← Product Code [MBX](/productcode/MBX) · P960009S219

# MEDTRONIC DBS THERAPY FOR EPILEPSY (P960009S219)

_Medtronic, Inc. · MBX · Apr 27, 2018 · Neurology · APPR_

**Canonical URL:** https://fda-staging.innolitics.com/device/P960009S219

## Device Facts

- **Applicant:** Medtronic, Inc.
- **Product Code:** [MBX](/productcode/MBX.md)
- **Decision Date:** Apr 27, 2018
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Neurology
- **Attributes:** Therapeutic

## Indications for Use

Bilateral stimulation of the anterior nucleus of the thalamus (ANT) using the Medtronic DBS System for Epilepsy is indicated as an adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to three or more antiepileptic medications. The Medtronic DBS System for Epilepsy has demonstrated safety and effectiveness for patients who average six or more seizures per month over the three most recent months prior to implant of the DBS system (with no more than 30 days between seizures). The Medtronic DBS System for Epilepsy has not been evaluated in patients with less frequent seizures.

## Device Story

Implantable deep brain stimulation (DBS) system delivers bilateral electrical stimulation to anterior nucleus of thalamus (ANT) to suppress seizures; system comprises Activa PC neurostimulator (subcutaneous, clavicle), leads (platinum/iridium electrodes), and extensions; clinician uses N'Vision programmer to set stimulation parameters (amplitude, pulse width, frequency, cycling); patient uses Intercept programmer to turn stimulation on/off, check battery, and record seizure events; device provides adjunctive therapy for refractory epilepsy; clinical benefit includes reduction in seizure frequency and improved quality of life; physician manages therapy based on seizure diaries and patient feedback.

## Clinical Evidence

Pivotal SANTÉ study: multicenter, prospective, randomized, double-blind, parallel-group trial (n=110 implanted). Primary endpoint: seizure frequency reduction in active vs. control group during 3-month blinded phase. Active group showed 17% greater reduction than control (p=0.045, outlier removed). Long-term follow-up (7 years) showed median seizure reduction of 75% and 74% responder rate. Safety profile stable; serious device-related AEs (34.5%), primarily infection (10.9%) and lead placement issues (8.2%).

## Technological Characteristics

Implantable dual-channel neurostimulator (HCSVO battery); platinum/iridium leads (1.5mm electrodes, 0.06 cm² surface area); polyurethane/silicone insulation; capacitive charge balancing; square wave output; ETO sterilization; radio-frequency telemetry; non-ML rule-based stimulation parameters.

## Predicate Devices

- Medtronic Activa Tremor Control System ([P960009](/device/P960009.md))
- Medtronic Kinetra Neurostimulation System ([P960009](/device/P960009.md)/S27)
- Medtronic Activa PC Neurostimulation System ([P960009](/device/P960009.md)/S52 & [P960009](/device/P960009.md)/S134)

## Reference Devices

- RNS System (Neurology 2011;77:1295-1304)
- Elekta/Leksell stereotactic frames
- Radionics stereotactic frames

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
> Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/).

{0}

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Implantable multi-programmable quadripolar deep brain stimulation system for epilepsy

Device Trade Name: Medtronic DBS System for Epilepsy, consisting of:

Model 37601 Activa PC Neurostimulator  
Model 3387S DBS Lead Kit  
Model 3389S DBS Lead Kit  
Model 37086 DBS Extension Kit  
Model 8840 N'Vision Programmer  
Model 8870 Software Application Card  
Model 37441 Intercept Patient Programmer  
Model 37022 External Neurostimulator  
Model 3353/3354 Lead Frame Kit  
Accessories

Device Procode: MBX

Applicant's Name and Address: Medtronic, Inc.  
Medtronic Neuromodulation  
7000 Central Ave., N.E.  
Minneapolis, MN 55432

Date(s) of Panel Recommendation: March 12, 2010

Premarket Approval Application (PMA) Number: P960009/S219

Date of FDA Notice of Approval: April 27, 2018

## II. INDICATIONS FOR USE

The original PMA (P960009) for Medtronic’s Deep Brain Stimulator (DBS) System was approved on July 31, 1997 and is indicated for unilateral thalamic stimulation for the suppression of tremor in the upper extremity in patients who are diagnosed with Essential tremor or Parkinsonian tremor not adequately controlled by medications and where the tremor constitutes a significant functional disability. The SSED to support the indication is available on the CDRH website and is incorporated by reference here.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?start_search=211&applicant=&tradename=&productcode=&pmanumber=P960009&supplementnumber=&advisorycommittee=&docketnumber=&supplementtype=&expeditedreview=&ivdproducts=off&combinationproducts=off&decisiondatefrom=&decisiondateto=08%2F14%2F2015

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 1

{1}

&noticedatefrom=&noticedateto=&znumber=&PAGENUM=10&sortcolumn=pn_desc_s_n_desc

With the exception of the Intercept Model 37441 Patient Programmer, all components of the Medtronic DBS System for Epilepsy are approved as part of the Activa PC Neurostimulation System (P960009/S052). The Activa PC Neurostimulation System includes Activa Parkinson's Control Therapy and Activa Tremor Control Therapy. Bilateral stimulation of the internal globus pallidus (GPi) or the subthalamic nucleus (STN) using Medtronic Activa Parkinson's Control Therapy is indicated for adjunctive therapy in reducing some of the symptoms of advanced, levodopa-responsive Parkinson's disease that are not adequately controlled with medication. Unilateral thalamic stimulation by the Medtronic Activa Tremor Control System is indicated for the suppression of tremor in the upper extremity. The system is intended for use in patients who are diagnosed with Essential Tremor or Parkinsonian tremor not adequately controlled by medications and where the tremor constitutes a significant functional disability. The current supplement was submitted to expand the indication for the Medtronic DBS System for Epilepsy.

# **The Medtronic DBS System for Epilepsy is indicated for the following:**

Bilateral stimulation of the anterior nucleus of the thalamus (ANT) using the Medtronic DBS System for Epilepsy is indicated as an adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to three or more antiepileptic medications.

The Medtronic DBS System for Epilepsy has demonstrated safety and effectiveness for patients who average six or more seizures per month over the three most recent months prior to implant of the DBS system (with no more than 30 days between seizures). The Medtronic DBS System for Epilepsy has not been evaluated in patients with less frequent seizures.

### III. CONTRAINDICATIONS

Implantation of a DBS system is contraindicated for:

**Diathermy** - Patients exposed to diathermy. Do not use shortwave diathermy, microwave diathermy or therapeutic ultrasound diathermy (all now referred to as diathermy) on patients implanted with a neurostimulation system. Energy from diathermy can be transferred through the implanted system and can cause tissue damage at the location of the implanted electrodes, resulting in severe injury or death.

Diathermy can also damage the neurostimulation system components, resulting in loss of therapy and requiring additional surgery for system explantation and replacement. Advise your patient to inform all their health care professionals that they should not be exposed to diathermy treatment.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 2

{2}

Injury to the patient or damage to the device can occur during diathermy treatment when:

- the neurostimulation system is turned on or off.
- diathermy is used anywhere on the body—not just at the location of the neurostimulation system.
- diathermy delivers heat or no heat.
- any component of the neurostimulation system (lead, extension, neurostimulator) remains in the body.

**Magnetic resonance imaging (MRI) using a full body transmit radio-frequency (RF) coil, a receive-only head coil, or a head transmit coil that extends over the chest area**

Some specific types of MRI are contraindicated for patients with any implanted DBS System or system component. Tissue lesions from component heating, especially at the lead electrodes, resulting in serious and permanent injury including coma, paralysis, or death can occur if performing an MRI procedure that involves the use of:

- a full body transmit radio-frequency (RF) coil
- a receive-only head coil
- a head transmit coil that extends over the chest area

**Refer to the MRI guidelines manual packaged with this product for comprehensive safety information and instructions.**

**Unable to operate patient devices** - Patients who are unable, or do not have the necessary assistance, to properly operate the DBS Therapy patient programmer, magnet, or a charging system (applicable to rechargeable DBS Systems only).

**Transcranial magnetic stimulation (TMS)** - Contraindicated for use in patients with an implanted DBS System.

#### **IV. WARNINGS AND PRECAUTIONS**

The warnings and precautions can be found in the Medtronic DBS System for Epilepsy labeling.

#### **V. DEVICE DESCRIPTION**

The Medtronic DBS System for Epilepsy is a totally implanted device that delivers bilateral stimulation to the anterior nucleus of the thalamus (ANT) in the brain. The main components of the Medtronic DBS System for Epilepsy are shown in Figure 1 below:

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 3

{3}

![img-0.jpeg](img-0.jpeg)

(a)

![img-1.jpeg](img-1.jpeg)

(b)

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

(c)

![img-3.jpeg](img-3.jpeg)

(d)

![img-4.jpeg](img-4.jpeg)

(e)

![img-5.jpeg](img-5.jpeg)

(f)

Figure 1: (a) Implantable Neurostimulator (INS), (b) Leads, (c) Extension, (d) External Neurostimulator (ENS), (e) Clinician Programmer, and (f) Patient Programmer

# A. Implanted Components

The implanted components of the Medtronic DBS System for Epilepsy include the following:

- Activa PC Neurostimulator (Model 37601)

The Activa PC neurostimulator is a dual channel, multi-programmable implantable neurostimulator (INS) which is implanted subcutaneously near the clavicle, and generates electrical signals that are delivered via the extensions and leads to the targeted brain structure. It is powered by a 6.3 amp hour, 3.2 V sealed primary cell HC silver vanadium oxide (HCSVO) battery. The electronic circuitry of the INS sends pulses of controlled electrical stimulation through the implanted lead-extensions to the brain. The connector assembly accommodates two extensions, forming a dual channel system. Setscrews and Bal Seals provide electrical contact between the INS and the leads/extensions. Approximate dimensions of the IPG are 65 mm (height), 49mm (width) and 15 mm (thickness). The stimulation parameters can be non-invasively adjusted via radio-frequency communication using the Model

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 4

{4}

8840 N'Vision programmer with the Model 8870 Software application card (see below). The stimulation output parameters are listed in Table 1 below:

Table 1: Stimulation Output Parametersᵃ

|  Waveform | Square Wave  |
| --- | --- |
|  Method of Charge Balancing | Capacitive Coupling  |
|  Current or Voltage Regulated | Either  |
|  Maximum Current Amplitude @ 500 Ω | 0 – 25.5 mA (current mode)  |
|  Maximum Output Voltage @ 500 Ω | 0 – 10.5 V (voltage mode)  |
|  Pulse Width | 60 – 450 μs  |
|  Frequencyᵇ | 30 – 250 Hz (current mode) 2 to 250 Hz (voltage mode)  |
|  Maximum Charge Densityᶜᵇ | 30 μC/cm²/phase  |
|  Current Path Optionsᵈ | 1 to 4 electrodes per lead as anode, cathode, or Off Case defined as anode or Off  |
|  Number of Channels | 2  |
|  Number of Defined Groupsᵉ | 1 to 4  |
|  Number of Programs per Group | 1 to 4  |

ᵃ Certain combinations of high amplitude, pulse width, and rate settings are not allowed by the clinician programmer. High-output interlocks can prevent certain values from being available for programming.

ᵇ Rate limited to 125 Hz when two programs are active on a single lead

ᶜ A survey of literature regarding electrical stimulation of neural tissue suggests that damage may occur above 30 μC/cm²/phase. The Medtronic DBS System is capable of producing charge densities in excess of 30 μC /cm²/phase on an electrode surface area of 0.06 cm² (for the DBS Model 3387 Lead and DBS Model 3389 Lead). If the maximum charge density threshold is reached, the Charge Density warning message appears and must be overridden to proceed.

ᵈ In constant current mode a maximum of 2 electrodes (including the case) can be configured as anode or cathode

ᵉ A program is a specific combination of pulse width, rate, and amplitude settings acting on a specific electrode combination. Up to four programs can be combined into a group. When using more than one program, the pulses are delivered sequentially—first a pulse from one program, then a pulse from the next program.

• DBS™ Lead Kits (Model 3387S and Model 3389S)

The DBS leads connect to a lead extension and deliver electrical signals to the targeted brain structure. The DBS leads have with four 1.5 mm platinum/iridium electrodes near the tip of each lead that deliver stimulation to the target site. Lead models include Model 3387S, in which the 4 electrodes are spaced 1.5 mm apart and Model 3389S, in which the electrodes are spaced 0.5 mm apart. The leads are stereotactically introduced into the target and fixed at the skull with a burr hole cap and ring. Accessories that come with the lead kit include the following: Straight and Short Stylets, Torque Wrench, Depth Stop Gauge (lead), Burr Hole Ring and Cap, Connector Boot, Tunneling Tools, and a Lead Cap. Lead specifications are provided in Table 2 below:

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 5

{5}

**Table 2: Lead Specifications**

|  Lead Length | 10-50 cm  |
| --- | --- |
|  Lead Diameter | 1.27 mm  |
|  Number of Electrodes | 4  |
|  Electrode Material | Platinum-Iridium  |
|  Electrode Length | 1.5 mm  |
|  Electrode Spacing (edge-to-edge) | 1.5 mm & 0.5 mm  |
|  Electrode Span | 10.5 mm & 7.5 mm  |
|  Electrode Surface Area | 0.06 cm^{2}  |
|  Impedance (Ω)^{†} | < 100 Ω  |
|  Conductor Wire Material | Platinum-Iridium  |
|  Lead Body Insulation | Polyurethane  |

$^{†}$ Electrical resistance is proportional to lead length.

# - • DBS Extension Kit (Model 37086)

The extension is a set of wires within silicone tubing and polyurethane insulation that provides an electrical path that allows stimulation to be delivered to the target site. The extension is subcutaneously passed from the scalp area, where it connects to the lead, through to the subclavicular area or upper abdominal region, where it connects to the INS. The extension comes in lengths of 10 to 110 cm. Accessories that come with the lead kit include the following: Connector Boots, In-line Neurostimulator Plug, Torque Wrench, and Extar Setscrews.

# **B. External Components**

The external components of the Medtronic DBS System for Epilepsy include the following:

# - • Intercept Patient Programmer (Model 37441)

The Intercept Model 37441 Patient Programmer is a hand-held device for use with the Activa PC neurostimulator. It allows the patient to turn the neurostimulator on and off, check whether the neurostimulator is on or off, check the status of the neurostimulator battery, adjust programmed parameters within physician-prescribed limits, reset the stimulation cycle, and record a seizure event.

# - • N'Vision Programmer (Model 8840) and Software Application Card (Model 8870)

The Model 8840 N’Vision Programmer is used to noninvasively interrogate and program implantable medical devices developed by Medtronic’s Neuromodulation Division. The programmer is a hand-held device containing hardware and software which provide the capabilities to program the implantable neurostimulators. The programmer is battery powered and uses a telemetry head for communication with the implanted devices. A graphical user interface allows the clinician access to the programming functions.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 6

{6}

The N'Vision Application Card contains the application software necessary to program Medtronic Neuromodulation neurostimulators, while also having the capability to store data from programming sessions. The neurostimulator application software on the Model 8870 Application Card contains the software to program the Activa PC Model 37601 Neurostimulator. The software applications are accessed by interrogating a neurostimulator via the programmer's telemetry module. Following interrogation, the programmer will automatically select the application software required for programming the interrogated neurostimulator.

- External Neurostimulator (Model 37022)
  The external neurostimulator is a temporary external power source used for perioperative testing. Parameters that can be adjusted include amplitude, pulse width, rate and electrode selection.
- Lead Frame Kits (Model 3353/3354)
  The lead frame kits (which are designed to fit legally-marketed Elekta/Leksell and Radionics or Radionics-like stereotactic frames) are used to stabilize the lead in the insertion cannula during implantation.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are currently three major treatment modalities for which there is evidence of effectiveness in the treatment of refractory epilepsy: Pharmacotherapy with antiepileptic drugs (AEDs), resective surgery, and device-based therapy including vagus nerve stimulation (VNS) and cortical stimulation of 1 or 2 seizure foci using the Responsive Neurostimulation (RNS®) System. Antiepileptic medications are the usual first line treatment for epilepsy. For those patients that do not respond to the initial AED, physicians generally will try other AEDs, either as monotherapy or in combination with other AEDs. In people with epilepsy for whom medications are not effective or who have unacceptable medication-related side effects, resective surgery and/or device-based therapies may be an option. Device-based therapies are often used as an adjunct to AED therapy. Resective surgery is most successful in patients with a clearly defined seizure onset location, where the location of the resection will not lead to postoperative deficits or morbidity. 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

Medtronic deep brain stimulation for the treatment of epilepsy is currently approved in Europe and other geographies. Medtronic markets devices for other deep brain stimulation therapies, as summarized below.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 7

{7}

|  Indication | Description | PMA/HDE  |
| --- | --- | --- |
|  Parkinson's disease and Essential Tremor | DBS™ Therapy | P960009  |
|  Dystonia | DBS™ Therapy | H020007  |
|  Obsessive-Compulsive Disorder | Reclaim® DBS™ Therapy | H050003  |

### **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.

- **Surgical complications.** Surgical complications may include, but are not limited to, the following:
  - Intracranial hemorrhage (which can lead to stroke, paralysis, or death)
  - Subcutaneous hemorrhage or seroma
  - Hematoma
  - Cerebrospinal fluid leakage and/or cerebrospinal fluid abnormality
  - Brain contusion
  - Infection and/or inflammation
  - Antibiotic anaphylaxis
  - Skin disorder
  - Edema
  - Persistent pain at surgery site and/or IPG site
  - Erosion
  - Brachial plexus injury (nerves to chest, shoulder and arm)
  - Postoperative pain, stress, or discomfort
  - Neuropathy (nerve degeneration)
  - Hemiparesis (muscular weakness or partial paralysis on one side of body)
  - Confusion – transient, nocturnal or ongoing
  - Cognitive impairment, including delirium, dementia, disorientation, psychosis and speech difficulties
  - Aphasia
  - Deep vein thrombosis
  - Complications from anesthesia
  - Phlebitis (vein inflammation)
  - Pulmonary embolism (sudden blood vessel obstruction)
  - Aborted procedures (air embolism, unable to find target, surgical complication, etc.)
  - Complications from unusual physiological variations in patients, including foreign body rejection phenomena
  - Pneumonia, seizure or convulsions
  - Paralysis (loss of motor function, inability to move)

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 8

{8}

- Stroke
- Death.
- **Deep brain stimulation complications.** Deep brain stimulation complications may include, but are not limited to, the following:
  - Device-related complications: Undesirable changes in stimulation possibly related to cellular changes in tissue around the electrodes, changes in the electrode position, or loose electrical connections and/or lead fracture
  - Loss of therapeutic benefit as a result of change in electrode positions, loose electrical connections or lead/extension fracture
  - Depression, suicidal thoughts, suicide
  - Memory impairment or déjà vu
  - Status epilepticus
  - Changes in seizures: new seizure type or worsening seizures (increased seizure frequency, duration and/or severity)
  - Anxiety, panic attack
  - Paresthesia (tingling, shocking, vibration, or buzzing sensation)
  - Stimulation not effective, insufficient seizure control
  - Agitation, anger, psychosis
  - Confusion
  - Abnormal thoughts
  - Dizziness
  - Vomiting
  - Tension
  - Abnormal face or body movements, convulsions
  - Trouble sleeping
  - Pain at implant site
  - Abnormal feelings or sensations
  - Discomfort
  - Headaches
  - Infection, including meningitis
  - Lead fracture, migration, or dislodgement
  - Misplaced lead
  - Extension malfunction, fracture or disconnect
  - Deep brain stimulation system failure or battery failure within the device
  - Deep brain stimulation system malfunction or dislodgement
  - Spontaneous turning on or off of the pulse generator (IPG)
  - Allergic or rejection response to implanted materials
  - Persistent pain, tightness, or redness at the incision sites or general pain
  - General erosion or local skin erosion over the pulse generator (IPG) or other device component
  - Persistent pain, tightness or discomfort around the implanted parts (e.g., along the extension path in the neck)

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 9

{9}

- Impaired wound healing (e.g., incision site drainage), infection or abscess formation
- Additional neurosurgical procedure to manage one of the above complications or to replace a malfunctioning component
- Death, including SUDEP

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

### IX. SUMMARY OF PRECLINICAL STUDIES

With the exception of the Intercept Model 37441 Patient Programmer, all components of the Medtronic DBS System for Epilepsy are commercially approved as part of the Medtronic Activa Tremor Control System (P960009, P960009/S3), the Medtronic Kinetra Neurostimulation System (P960009/S27) or the Medtronic Activa PC Neurostimulation System (P960009/S52 & P960009/S134). Therefore, the preclinical testing of these components provided in prior Medtronic Activa System PMA/PMA supplements is also applicable to the Medtronic DBS System for Epilepsy.

#### A. Laboratory Studies

##### 1. Model 37601 Activa PC Neurostimulator

The Model 37601 Activa PC Neurostimulator underwent various testing for electrical safety and mechanical verification. Key testing on the neurostimulator is summarized in Table 3 below. Testing demonstrated the Model 37601 Activa PC Neurostimulator operated according to specifications after exposure to the tested conditions (i.e., passed testing).

Table 3. Model 37601 Activa PC Neurostimulator Summary of Testing

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Mechanical Verification | Verifies the mechanical and electrical testing of the Activa PC IPG. Testing included: | Testing demonstrated that all acceptance criteria was met at a minimum, to the standards noted where applicable.  |
|   |  • Dimensions including weight | Device meets specified dimensional requirements.  |
|   |  • Exposures to multiple ETO sterilization cycles | Device meets device functional test specifications after multiple ETO cycles per EN 45502-1:1997-08.  |
|   |  • Radiopaque identification | Radiopaque is legible on x-ray.  |
|   |  • Environmental temperature exposure and thermal shock | Device meets functional specifications after static and transient exposures per 45502-1: 2003-12.  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 10

{10}

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|   | • Mechanical vibration • Mechanical shock • Free fall drop | Device meets functional test specifications after mechanical vibration and shock tests per 45502-2-1:2003, 45502-2-2: 2008 and multiple 30 cm drops on all axes.  |
|   |  • Shield deflection strength • Shield deflection fatigue | Device meets functional test specifications after low cycle testing at 18 lbs and high cycle testing at 3 lbs.  |
|   |  • Barometric pressure | Device meets functional test specifications after testing per BS EN 45502-1:1998.  |
|   |  • Lead insertion & extraction force with set screw loose | Lead/extension can be inserted into connector with less than 13.4 N and extracted with less than 1.75 lb.  |
|   |  • Lead retention force | Lead/extension is retained within the connector at specified force.  |
|   |  • Contact resistance | Contact impedance shall vary less than +/- 4.5 Ohms over life of device.  |
|   |  • Connector attach strength • Connector attach fatigue | Device meets leakage impedance requirements after low cycle static force testing for strength and 210,000 cycles for fatigue testing.  |
|   |  • Electrical leakage impedance | Device meets requirements when tested per method described in ISO 5841-3:2000-2010.  |
|  Electrical Output Verification | Verify the electrical output of the Activa PC IPG. (amplitude, pulse width, frequency, etc.) | The IPG output parameters are within specified tolerances.  |
|  Electrical Leakage Current and DC Imbalance | Verify that leakage currents and DC imbalance of the outputs are within limits | IPG outputs meet section 16.2 of EN45502-1 / ISO 14708-1.  |
|  Temperature rise during single fault condition | Temperature should not rise more than the specified limit | Temperature rise is less than or equal to 2°C limit during single fault conditions per EN 45502-1: 1997 17.1.  |

## 2. Model 3387 and 3389 DBS Leads

The Model 3387 and 3389 DBS leads underwent various testing for electrical and mechanical verifications. Key testing on the lead is summarized in Table 4 below. Testing demonstrated the Model 3387 and 3389 DBS leads operated according to specifications after exposure to the tested conditions (i.e., passed testing).

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 11

{11}

**Table 4. Model 3387 and 3389 DBS Lead Summary of Testing**

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Mechanical | To verify the mechanical and electrical properties of the DBS leads. | All tests successfully met acceptance criteria per requirements based on intended use.  |
|   |  • Lead Body | Lead body meets intended design requirements.  |
|   |  • Lead Length | Lead meets specific length requirements.  |
|   |  • Connector | Lead connector allows connection to extensions, Lead cap, and OR cables.  |
|   |  • Electrodes | Lead meets electrode dimensions.  |
|   |  • Flex Life | Lead body shall be flexed for a minimum number of cycles with no damage based on intended use.  |
|   |  • Bending Stiffness | Lead able to withstand 3 point bending test.  |
|   |  • Crush Strength | Static crush strength shall be greater than 50 lbs/in.  |
|   |  • Weld Neck Down Between Electrodes and Coil | Lead weld neck down is within specifications.  |
|   |  • Smoothness | OD of lead shall fit through specified ID tube.  |
|   |  • Straightness | Lead shall have maximum warp of 0.150 inches.  |
|   |  • Lead tip Straightness | Lead tip meets minimum straightness specification.  |
|   |  • Operating Temperature Range | Lead maintains properties within specified temperature ranges.  |
|   |  • Storage Temperature Range | Lead maintains properties within specified storage temperature ranges.  |
|   |  • Process Requirements | Lead exposure to controlled environments, temperatures, and solvents.  |
|   |  • Insertion /withdrawal Forces | Lead connector meets maximum insertion and withdrawal forces.  |
|   |  • Set Screw Exposure | Lead contacts shall withstand a minimum torque of 5 in-oz.  |
|   |  • No sharp corners or edges | Lead meets acceptance criteria per requirements.  |
|   |  • Sterilization | Lead to be ETO sterilized.  |
|   |  • Vibration | Reference ASTM D4169-86.  |
|   |  • Mechanical Shock | Reference ASTM D4169-86.  |
|  Electrical | • DC resistance | Less than 100 ohms.  |
|   |  • Cross Circuit Resistance | Lead meets minimum cross circuit resistance.  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 12

{12}

### 3. Model 37086 DBS Extension

The Model 3387 and 3389 DBS leads underwent various testing for electrical and mechanical verifications. Key testing on the lead is summarized in Table 5 below. Testing demonstrated the Model 3387 and 3389 DBS leads operated according to specifications after exposure to the tested conditions (i.e., passed testing).

**Table 5. Model 37086 DBS Extension Summary of Testing**

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Mechanical | To verify the mechanical and electrical properties of the DBS Extensions. | All tests successfully met acceptance criteria per requirements based on intended use.  |
|   |  • Electrode/Contact Configuration | Extension body meets intended design requirements.  |
|   |  • Extension Lengths | Extension meets specific length requirements.  |
|   |  • Surface Features | Extension meets specific surface feature requirements.  |
|   |  • Force at Maximum Extension | Extension lead body meets force requirements when extended 15%.  |
|   |  • Contact Strength (Proximal End) | Extension shall meet electrical and mechanical requirements when set screw contacts are tightened to 5 in-oz, with no permanent damage to contacts.  |
|   |  • Connector Block (Distal End) | Each extension set screw block shall be exposed to a maximum torque of 5 in-oz (minus specified tolerance).  |
|   |  • Tunneling Tool (exposure) | Extension shall be exposed to a force based on intended use conditions while inserted into carrier.  |
|   |  • Torque Limiting Wrench (compatibility) | Extension sets screws to be compatible with specific torque wrench.  |
|   |  • Particulate Matter | Per EN45502-1.  |
|   |  • Proximal Extension Body Kink | Extension proximal end meets specific kink requirements.  |
|   |  • Dynamic Axial Load | Extension shall meet cyclic requirements when stretched 15 percent.  |
|   |  • Dynamic Flex | Extension shall be flexed for a minimum number of cycles with no damage based on intended use.  |
|  Electrical | • DC resistance | Maximum 38 ohms.  |
|   |  • DC leakage Current | Leakage between circuits shall not affect INS out put.  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 13

{13}

#### 4. Model 37441 Intercept Patient Programmer

The Intercept Model 37441 Patient Programmer is a derivative of the patient programmer developed for use with the Activa PC Neurostimulation System for Parkinson’s Disease and Essential Tremor. Modifications were made to adapt the programmer for use by epilepsy patients. These included the incorporation of a seizure button, soft key control of neurostimulator on/off activations, and simplified navigation. To verify and validate these changes, software testing, system validation, and human factors validation were completed. Medtronic conducted design verification and validation testing pertaining to aspects of the patient programmers impacted by the design and software changes. The electrical, mechanical, and telemetry design verification testing was performed with a “verification by equivalence” approach. Key testing on the Intercept Patient Programmer is summarized in Table 6 below. In addition, the previous packaging validation is still applicable to the Intercept model.

**Table 6. Model 37441 Intercept Patient Programmer Summary of Testing**

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  Usability Validation | Validates the intended users can use the Intercept EP Patient Programmer, and that the Intercept EP Patient Programmer meets its intended use. | - All participants successfully complete selected patient programmer tasks using Simple Mode without errors of a hazardous nature. - All participants successfully complete the following patient programmer tasks using Simple Mode: record a seizure event, check neurostimulator battery, check patient programmer battery, and turn stimulation OFF.  |
|  Software Verification | Verifies functionality of the Patient Programmer software application and Patient Electronics Module (PEM, including: - 53 baseline (ie MvD) conditions confirmed - 13 Epilepsy conditions tested | All tests successfully met acceptance criteria per requirements including: - Application download and versions - General display and key press - Lead connection check - Advanced and simple mode - Seizure button features (count, display etc.) - Telemetry failures  |
|  Mechanical Testing | Verifies by similarity that the Model 37441 Intercept Patient Programmer meets mechanical requirements to Model 37642 DBS Patient Programmer. Tests included: | All tests successfully met acceptance criteria per requirements including:  |
|   |  - Operating/storage temperature | Device operates after exposed to the temperature extremes of 9°C (48°F) and 43°C (110°F).  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 14

{14}

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|   | • Thermal shock | Device operates per specification after being exposed to temperature cycles of –40°C (-40°F) and 65°C (150°F).  |
|   |  • Mechanical shock | Device operates after multiple drops from 1 meter on all axes.  |
|   |  • Humidity | Device operates after being exposed in a chamber at 95% relative humidity and 95°F for the listed number of days.  |
|   |  • Chemical resistance | Device labels and exposed surfaces are not damaged by exposure to standard household chemicals.  |
|   |  • Seizure button color | Seizure button is per color spec and has a different icon shape on the button surface.  |
|   |  • Front Lens/graphics | The front lens is made of the same material and is the same shape and size.  |
|  System Verification | Verifies that the Intercept EP patient programmer application supports the Activa PC INS. | Using the Intercept EP patient programmer, a Lead Connection Check is successfully performed on the DBS for Epilepsy System.  |
|   |  Verifies that the Intercept EP patient programmer is based off of the Activa RC/PC Patient Programmer platform. | Inspection of the mechanical assembly drawings and product specifications demonstrate that the Intercept EP patient programmer hardware design is based off of the Activa RC/PC Patient Programmer platform.  |
|   |  Verifies the Intercept EP patient programmer seizure key functionality, including: • Seizure key press to record a seizure • Seizure key press to restart the stimulation cycle • Maximum number of seizure key presses count • Seizure key press counts are stored by the system. • Seizure key press count data is reset after each programming session with the N’Vision 8840 Clinician Programmer. | • After pressing the seizure key once, the seizure confirmation screen appears and the seizure key count on the therapy screen increases by one. • With Intercept EP patient programmer restart stim feature ON, the Activa PC INS restarts the stimulation cycle after a single press of the seizure button. • The Intercept EP patient programmer increments the seizure count with each key press up to the maximum number • The DBS for Epilepsy system stores the seizure key press count. • The Intercept EP Patient Programmer displays a seizure key count of zero after each programming session with the N’Vision 8840 Clinician Programmer.  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 15

{15}

|  Test | Test Purpose | Acceptance Criteria  |
| --- | --- | --- |
|  System Validation | Validates that customer needs and intended uses are met by the DBS for Epilepsy System. Customer needs and intended uses include: • Seizure tracking • Therapy monitoring and configuration using the clinician programmer • Therapy monitoring and adjustment using the patient programmer • Patient Programmer Therapy ON/OFF | All tests successfully met acceptance criteria per requirements. DBS for Epilepsy therapy Customer Needs and Intended uses were validated through bench testing. • Seizure button presses are tracked between clinician programming sessions. • Amplitude, pulse width, rate can be adjusted using the patient programmer. Groups and programs can be selected using the patient programmer. • The stimulation cycle restarts with a seizure button press. • Therapy ON/OFF is programmable using the patient programmer.  |

##### 5. Sterilization

The Activa PC INS, leads and extensions are sterilized in their packaging using 100% ethylene oxide (EtO) gas sterilant. The EtO sterilization process includes all the requirements necessary to ensure product sterility. These requirements include sterilization process validation, which ensures a sterility assurance level (SAL) of at least 10⁻⁶, sterilization process monitoring requirements, sterile lot control requirements, and parametric release requirements. The method of sterilization cycle validation meets the requirements as stated in the applicable standards, including *EN/ISO 11135-1:2007, Medical Devices—Validation and Routine Control of Ethylene Oxide Sterilization*, to provide a 10⁻⁶ SAL. DBS leads are tested for product bacterial endotoxin not more than 2.15 EU/device. These limits were verified using Limulus Amebocye Lysate (LAL) testing.

##### 6. Packaging and Shelf-life

Packaging and shelf life verification testing was successfully completed for the DBS Leads, DBS Extensions, and Neurostimulator per BS EN ISO 11607-1:2006 - *Packaging for terminally sterilized devices – Part 1: Requirements for materials, sterile barrier systems and packaging systems*. Packaging verification testing was also successfully completed for the Patient Programmer, N’Vison Programmer, External Neurostimulator, and accessories per ASTM D4169:2008. The testing confirmed that the device packaging adequately protects the product during conditions that may be encountered during storage, shipping, and handling.

The Activa PC Neurostimulator has a maximum shelf life of 18 months from the date of battery attachment. The DBS Leads and DBS Extensions have a maximum shelf life of 4 years from the date of sterilization.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 16

{16}

# 7. Biocompatibility

Biocompatibility of materials of all patient-contacting components of the Medtronic DBS System for Epilepsy was tested according to the ISO 10993 Biological evaluation of medical devices (current at the time of testing) and/or other applicable standards, or in some cases a rationale for no additional testing was provided. The neurostimulator, DBS Leads and Extensions are considered permanent (> 30 days) implants with tissue/bone contact. Biocompatibility testing conducted on the tissue contacting materials is summarized in Table 7, Table 8, and Table 9 below. All pre-specified test acceptance criteria were met and all tests passed.

Table 7. Model 37601 Activa PC Biocompatibility Summary

|  Biological Effect | Test Reference | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Cytotoxicity | Cytotoxicity Test (MEM Elution) | Reactivity grade is not greater than mild reactivity (Grade 2). | Non-cytotoxic  |
|  Sensitization | Maximization Sensitization Test (Guinea Pig) | Grades of <1 in the test group provided grades of < 1 are observed on the control animals. | Non-sensitizing  |
|  Irritation or Intracutaneous Reactivity | Intracutaneous/Intradermal Test (Rabbit) | The difference between the test article and the control mean score is ≤ 1.0. | No evidence of significant irritation.  |
|  Systemic Toxicity (acute) | Systemic Toxicity (Mice) | None of the test animals show a significantly greater biological reaction than the animals treated with vehicle control. | No mortality or systemic toxicity  |
|   |  Material Mediated Pyrogenicity (Rabbit) | No rabbit shows an individual rise in temperature of 0.5 °C or more above the baseline temperature. | Non-pyrogenic  |
|  Genotoxicity | Reverse Mutation Test (Bacterial Cells) | No significant increase in the mutation frequency of the test article compared to the negative control article. | Non-mutagenic  |
|   |  In Vitro Mammalian Chromosome Aberration Test (Chinese Hamster Ovary Cells) | No statistically significant increase in the number of structural chromosomal aberrations compared to the negative control. | Did not induce chromosomal aberrations  |
|   |  Micronucleus Assay (Mice) | There is no statistically significant increase in micronucleated cells as compared to the negative control. | Non-mutagenic  |
|  Implantation | Intramuscular Implant in Rabbits (12 weeks) | Difference between mean test score and mean control score: Non-toxic < 1 Slightly toxic ≥ 1 and < 2 Mildly toxic ≥ 2 and < 3 Moderately toxic ≥ 3 and < 4 Severely toxic ≥ 4 | Non-toxic  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 17

{17}

Table 8. Model 3387/3389 Leads Biocompatibility Summary

|  Biological Effect | Test Reference | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Cytotoxicity | Cytotoxicity Test (MEM Elution) (All materials except platinum/iridium) | Reactivity grade is not greater than mild reactivity (Grade 2). | Non-cytotoxic  |
|  Sensitization | Maximization Sensitization Test (Guinea Pig) | Grades of <1 in the test group provided grades of < 1 are observed on the control animals. | Non-sensitizing  |
|  Irritation or Intracutaneous Reactivity | Intracutaneous / Intradermal Test (Rabbit) (All materials except platinum/iridium) | The difference between the test article and the control mean score is ≤ 1.0. | No evidence of significant irritation  |
|  Systemic Toxicity (acute) | Systemic Toxicity (Mice) (All materials except platinum/iridium) | None of the test animals show a significantly greater biological reaction than the animals treated with vehicle control. | No mortality or systemic toxicity  |
|   |  Material Mediated Pyrogenicity (Rabbit) (All materials except platinum/iridium) | No rabbit shows an individual rise in temperature of 0.5 °C or more above the baseline temperature. | Non-pyrogenic  |
|  Genotoxicity | Reverse Mutation Test (Bacterial Cells) (All materials except platinum/iridium) | No significant increase in the mutation frequency of the test article compared to the negative control article. | Non-mutagenic  |
|   |  In Vitro Mammalian Chromosome Aberration Test (Chinese Hamster Ovary Cells) (All materials except polyurethane 80A adhesive and platinum/iridium) | No statistically significant increase in the number of structural chromosomal aberrations compared to the negative control. | Did not induce chromosomal aberrations  |
|   |  Micronucleus Assay (Mice) (All materials except polyurethane 80A adhesive and platinum/iridium) | There is no statistically significant increase in micronucleated cells as compared to the negative control. | Non-mutagenic  |
|  Implantation | Intramuscular Implant in Rabbits (12 weeks) (All materials except platinum/iridium and MP35N) | Difference between mean test score and mean control score: Non-toxic < 1 Slightly toxic ≥ 1 and < 2 Mildly toxic ≥ 2 and < 3 Moderately toxic ≥ 3 and < 4 Severely toxic ≥ 4 | Non-toxic  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 18

{18}

Table 9. Model 37086 DBS Extension Biocompatibility Summary

|  Biological Effect | Test Reference | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Cytotoxicity | Cytotoxicity Test (MEM Elution) Cytotoxicity Test (Agar Diffusion) (epoxy) | Reactivity grade is not greater than mild reactivity (Grade 2). | Non-cytotoxic  |
|  Sensitization | Maximization Sensitization Test (Guinea Pig) (All materials except epoxy) | Grades of <1 in the test group provided grades of < 1 are observed on the control animals. | Non-sensitizing  |
|  Irritation or Intracutaneous Reactivity | Intracutaneous / Intradermal Test (Rabbit) | The difference between the test article and the control mean score is ≤ 1.0. | No evidence of significant irritation  |
|  Systemic Toxicity (acute) | Systemic Toxicity (Mice) | None of the test animals show a significantly greater biological reaction than the animals treated with vehicle control. | No mortality or systemic toxicity  |
|   |  Material Mediated Pyrogenicity (Rabbit) | No rabbit shows an individual rise in temperature of 0.5 °C or more above the baseline temperature. | Non-pyrogenic  |
|  Subacute and Subchronic Toxicity (ETR silicone rubber and ETR silicone rubber with barium sulfate) (N/A for MP35N, stainless steel 316L, and titanium 6Al-4V*) | Subchronic Toxicity (Mice) | No statistically significant difference in clinical observations, gross necropsy, histopathological findings, and hematological parameters between test and control articles. | Non-toxic  |
|  Genotoxicity (No testing for epoxy) (N/A for MP35N, stainless steel 316L, and titanium 6Al-4V*) | Reverse Mutation Test (Bacterial Cells) | No significant increase in the mutation frequency of the test article compared to the negative control article. | Non-mutagenic  |
|   |  *In Vitro* Mammalian Chromosome Aberration Test (Chinese Hamster Ovary Cells) | No statistically significant increase in the number of structural chromosomal aberrations compared to the negative control. | Did not induce chromosomal aberrations  |
|   |  Micronucleus Assay (Mice) | There is no statistically significant increase in micronucleated cells as compared to the negative control. | Non-mutagenic  |
|  Implantation (N/A for MP35N, | Intramuscular Implant in Rabbits | Difference between mean test score and mean control score: | Non-toxic  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 19

{19}

|  Biological Effect | Test Reference | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  stainless steel 316L, and titanium 6Al-4V*) | (12 weeks) | Non-toxic < 1 Slightly toxic ≥ 1 and < 2 Mildly toxic ≥ 2 and < 3 Moderately toxic ≥ 3 and < 4 Severely toxic ≥ 4 |   |

* The tissue contact of MP35N, stainless steel 316L, and titanium 6Al-4V is less than 24 hours. Therefore, the biological tests of Subacute and Subchronic Toxicity, Genotoxicity and Implantation are not applicable for these materials.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

### Pivotal Study

A Pivotal study, SANTÉ (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy), was performed to establish a *reasonable assurance of safety and effectiveness* of bilateral stimulation of the anterior nucleus of the thalamus (ANT) with the Medtronic DBS System for Epilepsy as an adjunctive therapy in individuals 18 years of age or older with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to three or more antiepileptic medications. Subjects in the SANTÉ study had an average of 6 or more partial-onset seizures per month, were refractory to at least 3 antiepileptic drugs (AEDs), and were taking 1-4 AEDs at the time of enrollment. This study was performed in the United States under IDE # G030065. Data from this clinical study (from the blinded and long-term open-label phases) was the basis for the PMA approval decision that demonstrated sustained improvements in seizure reduction. A summary of the clinical study is presented below.

#### A. Study Design

Patients were enrolled in the study beginning on December 11, 2003 and the last implant was June 27, 2007 and includes 110 subjects in the Pivotal trial. The database for this PMA supplement reflects data collected through April 15, 2014 and includes data for all subjects who had not discontinued the study. There were 17 investigational sites in the US.

The SANTÉ study was a multicenter, prospective, randomized, double-blind, parallel groups clinical study. The study design included a 3-month Baseline Phase, a 1-month Operative Phase, a 3-month Blinded Phase, and a 9-month Unblinded Phase, followed by a Long-Term Follow-up Phase.

Enrolled subjects collected baseline seizure data for three months prior to implantation of the DBS system. Subjects received a DBS system as adjunctive therapy if they met all inclusion and no exclusion criteria during the Baseline Phase.

Devices were implanted in a single surgical procedure under local or general anesthesia. Post-implant MRI was performed to confirm lead location. DBS leads

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 20

{20}

were implanted bilaterally in the ANT and connected subcutaneously to a neurostimulator via lead extensions tunneled down the side of the neck. Four weeks after device implant, subjects were randomized to active (treatment) or control groups in a 1:1 ratio. The active group received stimulation at 5 V, 145 Hz, 90 μs, a cycling on interval of 1 minute, and a cycling off interval of 5 minutes. The control group was programmed to 0 V, 145 Hz, 90 μs, a cycling on interval of 1 minute, and a cycling off interval of 5 minutes. Study subjects, the investigator, and study center staff were blinded to the randomization assignments. One programmer at each site was unblinded for purposes of programming and treatment of adverse events. Subjects kept seizure diaries and were seen in the clinic at 2 months, 3 months, and 4 months post-implant for follow-up during the Blinded (randomized) Phase of the study.

At the end of the Month 4 visit, the control group subjects had the stimulation programmed on, and active group subjects continued stimulation. Subjects in both groups continued to be unaware of their prior stimulation status during the previous Blinded Phase. Programming changes were restricted through the Unblinded Phase of the study (Months 4-13) and AEDs (antiepileptic drugs) remained stable. During the Long-Term Follow-Up Phase (beyond Month 13), there were no restrictions on programming or AED changes. Visits occurred monthly through the Blinded and Unblinded Phases, and every 6 months during the Long-Term Follow-Up Phase. In addition to the semi-annual and annual visits, subjects were contacted by phone once a month in the Long-Term Follow-Up Phase to review the diary and record health care utilization and adverse events. See Figure 2 for an overview of the study phases.

![img-6.jpeg](img-6.jpeg)

Figure 2. Study design schema.¹

¹ Abbreviations: wk(s), week(s); mo, month; DC, hospital discharge

The study was designed to have 80% power with an overall 1-sided Type 1 error rate of 0.025 (equivalent to two-sided Type 1 error of 0.05), assuming 25% difference between groups in seizure frequency reduction. To meet these criteria, 102 subjects were required at the end of the Blinded Phase. To ensure that patient enrollment was adequate to meet the minimum sample size requirement (taking into account an approximate 30% baseline dropout and losses to follow-up), the recommended enrollment sample size was 150 subjects. The sample size for the secondary outcome

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 21

{21}

measures and additional study measures was not pre-specified to show a statistically significant difference in those measures.

An independent Data Monitoring Committee (DMC) for the SANTÉ study was established. The DMC was responsible for independently monitoring the safety of interventions during the investigation by reviewing the data available by Medtronic acting in the capacity of the Coordinating Center. For the first year of the study, the DMC met every 6 months. After that time, the DMC met at least annually to review the safety data and study conduct. One preplanned interim analysis for futility was performed by DMC liaison statistician. The Clinical Events Committee (CEC), consisting of several Medtronic Clinical Study Team functions, periodically reviewed all adverse events reported during the study to assure appropriate and consistent classification. Central laboratory services for MRI (magnetic resonance imaging) analysis were provided by Hennepin County Medical Center, Department of Radiology.

1. Clinical Inclusion and Exclusion Criteria

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

- Partial-onset seizures with or without secondary generalization.
- An average of 6 or more partial-onset seizures (with or without secondary generalized seizures) per month during the Baseline Phase, with no more than 30 days between seizures.
- Refractory to antiepileptic drugs (subjects were considered refractory if they failed at least 3 AEDs due to lack of efficacy).
- Receiving 1 to 4 currently marketed AEDs.
- Aged 18 to 65 years, inclusive.
- If female, not pregnant.

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

- Multilobar (>3 different lobes) anatomic areas of seizure onset.
- Symptomatic generalized epilepsy.
- Averaged more than 10 complex partial seizures/day over the 3-month period prior to baseline.
- Experienced only simple partial seizures that had no outward clinical manifestations observable by either the subject or caregiver.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 22

{22}

- • Any episode of convulsive status epilepticus within the 12 months prior to baseline.
- • Previous diagnosis of psychogenic/nonepileptic seizures.
- • Surgical candidate for, and willing to undergo, partial temporal lobectomy or lesionectomy.
- • Diagnosis or evidence of a neurological disorder or condition affecting the brain likely to progress (e.g., brain tumor, active encephalitis, active meningitis or abscess, arteriovenous malformations or cavernous angiomas that were likely to progress).
- • Intelligence quotient (IQ) less than 70 based on the baseline WASI (Weschler Abbreviated Scale of Intelligence) test.
- • Presence of any of the following: psychiatric illness hospitalization, suicide attempt or symptoms of psychosis (e.g., hallucinations, delusions) unrelated to an ictal state, a postictal state or a medication.
- • Malignancy or history of malignancy (excluding resected basal cell carcinomas).
- • Presence of an implanted electrical stimulation medical device anywhere in the body (e.g., cardiac pacemakers, spinal cord stimulator) or any metallic implants in the head (e.g., aneurysm clip, cochlear implant). Vagus nerve stimulation (VNS) devices were allowed if the device had been turned off and the subject agreed to have the generator explanted.
- • Risk factors that would put the subject at risk for intraoperative or postoperative bleeding
- • Condition or disease that was known to require repeat MRIs.

## 2. Follow-up Schedule

A schematic of the study timeline is provided in Figure 2 above. The primary effectiveness analysis compared the change in the total seizure rates in active group and in the control group over the 3-month Blinded Phase. Primary safety analyses include adverse event data over the first 3 months post-implantation. Secondary safety and effectiveness analyses included data from all periods of the study.

Information regarding daily seizure counts, adverse events and subject well-being was collected at all visits by a physician investigator blinded to the subject’s randomization status. All patients were scheduled to return for follow-up examinations monthly during the Blinded and Unblinded Phases and every 6 months during the Long-Term Follow-Up Phase.

Preoperatively, a 3-month baseline seizure diary was completed by all subjects to gather data on seizure classification and frequency. The Liverpool Seizure

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 23

{23}

Severity Scale, Quality of Life (QOLIE-31), neuropsychological testing and health care utilization data were collected in addition to adverse event data during the Baseline Phase. Postoperatively, and during the Blinded Phase, the objective parameters measured during the study included the data administered during the Baseline Phase, as well as neurostimulator monitoring, subject satisfaction and a blinding assessment. Adverse events and complications were recorded at all visits.

The key timepoints are shown below in the tables summarizing safety and effectiveness.

### 3. Clinical Endpoints

#### **Safety:**

The primary safety objective for the Pivotal study was to characterize the adverse events and incidence of sudden unexplained death in epilepsy (SUDEP) experienced with the deep brain stimulation (DBS) system stimulating the anterior nucleus in subjects with refractory epilepsy. For safety and unblinded Phase effectiveness analyses, all implanted subjects that were followed during the time interval of interest were included in the analyses.

#### **Effectiveness:**

The primary effectiveness objective was to demonstrate that the reduction in the total seizure rate in the active group was greater than in the control group over the entire Blinded Phase compared to the Baseline Phase. The pre-specified analysis utilized a generalized estimating equations (GEE) model to test for the difference in seizure rates between groups and required that subjects record a minimum of 70 days of diary in the entire Blinded Phase. One subject was excluded for having less than the required number of diary days and one subject in the active group was also excluded as this subject was determined to be an outlier.

This “outlier” subject, randomized to the active group, was identified to be an extreme and highly influential observation from a statistical and medical perspective. Inclusion of this subject’s data markedly changes the estimate of the treatment effect. This subject experienced a nearly immediate increase in the occurrence of frequent and brief seizures of a new complex partial type subsequent to the initiation of stimulation (210 seizures in 3 days compared to this subject’s baseline seizure rate of 19 seizures per month) which immediately ceased when voltage was reduced. The subject later had voltage increased beyond the level that was associated with the initial increase in seizures, with no recurrence of those seizures. The subject experienced two more seizures of this type, on the same day, during the Long-Term Follow-Up Phase.

Sensitivity analyses were performed to assess the potential impact of missing data on the long-term effectiveness results. Two analyses were performed that included all randomized subjects: LOCF (last observation carried forward) and Worst case. For both of these analyses, if the subject had at least 28 days of diary in the last 3 months

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 24

{24}

prior to the annual visit, the percent change from baseline was calculated from those data. If there were less than 28 days, the percent change from the last visit was used to calculate missing values for the LOCF method. The Worst case imputation used 100% worsening if there were less than 28 days of diary.

For other effectiveness objectives, chi-square tests were used for categorical responses, Wilcoxon rank-sum (for comparison between active and control) and Wilcoxon signed-rank (for change from baseline) tests for non-normally distributed continuous endpoints, and t-tests (for comparison between active and control) or paired t-tests (for change from baseline) for normally distributed continuous endpoints.

Secondary effectiveness objectives were as follows:

- To demonstrate that the proportion of responders in the active group is greater than in the control group. Responders were defined as subjects whose seizure frequency was reduced by ≥50% as compared with baseline.
- To demonstrate that the mean percentage of seizure-free days and maximum length of seizure-free intervals in the active group is greater than in the control group.
- To demonstrate that the proportion of treatment failures in the active group is less than in the control group

Additional study measures:

- To characterize seizure type and severity experienced during the Baseline and Blinded Phases in the active and control groups.
- To characterize the number of patient programmer activations during the Blinded Phase in the active and control groups.
- To characterize the scores of the Quality of Life in Epilepsy (QOLIE-31), the subject satisfaction and subject outcome questions in the active and control groups.
- To characterize the results of the neuropsychological testing in the active and control groups.
- To characterize health care resource utilization in the active and control groups.
- To characterize the number of times subjects in the active and control groups used rescue medications.

### B. Accountability of PMA Cohort

At the time of database lock, of 157 patients enrolled in the PMA study, 110 were implanted and 66.3% (73) of subjects were available for analysis at the completion of the study, i.e. the 7 years post-operative visit. The safety analysis populations for the study included all 110 subjects that were implanted and the primary effectiveness

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 25

{25}

analysis population included 108 subjects, excluding the following 2 implanted subjects: one subject who exited the study before randomization (due to an infection), and one subject who did not have 70 days of diary entries in both the Baseline and Blinded Phases. One subject who was deemed to be an “outlier” was excluded from the post-hoc analysis.

Figure 3 summarizes the distribution of subjects entering each study phase and the number of subjects active in each phase at the time of the database cutoff.

## Withdrawals and discontinuations

Forty-seven subjects discontinued from the study prior to implant: eligibility or implant criteria not met (24), withdrawal of consent by subject (17), investigator decision due to safety reason (2), adverse event (1), death (1), lost to follow-up (1), and instability after VNS device turned off (1).

No subjects discontinued from the study during the Blinded Phase.

Five subjects discontinued from the study in the Unblinded Phase: death (1) and adverse event (implant site infection [2], implant site pain [1], and involuntary muscle contractions [1]).

Thirty-six subjects discontinued from the study in the Long-Term Follow-Up Phase: death (5), withdrawal of consent by subject (5), investigator decision (3), elective medical device removal (1), and adverse event (therapeutic product ineffective [13], implant site infection [3], anxiety [2], cognitive disorder [1], meningitis [1], psychotic disorder [1], and sensory disturbance [1]).

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 26

{26}

![img-7.jpeg](img-7.jpeg)

Figure 3. Subject disposition

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 27

{27}

### C. Study Population Demographics and Baseline Parameters

Demographic information is provided in Tables 10 and 11 below.

**Table 10. Demographic and baseline characteristics – age, years with epilepsy, baseline seizure counts**

|   | All implanted (n=110) Mean ± std | By treatment group |   |   |   | p-value  |
| --- | --- | --- | --- | --- | --- | --- |
|   |   |  Active (n=54) |   | Control (n=55)  |   |   |
|   |   |  Mean ± std | Range | Mean ± std | Range  |   |
|  Age (years) | 36.1 ± 11.2 | 35.3 ± 11.0 | 18.2 – 55.4 | 36.8 ± 11.5 | 19.6 – 60.9 | 0.484  |
|  Years with epilepsy | 22.3 ± 13.3 | 21.6 ± 13.3 | 2 – 48 | 22.9 ± 13.5 | 2 – 60 | 0.608  |
|  Baseline Phase seizure counts (per month) | 56.1 ± 101.0 median 19.5 | 57.9 ± 105.2 median 18.4 | 7 – 555 | 55.2 ± 98.4 median 20.4 | 6 – 604 | 0.985  |

**Table 11. Demographic and baseline characteristics – gender, surgical procedure for epilepsy, number of epilepsy medications, seizure types, seizure onset locations**

|   | All implanted (n=110) |   | By treatment group |   |   |   | p-value  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |  No. of subjects | % | Active (n=54) |   | Control (n=55)  |   |   |
|   |   |   |  No. of subjects | % | No. of subjects | %  |   |
|  **Gender**  |   |   |   |   |   |   |   |
|  Male | 55 | 50.0% | 25 | 46.3% | 30 | 54.5% | 0.389  |
|  Female | 55 | 50.0% | 29 | 53.7% | 25 | 45.5%  |   |
|  **Surgical procedure for epilepsy**  |   |   |   |   |   |   |   |
|  VNS system implant | 49 | 44.5% | 21 | 38.9% | 28 | 50.9% | 0.389  |
|  Previous epilepsy surgery | 27 | 24.5% | 11 | 20.4% | 16 | 29.1% | 0.292  |
|  **Number of epilepsy medications**  |   |   |   |   |   |   |   |
|  1 | 12 | 10.9% | 6 | 11.1% | 6 | 10.9% | 0.287  |
|  2 | 54 | 49.1% | 25 | 46.3% | 28 | 50.9%  |   |
|  3 | 41 | 37.3% | 23 | 42.6% | 18 | 32.7%  |   |
|  4 | 3 | 2.7% | 0 | 0.0% | 3 | 5.5%  |   |
|  **Seizure types ^{a}**  |   |   |   |   |   |   |   |
|  Complex partial | 102 | 92.7% | 51 | 94.4% | 50 | 92.6% | 0.716  |
|  Partial to generalized | 85 | 77.3% | 38 | 70.4% | 46 | 85.2% | 0.115  |
|  Simple partial | 74 | 67.3% | 37 | 68.5% | 36 | 66.7% | 0.839  |
|  Primary generalized | 5 | 4.5% | 3 | 5.6% | 2 | 3.7% | 0.679  |
|  Other | 1 | 0.9% | 0 | 0.0% | 1 | 1.9% | 1.000  |
|  **Seizure onset locations ^{b}**  |   |   |   |   |   |   |   |
|  Temporal lobe | 66 | 60.0% | 35 | 64.8% | 30 | 54.5% | 0.331  |
|  Frontal lobe | 30 | 27.3% | 15 | 27.8% | 15 | 27.3% | 1.000  |
|  Diffuse or multifocal | 10 | 9.1% | 5 | 9.3% | 5 | 9.1% | 1.000  |
|  Other | 10 | 9.1% | 5 | 9.3% | 5 | 9.1% | 1.000  |
|  Parietal lobe | 5 | 4.5% | 2 | 3.7% | 3 | 5.5% | 1.000  |
|  Occipital lobe | 4 | 3.6% | 3 | 5.6% | 1 | 1.8% | 0.363  |

$^{a}$ Subjects may experience more than 1 seizure type.

$^{b}$ Subjects may have seizures originating from more than 1 onset location.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 28

{28}

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of primary safety endpoint was based on the cohort of 110 implanted subjects available for the 3-month evaluation. Data from the study, including the open label period, were used to assess overall safety in which all subjects active in the study were followed for a minimum of 7 years after device implantation. The key safety outcomes for this study are presented below in tables 12 to 14. Adverse effects are reported in tables 15 to 32.

#### Adverse effects that occurred in the PMA clinical study:

The SANTÉ study evaluated the safety of bilateral stimulation of the ANT for the treatment of epilepsy in 110 implanted subjects with a combined 713 device-years of experience. The investigator classified each adverse event as serious or non-serious and as device-related or not device-related. Device-related adverse events include those related to the implanted device, programming/stimulation, surgery/anesthesia, or the implant procedure. Adverse events were considered serious if the event resulted in significant risks or consequences to the subject's acute or long-term health, serious injury or death, hospital admission, permanent impairment of a body function or permanent damage to a body structure or if invasive medical intervention was required to alleviate the adverse event. Adverse events are presented using MedDRA Coding according to the Preferred Term (PT).

#### Adverse events overview

Table 12 presents an overview of adverse events (AEs). As of the database cutoff, there were 2,845 adverse events reported in 110 subjects. Serious adverse events (SAEs) accounted for 5.9% of events and device-related SAEs were 1.7% of all events. A serious device-related adverse event was reported in 34.5% (38/110) of subjects. There were no unanticipated adverse device effects.

**Table 12. Adverse event summary by cause – total post-implant**

|  Event Type | No. of events (% of events) | Subjects (%) with an Event (n=110)^{a} | Number of serious events/ number of total events (% of total events) | Subjects (%) with SAE (n=110)^{a}  |
| --- | --- | --- | --- | --- |
|  Device | 394 (13.8%) | 101 (91.8%) | 47/2845 (1.7%) | 38 (34.5%)  |
|  Non-Device | 2451 (86.2%) | 110 (100.0%) | 121/2845 (4.3%) | 55 (50.0%)  |
|  **Total** | **2845** | **110 (100.0%)** | **168/2845 (5.9%)** | **73 (66.4%)**  |

$^{a}$ Column may not add to total as subjects may have experienced more than 1 type of event.

Due to the long duration of this study, an overview of the adverse events that occurred from implant to Year 1 and from implant to Year 7 is also provided.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 29

{29}

During the first year after device implant (Operative through the Unblinded Phases), 822 adverse events were reported in 109 subjects as shown in Table 13. The majority of events (70.8%) were not device-related. Serious adverse events accounted for 6.8% of all first year events and device-related SAEs accounted for 4.1% of all first year events. Overall, 25.5% (28/110) of subjects had a serious device-related adverse event in the first year after device implant.

**Table 13. Adverse event summary by cause – implant to Year 1**

|  Event Type | No. of events (% of events) | Subjects with an Event (n=110)^{a} | Number of serious events/ number of total events (% of total events) | Subjects (%) with SAE (n=110)^{a}  |
| --- | --- | --- | --- | --- |
|  Device | 240 (29.2%) | 93 (84.5%) | 34/822 (4.1%) | 28 (25.5%)  |
|  Non-Device | 582 (70.8%) | 107 (97.3%) | 22/822 (2.7%) | 20 (18.2%)  |
|  **Total** | **822** | **109 (99.1%)** | **56/822 (6.8%)** | **40 (36.4%)**  |

$^{a}$ Column may not add to total as subjects may have experienced more than 1 type of event.

During the first 7 years after device implant (Operative Phase through the Long-Term Follow-Up Phase Year 7 visit), 2,566 adverse events were reported in 110 subjects as shown in Table 14. The majority of events (85.5%) were not device-related. Serious adverse events accounted for 6.2% of events and device-related SAEs accounted for 1.7% of events. Overall, 32.7% (36/110) of subjects had a serious device-related adverse event in the first 7 years after device implant.

**Table 14. Adverse event summary by cause – implant to Year 7**

|  Event Type | No. of events (% of events) | Subjects with Event (n=110)^{a} | Number of serious events/ number of total events (% of total events) | Subjects (%) with SAE (n=110)^{a}  |
| --- | --- | --- | --- | --- |
|  Device | 371 (14.5%) | 100 (90.9%) | 44/2566 (1.7%) | 36 (32.7%)  |
|  Non-Device | 2195 (85.5%) | 110 (100.0%) | 114/2566 (4.4%) | 54 (49.1%)  |
|  **Total** | **2566** | **110 (100.0%)** | **158/2566 (6.2%)** | **71 (64.5%)**  |

$^{a}$ Column may not add to total as subjects may have experienced more than 1 type of event.

## Significant adverse events

### Deaths/SUDEP

There were 7 deaths in the study, with no death directly attributed by the investigator to the implant or therapy. One death occurred in the Baseline Phase prior to device implant, one in the Unblinded Phase, and 5 during the Long-Term Follow-Up Phase. Of the 7 deaths, four were attributed to definite (2 subjects), probable (1), or possible (1: drowning) SUDEP. Non-SUDEP deaths were attributed to completed suicide, cardiorespiratory arrest, and liver cancer.

Table 15 shows the SUDEP rates inclusive of definite or probable SUDEP determinations for the SANTÉ study and for the subjects who participated in the pilot studies. One probable SUDEP is not included in this table since it occurred during the Baseline Phase prior to device implant.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 30

{30}

**Table 15. Sudden unexplained death in epilepsy rate**

|  Source of Data | # of SUDEP^{a} | # of device years | SUDEP rate/1000 years | 95% Poisson Confidence Interval  |
| --- | --- | --- | --- | --- |
|  SANTÉ | 2 | 713 years | 2.8 /1000 years | [0.34, 10.13]  |
|  Pilot Follow-up^{b} | 0 | 76 years | 0 /1000 years | [0, 48.54]  |
|  Total | 2 | 789 years | 2.5 /1000 years | [0.31, 9.16]  |

$^{a}$ One probable SUDEP occurred during the Baseline Phase prior to device implant and is not included.

$^{b}$ Combined data from 3 pilot centers participating in the Brain Stimulation for Epilepsy Long-Term Follow-up study and 2 pilot centers not participating in the follow-up study.

### Intracranial hemorrhage

Intracranial hemorrhage events include those coded to MedDRA Preferred Terms of cerebral hemorrhage, hemorrhage intracranial, intraventricular hemorrhage, subdural hematoma, and post procedural hemorrhage. Eight intracranial hemorrhage events were reported in 8 of the 110 implanted subjects (7.3%). Six of the 8 events were categorized as device-related, corresponding to a device-related rate of 5.5%.

Of the 8 intracranial hemorrhage events, there was one SAE resulting in clinical manifestations reported in 1 subject (0.9%). This event was not device-related and was attributed to a head injury after 2 seizure-related falls. No surgical intervention was required and the event resolved without sequelae. The event occurred in the Long-Term Follow-Up Phase and was not related to a device implant or explant procedure.

Seven non-serious adverse events related to intracranial hemorrhage were reported in 7 subjects. None of these events resulted in clinical manifestations.

- Four of the events occurred during the Operative Phase and were radiologically detected after the initial implant procedure. Three of these 4 events were detected on the protocol-required postoperative MRI, and 1 was detected on a CT scan performed after a subject had worsening of seizures the day of implant. These 4 events resolved without sequelae.
- Three of the events occurred during the Long-Term Follow-Up Phase. One was noted on a postoperative MRI following device explant. This event resolved without sequelae. A second event was discovered on a CT scan that was performed after the subject experienced a seizure-related fall that occurred the same day following a complete system explant. The third event was discovered on postoperative CT scan following a complete system explant. The second and third events were both asymptomatic and subjects did not have imaging to confirm resolution at the time of discontinuation from the study.

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 31

{31}

### Device-related infection

A total of 13 SAEs of implant site infection were reported in 12 subjects (10.9%). Serious adverse events of implant site infection occurred at the neurostimulator pocket (6), lead-extension tract (5), and burr hole site (2). None of the infections were in the brain parenchyma. One event was mild in severity, 4 were moderate, and 8 were severe.

All implant site infections were treated with oral or intravenous antibiotics with or without wound drainage or debridement.

Nine subjects (8.2%) required partial or complete system explant. The device components were subsequently replaced in 3 of the 9 explanted subjects.

### Adverse events by study phase

#### Adverse events in the Operative Phase

Table 16 summarizes the 29 SAEs that occurred in 23 subjects (20.9%) during the Operative Phase. Of the 29 events, 25 were device-related in 22 subjects (20.0%). The most frequent serious adverse events during the Operative Phase were lead(s) not in target (8.2%) and implant site infection (3.6%). Fourteen leads were replaced in 9 subjects due to the lead not being placed within the targeted area as required by the protocol. The majority of subjects with a lead not within target were in the first half of implanted subjects (7/55). The incidence of lead not within target decreased in the last half of implanted subjects (2/55). Four subjects had a SAE of implant site infection, 3 requiring partial or complete system explant. No serious adverse events related to intracranial hemorrhage occurred in the Operative Phase.

Table 17 lists the device-related adverse events that occurred in ≥2.5% of subjects during the Operative Phase.

Table 18 lists all the adverse events that occurred in ≥2.5% of subjects during the Operative Phase.

**Table 16. Serious adverse events during the Operative Phase**

|  Preferred Term | No. of SAEs | Subjects (%) with SAE (n=110) ^{a}  |
| --- | --- | --- |
|  Lead(s) not within target | 12 | 9 (8.2%)  |
|  Implant site infection | 4 | 4 (3.6%)  |
|  Post procedural pain | 2 | 2 (1.8%)  |
|  Postoperative fever | 2 | 2 (1.8%)  |
|  Vomiting | 2 | 2 (1.8%)  |
|  Complex partial seizures | 1 | 1 (0.9%)  |
|  Partial seizures with secondary generalization | 1 | 1 (0.9%)  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 32

{32}

|  Preferred Term | No. of SAEs | Subjects (%) with SAE (n=110) ^{a}  |
| --- | --- | --- |
|  Pyrexia | 1 | 1 (0.9%)  |
|  Status epilepticus | 1 | 1 (0.9%)  |
|  Set screws not adequately secured | 1 | 1 (0.9%)  |
|  Urosepsis | 1 | 1 (0.9%)  |
|  Wound drainage | 1 | 1 (0.9%)  |
|  **Total** | **29** | **23 (20.9%)**  |

$^{a}$ Column may not add to total as subjects may have experienced more than 1 type of event.

**Table 17. Device-related events occurring in ≥ 2.5% of subjects during the Operative Phase**

|  Preferred Term | Subjects (%) with an Event (n=110)  |
| --- | --- |
|  Lead(s) not within target | 9 (8.2%)  |
|  Implant site pain | 8 (7.3%)  |
|  Post procedural pain | 7 (6.4%)  |
|  Implant site infection | 5 (4.5%)  |
|  Postoperative fever | 5 (4.5%)  |
|  Hypoaesthesia | 3 (2.7%)  |
|  Procedural complication | 3 (2.7%)  |
|  Vomiting | 3 (2.7%)  |

**Table 18. Adverse events occurring in ≥ 2.5% of subjects during the Operative Phase**

|  Preferred Term | Subjects (%) with an Event (n=110)  |
| --- | --- |
|  Lead(s) not within target | 9 (8.2%)  |
|  Implant site pain | 8 (7.3%)  |
|  Headache | 7 (6.4%)  |
|  Post procedural pain | 7 (6.4%)  |
|  Anticonvulsant toxicity | 5 (4.5%)  |
|  Implant site infection | 5 (4.5%)  |
|  Postoperative fever | 5 (4.5%)  |
|  Head injury | 4 (3.6%)  |
|  Contusion | 3 (2.7%)  |
|  Drug toxicity | 3 (2.7%)  |
|  Hypoaesthesia | 3 (2.7%)  |
|  Procedural complication | 3 (2.7%)  |
|  Simple partial seizures | 3 (2.7%)  |
|  Vomiting | 3 (2.7%)  |

The following events each occurred in 2 subjects: agitation, depression, dermatitis contact, documented hypersensitivity to administered drug, excoriation, implant site inflammation, incision site complication, injury, memory impairment, nasopharyngitis, pain in extremity, paraesthesia, pruritus, status epilepticus, tinnitus, and tremor.

The following events each occurred in 1 subject: anticonvulsant drug level decreased, anxiety, arthralgia, arthropod bite, asthenia, blister, blood magnesium

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 33

{33}

decreased, blood pressure increased, cerumen impaction, chest wall pain, chills, complex partial seizures, constipation, coordination abnormal, decreased appetite, deja vu, dizziness, dural tear, dyspnea, ecchymosis, extension fracture, face oedema, fatigue, gait disturbance, gastroenteritis viral, hemorrhage intracranial, hypoacusis, hyponatraemia, implant site effusion, implant site oedema, implant site scar, implant site swelling, incision site hemorrhage, influenza, insomnia, intraventricular hemorrhage, irritability, laceration, lead fracture, lead migration/dislodgment, musculoskeletal stiffness, nasal congestion, nausea, neck pain, onychomycosis, partial seizures with secondary generalization, peroneal muscular atrophy, pharyngolaryngeal pain, post procedural complication, post procedural drainage, post procedural hemorrhage, pyrexia, seasonal allergy, sensory disturbance, set screws not adequately secured, shoulder pain, sinusitis, skin infection, skin laceration, subdural hematoma, syncope vasovagal, tachycardia, thermal burn, urosepsis, visual disturbance, vocal cord disorder, wound dehiscence, and wound drainage.

### Adverse events in the Blinded Phase

Table 19 lists the serious adverse events by treatment group that occurred during the Blinded Phase. A total of 8 SAEs were reported: 2 in the active group and 6 in the control group. There were no statistically significant differences between groups in the rates of any individual serious adverse event.

Table 20 lists the device-related adverse events that occurred in ≥2.5% of subjects (in one or both treatment groups) during the Blinded Phase.

Table 21 presents adverse events occurring in ≥2.5% of subjects (in one or both treatment groups) during the Blinded Phase. Statistically significant differences between active and control groups were noted for depression and memory impairment (p<0.05). Depression and memory impairment are discussed in the Neuropsychological tests and adverse events section.

Table 19. Serious adverse events by treatment group during the Blinded Phase

|  Preferred Term | Active (n=54) | Control (n=55)  |
| --- | --- | --- |
|   |  Subjects (%) with SAE | Subjects (%) with SAE  |
|  Implant site infection | . | 2 (3.6%)  |
|  Complex partial seizures | . | 1 (1.8%)  |
|  Depression | 1 (1.9%) | .  |
|  Partial seizures with secondary generalization | . | 1 (1.8%)  |
|  Anxiety | . | 1 (1.8%)  |
|  Muscle contractions involuntary | . | 1 (1.8%)  |
|  Status epilepticus | 1 (1.9%) | .  |
|  Total | 2 (3.7%) | 6 (10.9%)  |

PMA P960009/S219: FDA Summary of Safety and Effectiveness Data

Page 34

{34}

**Ta…

---

**Source:** [https://fda-staging.innolitics.com/device/P960009S219](https://fda-staging.innolitics.com/device/P960009S219)

**Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact).

**Cite:** Innolitics at https://innolitics.com