronchitis | 7 | 6 (5.9%) | 5 | 5 (5.2%) |
| Therapeutic product ineffective | 2 | 2 (2.0%) | 7 | 7 (7.2%) |
| Device dislocation | 3 | 3 (3.0%) | 5 | 5 (5.2%) |
| Insomnia | 5 | 5 (5.0%) | 3 | 3 (3.1%) |
| Muscle spasms | 3 | 3 (3.0%) | 5 | 5 (5.2%) |
| Depression | 4 | 4 (4.0%) | 3 | 3 (3.1%) |
| Headache | 3 | 3 (3.0%) | 5 | 4 (4.1%) |
| Hypoaesthesia | 5 | 5 (5.0%) | 2 | 2 (2.1%) |
| Spinal osteoarthritis | 4 | 4 (4.0%) | 3 | 3 (3.1%) |
| Upper respiratory tract infection | 2 | 2 (2.0%) | 5 | 5 (5.2%) |
| Hypertension | 2 | 2 (2.0%) | 4 | 4 (4.1%) |
| Migraine | 3 | 2 (2.0%) | 4 | 4 (4.1%) |
| Nasopharyngitis | 4 | 4 (4.0%) | 2 | 2 (2.1%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{27}

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) |
| Nausea | 4 | 4 (4.0%) | 2 | 2 (2.1%) |
| Pain | 2 | 2 (2.0%) | 4 | 4 (4.1%) |
| Anxiety | 3 | 2 (2.0%) | 3 | 3 (3.1%) |
| Constipation | 3 | 3 (3.0%) | 2 | 2 (2.1%) |
| Fall | 2 | 2 (2.0%) | 4 | 3 (3.1%) |
| Fatigue | 2 | 2 (2.0%) | 3 | 3 (3.1%) |
| Oedema peripheral | 3 | 3 (3.0%) | 3 | 2 (2.1%) |
| Pneumonia | 4 | 3 (3.0%) | 2 | 2 (2.1%) |
| Chest pain | 1 | 1 (1.0%) | 3 | 3 (3.1%) |
| Hypothyroidism | 2 | 2 (2.0%) | 2 | 2 (2.1%) |
| Implant site effusion | 3 | 3 (3.0%) | 1 | 1 (1.0%) |
| Influenza | 2 | 2 (2.0%) | 2 | 2 (2.1%) |
| Neck pain | 1 | 1 (1.0%) | 3 | 3 (3.1%) |
| Oropharyngeal pain | 1 | 1 (1.0%) | 3 | 3 (3.1%) |
| Tinnitus | 2 | 2 (2.0%) | 2 | 2 (2.1%) |
| Bursitis | 1 | 1 (1.0%) | 2 | 2 (2.1%) |
| Cervicobrachial syndrome | 2 | 2 (2.0%) | 1 | 1 (1.0%) |
| Contusion | 1 | 1 (1.0%) | 2 | 2 (2.1%) |
| Diverticulitis | 2 | 2 (2.0%) | 1 | 1 (1.0%) |
| Fungal infection | 0 | 0 (0.0%) | 3 | 3 (3.1%) |
| Impaired healing | 3 | 3 (3.0%) | 0 | 0 (0.0%) |
| Influenza like illness | 3 | 3 (3.0%) | 0 | 0 (0.0%) |
| Intracranial hypotension | 1 | 1 (1.0%) | 2 | 2 (2.1%) |
| Ligament sprain | 1 | 1 (1.0%) | 2 | 2 (2.1%) |
| Muscular weakness | 1 | 1 (1.0%) | 2 | 2 (2.1%) |
| Musculoskeletal pain | 3 | 2 (2.0%) | 1 | 1 (1.0%) |
| Nephrolithiasis | 1 | 1 (1.0%) | 2 | 2 (2.1%) |
| Rash | 3 | 1 (1.0%) | 2 | 2 (2.1%) |
| Sinusitis | 0 | 0 (0.0%) | 3 | 3 (3.1%) |
| Vomiting | 1 | 1 (1.0%) | 2 | 2 (2.1%) |
| Amenorrhoea | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Ankle fracture | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Arthropathy | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Blood pressure increased | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Bradycardia | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Cellulitis | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Cholelithiasis | 1 | 1 (1.0%) | 2 | 1 (1.0%) |
| Dermatitis contact | 2 | 2 (2.0%) | 0 | 0 (0.0%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{28}

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) |
| Device stimulation issue | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Diarrhoea | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Dizziness | 1 | 1 (1.0%) | 2 | 1 (1.0%) |
| Drug withdrawal syndrome | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Dysphagia | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Dyspnoea | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Erythema | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Eyelid cyst | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Gastritis | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Gastroenteritis | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Gastroesophageal reflux disease | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Groin pain | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Herpes zoster | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Implant site haematoma | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Implant site irritation | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Implant site rash | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Implant site swelling | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Intervertebral disc degeneration | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Joint injury | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Malaise | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Memory impairment | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Motor dysfunction | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Muscle tightness | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Myalgia | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Neuroma | 3 | 2 (2.0%) | 0 | 0 (0.0%) |
| Piriformis syndrome | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Procedural pain | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Rib fracture | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Sciatica | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Seasonal allergy | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Sensory loss | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Sleep apnoea syndrome | 0 | 0 (0.0%) | 2 | 2 (2.1%) |
| Temperature intolerance | 1 | 1 (1.0%) | 2 | 1 (1.0%) |
| Toothache | 1 | 1 (1.0%) | 1 | 1 (1.0%) |
| Weight decreased | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Wound infection staphylococcal | 2 | 2 (2.0%) | 0 | 0 (0.0%) |
| Abdominal distension | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Abdominal pain | 0 | 0 (0.0%) | 1 | 1 (1.0%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{29}

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) |
| Abdominal pain upper | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Affect lability | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Amnesia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Androgen deficiency | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Antinuclear antibody positive | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Aortic valve incompetence | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Aphasia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Appetite disorder | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Arrhythmia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Arthritis | 3 | 1 (1.0%) | 0 | 0 (0.0%) |
| Asthenia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Asthma | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Back injury | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Bacterial infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Basal cell carcinoma | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Benign prostatic hyperplasia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Blood glucose increased | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Blood testosterone decreased | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Breast mass | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Breath sounds abnormal | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Burning sensation | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Cardiac arrest | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Carotid artery stenosis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Cataract | 2 | 1 (1.0%) | 0 | 0 (0.0%) |
| Chest injury | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Chills | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Chronic obstructive pulmonary disease | 2 | 1 (1.0%) | 0 | 0 (0.0%) |
| Clostridial infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Coccydynia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Colitis ischaemic | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Concussion | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Convulsion | 2 | 1 (1.0%) | 0 | 0 (0.0%) |
| Coronary artery disease | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Cough | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Cyst | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Cystitis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Dehydration | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Dental discomfort | 0 | 0 (0.0%) | 1 | 1 (1.0%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{30}

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 31

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N= 97) |
| Depressed level of consciousness | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Device battery issue | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Diabetes mellitus | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Diarrhoea haemorrhagic | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Discomfort | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Disorientation | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Dry eye | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Dysuria | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Ear infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Ear pain | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Electrocardiogram abnormal | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Encephalopathy | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Epicondylitis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Extradural abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Eyelid ptosis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Fibromyalgia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Flank pain | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Food poisoning | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Foot fracture | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Gastrointestinal viral infection | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Glaucoma | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Hallucination | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Hemiparesis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Hypercholesterolaemia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Hyperglycaemia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Hyponatraemia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Hypoxia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Implant site cellulitis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Implant site erythema | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Implant site pruritus | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Incision site cellulitis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Incision site pain | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Increased appetite | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Infected dermal cyst | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Intervertebral disc protrusion | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Intestinal obstruction | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Intraocular pressure increased | 1 | 1 (1.0%) | 0 | 0 (0.0%) |

{31}

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) |
| Joint range of motion decreased | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Keratitis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Kidney infection | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Laceration | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Ligament pain | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Limb discomfort | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Lip swelling | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Lumbar spinal stenosis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Lymphadenopathy | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Medical device complication | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Menorrhagia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Micturition urgency | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Muscle strain | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Muscle twitching | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Musculoskeletal chest pain | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Musculoskeletal stiffness | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Myocardial infarction | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Myositis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Nasal congestion | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Neuropathy peripheral | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Night sweats | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Nightmare | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Osteoarthritis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Osteoporosis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Palpitations | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Panic attack | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Paresis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Paronychia | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Pharyngitis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Pharyngitis streptococcal | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Pleurisy | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Pollakiuria | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Post herpetic neuralgia | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Post lumbar puncture syndrome | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Postoperative wound infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Proteinuria | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Pruritus | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Radicular pain | 0 | 0 (0.0%) | 1 | 1 (1.0%) |

PMA P130022: FDA Summary of Safety and Effectiveness Data

{32}

| MedDRA Preferred Term | Test | | Control | |
| --- | --- | --- | --- | --- |
| | No. of AEs | No. (%) of Subjects with AE (N=101) | No. of AEs | No. (%) of Subjects with AE (N=97) |
| Radiculitis cervical | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Renal cyst | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Restlessness | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Road traffic accident | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Rotator cuff syndrome | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Sacroiliitis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Seborrhoeic keratosis | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Sinus headache | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Small intestinal bacterial overgrowth | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Spinal compression fracture | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Spinal pain | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Spondylolisthesis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Stitch abscess | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Suture removal | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Syncope | 2 | 1 (1.0%) | 0 | 0 (0.0%) |
| Synovial cyst | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Tendonitis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Thermal burn | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Thirst | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Tongue oedema | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Tooth infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Torticollis | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Urinary incontinence | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Urinary retention | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Urinary tract infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Vaginal infection | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Vertigo | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Vitamin D deficiency | 0 | 0 (0.0%) | 1 | 1 (1.0%) |
| Weight increased | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Wound complication | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Wound dehiscence | 1 | 1 (1.0%) | 0 | 0 (0.0%) |
| Wound secretion | 2 | 1 (1.0%) | 0 | 0 (0.0%) |
| Wrist fracture | 1 | 1 (1.0%) | 0 | 0 (0.0%) |

Abbreviations: AE = adverse event; SAE = serious adverse event; IPG = implantable pulse generator.
Columns (no. $(\%)$ of subjects with AE) may not add to total as subjects may have experienced more than one event.
1 Device-related events include those related to the Trial Stimulator, Lead, Extension, IPG, or Charger.

PMA P130022: FDA Summary of Safety and Effectiveness Data

{33}

2 Includes events that were ongoing at the time of the March 19, 2014 database snapshot and also those events that were ongoing at study completion (in discontinued subjects).
3 131 of the 136 ongoing adverse events in the Test group are unrelated to the study.
4 119 of the 128 ongoing adverse events in the Control group are unrelated to the study. Abbreviations: No., number; AE, adverse event.
5 Death occurred following completion of 12 month visit.

In subjects who underwent a permanent implant (PS Subset), there were 11 additional surgical procedures in 9 (10.0%) Test subjects and 18 additional procedures in 15 (18.5%) Control subjects. A summary of these additional procedures is presented in Table 14 below.

Five (5.6%) Test subjects and 9 (11.1%) Control subjects underwent system explant. Four of the 5 Test subjects and all 9 of the Control subjects with system explant were discontinued from the study after the explant. One Test subject was explanted and then re-implanted a month later.

Table 14: Additional Surgical Procedures by Type and Treatment Group for the Permanent Implant Subset

| Procedure Type | Test | | Control | |
| --- | --- | --- | --- | --- |
| | Number of Procedures | Number (%) of Subjects (N=90) | Number of Procedures | Number (%) of Subjects (N=81) |
| Total | 11 | 9 (10.0%) | 18 | 15 (18.5%) |
| System (IPG and leads) | | | | |
| Repositioning | 0 | 0 (0.0%) | 1 | 1 (1.2%) |
| Replacement | 1 | 1 (1.1%) | 0 | 0 (0.0%) |
| Explant | 5^{1} | 5 (5.6%) | 9^{2} | 9 (11.1%) |
| IPG only | | | | |
| Repositioning | 3 | 3 (3.3%) | 2 | 2 (2.5%) |
| Replacement | 0 | 0 (0.0%) | 1 | 1 (1.2%) |
| Leads only | | | | |
| Repositioning | 1 | 1 (1.1%) | 4 | 4 (4.9%) |
| Replacement | 1 | 1 (1.1%) | 1 | 1 (1.2%) |

Abbreviations: IPG, implantable pulse generator.
1 Therapeutic product ineffective (2), wound infection staphylococcal (1) impaired healing (1) and due to incarceration (1).
2 Therapeutic product ineffective (3), paresthesia (1), stitch abscess (1), postoperative wound infection and extradural abscess (1), muscle weakness and paresthesia (1), back pain and pain in extremity (1), and device dislocation and bradycardia (1).

The safety of the device at $10\mathrm{kHz}$ was only studied at output levels that do not produce paresthesia and the safety of the device at paresthesia inducing amplitudes has not been studied. It should also be noted that the safety of the

PMA P130022: FDA Summary of Safety and Effectiveness Data

{34}

device for device settings between 2 and 1200 Hz with paresthesia was based on adverse events that occurred in the literature (see Section 3 below.)

## 2. Effectiveness Results

The Per Protocol (PP) analysis of effectiveness was based on the 179 evaluable subjects at the 3-month time point and the Intent-to-Treat (ITT) analysis of effectiveness was based on the 198 evaluable at the 3-month time point.

The following effective analyses were performed:

- PP: All randomized subjects who completed the Primary Endpoint Assessment.
- ITT: All subjects who met the enrollment criteria and received a randomization assignment.

One hundred and seventy-nine (179) subjects of the 198 randomized subjects are included in the PP population (92 in the Test group and 87 in the Control group.) All of the 198 randomized subjects are included in the ITT population (101 in the Test group and 97 in the Control group.)

For the Test group, only subjects receiving 10 kHz stimulation were included toward the primary endpoint analysis. Neurologic status (including motor, sensory and reflex functions) was characterized as improved, maintained, or a deficit as compared with baseline.

Subjects who did not have a successful Trial Phase were considered failures (non-responders) toward the primary endpoint. Additionally, a subject was classified as a non-responder for the 3-month primary effectiveness endpoint and subsequent assessments if there was an increase in morphine equivalent dose of a baseline opioid. Exceptions were temporary increases in dosage to treat the following:

- Post-operative pain (the clinical site’s standard practice for prophylactic pre-surgery antibiotics and post-surgery pain medications was followed)
- An acute co-morbidity unrelated to the initial indication that is not expected to respond to spinal cord stimulation.

A subject was also classified as a non-responder toward the primary endpoint if there was an increase from baseline in non-opiate pain medication used to treat their back and/or leg pain as indicated for this study for duration of greater than 5 days.

A subject was included in the PP population if the subject received a randomization assignment, met all eligibility criteria, reached an endpoint and there were no missing assessments required to determine the subject’s primary endpoint success. A subject was also included in the PP population if the subject received a randomization assignment, met all eligibility criteria, did not reach an endpoint but met either of the following criteria:

PMA P130022: FDA Summary of Safety and Effectiveness Data
Page 35

{35}

- Subject had a successful trial but did not reach the month 3 endpoint due to a device-related adverse event or device/procedure issue (subject was considered a non-responder)
- Subject had a successful trial (had &lt;50% reduction in back pain VAS during the trial phase), and elected not to have a permanent implant (subject was considered a non-responder)

The composite primary endpoint was met for the PP and ITT analysis populations. For the PP population, 75.0% of the Test subjects met the primary endpoint compared to 37.9% of the Control subjects. For the ITT population, 75.0% of the Test subjects met the primary endpoint compared to 37.9% of the Control subjects. Both the PP and ITT analyses demonstrated the non-inferio…