BRIO NEUROSTIMULATION SYSTEM

P140009 · ABBOTT MEDICAL · MHY · Jun 12, 2015 · Neurology

Device Facts

• Record ID: P140009
• Device Name: BRIO NEUROSTIMULATION SYSTEM
• Applicant: ABBOTT MEDICAL
• Product Code: MHY · Neurology
• Decision Date: Jun 12, 2015
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The St. Jude Medical (SJM) Deep Brain Stimulation (DBS) system is indicated for the following conditions: - Bilateral stimulation of the subthalamic nucleus (STN) as an adjunctive therapy to reduce some of the symptoms of advanced levodopa-responsive Parkinson’s disease that are not adequately controlled by medications. - Unilateral or bilateral stimulation of the ventral intermediate nucleus (VIM) of the thalamus for the suppression of disabling upper extremity tremor in adult essential tremor patients whose tremor is not adequately controlled by medications and where the tremor constitutes a significant functional disability.

Device Story

System delivers low-intensity electrical pulses to brain targets (STN or VIM) to treat Parkinsonian symptoms or essential tremor; consists of implantable pulse generator (IPG), leads, extensions, patient programmer, and external charger. IPG implanted in subcutaneous pocket; leads placed in brain via neurosurgery. Clinician uses programmer to set stimulation parameters (amplitude, pulse width, frequency); patient uses programmer to adjust amplitude or toggle stimulation. Constant current pulses travel from IPG through extensions/leads to electrodes. Therapy reduces motor symptoms/tremor, potentially improving patient function and quality of life. System requires periodic recharging via external antenna.

Clinical Evidence

Two pivotal studies: Parkinson's (n=136, prospective, randomized, controlled) and Essential Tremor (n=127, prospective, open-label). Parkinson's primary endpoint: change in 'on time' without dyskinesia at 90 days (p=0.003). Essential Tremor primary endpoint: postural tremor score reduction at 180 days (p<0.001). Safety data included adverse event rates, serious adverse events (infections, intracranial hemorrhage, stroke, death), and device revisions. Neuropsychological testing performed for both cohorts.

Technological Characteristics

16-channel rechargeable IPG in titanium case; 4-electrode leads (90% Platinum/10% Iridium); constant current stimulation; frequency 2-240Hz; pulse width 50-500μS; amplitude up to 12.75mA. Connectivity via RF telemetry. Sterilization: 100% ethylene oxide. Standards: ISO 14708-1, ISO 14708-3, ISO 10993, ANSI/AAMI NS 14.

Indications for Use

Indicated for adults with advanced levodopa-responsive Parkinson’s disease (symptoms not controlled by meds) or disabling upper extremity essential tremor (not controlled by meds). Contraindicated for patients unable to operate the system, those with unsuccessful test stimulation, or those requiring diathermy, electroshock therapy, or TMS.

Reference Devices

• Activa PC Deep Brain Neurostimulation System
• Activa RC Deep Brain Neurostimulation System
• Activa SC Deep Brain Neurostimulation System
• Eon Mini IPG (P010032/S023 and P010032/S066)

Submission Summary (Full Text)

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PMA P140009: FDA Summary of Safety and Effectiveness Data

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA

## I. GENERAL INFORMATION

Device generic name: Stimulator, Electrical, Implanted, For Parkinsonian Tremor

Device trade name: Brio Neurostimulation System

Device Procode: MHY

Applicant’s name and address: St. Jude Medical
6901 Preston Road
Plano, Texas, 75024

Date of Panel recommendation: None

Premarket Approval Application (PMA) Number: P140009

Date of FDA notice of approval: June 12, 2015

## II. INDICATIONS FOR USE

The St. Jude Medical (SJM) Deep Brain Stimulation (DBS) system is indicated for the following conditions:

- Bilateral stimulation of the subthalamic nucleus (STN) as an adjunctive therapy to reduce some of the symptoms of advanced levodopa-responsive Parkinson’s disease that are not adequately controlled by medications.
- Unilateral or bilateral stimulation of the ventral intermediate nucleus (VIM) of the thalamus for the suppression of disabling upper extremity tremor in adult essential tremor patients whose tremor is not adequately controlled by medications and where the tremor constitutes a significant functional disability.

## III. CONTRAINDICATIONS

This system is contraindicated for patients who:

- are unable to operate the system.
- test stimulation is unsuccessful

The following procedures are contraindicated for patients with a deep brain stimulation system. Advise patients to inform their healthcare professional that they cannot undergo the following procedures:

- Diathermy (short-wave diathermy, microwave diathermy, or therapeutic ultrasound diathermy)
- Electroshock therapy and transcranial magnetic stimulation (TMS)

## IV. WARNINGS AND PRECAUTIONS

Please refer to the device labeling for a list of warnings and precautions.

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# V. DEVICE DESCRIPTION

The St. Jude Medical Brio Neurostimulation System consists of:

1. A 16-channel, rechargeable, implantable pulse generator (IPG) (Brio IPG, Model 6789);
2. A patient programmer (Brio Patient Programmer, Model 6860);
3. An external charging system (Brio LE Charger, Model 6722); and
4. A lead kit (Models 6142, 6143, 6144, 6145, 6146, 6147, 6148, 6149) and extension kit (Models 6345 and 6346).

The Brio Neurostimulation System is a rechargeable system designed to deliver low-intensity electrical pulses to nerve/tissue in various combinations of amplitude, pulse width, and frequency. The electrical pulses travel from an IPG, through the leads and extensions, to electrodes near selected brain targets in order to provide therapeutic stimulation. The IPG is powered by a hermetically sealed battery within a titanium case. It uses microelectronic circuitry to generate constant current electrical stimulation.

Figure 1: The Brio Deep Brain NeuroStimulation System

# A. Implanted Components

Brio IPG, Model 6789

The Brio IPG Model 6789 is a programmable, 16 channel, rechargeable device that allows the connection of one or two leads with four electrodes. It is powered by a hermetically sealed battery within a titanium case. It uses microelectronic circuitry to generate constant current electrical stimulation. The Brio IPG is implanted in a subcutaneous pocket and receives near field telemetry communication via a wand connected to an external patient programmer. The Brio IPG stores programmed

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information and delivers stimulation pulses to a selected combination of output electrodes on the connected lead. The stimulation output parameters are listed in Table 1 below:

| Number of Programs | 1 |
| --- | --- |
| Number of Channels | 16 |
| Waveform | Charge Balanced Biphasic |
| Pulse Shape | Rectangular |
| Current or Voltage Regulated | Current |
| Maximum Current Amplitude @ 500 Ω | 12.75mA |
| Maximum Output Voltage @ 500 Ω | < 6.5V |
| Pulse Width | 50-500μS, 12.5μS steps |
| Frequency | 2-240Hz, 2Hz steps |
| Current Path Options | Unipolar or bipolar |

- DBS Leads, Model 6142, 6143, 6144, 6145, 6146, 6147, 6148, 6149

The DBS leads deliver electrical pulses to specific targets within the human brain. A DBS lead is comprised of four stimulating electrodes at its proximal end with edge-to-edge spacing defined to stimulate specific targets in the brain. Stranded conductor wires carry the current from the terminal end contacts to the stimulating electrodes. The conductor wires are further insulated and housed within a flexible sheath known as the lead body. The distal end of the lead contains 4 contacts that connect into the 4-channel extension.

Table 1: Stimulation Output Parameters

| | DBS Leads |
| --- | --- |
| Lead Length (cm) | 25, 30, 35, 40 |
| Lead Diameter (mm) | 1.4 |
| Number of Electrodes | 4 |
| Electrode Material | 90% Platinum/ 10% Iridium |
| Electrode Spacing (edge-to-edge) (mm) | 0.5 and 1.5 |
| Array Length (mm) | 6.5 or 10.5 |
| Electrode Surface Area (mm2) | 2.1 |
| Impedance (Ω) | 15.15 (average) |

Table 2: DBS Lead Specifications.

- DBS Extensions, Model 6345, 6346

The DBS extension physically and electrically connects the lead to the IPG and delivers electrical pulses from the IPG to the implanted lead. A typical DBS extension is comprised of contact electrodes at one end (distal end) and a connector assembly at the proximal end. The electrodes at the distal end are defined with edge-to-edge spacing to mate with electrical contacts of the DBS IPG header. Stranded conductor wires carry the current from the IPG to the lead. The conductor wires are further insulated and housed within a flexible sheath known as the lead body.

B. External Components

- Brio LE Charger, Model 6722

The battery charging system provides the capability to recharge the IPG battery while stimulation is either on or off. The charging system contains the following parts: AC line

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cord, AC power supply, power cable, charger, and charger antenna. The chargers transmit RF energy through the charger antenna to the IPG battery to recharge it.

- **Brio Patient Programmer, Model 6860**
The Brio Patient Programmer controls the creation and adjustment of all programming parameters for the Brio IPG. It is powered by three AAA batteries and communicates through the use of radio frequency signals from the programming wand to the implanted IPG. The programmer enables clinicians to create and modify programs for the IPG. It allows the patient the ability to adjust amplitude settings and turn the stimulation on and off. The shelf life of the patient programmer is 2 years.

Additionally the Brio Neurostimulation System includes the following accessories:
- A pocket sizer (used to check the IPG implant pocket);
- A torque wrench (used to tighten the setscrew on the connector assemblies of the IPG and extension) (Model 1101);
- Port plugs (used with the IPG to occupy unused lead ports in the header) (Model 1111);
- Lead stop (used to attach to the lead at a desired distance from the tip of the lead and set the depth of the implant) (Model 1140);
- Lead protection boot (protects the terminal end of the lead until the extension is attached) (Model 1149);
- Lead Stylet (Models 1143 and 1144);
- AAA battery pack (used to power the Patient Programmer) (Model 1254);
- Charger Accessory (Model 6720);
- AC power adapter and AC line cord (Models 3713 and 3714);
- Charger Antenna (Model 3717 and 3718);
- Programming Wand (used to program the IPG with stimulation parameters) (Model 1232); and
- Magnet (used turn on and off the IPG when the programming system is unavailable) (Model 1210).

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There is no cure for Parkinson’s disease (PD) and essential tremor (ET). Therefore, the first-line therapy treatment is medication. The standard medical therapy for PD is levodopa combined with a peripheral decarboxylase inhibitor, such as carbidopa. Other medical therapy may be used as an adjunct to levodopa to treat the multiple symptoms of PD. In patients with ET, both primidone and propranolol reduce the magnitude of upper extremity and postural tremor. Levodopa, anticholinergic medications, dopamine agonists, and beta-blockers such as propranolol are effective drugs for rest tremor. However, these medications come with a variety of side effects. For example, chronic levodopa use can result in disabling motor fluctuations that further impair the patient’s ability to function.

Surgical treatments are also available to PD and ET patients. Neurosurgical ablative procedures for the treatment of PD and ET are pallidotomy and thalamotomy. However, there is a risk of permanent neurological damage associated with the irreversible damage caused by these ablation procedures. The most disabling, permanent neurological complications reported include hemiparesis, dysarthria and dysphagia, and cognitive impairment.

Other Deep Brain Stimulation Devices are also currently marketed in the United States, these include: Activa® PC, Activa® RC, and Activa® SC Deep Brain Neurostimulation Systems.

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# VII. MARKETING HISTORY

The Brio Neurostimulation System including:
- Brio Implantable Pulse Generator (Model 6789);
- Brio Patient Programmer (Model 6860); and
- Brio LE Charger (Model 6722)

has not been marketed in any other country to date. However, the DBS Leads (Models 6142, 6143, 6144, 6145, 6146, 6147, 6148, 6149) and Extensions (Models 6345 and 6346) are CE marked and marketed in Europe since August 2008 for use in the indication of Parkinson’s Disease. Additionally, there is a version of the Brio IPG (Model 6788), and a Brio Patient Programmer (Model 6856) and Brio Clinician Programmer (Model 6851) that are CE marked and marketed in Europe.

# VIII. POTENTIAL ADVERSE DEVICE EFFECTS ON HEALTH

Deep brain stimulation potentially has the following adverse effects:

- Possible surgical complications. Surgical complications 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); ballism or hemiballism (uncontrollable movements on both or only one side of the 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); stroke and death.

- Possible deep brain stimulation complications. Deep brain stimulation complications 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
- Initial jolt or tingling during stimulation/Jolting or shocking sensation
- Infection
- Paresthesia
- 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

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- 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)
- Impaired wound healing (e.g., incision site drainage) or abscess formation
- Additional neurosurgical procedure to manage one of the above complications or to replace a malfunctioning component
- Stimulation-related complications or Other complications: Worsening of motor impairment and Parkinson’s Disease symptoms
- Rigidity (stiffness or inflexibility)
- Dyskinesia (fragmented or jerky movements)
- Worsening of motor fluctuations
- Tremor
- Abnormal gaitor incoordination
- Akinesia (absence of movement or freezing up)
- Bradykinesia (abnormally slow movement)
- Dysphagia (difficulty swallowing)
- Myoclonus (twitching or spasm of muscles)
- Neuropathy
- Neuralgia (acute nerve pain)
- Paresis (slight or partial paralysis)
- Hemiplegia (paralysis affecting one side of the body)
- Asthenia (lack or loss of strength)
- Ataxia (inability to coordinate voluntary muscular movements)
- Dystonia (involuntary distortions of trunk and limbs)
- Restless leg syndrome
- Disequilibrium
- Postural instability and/or increase in falls
- Headache
- Hearing and/or visual disturbances, including double vision, and loss or impairment of eye coordination
- Blepharospasm (involuntary eye winking)
- Eye apraxia (difficulty moving eye)
- Sensory deficit, including impairment of sensitivity/touch
- Supranuclear gaze palsy (gradual deterioration &amp; death of selected brain areas)
- Cognitive impairment, including confusion, disorientation, abnormal thinking, hallucinations, alteration of mentation, amnesia, delusions, dementia or inability to act or make decisions
- Long term memory impairment
- Attention deficit
- Aphasia or dysphagia (loss or impairment of power to use or comprehend words)
- Dysarthria (difficulty articulating words)
- Hypophonia (weak voice)
- Drowsiness and/or increased sleepiness
- Sleep disturbance

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- Psychiatric disturbances and/or mood changes
- Apathy (lack of feeling or emotion)
- Psychic akinesia (extreme passivity, apathy, &amp; loss of self-motivation)
- Anxiety
- Irritability and/or fatigue
- Mania or hypomania (mild state of mania)
- Psychosis (defective or loss of reality)
- Aggression
- Emotional lability (involuntary laughing or crying)
- Depression or depression with suicide attempt
- Hypersexuality or increased libido
- Nausea and/or vomiting
- Sweating
- Sialorrhea (increased salivation)
- Respiratory distress (e.g., difficulty breathing)
- Decreased therapeutic response
- Urinary incontinence or retention
- GI changes (e.g. Diarrhea, Constipation, Nausea or vomiting)
- Weight changes (loss or gain)
- Cardiac dysfunction (e.g. Hypotension, hypertension, heart rate changes, or syncope)
- Fever
- Hiccups
- Cough
- Cramps
- Worsening existing medical conditions

## IX. SUMMARY OF PRE-CLINICAL STUDIES

Verification testing was conducted to provide data to support the intended use of the device system. Testing was largely based on commonly recognized test methods and standards, such as International Standards Organization (ISO), European Standards (EN), and American Society of Testing and Materials (ASTM). All tests successfully met acceptance criteria per requirements.

## A. Brio IPG

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Electrical/ Leakage Current Verification and DC Imbalance | Verifies the magnitude of leakage currents and DC imbalance of the outputs of the IPG are within an acceptable range per ISO 14708-1: 2000 | • The IPG outputs are electrically isolated to meet section 16.2 of EN 45502-1/ISO 14708-1
• The IPG stimulation outputs are DC balanced to meet section 3.2.3 of NS14 |
| Electrical/ Output Characterization | Verify proper output (amplitude, pulse width, frequency, etc.) and detection parameters of the IPG function are within specified tolerances | The IPG stimulation output parameters: amplitude, pulse width, and frequency are within the specified tolerances across specified temperature and loading levels. |
| Electrical/Hardware Characterization | Verifies the proper functioning of the IPG Hardware. Hardware Verification testing is intended to verify that requirements related to the Brio IPG circuitry have been met. | Internal IPG circuits function within their specified limits. |

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| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Mechanical/ Hardware Verification | Verifies the mechanical testing of the Brio IPG.
Testing included:
• Test 1 Weight
• Test 2 Operational Temperature/Implantation Environment
• Test 3 Drop Test
• Test 4 Vibration Test
• Test 5 Operating Pressure
• Test 6 Heat Generation During Use
• Test 7 Ultrasound
• Test 8 Radiopaque Identification
• Test 9 Connection retention Force
• Test 10 Silicone Header adhesion to titanium.
• Test 11 Temperature Shock | Testing demonstrated that all acceptance criteria was met. |
| Mechanical/ Hermeticity | Verifies Neurostimulator hermetic seal | Testing demonstrates that the hermetic seal has a leak rate no greater than 5 X 10^{-8} cc atm/sec during Helium Leak Testing |
| Electrical/Battery | • Battery Capacity Verification (Longevity).
• Battery Qualification Testing under normal and sever conditions
• Charge/Discharge Testing
• Transportation Testing | • The IPG battery provides the specified time between the stimulation shutdown voltage and EOL voltage.
• The IPG battery meets the specified shelf life.
• The IPG battery meets the applicable sections of UN Transport of Dangerous Goods testing ST/SG/AC.10/11 |
| Particulate Matter | Verify there is no unacceptable release of particulate matter when the device is used as intended | Per ISO 14708-3:2008 |
| Firmware/System Verification Testing | • Patient Programmer Functional Verification
• Program Creation, Selection, modification
• IPG and Patient Programmer Error Notification and Handling
• Stimulation Parameter Adjustment
• Magnet Use
• Stimulation Frequency Limitation
• Pulse Width Limitation
• Electrode Testing
• Program Ramp and Ramp Time
• Output Amplitude Testing
prevent Stimulation Amplitude exceeding NS14 limitations | All tests successfully met acceptance criteria per requirements, including:
• Programs successfully created by the programmer and saved to the generator.
• Program data successfully created and changed. Different programs function as the active program.
• Unsuccessful communication reports an error.
• System inter-stim set Frequency is within tolerance.
• Magnet turns stimulation on and off.
• Stimulation frequency, pulse width, and amplitude limits are met per ANSI/AAMI NS 14
• Each electrode functioned as either an anode, cathode, or off.
• System completed ramping within specification. |
| Firmware/ Communication Testing | • Patient Programmer and IPG Connection Testing
• IPG Device Information Testing
• Patient Programmer Host Control Mode
• Patient Programmer Cycle and Bolus Mode | All tests successfully met acceptance criteria per requirements, including:
• Programmer sends wake-up command to the generator. ACK received from the generator following a wake-up command upon power up.
• Programmer displays IPG model number, |

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Table 3: Brio IPG Verification Testing

# B. Brio Patient Programmer

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Patient Usability Validation | Validates the intended user population can effectively use the Brio Patient Programmer System | All tests successfully met acceptance criteria per requirements. Users completed the relevant tasks successfully, including regulating stimulation and checking IPG battery status. |
| Clinician Usability Validation | Validates that the intended user population (clinicians) can effectively use the Brio Patient Programmer System | All tests successfully met acceptance criteria per requirements, including: • meet or exceed the battery capacity and longevity requirements; • The ERI time period is within the required accuracy limits of 10 years • The system notifies the user that the IPG requires a recharge; • System prevents charging when certain limits are reached; • The CHGR and IPG communicate throughout the Effective Charging Zone • The CHGR batteries have sufficient capacity to provide at least one full charge to the IPG battery • The system visually and audibly indicates an IPG charging error and turns off IPG charging • IPG battery enters the EOL state and prevents charging when the voltage reaches limit |

Table 3: Brio IPG Verification Testing

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Patient Usability Validation | Validates the intended user population can effectively use the Brio Patient Programmer System | All tests successfully met acceptance criteria per requirements. Users completed the relevant tasks successfully, including regulating stimulation and checking IPG battery status. |
| Clinician Usability Validation | Validates that the intended user population (clinicians) can effectively use the Brio Patient Programmer System | All tests successfully met acceptance criteria per requirements. Users completed the relevant tasks successfully, including establishing communication with IPG, configuring leads and stimulation, reviewing and clearing charge density limit warning and checking impedance and battery status. |
| System Verification | Verifies that the Brio Patient Programmer complies with product requirements regarding • IPG functions • Programmer functions • Indicators • Error Handling • Stimulation Settings • Electrode Settings • Program Modes • Program Management | All tests successfully met acceptance criteria per requirements, including: • IPG Battery voltage level displayed appropriately. • Successful adjustment of amplitude and turning stimulation on or off. • Continuous charge limit indictor displays appropriately. • Attempted communication with an unsupported device reports an error. • Successful setting of frequency, pulse |

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Table 4: Brio Patient Programmer Verification Testing

# C. Brio LE Charger

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Patient Usability Validation | Validates the intended user population can effectively use the Brio LE Charger. | All tests successfully met acceptance criteria per requirements. Users completed the relevant tasks successfully, including reviewing labeling, connecting system components, charging the IPG and charging the charger. |
| IPG Temperature During Charging | To verify that the outer surface of the IPG will not exceed specific temperature and exposure times during normal operation. | All tests successfully met acceptance criteria per requirements, including: · IPG surface temperatures meet section 17 of ISO 14708-3 |
| Effective Charging Zone Testing | To verify proper communication within the effective charging zone. | All tests successfully met acceptance criteria per requirements, including: · The charger and IPG communicate / charge throughout the effective charging zone defined in an internal SJM diagram. |
| Indicator Testing | To verify that all visual and audible indicators function as expected during power up and to verify that charging and reduced charging indicators are activated according to specification. | All tests successfully met acceptance criteria per requirements, including: · Charger indicates the "charging" and "reduced charging" states within the specified times. |
| Overcharging | To verify proper functioning of indicators which notify user of a fully charged battery and the cessation of charging at this point. | All tests successfully met acceptance criteria per requirements, including: · Charger turns off charging energy and gives a user indication when the IPG battery is fully charged. |
| Charging Current Limit | To verify that the Brio LE Charger shall limit the charging current | All tests successfully met acceptance criteria per requirements, including: |

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Table 5: Brio LE Charger Verification Testing

D. DBS Leads and Extensions

| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| Mechanical Verification | To verify the following: • Use with various Brio System surgical accessories • Stylet Extraction • Lead Stop • Cannula Insertion • Lead trajectory • Electrical testing | All tests successfully met acceptance criteria per requirements, including: • Lead does not deviate from intended target. • Stylet removal below specification • No damage to lead after five insertion and removal cycles of the stylet. • Lead stop supports weight of lead • No damage to lead after five actuations of lead stop • Lead shall pass through insertion cannula without buckling • No damage to lead after 5 pass-through cycles of the cannula. • Lead remains within electrical specifications on drawing throughout testing. |
| Lead and Extension Flex Testing | To verify that the DBS Leads and Extensions conductors do not fatigue under flexural stressors. | All tests successfully met acceptance criteria per requirements, including: • Lead/Extension able to be coiled • Dry conductor resistance and leakage current specifications after flex testing • No damage to lead after flex cycling • No damage to extension after flex cycling |
| Lead and Extension Visibility Testing | To verify the visibility of the DBS leads and Extensions under x-ray/fluoroscopy | All tests successfully met acceptance criteria per requirements, including: • Visible when using x-ray fluoroscopy equipment. • When placed on a standard blue surgical drape and viewed at 18” under normal lighting conditions |
| Connector Assembly Lead Insertion/Extraction Force Testing | To verify insertion/extraction into boot and extension does not damage lead or extension. | All tests successfully met acceptance criteria per requirements, including: • Lead inserts into boot without buckling. • No damage to lead after five insertion and removal cycles into the lead boot. • Lead inserts into extension without buckling • No damage to lead or extension after five |

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| Test | Test Purpose | Acceptance Criteria |
| --- | --- | --- |
| | | insertion and removal cycles. |
| Connector Assembly Lead Fixation Testing | To verify connector lead fixation force. | All tests successfully met acceptance criteria per requirements, including: • Lead withstands tensile load and remains within electrical specifications. • Extension connector assembly must retain lead when exposed to a load and remain within electrical specifications. |
| Particulate Matter Testing | To verify that no unacceptable release of particulate matter when the lead is used as intended. | All tests successfully met acceptance criteria per requirements per ISO 14708-3 section 14.2. |

# E. Biocompatibility Testing

Biocompatibility of all patient-contacting components of the Brio Neurostimulation System was evaluated in accordance with ISO 10993-1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process. The Brio IPG, DBS Leads and Lead Extensions are considered permanent (&gt;30 days) implants with tissue/bone contact. Biocompatibility of the Brio IPG was demonstrated by leveraging testing previously conducted on the Eon Mini IPG (P010032/S023 and P010032/S066). Leveraging this testing information was appropriate because the Brio IPG is identical to the Eon Mini IPG in terms of the patient-contacting materials, manufacturing and sterilization processes. Biocompatibility testing was conducted on the Brio DBS Lead and the Lead extension and is summarized in Table 7 below. All biocompatibility studies were conducted on the finished, sterilized devices in compliance with Good Laboratory Practices (GLP), 21 CFR Part 58. All pre-specified test acceptance criteria were met and all tests passed. The Brio Neurostimulation System also contains other implantable component with prolonged (24 hours – 30 days) tissue/bone contact and the components with limited (≤24 hours) skin contact. These components are either the identical components used for the Eon Mini System or use the same materials used for the permanently implantable components of the Brio Neurostimulation System.

Table 6: DBS Leads and Extension Verification Testing

| Biological Effect (Applicable Standard) | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| DBS Lead and Lead Extensionsa | | | |
| Cytotoxicity (ISO 10993-5) | ISO MEM Elution Assay | Reactivity grade is not greater than mild reactivity (Grade 2) | PASS |
| Sensitization (ISO 10993-10) | ISO Guinea Pig Maximization Sensitization Test | Grades of <1 in the test group provided grades of <1 are observed on the control animals. (If grades of ≥1 are noted on the control animals, then the reactions of the test animals which exceed most severe control reaction are presumed to be due to sensitization). | PASS |
| Irritation/Intracutaneous Reactivity (ISO 10993-10) | ISO Intracutaneous Reactivity Test | The difference between the test article and the control mean score is ≤1.0. | PASS |
| DBS Lead | | | |
| Systemic Toxicity (ISO 10993-11) | ISO Acute Systemic Toxicity Test | None of the test animals show a significantly greater biological reaction than the animals treated with vehicle control. | PASS |
| | Materials Mediated Rabbit Pyrogen Test | No rabbit shows an individual rise in temperature of 0.5°C or more above the baseline temperature. | PASS |
| Genotoxicity (ISO 10993-3) | Bacterial Mutagenicity Reverse Mutation Assay | There is less than 2-fold increase in the number of revertants when compared to the | PASS |
| | | permanent (24 hours - 30 days) tissue/bone contact. The reaction rate of the test animals is 0.5% or more. | |

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| Biological Effect (Applicable Standard) | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| | (Ames Test) | solvent controls in strains TA98, TA100, and WP2uvrA and less than 3-fold increase in the number of revertants when compared to the solvent control in strains TA1535 and TA1537. | |
| | Mouse Lymphoma Assay | The test article produces fewer than 90 mutants per 10^6 clonable cells over the background level. | PASS |
| | In Vivo Mouse Bone Marrow Micronucleus Assay | There is no statistically significant increase in the number of micronucleated polychromatic erythrocytes (PCEs) in the test group as compared to the concurrent negative control. | PASS |
| Implantation (ISO 10993-6) | 13-Week Rabbit Subcutaneous Implantation Test | The test results are considered acceptable based on an overall interpretation of the degree of biocompatibility exhibited by the test article based on gross and microscopic analysis comparing test to control article (High density polyethylene), as well as clinical observations. | PASS |
| Combined Neuroimplantation/Chronic Toxicity Study (ISO 10993-6 and ISO 10993-11) | A 26-week intrathalamic implantation study was conducted in rats to assess potential neurotoxicity, local tissue responses as well as long-term systemic effects following implantation of the device. Implantation of the DBS lead was not found to produce any unexpected mortality, clinical observations, neurobehavioral deficits or changes in clinical pathology. Treatment-related microscopic changes observed in the brain occurred at a similar incidence and severity in animals of both sexes that received the DBS lead when compared to the animals that received the control device. The functional observational parameters and other clinical parameters were unaffected. | | |
| Carcinogenicity (ISO 10993-3) | Adequately assessed by chemical characterization and genotoxicity testing on the final device and referencing data in a device master file | | |

a The testing performed on the DBS Lead, the data in the device master file, and the biocompatibility data on an U.S. marketed device were leveraged for assessment of acute systemic toxicity, subchronic toxicity, genotoxicity, implantation, chronic toxicity, and carcinogenicity potential of the lead extension.

Table 7: Biocompatibility Test Data on the Brio DBS Lead and Lead Extension

# F. Sterilization

The Brio Neurostimulation System components that are provided sterile are terminally sterilized using a $100\%$ ethylene oxide (EO) sterilization cycle. Validation of the sterilization process demonstrates a Sterility Assurance Level (SAL) of $10^{-6}$ and is in compliance with ANSI/AAMI/ISO 11135-1:2007. Sterilization of health care products - Ethylene oxide - Part 1: Requirements for development, validation, and routine control of a sterilization process for medical devices. Sterilant residuals conform to the maximum allowable limits of EO) and Ethylene Chlorohydrin (ECH) residuals specified in ISO 10993-7: 2008. Biological Evaluation of Medical Devices - Part 7: Ethylene Oxide Sterilization Residuals. The product bacterial endotoxin limits for intrathecal devices was selected as $0.06~\mathrm{EU / mL}$ or not more than 2.15 EU/device and device implant limits were tested at 20 EU/device. These limits were verified using Limulus Amebocye Lysate (LAL) testing.

# G. Packaging and Shelf Life

Distribution Test was completed for the DBS Leads, DBS Extensions, IPG, Charger, Charger Accessories and Patient Programmer in accordance with ASTM D4169:2009. All acceptance criteria were met. The testing confirmed that the device packaging adequately protects the product during conditions that may be encountered during storage, shipping, and handling. The packaging design and testing of the packaging for the IPG, DBS Leads, and DBS Extensions complies with the requirements of BS EN ISO 11607-1:2009.

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Shelf Life for the IPG, Leads and Extensions has been established as two (2) years from the date of manufacturing.

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of the safety and effectiveness of deep brain stimulation (DBS) with the Libra device for the treatment of tremor due to essential tremor and as an adjunctive treatment for reducing some of the symptoms of advanced, levodopa-responsive Parkinson's disease that are not adequately controlled with medication in patients with Parkinson's disease in the US under IDE # G040051 and G040172 respectively. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical studies is presented below.

| Clinical Study | Study Design | Objective | Number of Sites | Number of Subjects |
| --- | --- | --- | --- | --- |
| Pivotal (Parkinson's disease) G040172 | Prospective, multi-center, randomized, controlled clinical study | Demonstrate the safety and effectiveness of the SJM Deep Brain Stimulation System providing bilateral stimulation to the Subthalamic Nucleus (STN) as an adjunctive treatment for reducing some of the symptoms of advanced, levodopa-responsive Parkinson's disease that are not adequately controlled with medication | 15 | 136 subjects implanted/1 subject did not complete the study |
| Pivotal (Essential Tremor) G040051 | Prospective, multi-centered clinical study | Demonstrate the safety and effectiveness of the SJM Deep Brain Stimulation System providing unilateral or bilateral stimulation to the ventral intermediate (VIM) nucleus of the thalamus implanted for the treatment of tremor due to essential tremor. | 12 | 127 subjects implanted/11 subjects did not complete the study |

Table 8: Description of Supporting Clinical Studies

## X.1 Parkinson's Disease Study:

### A. Parkinson's Disease Study Design

Patients were treated between October, 2005 and April, 2009. The database for this PMA reflected data collected through August, 2010 and included 136 patients. There were 15 investigational sites.

The study was a prospective, multi-center, randomized, controlled clinical study, which compared patients randomized to receive immediate as compared to delayed stimulation.

All patients in the trial were implanted. Patients who had a successful implant were randomized in a 3:1 ratio (Active Stimulation Group or delayed stimulation Control Group). Patients remained in their assigned randomization group for 90 days. After 90 days, all patients received stimulation. Patients were followed for one year. After one year, patients were consented to the Long Term Follow-Up Study where they continued follow-up for a total duration of 5 years post-implant.

The study was not blinded, i.e. both investigators and patients were aware of the treatment assignment. DBS was used as an adjunct to anti-Parkinsonian medications. Medication

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adjustments were made by the investigators at each site depending on the randomization assignment.

A Data Safety Monitoring Board (DSMB) was used to continuously review the adverse event data for entire study duration. The DSMB was designed to alert the Sponsor of any safety concerns or study execution concerns.

## B. Parkinson’s Disease Study Clinical Inclusion and Exclusion Criteria

Enrollment in the PD study was limited to patients who met the following selection criteria:

### Inclusion Criteria

1. Patient signed an informed consent;
2. Patient was 18 to 80 years of age;
3. Patient diagnosed with Parkinson’s disease for at least five (5) years according to standard practice;
4. Patient experienced six (6) hours or more of daily “non-on time” illustrated by a dyskinesia diary as off time or moderate to severe dyskinesias due to Parkinson’s disease (PD) during waking hours;
5. Patient had a history of improvement of Parkinson’s symptoms as a direct result of administering L-dopa to the patient with at least a 33% improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) motor score;
6. Patient was willing to maintain a constant dose of anti-Parkinson’s disease medication indicated as best medical management for at least one month prior to study enrollment;
7. Patients were available for appropriate follow-up times for the length of the study; and
8. Patients completed diary training and each patient’s diary response indicating their level of dyskinesia severity during training must agree with study personnel responses a minimum of 75% of the time.

### Exclusion Criteria

1. Patient was not a surgical candidate;
2. Patient had any major illness or medical condition that in the opinion of the physician would interfere with participation in the study;
3. Patient had untreated clinically significant depression;
4. Patient had an electrical or electromagnetic implant (e.g. cochlear prosthesis or pace maker);
5. Patient had any condition requiring repeated MRI scans;
6. Patient had any condition requiring diathermy;
7. Patients were on anticoagulant medications;
8. Patient had a prior surgical ablation procedure or any other previous neurosurgical procedure for the treatment of PD symptoms on either side of the brain;
9. Patient had dementia that interferes with their ability to co-operate or comply with study requirements or comprehend the informed consent as determined by the investigator;
10. Patient abused drugs or alcohol;
11. Patient had a history of cranial surgery;
12. Patients had a history of seizures;
13. Patient had any MRI non-compatible metallic implants that may interfere with the functioning of the device (e.g. aneurysm clips);
14. Patient had a history of stimulation intolerance in any area of the body;
15. Patient was a female that is lactating or of child bearing potential with a positive urine pregnancy test or not using adequate contraception; and
16. Patient was a participant in a drug, device, or biologics trial within the preceding 30 days;

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17. Patient had confirmation of diagnosis of a terminal illness associated with survival &lt; 12 months.

## C. Parkinson’s Disease Study Follow-Up Schedule

All study participants were screened according to the criteria listed above and all participants signed an informed consent prior to undergoing any study procedures. The baseline evaluations are shown in Table 9. Implantation was performed according to each individual site’s standard procedures. Implant assessments are shown in Table 9. Either one or two SJM IPG devices were implanted based on physician discretion. After all components of the system were implanted and prior to programming, patients were randomized to the Active Stimulation Group or the Control Group. Patients in the Active Stimulation Group were programmed to receive stimulation within 7 days after implant. Patients in the Control Group were not programmed to receive stimulation until after the 90 day follow-up visit assessment was complete. After the randomization visit, patients returned to clinic at 30 days, 90 days, 180 days and 365 days post implant. The assessments required at each visit are shown in Table Table 9.

| Procedures | Screening/Baseline | Implant | Randomization (Day 0) | Day 30 (± 7 d) | Day 90 (± 14 d) | Day 180 (± 30 d) | Day 365 (± 30 d) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Informed Consent | ✓ | | | | | | |
| Neuropsychological Exam | ✓ | | | | ✓ | | ✓ |
| History | ✓ | | | | | | |
| UPDRS | ✓ | | | | ✓ | ✓ | ✓ |
| Hoehn & Yahr Staging | ✓ | | | | ✓ | ✓ | ✓ |
| Schwab & England | ✓ | | | | ✓ | ✓ | ✓ |
| PDQ-39 | ✓ | | | | | ✓ | ✓ |
| Pittsburgh Quality Sleep Index | ✓ | | | | | ✓ | ✓ |
| Global Outcome Measure | ✓ | | | | ✓ | ✓ | ✓ |
| Dyskinesia Diary | | ✓ | | ✓ | ✓ | ✓ | ✓ |
| Implant Information | | ✓ | | | | | |
| Randomization | | | ✓ | | | | |
| Device Information | | | ✓ | | ✓ | ✓ | ✓ |
| Patient Satisfaction | | | | | | ✓ | ✓ |
| Adverse Events | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |

Table 9: Follow-up Schedule

## D. Clinical Endpoints

The safety endpoint compared the adverse event incidence rates between the Active Stimulation Group and the Control Group throughout the duration of the study.

The primary effectiveness endpoint was a comparison of the increase in the duration of “on time” without dyskinesias or with nonbothersome dyskinesias as demonstrated by the change in diary responses after 90 Days of stimulation with medication "on" compared to the control group. Nonbothersome dyskinesias were defined by the Hauser Dyskinesia Diary as “mild”, i.e. present but do not interfere with activities and daily functions.

The secondary effectiveness endpoints assessed at 90 days were a comparison of:

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- The percent of patients with an increase from baseline in “on time” without dyskinesias or with non-bothersome dyskinesias of at least 2 hours with medication "on";
- UPDRS motor scores in the medication “on” state;
- Activities of Daily Living from the UPDRS and Schwab England scale;
- Comparison of the Hoehn and Yahr Staging in the medication on state;
- Global outcome evaluations by both the patient and caregiver; and
- Rate of patient satisfaction.

Additional endpoints assessed at one year as compared to baseline include:
- Reduction in Parkinson’s symptoms as demonstrated by the UPDRS motor scores in the medication on state with stimulation on through one year compared to baseline medication on and off scores;
- Activities of Daily Living as determined from the UPDRS and Schwab England scale;
- Total UPDRS scores and each individual component of the UPDRS in the medication on and off state with stimulation;
- Quality of Life as measured by the PDQ 39;
- Pittsburgh Quality Sleep Index;
- Hoehn and Yahr Staging in the medication on and off, stimulation on state;
- Global outcome evaluations by the patient;
- Levodopa reduction over time; and
- Patient satisfaction.

## E. Parkinson’s Disease Study Pre-specified Statistical Analysis Plan

The primary hypothesis was a two-sided test of the difference in mean changes from baseline between the Active Stimulation Group and the delayed stimulation Control Group at 90 days post-implant. The primary analysis was a two-way analysis of covariance that included the effects of treatment, study center and baseline “on time”. The sample size of 136 was chosen to provide 80% power to detect a 3-hour difference in “on time” between treatment groups at the 0.05 level of significance. Missing data at 90 days were imputed by using data from the last available patient diary.

There was no prespecified method for multiplicity testing of the secondary endpoints. Therefore, 95% confidence intervals are provided for the secondary endpoints.

## F. Accountability of PMA Cohort

A total of one hundred sixty-eight (168) were enrolled at 15 investigational sites. A total of 136 patients were implanted with the Libra™ or LibraXP™ DBS System from October 2005 to April 2009. A total of 133 patients completed the 90 day visit for the primary endpoint analysis. A total of 135 patients completed the 12 month visit. A summary of the patient accounting is provided in Figure 2.

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Figure 2: Patient Accounting

# G. Parkinson's Disease Study Population Demographics and Baseline Parameters

A total of 136 patients were randomized in this study. The demographics of the study population are typical for a study evaluating Parkinson's disease patients in the United States.

| | Stimulation (N=101) | Control (N=35) | P-Value |
| --- | --- | --- | --- |
| Gender: n (%) | | | |
| Male | 63 (62.4%) | 21 (60.0%) | 0.803 |
| Female | 38 (37.6%) | 14 (40.0%) | |
| Race: n (%) | | | |
| Caucasian | 91 (90.1%) | 31 (88.6%) | 0.7551 |
| African American | 1 (1.0%) | 0 (0%) | |
| Hispanic | 8 (7.9%) | 3 (8.6%) | |
| Other | 1 (1.0%) | 1 (2.9%) | |
| Age(yr) | | | |
| Mean ± std | 60.6 ± 8.3 | 59.5 ± 8.2 | 0.519 |

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| Range | 41 – 78 | 41 – 76 | |
| --- | --- | --- | --- |
| Weight (lb) | | | |
| Mean ± std | 177.7 ± 40.0 | 164.9 ± 34.4 | 0.093 |
| Range | 95 – 298 | 98 – 226 | |
| Height (in) | | | |
| Mean ± std | 68.3 ± 4.4 | 67.4 ± 4.1 | 0.296 |
| Range | 59 – 79 | 62 – 76 | |
| Years since symptom onset | | | |
| Mean ± std | 12.1 ± 4.9 | 11.7 ± 4.1 | 0.684 |
| Range | 5 – 29 | 5 – 19 | |

Caucasian vs. non-Caucasian

The following stimulation parameters were used during the study.

Table 710: Demographic Summary

| Parameter | Initial Programming | One Year |
| --- | --- | --- |
| Left Side Pulse: | | |
| Mean | 72.5 | 74.0 |
| Median | 65 | 65 |
| Left Side Frequency | | |
| N | 101 | 133 |
| Mean | 147.9 | 151.5 |
| Median | 136.0 | 150.0 |
| Range | 100 – 200 | 40 – 200 |
| Left Side Amplitude | | |
| N | 101 | 133 |
| Mean | 1.55 | 2.31 |
| Median | 1.50 | 2.20 |
| Range | 0.2 – 5.0 | 0.5 – 5.0 |
| Right Side Pulse: | | |
| Mean | 72.4 | 74.3 |
| Median | 65 | 65 |
| Right Side Frequency | | |
| N | 101 | 133 |
| Mean | 147.3 | 151.1 |
| Median | 136.0 | 140.0 |
| Range | 100 – 210 | 40 – 202 |
| Right Side Amplitude | | |
| N | 101 | 133 |
| Mean | 1.40 | 2.32 |
| Median | 1.30 | 2.00 |
| Range | 0.05 – 4.0 | 0.5 – 4.5 |

Table 11: Programming Parameters Initially and at One Year

# H. Parkinson's Disease Study Safety Results

The analysis of safety was based on the 136 patients implanted in the trial. The safety profile was based on a comparison of adverse events that occurred during the randomized phase as well as a comparison of all adverse events that occurred through the last follow-up visit. The Data Safety Monitoring Board used their previous experience, knowledge of the literature, comments from the site and information from the clinical research staff to evaluate each event and classify them into the categories listed in the tables.

Patients were randomized in a 3:1 ratio to the stimulation or control groups. $58.4\%$ (59/101) of the subjects in the stimulation group had a total of 144 adverse events and $45.7\%$ (16/35) of the subjects in the control group had a total of 25 adverse events. (Table 12). There were no

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significant differences between the occurrence of adverse events in the Stimulation Group compared to the Control Group between implant and 90 days.

| Adverse Event | Stimulation (N=101) n (%) | Control (N=35) n (%) | P Value* |
| --- | --- | --- | --- |
| Number with at least 1 AE | 59 (58.4%) | 16 (45.7%) | 0.238 |
| Gait disorder including balance problem | 14 (13.9%) | 1 (2.9%) | 0.115 |
| Dysarthria | 9 (8.9%) | 0 (0.0%) | 0.111 |
| Edema | 7 (6.9%) | 0 (0.0%) | 0.190 |
| Disequilibrium | 5 (5.0%) | 1 (2.9%) | 1.0 |
| Dyskinesias | 5 (5.0%) | 1 (2.9%) | 1.0 |
| Infection | 5 (5.0%) | 1 (2.9%) | 1.0 |
| Post operative pain, stress, or discomfort | 6 (5.9%) | 0 (0.0%) | 0.338 |
| Anxiety | 4 (4.0%) | 1 (2.9%) | 1.0 |
| Confusion | 4 (4.0%) | 1 (2.9%) | 1.0 |
| Depression | 4 (4.0%) | 0 (0.0%) | 0.572 |
| Headache | 4 (4.0%) | 1 (2.9%) | 1.0 |
| Intracranial Hemorrhage | 4 (4.0%) | 1 (2.9%) | 1.0 |
| Paresthesia | 4 (4.0%) | 0 (0.0%) | 0.572 |
| Dysphasia | 3 (3.0 %) | 1 (2.9%) | 1.0 |
| Lead migration | 3 (3.0 %) | 0 (0.0%) | 0.569 |
| Psychiatric changes/disturbance | 3 (3.0 %) | 0 (0.0%) | 0.569 |
| Sleep disturbances | 3 (3.0 %) | 0 (0.0%) | 0.569 |
| Subcutaneous hemorrhage or seroma | 3 (3.0 %) | 1 (2.9%) | 1.0 |
| Asthenia | 2 (2.0%) | 0 (0.0%) | 1.0 |
| Rigidity | 2 (2.0%) | 0 (0.0%) | 1.0 |
| Seizure or convulsions | 2 (2.0%) | 0 (0.0%) | 1.0 |
| Tremor | 2 (2.0%) | 1 (2.9%) | 1.0 |
| Cerebrospinal fluid leakage | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Diarrhea | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Dystonia | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Hallucinations | 1 (1.0%) | 1 (2.9%) | 0.450 |
| Hearing disturbances | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Increased salivation | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Jolting or shocking sensations | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Lead fracture | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Motor fluctuations | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Nausea | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Persistent pain at IPG site | 1 (1.0%) | 1 (2.9%) | 0.450 |
| Visual disturbances | 1 (1.0%) | 0 (0.0%) | 1.0 |
| Abnormal thinking | 0 (0.0%) | 1 (2.9%) | 0.257 |
| Dementia | 0 (0.0%) | 1 (2.9%) | 0.257 |

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Table 12: Summary of the First Occurrence of All Adverse Events During the First 90 Days

| Pneumonia | 0 (0.0%) | 1 (2.9%) | 0.257 |
| --- | --- | --- | --- |
| Vomiting | 0 (0.0%) | 1 (2.9%) | 0.257 |
| Other | 34 | 8 | * |
| Total AEs | 144 | 25 | ** |

*No p-value is included since the event types are mixed.
**Fisher's Exact Test used to compute P-values

A total of 18 patients, $13.9\%$ (14/101) in the stimulation group and $11.4\%$ (4/35) in the control group experienced a serious adverse event during the first 90 days (Table 13). There were a total of 18 SAEs in the stimulation group and 7 in the control group.

Table 13: Summary of the First Occurrence of Serious Adverse Events During the First 90 Days

| Serious Adverse Event | Stimulation (N=101) n (%) | Control (N=35) n (%) | P-Value |
| --- | --- | --- | --- |
| Number with at least 1 SAE | 14 (13.9%) | 4 (11.4%) | 1.0 |
| Intracranial Hemorrhage | 3 (3.0%) | 1 (2.9%) | 1.0 |
| Infection | 2 (2.0%) | 1 (2.9%) | 1.0 |
| Lead migration | 2 (2.0%) | 0 (0%) | 1.0 |
| Motor fluctuations | 1 (1.0%) | 0 (0%) | 1.0 |
| Cerebrospinal fluid leakage | 1 (1.0%) | 0 (0%) | 1.0 |
| Confusion | 1 (1.0%) | 0 (0%) | 1.0 |
| Gait disorder including balance problems | 1 (1.0%) | 0 (0%) | 1.0 |
| Lead fracture | 1 (1.0%) | 0 (0%) | 1.0 |
| Pneumonia | 0 (0%) | 1 (2.9%) | 0.257 |
| Seizure or convulsions | 1 (1.0%) | 0 (0%) | 1.0 |
| Tremor | 1 (1.0%) | 0 (0%) | 1.0 |
| Other | 4 (4.0%) | 4 (11.4%) | 0.204 |
| Total SAEs | 18 | 7 | * |

*No p-value is included since the event types are mixed.

107 patients $(78.7\%)$ experienced a total of 409 adverse events during the first year of the study.

Table 10: Summary of the First Occurrence of Serious Adverse Events During the First 90 Days

| Adverse events | AEs | SAE | Number of patients | Incidence Rate |
| --- | --- | --- | --- | --- |
| Total AEs | 359 | 50 | 107 | |
| | | | | |
| Accidental event | 22 | 4 | 22 | 16.2% |
| Car Accident | 1 | | 1 | 0.7% |
| Single event (Fall/Slip/Trip) | 13 | 1* | 12 | 9.5% |
| Fracture/dislocation/stitches/hit on head/injured finger | 8 | 3* | 11 | 8.1% |
| Disease Progression | 6 | | 6 | 4.4% |
| Gait disorder including balance problems | 4 | | 4 | 2.9% |
| Worsened Parkinson's disease | 1 | | 1 | 0.7% |
| Motor fluctuations | 1 | | 1 | 0.7% |
| General | 38 | | 28 | 20.6% |
| Headache | 5 | | 5 | 3.7% |
| Nausea/Vomiting | 5 | | 4 | 2.9% |
| Weight gain/loss | 4 | | 4 | 2.9% |
| Edema | 2 | | 2 | 1.5% |
| Gait disorder including balance problems | 1 | | 1 | 0.7% |
| Sweating | 1 | | 1 | 0.7% |
| Other (pain/cramps (9), erectile dysfunction constipation, fever, weakness (3), fatigue (2), difficulty turning in bed, leg extra movement, and lightheadedness) | 20 | | 17 | 12.5% |

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| Adverse events | AEs | SAE | Number of patients | Incidence Rate |
| --- | --- | --- | --- | --- |
| Hardware related | 10 | 4 | 13 | 9.6% |
| Extension Malfunction | 4 | | 4 | 2.9% |
| IPG Malfunction | 2 | 1 | 3 | 2.2% |
| Jolting or shocking sensations | 2 | | 2 | 1.5% |
| Lead Migration | 1 | 1 | 2 | 1.5% |
| Erosion | 0 | 1 | 1 | 0.7% |
| Lead Malfunction(lead break due to blow on the head) | 0 | 1 | 1 | 0.7% |
| Pain at connection | 1 | | 1 | 0.7% |
| Medication related | 27 | | 18 | 13.2% |
| Edema | 5 | | 4 | 2.9% |
| Sleep disturbances | 4 | | 4 | 2.9% |
| Confusion | 2 | | 1 | 0.7% |
| Gait disorder including balance problems | 2 | | 1 | 0.7% |
| Increased salivation | 2 | | 2 | 1.5% |
| Jolting or shocking sensations (Tingling in foot at night) | 1 | | 1 | 0.7% |
| Anxiety | 1 | | 1 | 0.7% |
| Diarrhea | 1 | | 1 | 0.7% |
| Disequilibrium | 1 | | 1 | 0.7% |
| Dystonia | 1 | | 1 | 0.7% |
| Hallucinations | 1 | | 1 | 0.7% |
| Motor fluctuations | 1 | | 1 | 0.7% |
| Tremor | 1 | | 1 | 0.7% |
| Psychiatric changes/disturbances | 1 | | 1 | 0.7% |
| Other (Erectile dysfunction, fatigue, and facial swelling) | 3 | | 3 | 2.2% |
| PD Symptoms | 36 | 3 | 29 | 21.3% |
| Gait disorder including balance problems | 5 | 2 | 7 | 5.1% |
| Dysarthria | 7 | | 7 | 5.1% |
| Sleep disturbances | 4 | | 4 | 2.9% |
| Asthenia | 2 | | 2 | 1.5% |
| Disequilibrium | 2 | | 2 | 1.5% |
| Dysphagia | 2 | | 2 | 1.5% |
| Dystonia | 2 | | 2 | 1.5% |
| Amnesia | 1 | | 1 | 0.7% |
| Bradykinesia | 1 | | 1 | 0.7% |
| Depression | 1 | | 1 | 0.7% |
| Dyskinesias | 1 | | 1 | 0.7% |
| Rigidity | 1 | | 1 | 0.7% |
| Other (pain (2), coughing, hypotension (2), worsening of PD features, torn rotator cuff, and leg “gives out”) | 7 | 1* | 6 | 4.4% |
| Pre-Existing Event | 4 | 1 | 5 | 3.7% |
| Pain | 1 | 1 | 2 | 1.5% |
| Anxiety | 1 | | 1 | 0.7% |
| Difficulty breathing | 1 | | 1 | 0.7% |
| Sleep Apnea | 1 | | 1 | 0.7% |
| Pre-Existing Event – Worsened | 18 | 1 | 18 | 13.2% |
| Depression | 10 | 1 | 10 | 7.4% |
| Hallucinations | 3 | | 3 | 2.2% |
| Anxiety | 1 | | 1 | 0.7% |
| Gait disorder including balance problems | 1 | | 1 | 0.7% |
| Psychiatric changes/disturbances | 1 | | 1 | 0.7% |
| Seizure or convulsions | 1 | | 1 | 0.7% |
| Other (increased stuttering) | 1 | | 1 | 0.7% |
| Stimulation related | 32 | | 21 | 15.4% |
| Dysarthria | 7 | | 6 | 4.4% |
| Disequilibrium | 3 | | 3 | 2.2% |
| Gait disorder including balance problems | 3 | | 2 | 1.5% |
| Paresthesia | 3 | | 3 | 2.2% |

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| Adverse events | AEs | SAE | Number of patients | Incidence Rate |
| --- | --- | --- | --- | --- |
| Anxiety | 2 | | 2 | 1.5% |
| Dysphasia | 2 | | 2 | 1.5% |
| Post operative pain, stress, or discomfort | 2 | | 2 | 1.5% |
| Psychiatric changes/disturbances | 2 | | 2 | 1.5% |
| Confusion | 1 | | 1 | 0.7% |
| Depression | 1 | | 1 | 0.7% |
| Dystonia | 1 | | 1 | 0.7% |
| Dyskinesias | 1 | | 1 | 0.7% |
| Edema | 1 | | 1 | 0.7% |
| Hearing disturbances | 1 | | 1 | 0.7% |
| Increase salivation | 1 | | 1 | 0.7% |
| Jolting or shocking sensations | 1 | | 1 | 0.7% |
| Surgery related | 44 | 16 | 37 | 27.2% |
| Infection | 4 | 5 | 7 | 5.1% |
| Confusion | 4 | 1 | 5 | 3.7% |
| Intracranial hemorrhage | 1 | 4 | 5 | 3.7% |
| Edema | 3 | | 3 | 2.2% |
| Subcutaneous hemorrhage or seroma | 3 | | 3 | 2.2% |
| Anxiety | 2 | | 2 | 1.5% |
| Dysphasia | 2 | | 2 | 1.5% |
| Headache | 2 | | 2 | 1.5% |
| Persistent pain at device site | 2 | | 2 | 1.5% |
| Post operative pain, stress, or discomfort | 2 | | 2 | 1.5% |
| Psychiatric changes/disturbances | 2 | | 2 | 1.5% |
| Seizure or convulsions | 1 | 1 | 2 | 1.5% |
| Abnormal thinking | 1 | | 1 | 0.7% |
| Apathy | 1 | | 1 | 0.7% |
| Cerebrospinal fluid leakage | 0 | 1 | 1 | 0.7% |
| Dementia | 1 | | 1 | 0.7% |
| Disequilibrium | 1 | | 1 | 0.7% |
| Dysarthria | 1 | | 1 | 0.7% |
| Gait disorder including balance problems | 1 | | 1 | 0.7% |
| Hallucinations | 1 | | 1 | 0.7% |
| Lead Migration | 0 | 1 | 1 | 0.7% |
| Paresthesia | 1 | | 1 | 0.7% |
| Pneumonia | 0 | 1 | 1 | 0.7% |
| Tremor | 1 | | 1 | 0.7% |
| Visual disturbances | 1 | | 1 | 0.7% |
| Other (fatigue (2), numbness, increase somnolence, dysphagia, urosepsis, urinary retention, and DVT) | 6 | 2 | 6 | 4.4% |
| Titration related | 35 | 2 | 22 | 16.2% |
| Dyskinesias | 10 | | 7 | 5.1% |
| Dysphasia | 1 | | 1 | 0.7% |
| Gait disorder including balance problems | 7 | | 7 | |
| Rigidity | 2 | | 2 | 1.5% |
| Disequilibrium | 1 | | 1 | 0.7% |
| Dysarthria | 2 | | 2 | 1.5% |
| Motor fluctuations | 0 | 1 | 1 | 0.7% |
| Dystonia | 1 | | 1 | 0.7% |
| Paresthesia | 1 | | 1 | 0.7% |
| Psychiatric changes/disturbances | 2 | | 2 | 1.5% |
| Sleep disturbances | 2 | | 2 | 1.5% |
| Other (foot drop, fatigue (2), increased PD symptoms, increased freezing, symptomatic orthostasis, and pain) | 6 | 1 | 7 | 5.1% |
| Unable to Determine | 13 | 1 | 9 | 6.6% |
| Depression | 4 | | 4 | 2.9% |
| Disequilibrium | 2 | | 1 | 0.7% |

{23}

| Adverse events | AEs | SAE | Number of patients | Incidence Rate |
| --- | --- | --- | --- | --- |
| Hallucinations | 1 | | 1 | 0.7% |
| Psychiatric changes/disturbances | 0 | 1 | 1 | 0.7% |
| Other (dry mouth (2), illusion, pressure ulcer, sores, and weakness) | 6 | | 3 | 2.2% |
| Unrelated event | 74 | 18 | 53 | |
| Anxiety | 1 | | 1 | 0.7% |
| Disequilibrium | 1 | | 1 | 0.7% |
| Edema | 1 | | 1 | 0.7% |
| Hearing disturbance | 1 | | 1 | 0.7% |
| Infection | 0 | 1 | 1 | 0.7% |
| Paresthesia | 2 | | 2 | 1.5% |
| Pneumonia | 1 | | 1 | 0.7% |
| Urinary incontinence | 1 | | 1 | 0.7% |
| Tremor | 0 | 1 | 1 | 0.7% |
| Other (pain (2/17 SAE), arthritis (1/2 SAE), prostate enlarged, diagnosed with cancer (1/3 SAE), Flu/cold/URI (5), cyst, UTI (3/10 SAE), bruising, low platelets, hair texture change, photophobia, Bronchitis (2), elevated cholesterol, diverticulitis, anemia, infection in mouth, hernia repair, atrial flutter, teeth breaking (2), noise, sciatica (3), cervical myelopathy, spinal stenosis, congestive heart failure, cholecystitis, hip surgery, fatigue, hospitalization to rule out stroke, wrist surgery (2), carpal tunnel, coughing, dermatitis, phlebitis, torn muscle, gastroparesis, rotator cuff repair, open eustachian tube, shoulder surgery, abdominal mass, PICC blockage, diabetes, conversion of left foot, neck sprain, tachycardia, and over active bladder | 66 | 16 | 48 | 35.3% |

# Device revisions

The following table provides a summary of device revisions through one year. In addition to the revisions, one patient was explanted.

Table 14: Frequency of All Adverse Events During 1 Year Study by DSMB Classification (All AEs include serious AEs and non serious AEs)

| Revision | N = 136 Patients Implanted n (%) |
| --- | --- |
| Lead | 4 (2.9%) |
| Extension | 7 (5.1%) |
| IPG | 7 (5.1%) |

Table 15: Device Revision Summary

# Deaths

There were 3 deaths in the long-term follow-up study. The cause of these deaths were unrelated to the device and include sepsis secondary from a UTI, cancer and multiple infections which started with osteomyelitis of the big toe.

# Neuropsychological Testing

Neuropsychological testing was done at baseline and at 90 days to compare the assessments in the stimulation and control groups. The following table provides these results.

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| | Stimulation | | Control | | |
| --- | --- | --- | --- | --- | --- |
| Characteristic | Baseline | 90 days | Baseline | 90 days | P-value |
| Dementia Rating Scale | | | | | |
| Attention | 10.9 (2.2) | 10.9 (2.1) | 10.6 (2.6) | 10.8 (2.1) | 0.945 |
| Initiation | 9.5 (2.3) | 9.1 (2.8) | 9.6 (2.7) | 8.3 (3.1) | 0.079 |
| Construction | 9.3 (1.7) | 9.4 (1.4) | 9.4 (1.9) | 9.1 (2.0) | 0.156 |
| Conceptualization | 9.2 (2.2) | 9.1 (2.0) | 8.9 (2.6) | 9.2 (2.2) | 0.719 |
| Memory | 9.1 (3.0) | 9.4 (3.2) | 8.7 (3.1) | 9.2 (2.9) | 0.781 |
| | | | | | |
| Stroop | | | | | |
| Word | 38.8 (11.3) | 37.4 (10.6) | 38.3 (11.5) | 38.7 (10.5) | 0.214 |
| Color | 39.5 (10.3) | 37.4 (10.7) | 38.0 (11.1) | 37.3 (10.7) | 0.308 |
| Color-Word | 44.4 (9.4) | 41.5 (9.1) | 43.6 (11.4) | 42.0 (10.2) | 0.458 |
| Interference | 47.7 (6.9) | 45.9 (7.9) | 46.9 (8.3) | 46.7 (8.1) | 0.432 |
| | | | | | |
| Delis-Kaplan | | | | | |
| Letter Fluency | 10.6 (4.2) | 9.1 (3.7) | 10.2 (4.5) | 9.3 (4.7) | 0.642 |
| Category Fluency | 10.6 (3.8) | 8.7 (3.6) | 9.9 (3.6) | 8.6 (3.6) | 0.459 |
| Switching Fluency | 10.4 (3.9) | 9.2 (4.1) | 11.1 (2.9) | 9.2 (3.8) | 0.696 |
| Switching Accuracy | 10.2 (3.6) | 9.5 (3.9) | 10.9 (2.9) | 9.2 (3.5) | 0.417 |
| | | | | | |
| Wisconsin (WCST) | | | | | |
| Categories | 2.71 (1.50) | 2.54 (1.58) | 3.13 (1.41) | 3.13 (1.45) | 0.269 |
| Perseverative | | | | | |
| Raw Scores | 11.1 (7.4) | 10.4 (6.5) | 10.5 (6.6) | 9.2 (6.0) | 0.452 |
| T-Scores | 46.5 (13.8) | 47.5 (13.2) | 46.1 (11.4) | 49.5 (12.6) | 0.442 |
| Non-perseverative | | | | | |
| Raw Scores | 9.1 (5.8) | 10.2 (6.1) | 7.8 (5.3) | 8.7 (5.0) | 0.538 |
| T-Scores | 45.5 (13.3) | 42.9 (13.2) | 47.9 (10.6) | 44.8 (9.7) | 0.791 |
| | | | | | |
| Trail Making A | 44.6 (11.6) | 43.1 (12.4) | 40.3 (14.4) | 40.0 (12.2) | 0.960 |
| Trail Making B | 41.6 (12.6) | 40.7 (14.3) | 39.2 (12.4) | 36.7 (15.7) | 0.388 |
| | | | | | |
| Hopkins Verbal Learning | | | | | |
| Total Recall | 39.1 (11.5) | 40.0 (11.3) | 36.6 (10.8) | 38.3 (10.6) | 0.837 |
| Delayed Recall | 40.5 (12.8) | 39.3 (13.0) | 39.0 (10.8) | 38.7 (11.5) | 0.921 |
| Retention | 44.7 (14.3) | 42.6 (13.2) | 42.9 (11.4) | 43.9 (12.7) | 0.397 |
| Recognition | 41.2 (12.4) | 42.5 (11.5) | 43.6 (13.3) | 44.8 (13.3) | 0.430 |
| | | | | | |
| Wechsler Memory | | | | | |
| Logical Memory I | 9.7 (3.7) | 9.9 (3.6) | 10.1 (2.7) | 10.2 (2.3) | 0.760 |
| Logical Memory II | 10.3 (3.4) | 10.9 (3.4) | 10.6 (2.9) | 10.8 (3.1) | 0.616 |
| Family Pictures I | 8.9 (3.6) | 9.6 (3.2) | 8.6 (2.4) | 8.5 (3.0) | 0.069 |
| Family Pictures II | 9.0 (3.4) | 9.8 (3.3) | 8.6 (2.9) | 8.9 (3.4) | 0.229 |
| | | | | | |
| Hamilton Depression* | | | | | |
| Total T-Score | 66.1 (13.2) | 57.4 (13.7) | 69.3 (13.7) | 66.2 (11.9) | 0.005 |
| | | | | | |
| Frontal Systems Behavior | | | | | |
| Apathy | 64.8 (18.3) | 61.3 (16.1) | 69.0 (16.8) | 65.8 (14.2) | 0.484 |
| Disinhibition | 56.6 (18.3) | 55.6 (15.2) | 60.4 (13.4) | 60.3 (14.7) | 0.284 |
| Executive Dysfunction | 62.4 (16.0) | 59.7 (14.1) | 64.4 (17.6) | 65.4 (13.3) | 0.102 |
| Total | 64.4 (18.2) | 61.2 (15.8) | 68.3 (14.8) | 66.4 (13.6) | 0.372 |

Note: An increase in score represents an improvement except test noted with *. * indicates a decrease in score represents an improvement.

Table 16: 90 Days Neuropsychological testing summary

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Neuropsychological testing was also done at 12 months. The following table provides a comparison of the neuropsychological testing results from baseline to 12 months.

| Characteristic | Baseline | 12-month | P-value |
| --- | --- | --- | --- |
| Dementia Rating Scale | | | |
| Attention | 10.9 (2.0) | 10.9 (2.5) | 0.918 |
| Initiation | 9.5 (2.4) | 8.9 (2.8) | 0.010 |
| Construction | 9.4 (1.6) | 9.3 (1.7) | 0.493 |
| Conceptualization | 9.1 (2.2) | 9.5 (2.4) | 0.076 |
| Memory | 9.2 (2.9) | 9.4 (2.9) | 0.419 |
| | | | |
| Stroop | | | |
| Word | 38.8 (11.2) | 35.3 (11.8) | <0.001 |
| Color | 39.1 (10.6) | 35.2 (11.1) | <0.001 |
| Color-Word | 44.7 (9.2) | 41.6 (10.2) | <0.001 |
| Interference | 47.9 (7.0) | 46.9 (8.3) | 0.257 |
| | | | |
| Delis-Kaplan | | | |
| Letter Fluency | 10.5 (4.3) | 9.1 (4.0) | <0.001 |
| Category Fluency | 10.4 (3.7) | 8.5 (3.6) | <0.001 |
| Switching Fluency | 10.7 (3.5) | 9.0 (3.9) | <0.001 |
| Switching Accuracy | 10.5 (3.4) | 9.2 (3.9) | 0.001 |
| | | | |
| Wisconsin (WCST) | | | |
| Categories | 2.82 (1.49) | 2.64 (1.7) | 0.191 |
| Perseverative | | | |
| Raw Scores | 11.1 (7.5) | 10.7 (6.3) | 0.571 |
| T-Scores | 46.1 (12.9) | 48.1 (12.8) | 0.122 |
| Non-perseverative | | | |
| Raw Scores | 8.8 (5.8) | 9.8 (6.0) | 0.069 |
| T-Scores | 46.0 (12.4) | 44.4 (12.2) | 0.248 |
| | | | |
| Trail Making A | 43.4 (12.6) | 42.6 (13.0) | 0.388 |
| Trail Making B | 41.6 (11.8) | 40.3 (14.0) | 0.231 |
| | | | |
| Hopkins Verbal Learning | | | |
| Total Recall | 38.5 (11.2) | 39.4 (11.4) | 0.391 |
| Delayed Recall | 40.7 (12.2) | 40.3 (13.0) | 0.761 |
| Retention | 45.0 (13.4) | 44.6 (13.2) | 0.749 |
| Recognition | 41.9 (12.6) | 43.1 (12.6) | 0.299 |
| | | | |
| Wechsler Memory | | | |
| Logical Memory I | 9.9 (3.4) | 10.5 (3.2) | 0.014 |
| Logical Memory II | 10.6 (3.2) | 11.2 (3.3) | 0.007 |
| Family Pictures I | 8.8 (3.3) | 9.4 (3.5) | 0.019 |
| Family Pictures II | 8.9 (3.3) | 9.7 (3.5) | 0.003 |
| | | | |
| Hamilton Depression* | | | |
| Total T-Score | 66.9 (13.3) | 60.2 (14.5) | <0.001 |
| | | | |
| Frontal Systems Behavior | | | |
| Apathy | 65.5 (17.5) | 64.8 (16.2) | 0.624 |
| Disinhibition | 58.1 (17.4) | 58.1 (16.9) | 0.970 |
| Executive Dysfunction | 62.7 (16.0) | 61.3 (15.0) | 0.332 |
| Total | 65.2 (17.1) | 63.6 (16.8) | 0.261 |

Note: An increase in score represents an improvement except test noted with *. * indicates a decrease in score represents an improvement.

Table 17: 12 Month Neuropsychological testing summary

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# I. Parkinson's Disease Study Effectiveness Results

The analysis of effectiveness was based on the 136 evaluable patients at the 90 day time point. Key effectiveness outcomes are presented in tables 18 to 34.

As seen in the table below, the primary endpoint was met at 90 days with a statistically significant $(p = 0.003)$ improvement in "on time" without dyskinesias or with non-bothersome dyskinesias for the Stimulation Group (4.27 hours of "on time") compared to the control group (1.77 hours of "on time"). One patient in the Control Group did not have diary information at the 90 day visit due to the nursing personnel miss-placing the 90 day diary information so the 1 month information was used for this analysis. In addition, two patients in the Stimulation Group were missing the 90 day diary information so the 1 month information was used for this analysis. Thus, Stimulation Group improves "on time" without dyskinesias or with non-bothersome dyskinesias by a mean of 2.51 hours as compared to the control group.

| | Stimulation (N=101) | Control (N=34) | P-Value |
| --- | --- | --- | --- |
| Baseline | | | |
| Mean ± std | 6.7 ± 3.1 | 7.4 ± 2.5 | 0.262 |
| Range | 0 – 14.8 | 3.0 – 13.8 | |
| 90 Days1 | | | |
| Mean ± std | 11.2 ± 4.5 | 8.9 ± 2.9 | |
| Range | 0 – 18.8 | 3 – 13.8 | |
| Change from baseline2 | | | |
| Mean | 4.27 | 1.77 | 0.003 |
| Difference (95% CI) | 2.51 (0.87 – 4.16) | | |

1 The one-month visit was carried forward to 90 days for patients who were missing Month 3
2 Adjusted for study site and baseline "on time"
Note: An increase in hours represents an improvement.

Table 18: Mean Baseline and Change from Baseline to 90 Days in the Duration of "on time" (hours) Without Dyskinesias or with Non-Bothersome Dyskinesias

See Figure 3Figure 3 for results of the "good quality "on" time over the study duration.

Figure 3: Duration of "Good Quality On Time"

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# Secondary Endpoints

This section provides a summary of the results of the secondary endpoints. Since a multiplicity adjustment procedure was not pre-specified for the secondary endpoints, the results are presented with 95% CIs instead of p-values. In addition, a number of the secondary endpoints could be assessed under various conditions, i.e. meds on/off and stim on/off. In some cases, the condition for assessment of the endpoints was not prespecified. Therefore, multiple tables for the same assessment are included to address this concern.

A secondary analysis of the primary endpoint was performed as a responder analysis. A responder was defined as an increase from baseline of 2.0 hours or more in "on time". The Stimulation Group demonstrated a 72.3% response rate and the Control Group demonstrated a 38.2% responder rate, with an odds ratio of 4.70 (1.96-11.28).

| | Stimulation (N=101) | Control (N=34) |
| --- | --- | --- |
| Responders: n (%)^{1} | 73 (72.3%) | 13 (38.2%) |
| Odds Ratio (95% CI) | 4.70 (1.96 – 11.28) | |

1 Increase of "on time" from baseline of 2 hours or greater

The Stimulation Group demonstrated a greater improvement in Parkinson's symptoms as measured by the UPDRS Motor Examination at 90 days from baseline compared to the Control Group as demonstrated in Table 20 and 21.

Table 19: Number of Responders

| | Stimulation | Control |
| --- | --- | --- |
| Baseline | | |
| N | 99 | 35 |
| Mean ± std | 40.8±10.8 | 44.1±14.0 |
| 90 Days | | |
| Mean ± std | 24.8±10.1 | 40.4±11.6 |
| Change^{1} | | |
| Mean | -16.1 | -2.1 |
| Difference (95% CI) | -14.0 (-17.5, -10.5) | |

1 Adjusted for study site and baseline
Note: A decrease in score represents an improvement.

Table 20: Change from Baseline to 90 Days in the UPDRS Motor Examination with Medications "off" at Baseline Compared to Medications "off" and Stimulation "on" in Stimulation Group and Stimulation "off" in Control Group

| | Stimulation Group | Control Group |
| --- | --- | --- |
| Baseline | | |
| N | 99 | 35 |
| Mean ± std | 18.3 ± 9.5 | 17.8 ± 10.1 |
| 90 Days | | |
| Mean ± std | 15.1 ± 8.2 | 22.3 ± 10.5 |
| Change | | |
| Mean | -3.01 | 4.37 |
| Difference 95% (CI) | -7.38 (-10.18, -4.57) | |

Note: A decrease in score represents an improvement.

Table 21: Change from Baseline to 90 Days in the UPDRS Motor Examination with Medications "on" at Baseline Compared to Medications "on" and Stimulation "on" in Stimulation Group and Stimulation "off" in Control Group

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The Stimulation Group demonstrated an improvement in the Schwab and England ADL assessment when the assessment was performed under the medication on at baseline compared to the medication on stimulation on condition at 90 Days demonstrated in Table 22.

| | Stimulation | Control |
| --- | --- | --- |
| Baseline | | |
| N | 99 | 34 |
| Mean ± std | 77.6 ± 16.8 | 76.5 ± 16.3 |
| 90 Days | | |
| N | 99 | 34 |
| Mean ± std | 86.1 ± 11.4 | 76.8 ± 17.7 |
| Change† | | |
| Mean | 8.8 | -0.5 |
| Difference (95% CI) | 9.3 (4.4, 15.3) | |

Results are "on" medications at baseline compared to medication and stimulation "on" at 90 Days
† Adjusted for study site and baseline
Note: An increase in score represents an improvement.

The Stimulation Group demonstrated a greater improvement in Hoehn and Yahr Scale at 90 days from baseline compared to the Control when the assessment was performed under the medication off baseline score compared to the medication off stimulation on condition at 90 Days (Table 23). However, minimal improvement was seen in the Hoehn and Yahr scale when the assessment was performed under the medication on at baseline compared to the medication on stimulation on condition at 90 Days (Table 24).

Table 22: Mean Baseline and Change From Baseline to 90 Days in the Schwab and England Activities of Daily Living

| | Stimulation | Control |
| --- | --- | --- |
| Baseline | | |
| N | 99 | 35 |
| Mean ± std | 2.94 ± 0.80 | 3.30 ± 0.89 |
| 90 Days | | |
| Mean ± std | 2.38 ± 0.67 | 3.14 ± 0.95 |
| Change† | | |
| Mean | -0.64 | -0.07 |
| Difference (95% CI) | -0.57 (-0.81, -0.32) | |

†Adjusted for study site and baseline score
Note: A decrease in score represents an improvement.

Table 23: Baseline and 90 Days Hoehn and Yahr Staging Mean Results Off Medication at Baseline, Off Medication at 90 Days, On Stimulation at 90 Days

| | Stimulation | Control |
| --- | --- | --- |
| Baseline | | |
| N | 96 | 35 |
| Mean ± std | 2.15 ± 0.49 | 2.39 ± 0.64 |
| 90 Days | | |
| Mean ± std | 2.13 ± 0.65 | 2.44 ± 0.76 |
| Change† | | |
| Mean | -0.11 | 0.11 |
| Difference (95% CI) | -0.23 (-0.46, 0.01) | |

†Adjusted for study site and baseline score
Note: A decrease in score represents an improvement.

Table 24: Baseline and 90 Days Hoehn and Yahr Staging Mean Results On Medication at Baseline, On Medication and On Stimulation at 90 Days

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A comparison of the stimulation and control groups on global outcome measures were performed at 90 Days. These assessments were performed by the examiner, caregiver and patients (Table 25).

| | Stimulation n (%) | | Control n (%) | |
| --- | --- | --- | --- | --- |
| | Baseline | 90 Days | Baseline | 90 Days |
| Examiner | N=101 | | N=35 | |
| No Disability | 0 | 5 (5.0%) | 1 (2.9%) | 0 (0%) |
| Mild Disability | 17 (16.8%) | 62 (61.4%) | 3 (8.6%) | 7 (20.0%) |
| Moderate Disability | 50 (49.5%) | 31 (30.7%) | 15 (42.9%) | 18 (51.4%) |
| Marked Disability | 28 (27.7%) | 2 (2.0%) | 10 (28.6%) | 6 (17.1%) |
| Severe Disability | 6 (5.9%) | 1 (1.0%) | 6 (17.1%) | 4 (11.4%) |
| Caregiver | N=85 | N=77 | N=28 | N=27 |
| No Disability | 2 (2.0%) | 8 (10.4%) | 0 (0%) | 1 (3.7%) |
| Mild Disability | 11 (10.9%) | 38 (49.4%) | 5 (14.3%) | 3 (11.1%) |
| Moderate Disability | 33 (32.7%) | 24 (31.2%) | 11 (31.4%) | 13 (48.2%) |
| Marked Disability | 32 (31.7%) | 6 (7.8%) | 7 (20.0%) | 8 (29.6%) |
| Severe Disability | 7 (6.9%) | 1 (1.3%) | 5 (14.3%) | 2 (7.4%) |
| Patient | N=101 | | N=35 | |
| No Disability | 4 (4.0%) | 9 (8.9%) | 1 (2.9%) | 1 (2.9%) |
| Mild Disability | 17 (16.8%) | 54 (53.5%) | 5 (14.3%) | 5 (14.3%) |
| Moderate Disability | 40 (39.6%) | 30 (29.7%) | 12.(34.3%) | 19 (54.3%) |
| Marked Disability | 30 (29.7%) | 6 (5.9%) | 11 (31.4%) | 7 (20.0%) |
| Severe Disability | 10 (9.9%) | 2 (2.0%) | 6 (17.1%) | 3 (8.6%) |

Table 25: Global Outcome Measures at 90 Days

## Additional Endpoints

This section provides the results of additional endpoints (assessments performed through one year). Since a multiplicity adjustment procedure was not pre-specified for these endpoints, the results are presented with 95% Cis instead of p-values.

After the 90 Day visit, all patients recieved stimulation. The UPDRS activities of daily living, motor examination, complications and total scores were assessed at 12 months. The motor examination of the UPDRS (also known as UPDRS Part III) demonstrated a reduction over time through one year as compared to baseline off medication condition compared to the off medication/on stimulation for both groups (Table 26).

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Table 26: Change from Baseline through 12 Months in the UPDRS with Medication "off" at Baseline and medication "off" at 12 Months and Stimulation "on" at 12 Months

| UPDRS Component | | Baseline* | 12 Months | |
| --- | --- | --- | --- | --- |
| | | | Actual | Change |
| Activities of Daily Living | N | 121 | 115 | 115 |
| | Mean ± std | 22.1±7.2 | 12.7±6.8 | -9.4±8.5 |
| | 95% CI | | | -10.2 to -8.6 |
| Motor Examination | N | 136 | 130 | 130 |
| | Mean ± std | 41.6 ± 11.8 | 17.5±10.2 | -24.1±13.9 |
| | 95% CI | | | -25.4 to -22.8 |
| Complications | N | 130 | 125 | 125 |
| | Mean ± std | 8.93±3.77 | 4.32±2.46 | -4.61±4.04 |
| | 95% CI | | | -4.99 to -4.23 |
| Total | N | 116 | 109 | 109 |
| | Mean ± std | 76.8±18.3 | 37.9±16.8 | -38.4±21.8 |
| | 95% CI | | | -40.4 to -36.4 |

*Patients with a value at 3, 6 or 12 months.
Note: A decrease in score represents an improvement.

Table 27: Change from Baseline through 12 Months in the UPDRS with Medication "on" at Baseline and medication "on" at 12 Months and Stimulation "on" at 12 Months

| UPDRS Component | | Baseline* | 12 Months | |
| --- | --- | --- | --- | --- |
| | | | Actual | Change |
| Activities of Daily Living | N | 118 | 112 | 112 |
| | Mean ± std | 9.4±5.7 | 12.6±6.8 | 3.22±6.87 |
| | 95% CI | | | 2.57 to 3.87 |
| Motor Examination | N | 135 | 130 | 130 |
| | Mean ± std | 18.2±9.6 | 17.5±10.2 | -0.8±11.1 |
| | 95% CI | | | -1.8 to 0.2 |
| Complications | N | 125 | 121 | 121 |
| | Mean ± std | 9.00…