← Product Code [POH](/productcode/POH) · P150038S037

# Exablate Model 4000 Type-1 System (P150038S037)

_Insightec · POH · Jul 3, 2025 · Neurology · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P150038S037

## Device Facts

- **Applicant:** Insightec
- **Product Code:** [POH](/productcode/POH.md)
- **Decision Date:** Jul 3, 2025
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Neurology
- **Attributes:** Therapeutic, Real-World Evidence

## Real-World Evidence

| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
| --- | --- | --- | --- | --- | --- |
| P150038S037 · Jul 3, 2025 | Exablate Model 4000 Type-1 System | Insightec | Post-Approval Study (PAS) registry/clinical data; Prior IDE clinical study (G170237) data | The FDA mandated a Post-Approval Study to evaluate safety and effectiveness in real-world clinical practice. Additionally, data from a prior IDE study (G170237) was used to establish a performance goal for the primary effectiveness endpoint in the current pivotal study. | Post-Approval Study; Real-world use; Performance goal; Retrospective clinical data |

### Clinical Evidence

| Study Design | Population | Comparator | Key Endpoints |
| --- | --- | --- | --- |
| Post-Approval Study (PAS); Prospective observational study (post-market); Follow-up/Duration: Baseline, 3 months, 6 months, and 1 year post-bilateral procedure; Study Period: Post-approval | Patients with advanced, idiopathic Parkinson's Disease with medication-refractory moderate to severe motor complications undergoing staged bilateral pallidothalamic tractotomy.; Sample Size: Minimum of 60 subjects | Not applicable for this study | Incidence/severity of device/procedure-related AEs; improvement in MDS-UPDRS Part III OFF-Medications score at 3 months post-bilateral treatment. |
| IDE G170237; Randomized, sham-controlled study; Study Period: Prior to current study | Patients with medication-refractory motor complications of Parkinson's Disease | Sham control | MDS-UPDRS Part III OFF-Medications score |

## Indications for Use

The Exablate Neuro is indicated for use in the unilateral pallidothalamic tractotomy of advanced idiopathic Parkinson's Disease with medication-refractory moderate to severe motor complications as an adjunct to Parkinson's disease medication treatment, and in the staged (by at least 6 months from the first pallidothalamic tractotomy), unilateral pallidothalamic tractotomy of idiopathic Parkinson's Disease with medication-refractory motor complications of their contralateral side that was not previously treated in the first unilateral pallidothalamic tractotomy. Patients must be at least age 30. The designated area in the brain responsible for the motor complications symptoms (pallidothalamic tract) must be identified and accessible for targeted thermal ablation by the Exablate device.

## Device Story

Exablate Neuro is a transcranial MR-guided focused ultrasound system; combines multi-channel phased-array transducer with 1.5T or 3T MRI. Used in clinical settings by physicians to perform thermal ablation of brain tissue (pallidothalamic tract). System includes treatment table, transducer helmet, operator console (PC), equipment cabinet, and water cooling/degassing system. Operator uses real-time MR images to guide ultrasound energy to target; closed-loop thermal feedback monitors procedure. Confirms outcome with post-treatment MRI. Benefits patients with medication-refractory Parkinson's motor complications by providing non-invasive alternative to surgical resection or deep brain stimulation; reduces motor symptoms and complications.

## Clinical Evidence

Prospective, multi-center, global, single-arm pivotal study (IDE G200238) of 54 subjects (40 bilateral). Primary endpoint: mean percent change in MDS-UPDRS Part III OFF-meds motor score (upper/lower extremity) at 3 months post-bilateral treatment vs baseline. Results: median improvement of 10.2 points (32.7%) at 3 months (p<.0001). Confirmatory endpoints: MDS-UPDRS Part IV (66.1% reduction) and Part III Total (33% reduction). Safety: 280 AEs in 54 subjects; 96.4% mild/moderate. Speech-related events (28%) and axial symptoms (25%) higher after second procedure. No device-related severe/life-threatening events.

## Technological Characteristics

Transcranial MR-guided focused ultrasound system. Components: multi-channel phased-array transducer helmet, treatment table, operator console (PC), equipment cabinet, water cooling/degassing system. Operates with 1.5T/3T MRI scanners. Software version 7.33. Closed-loop thermal feedback control. Non-invasive thermal ablation.

## Regulatory Identification

An MR-Guided Focused Ultrasound System is intended to use high intensity focused ultrasound (HiFU) to heat and ablate soft tissue in the brain to treat neurological disorders. MR imaging and thermal mapping are used to plan and monitor the use of the device during the procedure.

## 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: Magnetic Resonance (MR)-Guided Focused Ultrasound System

Device Trade Name: Exablate Model 4000 Type 1.0 & 1.1 System (“Exablate Neuro”)

Device Procode: POH

Applicant’s Name and Address: INSIGHTEC, Inc.
4851 LBJ Freeway, Suite 400
Dallas, Texas 75244

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P150038/S037

Date of FDA Notice of Approval: July 3, 2025

The original PMA P150038 was approved on July 11, 2016, and is indicated for use in the unilateral thalamotomy treatment of idiopathic essential tremor patients with medication-refractory tremor. Patients must be at least age 22. The designated area in the brain responsible for the movement disorder symptoms (ventralis intermedius) must be identified and accessible for targeted thermal ablation by the Exablate device. The indications for use of the Exablate Neuro was expanded in the following PMA supplements:

- P150038/S006, approved on December 16, 2018, for the unilateral thalamotomy (ventralis intermedius) treatment of tremor-dominant Parkinson’s disease with medication-refractory tremor. Patients must be at least age 30.
- P150038/S014, approved on October 29, 2021, for the unilateral pallidotomy treatment of patients with advanced, idiopathic Parkinson’s disease with medication-refractory moderate to severe motor complications as an adjunct to Parkinson’s disease medication treatment. Patients must be at least age 30.
- P150038/S022, approved on December 8, 2022, for the staged (by at least 9 months from the first thalamotomy, which was approved in the original P150038 PMA), unilateral thalamotomy of idiopathic Essential tremor patients with medication-refractory tremor of their contralateral side that was not previously treated in the index unilateral thalamotomy. Patients must be at least age 22.

The SSEDs to support the indication are available on the following FDA websites and are incorporated by reference herein:

- https://www.accessdata.fda.gov/cdrh_docs/pdf18/P180031B.pdf
- https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150038S006B.pdf
- https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150038S014B.pdf

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

1 of 37

{1}

The current submission expands the indications for Exablate Neuro to include use in the unilateral pallidothalamic tractotomy of advanced, idiopathic Parkinson's Disease with medication-refractory moderate to severe motor complications as an adjunct to Parkinson's disease medication treatment, and in the staged (by at least 6 months from the first pallidothalamic tractotomy), unilateral pallidothalamic tractotomy of idiopathic Parkinson's Disease with medication-refractory motor complications of their contralateral side that was not previously treated in the first unilateral pallidothalamic tractotomy.

## II. INDICATIONS FOR USE

The Exablate Neuro is indicated for use in the unilateral pallidothalamic tractotomy of advanced idiopathic Parkinson's Disease with medication-refractory moderate to severe motor complications as an adjunct to Parkinson's disease medication treatment, and in the staged (by at least 6 months from the first pallidothalamic tractotomy), unilateral pallidothalamic tractotomy of idiopathic Parkinson's Disease with medication-refractory motor complications of their contralateral side that was not previously treated in the first unilateral pallidothalamic tractotomy. Patients must be at least age 30. The designated area in the brain responsible for the motor complications symptoms (pallidothalamic tract) must be identified and accessible for targeted thermal ablation by the Exablate device.

### III. CONTRAINDICATIONS

The Exablate Neuro treatment is contraindicated for use in:

- Patients with standard contraindications for MR imaging, such as non-magnetic resonance imaging (MRI) compatible implanted metallic devices including cardiac pacemakers, size limitations, allergies to MR contrast agent.
- Patients who are pregnant.
- Patients with advanced kidney disease or on dialysis.
- Patients with unstable cardiac status or severe hypertension.
- Patients exhibiting any behavior(s) consistent with ethanol or substance abuse.
- Patients with history of abnormal bleeding, hemorrhage, and/or coagulopathy.
- Patients receiving anticoagulant or drugs known to increase risk of hemorrhage within one month of focused ultrasound procedure.
- Patients with cerebrovascular disease.
- Patients with brain tumors.
- Patients who are not able or unwilling to tolerate the required prolonged stationary position during treatment. The average treatment time (the time from the first scan to allocate transducer position and ending with the last energy delivery) is 1:56 ± 0.41 hours (hrs) (min: 0.48 hrs, max: 5:54 hrs).
- Patients who have an Overall Skull Density Ratio of less than 0.40 as calculated from the screening computed tomography (CT).
- Parkinson's disease patients with unstable psychiatric disease, uncontrolled depressive symptoms, psychosis, delusions, hallucinations, or suicidal ideation.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

2 of 37

{2}

For Staged, contralateral Essential Tremor or Parkinson Disease

- Patients with clinically significant dysphagia, abnormal speech function, or gait abnormalities that are moderate to severe following an Exablate unilateral procedure.

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Exablate Neuro labeling.

# V. DEVICE DESCRIPTION

The Exablate Model 4000 Type 1.0 & 1.1 System (“Exablate Neuro”) is a transcranial MR image-guided focused ultrasound system that combines a multi-channel phased-array focused ultrasound transducer and magnetic resonance imaging (MRI) in a closed-loop procedure for the thermal treatment of brain tissue. The Exablate Model 4000 Type 1.0 & 1.1 System uses software version 7.33 in conjunction with GE Medical Systems (“GE”) and Siemens 3 Tesla (T) MRI scanners or GE 1.5 T MRI scanners with a dedicated Exablate Neuro 1.5 T MR Head Coil. The device operates by guiding the focus of the ultrasound energy to the target region in the brain. The energy is then repeatedly transmitted to the target until the desired outcome is achieved. The targeted area is defined based on MR images taken during the procedure. The treatment procedure is constantly monitored by real-time closed-loop thermal feedback. Once targeting is complete, the treatment outcome is confirmed with adequate post-treatment MRI sequences.

The Exablate Model 4000 Type 1.0 & 1.1 System is comprised of three main components:

1. Exablate Neuro Treatment Table and Transducer Helmet (for Type 1.0) or Transducer Helmet with Cart for storage/transport (for Type 1.1), which contains the actual transducer and its supporting hardware and electronics and the stabilization system (Figure 1).

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

3 of 37

{3}

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

Figure 1: Exablate Neuro Patient Table

2. Exablate Neuro Operator Console/Workstation (WS) is a personal computer (PC) that allows the clinical user to run the device system through the clinical application software.
3. Exablate Neuro Equipment, including:

a. Equipment Cabinet contains the control PC, power supplies, and control and data acquisition electronics.
b. Front-End (FE) Unit contains the power amplifiers that drive the focused ultrasound transducer, as well as the control and monitoring electronics.
c. Water System contains equipment to cool and degas the water that is used as the interface between the transducer and the patient's head in order to remove excess heat deposited in the skull by the ultrasound energy.

A more detailed device description can be found in the Exablate Neuro labeling.

### VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of medication-refractory moderate to severe motor complications in patients with idiopathic Parkinson's disease, including medication, surgical resection of the area in the brain responsible for the motor complications, radiofrequency pallidotomy or thalamotomy, and implantation of a deep brain stimulator. 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.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

4 of 37

{4}

## **VII. MARKETING HISTORY**

The Exablate Neuro is approved for marketing in the following countries: United States, Canada, Europe (inclusive of United Kingdom and Switzerland) under CE (Conformité Européenne) mark, South Korea, Japan, China, Russia, Taiwan, Mexico, Brazil, Chile, Australia, Argentina, Columbia, Peru, Singapore, Thailand, Philippines, UAE, Turkey, Hong Kong and in Israel.

The Exablate Neuro has not been withdrawn from the market outside of the United States for safety or effectiveness reasons.

## **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 or procedure.

- Headache
- Gait disturbances
- Ataxia
- Imbalance
- Unsteadiness
- Dysmetria
- Decrease in synchronicity between hands
- Dysarthria
- Slurred speech
- Voice change
- Pain
- Dizziness
- Nausea
- Diplopia
- Nystagmus
- Numbness/tingling
- Tilting sensation
- Warm sensation
- Dysgeusia
- Hypogeusia
- Dysphagia
- Dry mouth
- Sialorrhea
- Fatigue
- Weakness
- Hypoesthesia
- Facial droop
- Transient fever, oral temperature, skin pain
- Tissue damage
- Hemorrhage in the treated brain area requiring emergency treatment

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

5 of 37

{5}

- Skin burns
- Skin retraction and scar formation
- Venous thromboembolic events

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

# IX. SUMMARY OF NON-CLINICAL STUDIES

The Exablate Neuro was first approved in P150038 on July 11, 2016, for use in the unilateral thalamotomy treatment of idiopathic essential tremor patients with medication-refractory tremor. No additional non-clinical performance testing was conducted to support the current PMA supplement. A summary of the non-clinical studies conducted on the Exablate Neuro can be found in the Summary of Safety and Effectiveness Data (SSED) for P150038 at the following location:
https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150038B.pdf.

# X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of staged bilateral pallidothalamic tractotomy with the Exablate Neuro in patients with advanced, idiopathic Parkinson's disease with medication-refractory moderate to severe motor complications as an adjunct to Parkinson's disease medication treatment. The study was conducted in the US, Spain, and Taiwan, under IDE G200238. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

# A. Study Design

Patients were treated between July 12, 2020 and November 1, 2023. The database for this Panel Track Supplement reflected data collected through September 14, 2024, and included 84 enrolled subjects who signed the informed consent. Of the enrolled subjects, 54 subjects met the enrollment criteria for the study and underwent the unilateral index procedure (unilateral cohort), 40 of which proceeded to receive the contralateral procedure (bilateral cohort), which was staged by at least 6 months from the first procedure. There were 9 investigational centers (6 United States and 3 outside United States).

The study was a prospective, multi-center, global, single-arm, open label, pivotal study titled "Evaluation of the Safety and Effectiveness of Exablate Ablation of the Pallidothalamic Tract (PTT) for the Treatment of Bilateral Motor Complications of Parkinson's Disease (PD) (PD014)." Subjects underwent an Exablate procedure (i.e. Treatment 1, "T1") targeting the PTT. Six months after the first treatment, subjects were evaluated for a contralateral Exablate procedure (i.e. Treatment 2, "T2"). Subjects who did not qualify at 6 months for the second side treatment or did not wish to proceed were seen at 12 months for their final unilateral follow-up. Subjects who

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

6 of 37

{6}

qualified for the staged PTTractotomy procedure and wished to proceed, underwent a second procedure for the contralateral side at least 6 months after T1.

The clinical study included a Data Safety Monitoring Board (DSMB) that reviewed all AEs and adjudicated the serious adverse events (SAEs) for their relationship to the investigational device or procedure. The role of the DSMB was to monitor the safety of the clinical study and make recommendations for study continuation or stoppage.

1. Clinical Inclusion and Exclusion Criteria

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

1. Men and women, age 30 years and older, desiring bilateral treatment option with second side staged at 6 months.
2. Subject is able and willing to give informed consent and able to attend all study visits.
3. Subject with a diagnosis of idiopathic PD by UK Brain Bank Criteria as confirmed by a movement disorder neurologist at the site.
4. Subject has Levodopa responsive as defined by at least a 30% reduction in MDS-UPDRS motor subscale in the ON vs OFF medication state.
5. Subject has MDS-UPDRS score of 30 or greater in the meds OFF condition.
6. Motor complications of PD on optimum medical treatment characterized dyskinesia (MDS-UPDRS item 4.2 score of 2 or greater in the meds ON condition)

OR

Motor fluctuations (MDS-UPDRS item 4.4 score of 2 or greater in the meds ON condition)

7. Subject is on a stable dose of all PD medications for 30 days prior to screening visit PD assessments as determined by medical records
8. Subject is able to communicate sensations during the Exablate procedure.
9. Subject's Pallido-thalamic region can be targeted by the Exablate device.

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

1. Subject has a score of 3 or greater on the PULL test.
2. Subject with severe premorbid risks as specified in the MDS-UPDRS Part II subsection motor aspects of experiences of daily living scores:

3 or 4 on question 2.1 (speech)

OR

3 or 4 on question 2.3 (chewing and swallowing)

OR

4 on question 2.2 (saliva and drooling).

3. Subject where there is suspicion that Parkinsonian symptoms are a side effect from neuroleptic medications.
4. Subject with significant cognitive impairment as determined by the neuropsychologist.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

7 of 37

{7}

5. Subject has other central neurodegenerative disease suspected on neurological examination. These include: multisystem atrophy, progressive supranuclear palsy, corticobasal syndrome, dementia with Lewy bodies, and Alzheimer's disease.
6. Subject with unstable psychiatric disease, defined as active uncontrolled depressive symptoms, psychosis, delusions, hallucinations, or suicidal ideation
7. Women of childbearing potential who are pregnant or lactating
8. Subjects exhibiting any behavior(s) consistent with ethanol or substance abuse
9. Subject with unstable cardiac status or severe hypertension including:
- Documented myocardial infarction within six months of enrollment
- Unstable angina on medication
- Unstable or worsening congestive heart failure
- Left ventricular ejection fraction below the lower limit of normal
- History of a hemodynamically unstable cardiac arrhythmia
- Cardiac pacemaker
- Diastolic BP > 100 on medication
10. Subject with history of abnormal bleeding, hemorrhage, or coagulopathy including:
- Subject with risk factors for intraoperative or postoperative bleeding as indicated by: platelet count less than 100,000 per cubic millimeter; a documented clinical coagulopathy; or INR coagulation studies exceeding the institution's laboratory standard.
- History of intracranial hemorrhage, multiple strokes, or a stroke within past 6 months
- Subjects with intracranial aneurysms requiring treatment or arterial venous malformations (AVMs) requiring treatment
11. Subject is receiving anticoagulant (e.g., warfarin) or antiplatelet (e.g., aspirin) therapy within one week of focused ultrasound procedure or drugs known to increase risk or hemorrhage (e.g., Avastin) within one month of focused ultrasound procedure.
12. Subject with severely impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2 (or per local standards should that be more restrictive) and/or who is on dialysis.
13. Subjects with a history of seizures within the past year.
14. Subject with an intracranial brain tumor
15. Subjects with life-threatening systemic disease that include and not limited to the following will be excluded from the study participation: HIV, liver failure, blood dyscrasias, etc.
16. Any illness that in the investigator's opinion preclude participation in this study.
17. Subject with standard contraindications for MR imaging such as implanted metallic devices
18. Subject who had prior deep brain stimulation of the basal ganglia or thalamus.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

8 of 37

{8}

19. Subjects who are unable to tolerate the required prolonged stationary supine position during treatment.
20. Subjects who have an Overall Skull Density Ratio of less than 0.40 as calculated from the screening CT.
21. Subject who is participating in another clinical investigation with an active treatment arm in the last 30 days.
22. Subject who is unable to communicate with the investigator and staff.

# **Additional Exclusion Criteria for Staged Bilateral PTT procedure:**

23. Subject who had moderate to severe neurological event such as dysphagia, speech, gait imbalance, cognitive impairment, and visual field deficit following index procedure.

# 2. Follow-up Schedule

Treatments were scheduled so that treatment 1 (T1) and treatment 2 (T2) were performed at least 6 months apart. A baseline assessment (B1) took place prior to T1. A second baseline assessment (B2) was later defined as the 6 months post-T1 timepoint, which was the last follow up prior to T2 for bilateral subjects. Follow-up visits were scheduled at week 1 ± 3 days, month 1 ± 7 days, month 3 ± 14 days, and month 6 ± 21 day, and per the following and Figure 2:

- Following the index procedure, subjects were evaluated for the second procedure after their month 6 visit. If they did not qualify, they would complete an annual visit at month 12 ± 60 days. The scheduled visit timepoints were calculated from the Exablate procedure date.
- If subjects were eligible and willing to proceed to the second Exablate procedure, the following visits were scheduled: week 1 ± 3 days, month 1 ± 7 days, month 3 ± 14 days, month 6 ± 21 days, month 12 ± 60 days, and annually out to 5 years. The post-bilateral scheduled visit timepoints were calculated from the second Exablate procedure date.

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

Figure 2: Treatment and Follow up timelines. T1 and T2 indicate treatment timepoints for the unilateral and bilateral procedures, respectively. B1 and B2 indicate baseline measurements prior to unilateral and bilateral treatments.

Pre- and post- procedural assessments included physical and neurological exams,

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

9 of 37

{9}

functional assessments, medication review, patient reported outcomes including quality of life from patient surveys and functional assessments, and neuropsychological exams. Adverse events and complications were recorded at all visits.

### 3. Clinical Endpoints

With regards to safety, the primary safety endpoint evaluated the incidence and severity of AEs, including treatment-emergent AEs, SAEs and Unanticipated Adverse Device Effects (UADEs) occurring at any time during the trial from the bilateral treatment through all study visits. Treatment-emergent AEs are defined as AEs starting on or after the day of treatment. AEs were reported and categorized by investigators by relation: device-related, procedure-related, PTT-related, PD-related, or unrelated. The secondary safety endpoints evaluated AEs that occurred prior to T2 or up to 12 months post T1 for subjects that did not proceed to T2.

With regards to effectiveness, the PD scale, *MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)*, from the International Movement Disorder Society (IMDS) was used for effectiveness evaluations:

# - • **MDS-UPDRS Part III OFF Meds: Motor Examination**

Part III of the MDS UPDRS motor exam is an objective physician-scored measure which focuses specifically on the motor complications of PD. This measure is used to evaluate the direct effect of the procedure on the treated side and both sides of the brain. The assessment is taken twice, first with patients off their PD medications (OFF-state) and then on medication (ON-state). The MDS-UPDRS Part III Motor Exam measures function in the following areas: speech, facial expression, rigidity, finger tapping, hand movements, pronation-supination movement of hands, toe tapping, leg agility, gait, postural stability, postural tremor of hands, kinetic tremor of hands and rest tremor amplitude.

The analysis for the study focused on the OFF-medication assessment, both in its entire form (Total Score) and as a subset for upper and lower extremity only.

# - • **MDS-UPDRS Part IV: Motor Complication**

In Part IV of the MDS UPDRS, the physician uses objective information to assess motor complications of dyskinesias including those of OFF-state dystonia. Assessment items include time spent with dyskinesia, functional impact of dyskinesia, time spent in the OFF-state, functional impact of fluctuations, complexity of motor fluctuations and painful OFF-state dystonia.

---PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

10 of 37

{10}

### Primary Effectiveness Endpoint

The primary effectiveness endpoint of the study was pre-specified as the mean percent change of the bilateral upper and lower extremity motor score from the MDS-UPDRS Part III OFF-Medications at 3 months post-bilateral treatment (T2), assessed on both treated sides compared to baseline prior to any treatment (B1).

All measurements were taken in the OFF-state condition for both treated sides and have a maximum total score of 88 points. An individual's score for the upper and lower extremity measure was defined as the sum of the following items from the MDS UPDRS Part III:

- Item 3.3 Rigidity,
- Item 3.4 Finger Tapping,
- Item 3.5 Hand Movements,
- Item 3.6 Pronation-Supination Movement of Hands,
- Item 3.7 Toe Tapping,
- Item 3.8 Leg Agility,
- Item 3.15 Postural Tremor of the Hands,
- Item 3.16 Kinetic Tremor of the Hands, and
- Item 3.17 Rest Tremor Amplitude on both sides of the body.

The score of the upper and lower extremity fields were summed to obtain the total score at the subject level at 3 months. The primary endpoint was calculated for each patient as follows:

% Change = 100*(B1 score – T2 score, month 3) / (B1 score)

where 'B1 score' is the score at B1 and 'T2 score, month 3' is the score at 3 months post-T2.

The pre-specified effectiveness endpoint was a comparison of the mean percent change across all bilateral patients with a performance goal of 5.6% using the following hypothesis:

H0: percent change in MDS-UPDRS Part III OFF Meds score at 3 Months from Baseline ≤ 0.056

H1: percent change in MDS-UPDRS Part III OFF Meds score at 3 Months from Baseline > 0.056

This hypothesis was analyzed using linear regression on each imputed dataset.

The performance goal of 5.6% was selected based on data collected for a sham control in a prior IDE (G170237). G170237 was a randomized study comparing Exablate Neuro to a sham control in the unilateral treatment of motor complications in patients with Parkinson's Disease. Study results from G170237 demonstrated a mean percent of change from baseline of 5.6% in the sham control

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

11 of 37

{11}

arm which was incorporated into the current study (G200238) as the performance goal of the primary effectiveness endpoint. Compared to the current study, the G170237 study enrolled the same PD population, used the same Exablate device, and performed unilateral procedures on the globus pallidus (GPi) following similar procedural methods.

### **Confirmatory Endpoints**

The confirmatory endpoints of this study were the percent change improvement from baseline (B1) to 3 months post T2 of the following assessments:

- MDS-UPDRS Part IV score (Motor Complications) assessing dyskinesias that include OFF-state dystonia; items include time spent with dyskinesia, functional impact of dyskinesia, time spent in the OFF-state, functional impact of fluctuations, complexity of motor fluctuations and painful OFF-state dystonia. An individual's score was calculated as the sum of the items in the MDS-UPDRS Part IV ON-state (items 4.1 to 4.6).
- MDS-UPDRS Part III total score was defined as the sum of all items included in part III (items 3.1 to 3.18) taken in the OFF-state.

The confirmatory endpoints were calculated for each individual as percent change from baseline (B1) to 3 months post-bilateral procedure (T2) as follows:

$$\% \text{ Change} = 100 * (\text{B1 score} - \text{T2 score, month 3}) / (\text{B1 score})$$

where 'B1 score' is the score at B1 and 'T2 score, month 3' is the score at 3 months post-T2.

### **Secondary Endpoints**

The secondary endpoints of this study were the evaluations at each visit through 12 months for the following assessments compared to baseline (B1):

- OFF-medication, Upper + Lower Extremity motor score from the MDS-UPDRS Part III for Treatment 1, and for Treatment 2 for both sides
- MDS-UPDRS Part IV at all bilateral visits
- MDS-UPDRS Part III total score at all bilateral visits

### **Additional Study Outcomes**

The additional endpoints of this study were the evaluations at each visit through 12 months for the following assessments:

- Clinician Global Impression of Change
- Patient Global Impression of Change
- Patient Satisfaction Questionnaire

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

12 of 37

{12}

## B. Accountability of PMA Cohort

At the time of database lock, 84 subjects signed the informed consent, and 54 eligible study participants were treated with unilateral or bilateral PTT. Of the 54 treated subjects, 40 of 54 (74%) subjects were treated bilaterally. Out of the 40 bilateral subjects, 90% (36/40) completed the 6-month follow-up visit. Out of the 4 subjects missing the 6-month follow-up, two subjects exited from the study prior to their scheduled 6-month visit due to unrelated serious adverse events (SAEs) including sepsis and pulmonary embolism, one subject exited due to death, and one subject missed their 6-month post-T2 follow up visit. Out of the 37 subjects that were accounted for at the 6-month post-T2 visit, 36 subjects completed the 12-month visit and 1 subject missed the visit (Figure 3 and Table 1).

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

Figure 3: Subject Disposition Flow Chart

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

13 of 37

{13}

Table 1: Bilateral Subject Disposition through Month-12

|   | Treatment 2 | Week 1 | Month 1 | Month 3 | Month 6 | Month 12  |
| --- | --- | --- | --- | --- | --- | --- |
|  Treated^{1} | 40 |  |  |  |  |   |
|  Eligible^{2} |  | 40 | 40 | 40 | 40 | 37  |
|  Exited: Death^{3} |  | 0 | 0 | 0 | 1 | 0  |
|  Exited: Failure^{3} |  | 0 | 0 | 0 | 0 | 0  |
|  Exited: Other Reasons^{3} |  | 0 | 0 | 0 | 2 | 0  |
|  Not Yet Due |  | 0 | 0 | 0 | 0 | 0  |
|  Expected^{4} |  | 40 | 40 | 40 | 37 | 37  |
|  Missed Visit |  | 2 | 2 | 1 | 1 | 1*  |
|  Actual^{5} |  | 38 | 38 | 39 | 36 | 36  |
|  Actual %^{6} |  | 95.0 | 95.0 | 97.5 | 97.3 | 97.3  |

1 Subjects who have received at least one sonication on the second side.

2 Eligible is the total number of subjects eligible for each visit.

3 Exited is the number of subjects who have exited the study at specific visit and reason for exit.

4 Expected is Eligible minus Exited minus Not Due Yet.

5 Actual is the number of subjects who have completed the follow-up visit.

6 Actual % is the number of Actual subjects divided by Expected.

*One subject is listed as a missed Month 12 visit for accountability purposes. All consented subjects are / will be followed up through year-5 as per protocol.

### Analysis Populations

The study defined the following analysis populations. The bilateral modified Intent to Treat (mITT) population was used for the primary effectiveness analyses and the safety analysis population was used for the primary safety analysis. All analysis populations for the bilateral and unilateral cohorts are shown in Table 2 below.

### Safety Analysis (SA) Population

The unilateral and bilateral SA populations include all subjects who received at least one sonication at T1 (unilateral) and at T2 (bilateral). The bilateral SA population was used for the primary safety analysis (n=40). The unilateral SA population was used for secondary safety analyses (n=54).

### Effectiveness Analysis Populations

#### Intent to Treat (ITT) Populations

The unilateral and bilateral ITT populations include all subjects who signed the informed consent form and received at least one sonication at T1 (unilateral, n=54) and T2 (bilateral, n=40).

#### Modified Intent to Treat (mITT) Populations

The unilateral mITT population includes all subjects in the unilateral ITT population for whom there exist a valid baseline (B1) MDS-UPDRS Part III OFF meds assessment and at least one post-unilateral treatment (T1) MDS-UPDRS Part III OFF

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

14 of 37

{14}

meds assessment. The unilateral mITT population was used to assess unilateral outcomes (n=54).

The bilateral mITT population includes all subjects in the bilateral ITT population for whom there exist a valid baseline (B1) MDS-UPDRS Part III OFF meds assessment and at least one post-bilateral treatment (T2) MDS-UPDRS Part III OFF meds assessment. Two subjects in the ITT population did not have at least one post-bilateral treatment MDS-UPDRS Off Meds assessment and were excluded from the mITT population (n=38). The bilateral mITT population was used for the primary and confirmatory secondary analyses.

# Per Protocol (PP) Populations

The unilateral and bilateral PP populations include all subjects in the unilateral and bilateral mITT populations for whom there were no major protocol violations.

Table 2: Analysis Population

|  Analysis Population | Unilateral (T1) Cohort |   | Bilateral (T2) Cohort  |   |
| --- | --- | --- | --- | --- |
|   |  N | % | N | %  |
|  Safety | 54 | 100.0 | 40 | 100.0  |
|  ITT | 54 | 100.0 | 40 | 100.0  |
|  mITT | 54 | 100.0 | 38 | 95.0  |
|  PP | 54 | 100.0 | 38 | 95.0  |

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a study on patients with advanced idiopathic PD. The demographic and baseline characteristics of the unilaterally treated cohort and of the bilaterally treated cohort are presented in Table 3 and Table 4. Overall, the unilateral and bilateral populations are similar in all characteristics.

Table 3: Demographics

|  Demographic Characteristics |   | Unilateral Safety | Bilateral Safety  |
| --- | --- | --- | --- |
|  Age [Years] | Mean | 63.8 | 63.0  |
|   |  N | 54 | 40  |
|  BMI [kg/m²] | Mean | 25.8 | 26.0  |
|   |  N | 54 | 40  |
|  Height [cm] | Mean | 170.5 | 170.0  |
|   |  N | 54 | 40  |
|  Weight [kg] | Mean | 75.7 | 75.8  |
|   |  N | 54 | 40  |
|  Gender | Female | 17 (31.5%) | 14 (35%)  |
|   |  Male | 37 (68.5%) | 26 (65%)  |
|   |  N | 54 (100%) | 40 (100%)  |
|  Race | White | 40 (74.1%) | 30 (75%)  |
|   |  Black or African American | 1 (1.9%) | 1 (2.5%)  |
|   |  Asian | 12 (22.2%) | 8 (20%)  |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

15 of 37

{15}

|  Demographic Characteristics |   | Unilateral Safety | Bilateral Safety  |
| --- | --- | --- | --- |
|  Ethnicity | Other | 1 (1.9%) | 1 (2.5%)  |
|   |  N | 54 (100%) | 40 (100%)  |
|   |  Hispanic | 7 (13%) | 6 (15%)  |
|   |  Non-Hispanic | 47 (87%) | 34 (85%)  |
|   |  N | 54 (100%) | 40 (100%)  |

Table 4: Baseline Characteristics (n=54)

|  Mean Time from Initial PD Symptoms [Years] | 10.1  |
| --- | --- |
|  Mean Time from Initial PD Diagnosis [Years] | 7.7  |
|  Mean Time from Initial PD Medical Therapy [Years] | 7.3  |
|  Mean Levodopa Equivalent Dosage (mg) | 1037.0  |

### D. Safety and Effectiveness Results

#### 1. Safety Results

The primary safety analysis was based on the bilateral SA cohort of 40 patients, available for the 12-month evaluation. The key safety outcomes for this analysis are presented in Table 5 to Table 9. A list of serious adverse effects is reported in Table 8 for events occurring through 12 months.

Although not presented in detail in this document, the secondary safety analysis evaluated adverse events in the unilateral SA cohort of 54 patients including events that occurred prior to T2 or up to 1 year after the unilateral procedure for patients that did not continue on to bilateral treatment. A total of 151 events in 44 out of 54 subjects were reported. The unilateral SA cohort did not experience device-related AEs. The majority of events were mild (74%) or moderate (25%). Three events were considered SAEs including one visual hallucination, one pulmonary embolism, and one hallucination.

A full list of adverse effects is reported in Table 10 for all events of the 54 subjects that underwent at least one treatment occurring from day 0 post-T1 through 12 months post-final treatment.

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

The primary safety analysis for the study was based upon the collection of adverse events in the bilateral SA population (n=40) following the bilateral treatment as collected by the investigators at each site during the study. Overall, a total of 129 events were recorded in 33 of the 40 bilateral subjects as shown in Table 5. A summary of the safety profile by severity is presented in Table 6. Approximately 94% of the 129 AEs were either mild (63.6%) or moderate (30.2%) in severity. Five events (3.9%) were severe in nature and three (2.3%) were life-threatening. None of the severe or life-threatening events were device related.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

16 of 37

{16}

All adverse events were coded by grouping term, body system and coded term for analysis as presented in **Table 7**.

**Table 5:** Number of Subjects with any AEs at 12 Months (Bilateral Safety, n=40)

|  Patients Experiencing at least one AE | N | %  |
| --- | --- | --- |
|  Yes | 33 | 82.5  |
|  No | 7 | 17.5  |
|  Total | 40 | 100.0  |

**Table 6:** Adverse Events by Severity through Month-12 (Bilateral Safety, n=40)

|  Severity | Number of Events N=129 | Number of Subjects with Events N=40  |
| --- | --- | --- |
|  Mild | 82 (63.6%) | 28 (70.0%)  |
|  Moderate | 39 (30.2%) | 19 (47.5%)  |
|  Severe | 5 (4.0%) | 4 (10.0%)  |
|  Life-Threatening | 3 (2.3%) | 3 (7.5%)  |
|  **Total** | **129 (100%)** | **33 (82.5%)**  |
|  Related SAE | 1 (0.8%) | 1 (2.5%)  |
|  Unrelated SAE | 6 (4.7%) | 5 (12.5%)  |

**Table 7:** Adverse Events by Grouping Term through Month 12 (Bilateral Safety, n=40)

|  Grouping Term | Number of Events (N= 129) | Number of Subjects with Events (N=40)  |
| --- | --- | --- |
|  Unrelated | 39 (30.2%) | 21 (52.5%)  |
|  Parkinson's Disease Related | 28 (21.7%) | 12 (30.0%)  |
|  **Subtotal** | **67 (51.9%)** | **25* (62.5%)**  |
|  Pallidothalamic Tract Related | 33 (25.6%) | 17 (42.5%)  |
|  Procedure Related | 10 (7.8%) | 8 (20.0%)  |
|  Transient Events – (Procedure related and Resolved within 72 hours) | 19 (14.7%) | 11 (27.5%)  |
|  Device Related | 0 | 0  |
|  **Subtotal** | **62 (48.1%)** | **27* (67.5%)**  |
|  **Grand Total** | **129 (100%)** | **33* (82.5%)**  |

\* Subjects may have experienced more than one event

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

17 of 37

{17}

**Table 8:** Listing of Serious Adverse Events – Bilateral Safety (n=40)

|  Grouping Term | Body System | Preferred Term | Severity  |
| --- | --- | --- | --- |
|  **Related to PTT Procedure**  |   |   |   |
|  Pallidothalamic Tractotomy Related | Nervous | Anarthria | Severe  |
|  **Unrelated to Device and Procedure**  |   |   |   |
|  Unrelated | Gastrointestinal | Intestinal Obstruction | Life-threatening  |
|  Unrelated | Nervous | Stroke | Life-threatening  |
|  Unrelated | Nervous | Stroke | Severe  |
|  Unrelated | General | Fall | Severe  |
|  Unrelated | Cardiovascular | Embolism | Life-threatening  |
|  Unrelated | Infection | Sepsis | Moderate  |

* Anarthria was due to user error.

### Speech Related Events

During the course of the study, the sponsor incorporated three additional speech assessments conducted by speech pathologists: Dysphagia Handicap Index (DHI), Voice Handicap Index (VHI-10), and speech function assessments. Subjects underwent these speech assessments at two separate time points: prior to the bilateral treatment and at the 3-month 3 post-bilateral follow-up visit. Due to the timing of introducing the additional speech assessments, ten subjects had already completed their 3-month post-bilateral visit. Hence, these 10 subjects did not have the additional speech assessments but were evaluated for speech and for other requirements per study protocol. Hence, the additional assessment is limited to 30 patients within the mITT bilateral population.

Speech function was adjudicate as Clinically Significant (CS) or Non-Clinically Significant (NCS) based on DHI, VHI-10, language assessment, and speech assessment. Overall, a total of 19 speech events in 15 of the 40 subjects were reported in this study. Out of the 19 events, 14 speech events in 11 subjects (11/40, 28%) were related to PD, bilateral PTTractotomy and lesioning. In this study, 5 events in 4 of the 40 (4/40, 10%) subjects were reported with clinically significant (moderate to severe) speech worsening:

- Four moderate events in four subjects (1 Dysphagia, 1 Dysarthria, 1 Hypophonia, 1 Stutter), and
- One severe event (Anarthria) in one subject which occurred as a result of operator error.

### Common Adverse Events

**Table 9** shows more commonly observed adverse events in bilateral subjects stratifying the incidence after the first and second treatments, respectively. A higher incidence of speech related events occurred after the second procedure (11/40, 28%) compared to the first (2/40, 5%). Similarly, a higher incidence of

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

18 of 37

{18}

axial symptoms occurred after the second procedure (10/40, 25%) compared to the first (5/40, 13%).

**Table 9:** Common adverse events observed in the study for patients who received two treatments.

|  Adverse Event | Incidence after T1 (% subjects) | Incidence after T2 (% subjects)  |
| --- | --- | --- |
|  **Speech related (TOTAL)** | **(2/40) 5%** | **(11/40) 28%**  |
|  Dysarthria | 0 | 5 (13%)  |
|  Hypophonia | 2 (5%) | 4 (10%)  |
|  slurred speech | 0 | 2 (5%)  |
|  **Axial symptom related (TOTAL)** | **(5/40) 13%** | **(10/40) 25%**  |
|  Gait disturbances | 2 (5%) | 2 (5%)  |
|  gait freezing | 0 | 3 (8%)  |
|  unsteadiness | 2 (5%) | 1 (3%)  |
|  imbalance | 1 (3%) | 7 (18%)  |
|  **Other (TOTAL)** | **(1/40) 3%** | **(6/40) 15%**  |
|  Dysphagia | 0 | 3 (8%)  |
|  increased salivation / drooling | 1 (3%) | 3 (8%)  |

**Table 10:** Adverse Event (Frequency/Incidence) Post T1 and T2 – Full Listing (n=54)

|  Grouping Term | Body System | Preferred Term | NE* (%E) | NS** (%S)  |
| --- | --- | --- | --- | --- |
|  Pallidothalamic Tractotomy Related | EENT (eye, ear, nose, and throat) | Visual Field Deficit | 1 (0.4) | 1 (1.9)  |
|   |   |  Drowsiness | 1 (0.4) | 1 (1.9)  |
|   |  General | Leg Weakness | 1 (0.4) | 1 (1.9)  |
|   |   |  Lethargy | 1 (0.4) | 1 (1.9)  |
|   |   |  Reduced Ld Effect | 1 (0.4) | 1 (1.9)  |
|   |   |  Weight Gain | 2 (0.7) | 1 (1.9)  |
|   |  Nervous | Anarthria | 1 (0.4) | 1 (1.9)  |
|   |   |  Dysarthria | 3 (1.1) | 3 (5.6)  |
|   |   |  Dyskinesia | 1 (0.4) | 1 (1.9)  |
|   |   |  Dysphagia | 2 (0.7) | 2 (3.7)  |
|   |   |  Facial Weakness | 1 (0.4) | 1 (1.9)  |
|   |   |  Gait Disturbance | 2 (0.7) | 2 (3.7)  |
|   |   |  Gait Freezing | 2 (0.7) | 2 (3.7)  |
|   |   |  Gait Unsteadiness | 3 (1.1) | 3 (5.6)  |
|   |   |  Hypophonia | 7 (2.5) | 7 (13.0)  |
|   |   |  Imbalance | 4 (1.4) | 4 (7.4)  |
|   |   |  Increased Salivation/Drooling | 2 (0.7) | 2 (3.7)  |
|   |   |  Slurred Speech | 3 (1.1) | 3 (5.6)  |
|   |   |  Somnolence | 3 (1.1) | 2 (3.7)  |
|   |   |  Stutter | 1 (0.4) | 1 (1.9)  |
|   |   |  Task Specific Apraxia | 1 (0.4) | 1 (1.9)  |
|   |   |  Uncontrolled Laughter | 1 (0.4) | 1 (1.9)  |
|   |   |  Vhi Score Elevated | 2 (0.7) | 2 (3.7)  |
|   |   |  Voice Hoarseness | 1 (0.4) | 1 (1.9)  |
|   |   |  Word-Finding Difficulty | 1 (0.4) | 1 (1.9)  |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

19 of 37

{19}

|   | Psychological | Altered Mental Status: Confusion | 1 (0.4) | 1 (1.9)  |
| --- | --- | --- | --- | --- |
|   |  | Cognitive Impairment | 1 (0.4) | 1 (1.9)  |
|  Total Pallidothalamic Tractotomy Related |  |  | 50 (17.9) | 24 (44.4)  |
|  Parkinson's Disease Related | Gastrointestinal | Nausea/Vomiting | 1 (0.4) | 1 (1.9)  |
|   |  General | Apathy | 1 (0.4) | 1 (1.9)  |
|   |   |  Fall | 6 (2.1) | 5 (9.3)  |
|   |   |  Fatigue | 2 (0.7) | 1 (1.9)  |
|   |   |  Night Sweats | 1 (0.4) | 1 (1.9)  |
|   |  Musculoskeletal | Arthralgias | 1 (0.4) | 1 (1.9)  |
|   |   |  Muscle Cramps | 1 (0.4) | 1 (1.9)  |
|   |   |  Muscular Weakness | 1 (0.4) | 1 (1.9)  |
|   |   |  Musculoskeletal Weakness | 2 (0.7) | 2 (3.7)  |
|   |   |  Restless Abdomen | 1 (0.4) | 1 (1.9)  |
|   |   |  Restless Legs | 1 (0.4) | 1 (1.9)  |
|   |   |  Slouched Posture | 1 (0.4) | 1 (1.9)  |
|   |  Nervous | Apraxia Of Eyelid | 1 (0.4) | 1 (1.9)  |
|   |   |  Concentration Issues | 1 (0.4) | 1 (1.9)  |
|   |   |  Decreased Short Term Recall | 1 (0.4) | 1 (1.9)  |
|   |   |  Dizziness | 1 (0.4) | 1 (1.9)  |
|   |   |  Dysphagia | 1 (0.4) | 1 (1.9)  |
|   |   |  Dystonia | 1 (0.4) | 1 (1.9)  |
|   |   |  Finger Tremor | 1 (0.4) | 1 (1.9)  |
|   |   |  Freezing | 5 (1.8) | 4 (7.4)  |
|   |   |  Freezing Gait | 2 (0.7) | 2 (3.7)  |
|   |   |  Gait Disturbance | 1 (0.4) | 1 (1.9)  |
|   |   |  Gait Freezing | 1 (0.4) | 1 (1.9)  |
|   |   |  Gait Imbalance | 1 (0.4) | 1 (1.9)  |
|   |   |  Hypophonia | 1 (0.4) | 1 (1.9)  |
|   |   |  Imbalance | 2 (0.7) | 2 (3.7)  |
|   |   |  Increased Salivation/Drooling | 1 (0.4) | 1 (1.9)  |
|   |   |  Motor Fluctuations | 1 (0.4) | 1 (1.9)  |
|   |   |  Myoclonus | 1 (0.4) | 1 (1.9)  |
|   |   |  Paraphonia | 1 (0.4) | 1 (1.9)  |
|   |   |  Slowness | 1 (0.4) | 1 (1.9)  |
|   |   |  Visual Hallucinations | 1 (0.4) | 1 (1.9)  |
|   |  Psychological | Depression | 2 (0.7) | 2 (3.7)  |
|  Hallucination |   | 2 (0.7) | 2 (3.7)  |   |
|  Total Parkinson's Disease Related |  |  | 49 (17.5) | 22 (40.7)  |
|  Procedure Related | EENT | Disconjugate Gaze | 1 (0.4) | 1 (1.9)  |
|   |  Gastrointestinal | Nausea/Vomiting | 1 (0.4) | 1 (1.9)  |
|   |  General | Drowsiness | 2 (0.7) | 2 (3.7)  |
|   |   |  Fatigue | 7 (2.5) | 7 (13.0)  |
|   |   |  Weakness | 1 (0.4) | 1 (1.9)  |
|   |  Nervous | Cerebellar Ataxia | 1 (0.4) | 1 (1.9)  |
|   |   |  Decreased Short Term Memory | 1 (0.4) | 1 (1.9)  |
|   |   |  Dysarthria | 2 (0.7) | 2 (3.7)  |
|   |   |  Gait Unsteadiness | 1 (0.4) | 1 (1.9)  |
|   |   |  Hiccups | 1 (0.4) | 1 (1.9)  |
|   |   |  Imbalance | 1 (0.4) | 1 (1.9)  |
|   |   |  Leg Weakness | 1 (0.4) | 1 (1.9)  |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

20 of 37

{20}

|  |  | Numbness/Tingling | 1 (0.4) | 1 (1.9) |
| --- | --- | --- | --- | --- |
|  | Pain/Discomfort | Head Pain | 1 (0.4) | 1 (1.9) |
|  | Psychological | Confusion | 1 (0.4) | 1 (1.9) |
| **Total Procedure Related** |  |  | **23 (8.2)** | **16 (29.6)** |
| Transient | Cardiovascular | Fainting | 1 (0.4) | 1 (1.9) |
| Hypertension | 19 (6.8) | 16 (29.6) |
| Hypotension | 1 (0.4) | 1 (1.9) |
| Gastrointestinal | Constipation | 1 (0.4) | 1 (1.9) |
| Nausea/Vomiting | 5 (1.8) | 4 (7.4) |
| General | Fall | 1 (0.4) | 1 (1.9) |
| Musculoskeletal | Positional Pain | 1 (0.4) | 1 (1.9) |
| Nervous | Agitation | 1 (0.4) | 1 (1.9) |
| Dizziness | 8 (2.9) | 6 (11.1) |
| Dyskinesia | 2 (0.7) | 1 (1.9) |
| Gait Disturbance | 1 (0.4) | 1 (1.9) |
| Hiccups | 1 (0.4) | 1 (1.9) |
| Hypersalivation | 1 (0.4) | 1 (1.9) |
| Hypophonia | 1 (0.4) | 1 (1.9) |
| Pain/Discomfort | Head Pain | 1 (0.4) | 1 (1.9) |
| Headache | 6 (2.1) | 5 (9.3) |
| Positional Pain | 1 (0.4) | 1 (1.9) |
| Sonication Head Pain | 1 (0.4) | 1 (1.9) |
| Psychological | Anxiety | 5 (1.8) | 4 (7.4) |
| **Total Transient** |  |  | **58 (20.7)** | **25 (46.3)** |
| Unrelated | Cardiovascular | Edema - Le | 1 (0.4) | 1 (1.9) |
| Hypertension | 1 (0.4) | 1 (1.9) |
| Pulmonary Embolism | 2 (0.7) | 2 (3.7) |
| Dermatologic | Livido Reticularis | 1 (0.4) | 1 (1.9) |
| Scalp Redness | 1 (0.4) | 1 (1.9) |
| Skin Rash | 1 (0.4) | 1 (1.9) |
| EENT | Blepharospasm | 1 (0.4) | 1 (1.9) |
| Blurry Vision | 1 (0.4) | 1 (1.9) |
| Conjunctivitis | 1 (0.4) | 1 (1.9) |
| Decreased Visual Acuity | 1 (0.4) | 1 (1.9) |
| Double Vision | 1 (0.4) | 1 (1.9) |
| Dry Eyes | 4 (1.4) | 4 (7.4) |
| Eye Redness | 1 (0.4) | 1 (1.9) |
| Eye Swelling | 1 (0.4) | 1 (1.9) |
| Post-Nasal Drip | 1 (0.4) | 1 (1.9) |
| Squinting | 1 (0.4) | 1 (1.9) |
| Visual Field Deficit | 1 (0.4) | 1 (1.9) |
| Worsening Eyesight | 1 (0.4) | 1 (1.9) |
| Gastrointestinal | Constipation | 1 (0.4) | 1 (1.9) |
| Gastrointestinal Symptoms | 1 (0.4) | 1 (1.9) |
| Incontinence | 1 (0.4) | 1 (1.9) |
| Intestinal Obstruction | 1 (0.4) | 1 (1.9) |
| General | Anemia | 1 (0.4) | 1 (1.9) |
| Dehydration | 1 (0.4) | 1 (1.9) |
| Dizziness | 1 (0.4) | 1 (1.9) |
| Edema - Le | 2 (0.7) | 2 (3.7) |
| Fall | 4 (1.4) | 4 (7.4) |
| Fatigue | 1 (0.4) | 1 (1.9) |
| Leg Swelling | 1 (0.4) | 1 (1.9) |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

21 of 37

{21}

|   | Sleep Apnea | 1 (0.4) | 1 (1.9)  |
| --- | --- | --- | --- |
|   | Syncope | 1 (0.4) | 1 (1.9)  |
|  Genitourinary | Kidney Stone | 1 (0.4) | 1 (1.9)  |
|   |  Renal Insufficiency | 1 (0.4) | 1 (1.9)  |
|   |  Urinary Tract Infection | 1 (0.4) | 1 (1.9)  |
|  Infection | Cold Symptoms | 1 (0.4) | 1 (1.9)  |
|   |  Covid-19 | 6 (2.1) | 5 (9.3)  |
|   |  Flu | 2 (0.7) | 2 (3.7)  |
|   |  Sepsis | 1 (0.4) | 1 (1.9)  |
|   |  Viral Infection | 2 (0.7) | 2 (3.7)  |
|  Musculoskeletal | Arthritis | 1 (0.4) | 1 (1.9)  |
|   |  Back Sprain | 1 (0.4) | 1 (1.9)  |
|   |  Bunion Removal | 1 (0.4) | 1 (1.9)  |
|   |  Decreased Mouth Movement | 1 (0.4) | 1 (1.9)  |
|   |  Hip Injury | 1 (0.4) | 1 (1.9)  |
|   |  Hypotonia | 1 (0.4) | 1 (1.9)  |
|   |  Muscle Pain | 1 (0.4) | 1 (1.9)  |
|   |  Neck Pain | 1 (0.4) | 1 (1.9)  |
|   |  Piriformis | 1 (0.4) | 1 (1.9)  |
|  Nervous | Clumsiness | 1 (0.4) | 1 (1.9)  |
|   |  Insomnia | 2 (0.7) | 2 (3.7)  |
|   |  Paresthesia | 1 (0.4) | 1 (1.9)  |
|   |  Stroke | 2 (0.7) | 2 (3.7)  |
|  Pain/Discomfort | Back Pain | 3 (1.1) | 3 (5.6)  |
|   |  Headache | 1 (0.4) | 1 (1.9)  |
|   |  Sciatica Pain | 1 (0.4) | 1 (1.9)  |
|   |  Visual Discomfort | 1 (0.4) | 1 (1.9)  |
|  Psychological | Anxiety | 1 (0.4) | 1 (1.9)  |
|   |  Delusion | 1 (0.4) | 1 (1.9)  |
|  Respiratory | Decreased Lung Function | 1 (0.4) | 1 (1.9)  |
|  Stereotactic Frame | Eye Swelling | 2 (0.7) | 2 (3.7)  |
|   |  Facial Droop | 2 (0.7) | 1 (1.9)  |
|   |  Head Discomfort | 1 (0.4) | 1 (1.9)  |
|   |  Headache | 5 (1.8) | 5 (9.3)  |
|   |  Numbness/Tingling | 1 (0.4) | 1 (1.9)  |
|   |  Pin Site Bleeding | 1 (0.4) | 1 (1.9)  |
|   |  Pin Site Edema | 1 (0.4) | 1 (1.9)  |
|   |  Pin Site Pain | 8 (2.9) | 7 (13.0)  |
|  Vision | Vision Problem | 1 (0.4) | 1 (1.9)  |
|  Total Unrelated |  | 100 (35.7) | 36 (66.7)  |
|  Grand Total |  | 280 (100.0) | 48 (88.9)  |
|  *N_{E}=number of events; %_{E} = Percent out of all events (N=280)  |   |   |   |
|  **N_{S}=number of subjects; %_{S} = Percent out of all subjects (N=54)  |   |   |   |

## 2. Effectiveness Results

Key effectiveness outcomes are presented in **Table 11** and **Figure 4** to **Figure 8**.

The primary, confirmatory secondary, and secondary effectiveness endpoints were pre-specified to evaluate the mean of each endpoint metric. However, for some combinations of endpoints and visits, the assumption of a normal distribution did not hold for the observed data. Therefore, for the hypothesis driven endpoint (primary effectiveness endpoint), the statistical test was

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

22 of 37

{22}

performed on median rather than the mean value. For completeness, the tables presented below report the confidence interval for the mean and median.

### Primary Effectiveness Endpoint

The analysis of effectiveness was based on the bilateral ITT (n=40) and mITT (n=38) populations for the primary effectiveness endpoint.

Table 11 presents the primary effectiveness endpoint of the study for ITT and mITT populations as defined as the median percent change of the bilateral upper and lower extremity motor score from the MDS-UPDRS Part III OFF-Medications at 3 months post-bilateral treatment (T2), assessed on both treated sides compared to baseline prior to any treatment (B1). As shown in Table 11 and Figure 4, the analysis on mITT data demonstrated a median score improvement of 10.2 points and 32.7% at 3 months in the MDS-UPDRS part-III score compared to baseline (B1). The primary effectiveness endpoint was met. The 14/54 enrolled subjects that did not proceed to bilateral treatment experienced an average improvement in mean score from B1 of 12.1 points (32.8%) at 3 months, 13.1 points (36.3%) at 6 months, and 12.4 (30.1%) at 12 months when considering both sides of the brain.

Table 11: Primary Efficacy Endpoint: MDS-UPDRS Part III OFF Medication Upper / Lower Extremity Motor Score

|  Visit | Statistic | Calculated Score | Change in score from B1 (points) | Percent Change in score from B1 (%)  |
| --- | --- | --- | --- | --- |
|  **Bilateral mITT Analysis Set (N=38)**  |   |   |   |   |
|  **Baseline** | Mean | 34.7 |  |   |
|   |  SD | 9.7 |  |   |
|   |  Min | 19.0 |  |   |
|   |  Median | 32.5 |  |   |
|   |  Max | 57.0 |  |   |
|   |  Mean Lower 95% CL | 31.5 |  |   |
|   |  Mean Upper 95% CL | 37.9 |  |   |
|  **Month 3** | **Mean** | **21.5** | **13.2** | **34.0**  |
|   |  SD | 7.9 | 12.4 | 27.0  |
|   |  Mean Lower 95% CL | 18.9 | 9.2 | 25.0  |
|   |  Mean Upper 95% CL | 24.1 | 17.2 | 42.9  |
|   |  **Median** | **21.0** | **10.2** | **32.7**  |
|   |  Median Lower 95% CL |  |  | 21.8  |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

23 of 37

{23}

|  Visit | Statistic | Calculated Score | Change in score from B1 (points) | Percent Change in score from B1 (%)  |
| --- | --- | --- | --- | --- |
|   | Median Upper 95% CL |  |  | 43.6  |
|   |  P-Value^{1} |  |  | <.0001  |
|  **Bilateral ITT Analysis Set (N=40)**  |   |   |   |   |
|  Baseline | Mean | 34.8 |  |   |
|   |  Median | 33.0 |  |   |
|   |  SD | 9.5 |  |   |
|  Month 3 | **Mean** | **21.6** | **13.1** | **33.9**  |
|   |  **Median** | **21.0** | **10.4** | **32.6**  |
|   |  SD | 8.1 | 12.3 | 26.9  |
|   |  P-Value |  |  | <.0001  |
|  NOTE: Lower scores indicate better clinical outcome. Higher percent changes demonstrate greater improvement. 1: P-values reflect the analysis performed with the median rather than the mean values.  |   |   |   |   |

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

Figure 4: Primary Endpoint – MDS-UPDRS Part III Off Medication Upper and Lower Extremity Score for Both Treated Side – Score and Percent Change from Baseline (B1) in the bilateral mITT population.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

24 of 37

{24}

Figure 5 presents raw median MDS-UPDRS Part III Off Medication Upper and Lower Extremity Scores for first side treated, second side treated, and both sides. While fluctuations in score are observed throughout the follow up period, in general, trends show decreasing scores in the first side treated after the unilateral treatment was conducted on the first side. Decreasing scores are observed for the second side treated only after the T2 treatment (T2 timing depicted by the green dotted line in Figure 5). Overall, a larger improvement in the score on both sides was observed after T1 in comparison to that observed for both sides after T2. This finding is not unexpected as the unilateral procedure targeted the side with more significant symptoms first.

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

Figure 5: Median MDS-UPDRS Part III Off Medication Upper and Lower Extremity Scores for first side treated, second side treated, and both sides throughout study follow up. The green dotted line indicates timing of the T2 treatment.

### Additional Primary Effectiveness Analyses (post-hoc)

Additional post-hoc effectiveness analyses were conducted for the primary effectiveness endpoint (MDS-UPDRS Part III Off Medication Upper and Lower Extremity) on the bilateral mITT population to isolate improvement observed for the second treatment of the bilateral PTTractotomy. These analyses evaluated the primary effectiveness endpoint using a the 6-month post-unilateral timepoint as the baseline comparison (B2 depicted in Figure 2). The percent change of the primary endpoint was recalculated for each patient as follows:

$$\% \text{ Change} = 100 * (\text{B2 score} - \text{T2 score, month 3 score}) / (\text{B2 score})$$

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

25 of 37

{25}

where ‘B2 score’ is the score at B2 and ‘T2 score, month 3’ is the score at 3 months post-T2.

Results of this analysis are presented descriptively for percent change (**Figure 6**) and score change (**Figure 7**). Larger improvements are observed for the second side treated in comparison to both sides at timepoints following the bilateral treatment. Percent change in score (**Figure 6**) and change in score (**Figure 7**) indicate improvement in median MDS-UPDRS Part III Off Medication Upper and Lower Extremity Scores for second side treated and both sides following the bilateral treatment. The percent and score changes in “Both Sides” are smaller than changes in the side treated at the second procedure, because percent/score change for the side treated in the first procedure was negative, i.e., the first treatment side worsened during the period of the second treatment.

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

**Figure 6:** Percent change in Median MDS-UPDRS Part III Off Medication Upper and Lower Extremity Scores with respect to median score at B2 for second side treated, and both sides. Baseline is defined as B2 (6-month post-unilateral timepoint). Positive values indicate reduction in score (improvement).

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

26 of 37

{26}

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

**Figure 7:** Median improvement in MDS-UPDRS Part III Off Medication Upper and Lower Extremity Score after T2 with respect to median score at B2 for the second side treated, and both sides. Baseline is defined as score at B2 (6-month post-unilateral timepoint). Positive values indicate reduction in score (improvement).

**Figure 8** presents the median improvement in MDS-UPDRS Part III Off Medication Upper and Lower Extremity Score for the side treated and both sides at 3 months after the unilateral and bilateral procedures. **Figure 8** demonstrates that a larger improvement was observed for the treated side and both sides after the unilateral procedure compared to the bilateral procedure. A responder rate analysis was conducted on the MDS-UPDRS Part III Off Medication Upper and Lower Extremity Score using a minimal clinical important difference (MCID) of 3 points. The responder rate for T2 on the second treated side (when compared to B2) is 61.43% (N=38). In comparison, the responder rate of T1 on the first treated side (when compared to B1) is 90.7% (49/54). This finding is not unexpected given the higher magnitude of symptoms occurring on the side treated during the unilateral procedure.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

27 of 37

{27}

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

Figure 8: Median improvement in MDS-UPDRS Part III Off Medication Upper and Lower Extremity Score for the side treated and both sides 3 months after unilateral and bilateral procedures. Scores at B1 and B2 were used as baseline scores for the unilateral and bilateral procedures, respectively.

### Summary of effectiveness of unilateral population

Although not presented in detail, the 14/54 enrolled subjects that did not proceed to bilateral treatment experienced a median improvement in score from B1 of 9.5 points (33.4%) at 3 months, 12.5 points (41.5%) at 6 months, and 13.3 (39.1%) at 12 months after their only procedure, when considering both sides. The unilateral procedure (n=54) showed an improvement of 11 points in median score which equates to an approximate improvement of (52.6%) in the MDS-UPDRS part-III Upper and Lower Extremity score at 3 months post treatment when considering both sides.

### Confirmatory endpoints

The descriptive analyses of the confirmatory endpoints are provided in Table 12 and Table 13. For confirmatory endpoint 1, the median MDS-UPDRS Part IV score dropped from 11.5 points at B1 to 4.0 points at 3 months post T2 (median percent reduction of 66.1%). For confirmatory endpoint 2, the median MDS-UPDRS Part III Total Score OFF medication dropped from 49.5 at B1 to 32.5 (median percent reduction of 33%) at 3 months post T2.

Table 12: Confirmatory Endpoint 1: MDS-UPDRS Part IV (Bilateral mITT Analysis Set (N=38))

|  Visit | Statistic | Calculated Score | Change from B1 | Percent Change from B1  |
| --- | --- | --- | --- | --- |
|  Baseline | Mean | 10.6 |  |   |
|   |  SD | 3.2 |  |   |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

28 of 37

{28}

|   | Min | 5.0 |  |   |
| --- | --- | --- | --- | --- |
|   | Median | 11.5 |  |   |
|   | Max | 17.0 |  |   |
|  **Month 3** | Mean | 3.6 | 7.0 | 67.9  |
|   |  Median | 4.0 | 7.0 | 66.1  |
|   |  SD | 3.0 | 3.0 | 25.3  |
|  Lower scores indicate better clinical outcome. Higher percent changes demonstrate greater improvement.  |   |   |   |   |

**Table 13:** Confirmatory Endpoint 2: MDS-UPDRS Part III Total Score (Bilateral mITT Analysis Set (N=38))

|  Visit | Statistic | Calculated Score | Change from B1 | Percent Change from B1  |
| --- | --- | --- | --- | --- |
|  **Baseline** | Mean | 51.0 |  |   |
|   |  SD | 12.6 |  |   |
|   |  Median | 49.5 |  |   |
|  **Month 3** | Mean | 33.3 | 17.7 | 31.8  |
|   |  Median | 32.5 | 16.0 | 33.0  |
|   |  SD | 11.3 | 15.8 | 24.7  |
|  Lower scores indicate better clinical outcome. Higher percent changes demonstrate greater improvement.  |   |   |   |   |

## Secondary endpoints

Three secondary effectiveness analyses were performed on the bilateral mITT population out to 12 months. These are the same analyses performed for the primary and confirmatory endpoints, except now assessed to reflect the outcomes through all follow up visits.

Change as compared to B1 for MDS-UPDRS Part III OFF Medications Upper and Lower Extremity Score through 12 months post T2 is shown in **Table 14**. This analysis shows a median percent score reduction of 43.8%, 32.7%, 36.9%, and 35.5% at 1, 3, 6, and 12 months, respectively. The calculated median score dropped from 32.5 at baseline to 17.0, 21.0, 21.9, and 21.7 at 1, 3, 6, and 12 months, respectively.

**Table 14:** Secondary Endpoint 1: MDS-UPDRS Part III OFF Med Upper and Lower Extremity Score Bilateral Effect through Month 12 (Bilateral mITT Analysis Set (N=38))

|  Visit | Statistic | Calculated Score | Change from Baseline | Percent Change from Baseline  |
| --- | --- | --- | --- | --- |
|  **Baseline** | Mean | 34.7 |  |   |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

29 of 37

{29}

|   | Median | 32.5 |  |   |
| --- | --- | --- | --- | --- |
|   |  SD | 9.7 |  |   |
|  Month 1 | Mean | 18.4 | 16.3 | 44.5  |
|   |  Median | 17.0 | 15.0 | 43.8  |
|   |  SD | 8.6 | 12.0 | 27.0  |
|  Month 3 | Mean | 21.5 | 13.2 | 34.0  |
|   |  Median | 21.0 | 10.2 | 32.7  |
|   |  SD | 7.9 | 12.4 | 27.0  |
|  Month 6 | Mean | 21.7 | 13.0 | 35.5  |
|   |  Median | 21.9 | 11.0 | 36.9  |
|   |  SD | 8.6 | 11.0 | 25.6  |
|  Month 12 | Mean | 21.9 | 12.8 | 35.0  |
|   |  Median | 21.7 | 10.6 | 35.5  |
|   |  SD | 7.9 | 9.8 | 22.2  |

Change as compared to B1 for MDS-UPDRS Part IV – Motor Complications Score through 12 months post T2 is shown in Table 15. This analysis shows a median percent score reduction of 69.9%, 66.1%, 66.8%, and 71.1% at 1, 3, 6, and 12 months, respectively. The calculated median score dropped from 11.5 at baseline to 3.8, 4.0, 4.0, and 3.2 at 1, 3, 6, and 12 months, respectively.

Table 15: Secondary Endpoint 2: MDS-UPDRS Part IV through Month 12 (Bilateral mITT Analysis Set (N=38))

|  Visit | Statistic | Calculated Score | Change from B1 | Percent Change from B1  |
| --- | --- | --- | --- | --- |
|  Baseline | Mean | 10.6 |  |   |
|   |  SD | 3.2 |  |   |
|   |  Median | 11.5 |  |   |
|  Month 1 | Mean | 4.1 | 6.5 | 62.1  |
|   |  Median | 3.8 | 6.1 | 69.9  |
|   |  SD | 3.7 | 4.0 | 35.2  |
|  Month 3 | Mean | 3.6 | 7.0 | 67.9  |
|   |  Median | 4.0 | 7.0 | 66.1  |
|   |  SD | 3.0 | 3.0 | 25.3  |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

30 of 37

{30}

|  **Month 6** | Mean | 4.0 | 6.6 | 62.6  |
| --- | --- | --- | --- | --- |
|   |  Median | 4.0 | 6.5 | 66.8  |
|   |  SD | 3.4 | 3.9 | 33.5  |
|  **Month 12** | Mean | 3.8 | 6.8 | 67.1  |
|   |  Median | 3.2 | 6.4 | 71.1  |
|   |  SD | 3.7 | 3.5 | 31.1  |

Change as compared to B1 for MDS-UPDRS – Part III OFF Medication Total Score through 12 months post T2 is shown in **Table 16**. This analysis shows a median score reduction of 39.8%, 33.0%, 36.8%, and 33.6% at 1, 3, 6, and 12 months, respectively. The calculated median score dropped from 49.5 at baseline to 28.1, 32.5, 32.7, and 35.2 at 1, 3, 6, and 12 months, respectively.

**Table 16:** Secondary Endpoint 3: MDS-UPDRS Part III OFF Med Total Score through Month 12 (Bilateral mITT Analysis Set (N=38))

|  Visit | Statistic | Calculated Score | Change from B1 | Percent Change from B1  |
| --- | --- | --- | --- | --- |
|  **Baseline** | Mean | 51.0 |  |   |
|   |  SD | 12.6 |  |   |
|   |  Median | 49.5 |  |   |
|  **Month 1** | Mean | 29.5 | 21.5 | 40.0  |
|   |  Median | 28.1 | 18.7 | 39.8  |
|   |  SD | 12.5 | 16.8 | 27.4  |
|  **Month 3** | Mean | 33.3 | 17.7 | 31.8  |
|   |  Median | 32.5 | 16.0 | 33.0  |
|   |  SD | 11.3 | 15.8 | 24.7  |
|  **Month 6** | Mean | 32.8 | 18.2 | 34.4  |
|   |  Median | 32.7 | 16.5 | 36.8  |
|   |  SD | 12.2 | 14.3 | 23.7  |
|  **Month 12** | Mean | 34.7 | 16.3 | 30.5  |
|   |  Median | 35.2 | 16.1 | 33.6  |
|   |  SD | 11.1 | 12.9 | 21.3  |

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

31 of 37

{31}

## Patient and Clinical Global Impression of Change

The clinician-reported rating of subject [Clinician Global Impression of change (CGIC)] overall change at the 3 months post bilateral treatment showed that 97% of the patients that underwent the contralateral procedure had at least some improvement, with 70% being rated as having been much or very much improved.

The self-reported patient Global Impression of change (PGIC) rating of overall change at 3-months post bilateral treatment showed that 86% of the patients that underwent the bilateral treatment felt they had at least some improvement, with 43% rating themselves as having much or very much improved. A total of 2.7% of subjects rated themselves as having no change and 10.8% of subjects had some extent of worsening.

## Patient Surveys

The self-reported patient questionnaire indicated the following at the 3 months post bilateral treatment:

- 65% of the patients that underwent the bilateral treatment felt that, taking everything into account, they would have the procedure again while the remaining 35.1% would not repeat the procedure.
- 62% felt satisfied that the good things outweighed the bad things and the same percentage were overall satisfied with the procedure.
- 76% felt that the procedure reduced PD symptoms well on one side while the remainder indicated no change occurred or symptoms were not well reduced.
- 68% felt that the procedure reduced their PD symptoms well at least to some degree on both sides, while the remainder indicated no change occurred or symptoms were not well reduced.

# 3. Subgroup Analyses

The potential association between primary and confirmatory effectiveness outcomes and geographic location of sites was evaluated in the study. Improvement from baseline was observed in every region for the primary and confirmatory secondary endpoints (Table 17). Heterogeneity was observed across regions in an exploratory regional poolability analysis considering mean and median percent reduction in score for primary and confirmatory endpoints. However, limited sample sizes in regions outside of the US resulted in wide confidence intervals limiting the interpretability of this regional subgroup analysis.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

32 of 37

{32}

**Table 17: Poolability Analysis by Region**

|  Region | Statistic | Primary Effectiveness Endpoint | Confirmatory Secondary Effectiveness Endpoint  |   |
| --- | --- | --- | --- | --- |
|   |   |  MDS-UPDRS Part III Off Medication Upper and Lower Extremity Motor Score | MDS-UPDRS Part III Off Medication Total Score | MDS-UPDRS Part IV Motor Complications Score  |
|  US (N=29) | Mean percent change from baseline at 3 months | 32.2 | 30.7 | 65.1  |
|   |  Median percent change from baseline at 3 months | 29.7 | 32.3 | 65.6  |
|   |  Median 95% CI* | 16.4, 43.1 | 20.6, 44.0 | 54.3, 76.9  |
|  Taiwan (N=6) | Mean percent change from baseline at 3 months | 54.9 | 48.8 | 90  |
|   |  Median percent change from baseline at 3 months | 59.9 | 53.3 | 100.0  |
|   |  Median 95% CI* | 45.0, 64.8 | 26.8, 62.3 | 40.0, 100.0  |
|  Spain (N=3) | Mean percent change from baseline at 3 months | 9.6 | 8.5 | 50  |
|   |  Median percent change from baseline at 3 months | 9.5 | 11.5 | 50  |
|   |  Median 95% CI* | -8.0, 27.3 | -7.9, 21.9 | 42.9, 57.1  |

\*CIs are not adjusted for multiplicity

The study was not specifically powered for sex, age, race, ethnicity, or any other relevant characteristic specific subgroups.

#### 4. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

### **XI. FINANCIAL DISCLOSURE**

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 9 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data.

### **XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION**

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

33 of 37

{33}

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Neurological Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

### XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

#### A. Effectiveness Conclusions

The Exablate bilateral PTTractotomy had a median score improvement of 10.2 points and 32.7% at 3 months after the second procedure in the MDS-UPDRS part-III Upper and Lower Extremity score OFF-Medications compared to baseline (B1, prior to any treatment). The 14/54 enrolled subjects that did not proceed to bilateral treatment experienced an median improvement in score from B1 of 9.5 points (33.4%) at 3 months, 12.5 points (41.5%) at 6 months, and 13.3 (39.1%) at 12 months after their only procedure, when considering both sides. The unilateral procedure (n=54) showed an improvement of 11 points in median score which equates to an approximate improvement of (52.6%) in the MDS-UPDRS part-III Upper and Lower Extremity score at 3 months post treatment when considering both sides. A smaller magnitude of improvement (3.8 points in median score change) was observed after the second procedure which met clinical significance when considering the treated side of the brain. The relative difference in benefit observed after the first and second treatments is not unexpected as the unilateral procedure targeted the side with more significant symptoms first. Overall, the changes observed throughout the staged procedure reflect clinically meaningful improvements.

A post hoc responder rate analysis was conducted post-hoc on the MDS-UPDRS Part III Off Medication Upper and Lower Extremity Score at 3 months post bilateral treatment using a minimal clinical important difference (MCID) of 3 points. The responder rate for T2 on the second treated side (when compared to B2) was 61.43% (N=38). In comparison, the responder rate of T1 on the first treated side at 3 months post treatment (when compared to B1) was 90.7% (49/54). As discussed above, this finding is not unexpected given the higher magnitude of symptoms occurring on the side treated during the unilateral procedure.

The clinician-reported rating of subject [Clinician Global Impression of Change (CGIC)] overall change at the 3 months post bilateral treatment showed that 97% of the patients that underwent the contralateral procedure had at least some improvement, with 70% being rated as having been much or very much improved. The self-reported patient Global Impression of Change (PGIC) rating of overall change at 3-months post bilateral treatment showed that 86% of the patients that underwent the bilateral treatment felt they had at least some improvement, with 43% rating themselves as having much or very much improved. A total of 2.7% of subjects

---PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

34 of 37

{34}

rated themselves as having no change and 10.8% of subjects had some extent of worsening.

### **B. Safety Conclusions**

The risks of the device are based on nonclinical laboratory and animal studies as well as data collected in a clinical study conducted to support PMA approval as described above. A total of 280 events were reported in 54 subjects that received at least 1 treatment with 129 events recorded in 33 of the 40 bilateral subjects. Approximately 96.4% of the 280 AEs were either mild (68.9%) or moderate (27.5%) in severity. Seven events (2.5%) were severe in nature and three (1.1%) were life-threatening. None of the severe or life-threatening events were device related.

A total of 19 speech events in 15 of the 40 bilateral cohort subjects were reported. Out of the 19 events, 14 speech events in 11 subjects (11/40, 28%) were related to PD, bilateral PTTractotomy and lesioning. In this study, 5 events in 4 of the 40 (4/40, 10%) subjects were reported with clinically significant (moderate to severe) speech worsening. A total of 10 axial (gait, freezing, imbalance) AEs in 10 of the 40 bilateral cohort subjects were reported as PTTractotomy-related or PD-related. The incidence of speech- and axial symptom-related adverse events occurred after the 2$^{nd}$ treatment is higher than that of the 1$^{st}$ treatment.

### **C. Benefit-Risk Determination**

The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The response to treatment is evaluated by whether a patient had a clinically meaningful improvement on the MDS-UPDRS Part III OFF-Medications at 3 months post-bilateral treatment as compared to baseline prior to any treatment. The Exablate bilateral PTTractotomy Exhibited a clinically meaningful improvement (>3.25 points) with respect to baseline prior to any treatment.

The probable risks of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The AEs observed in the study are of expected types, and rates for patients with advanced, idiopathic Parkinson's Disease with medication-refractory moderate to severe motor complications. The AEs observed in the study were primarily mild or moderate in severity.

Additional factors to be considered in determining probable risks and benefits for the Exablate Neuro device include that the clinical study (G200238) was designed to measure the safety and effectiveness of staged bilateral PTTractotomy. The clinical outcomes and the assessment of MDS-UPDRS part-III Upper and Lower Extremity score OFF-Medications scores showed improvement in the bilateral treated subjects and the improvement was sustained through 12 months post procedure. The clinical

---PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

35 of 37

{35}

study was not designed to evaluate the isolated effectiveness of the second treatment but when considered descriptively, a clinically meaningful improvement was observed after both the first and second treatments with less improvement noted after the second procedure. The AEs reported in the clinical study are as expected and consistent with the AEs reported in the clinical studies supporting P150038/S014. However, the clinical data identified risks associated with speech difficulties and axial symptoms, which occurred at a higher rate after the second treatment. While observed trends in AEs and descriptive effectiveness outcomes support a positive benefit risk profile, the results highlight the importance of discussions between patients and clinicians regarding expected treatment benefits for patients considering a staged bilateral therapy. Overall, a positive benefit risk profile was observed for use of the Exablate Neuro for PTTractotomy when considering the clinically meaningful improvements and types and frequency of adverse events observed in the study.

# 1. Patient Perspective

Patient perspectives considered during the review included:

- The PGIC assessment, which is a 7-point scale where the patient rates the severity of their own condition at the time of assessment, found that the majority of patients experienced some level of improvement relative to before Exablate treatment.
- Patient Satisfaction Questionnaire that comprised of 5 questions assessing treatment satisfaction found that the majority (62.2%) of subjects were satisfied with the bilateral procedure.

In conclusion, given the available information above, the data support that for unilateral pallidothalamic tractotomy of advanced idiopathic Parkinson's Disease with medication-refractory moderate to severe motor complications as an adjunct to Parkinson's disease medication treatment, and in the staged (by at least 6 months from the first pallidothalamic tractotomy), unilateral pallidothalamic tractotomy of idiopathic Parkinson's Disease with medication-refractory motor complications of their contralateral side that was not previously treated in the first unilateral pallidothalamic tractotomy the probable benefits outweigh the probable risks.

# D. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. Based on the results of the pivotal study, the bilateral ablation of the pallidothalamic tract adjunctive to medication using the Exablate Neuro may provide benefit as an alternative to other existing treatments relative to the risks in selected patients with severe disabling motor complications of advanced, idiopathic Parkinson's disease.

PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

36 of 37

{36}

#### **XIV. CDRH DECISION**

CDRH issued an approval order on July 3, 2025. The final clinical conditions of approval cited in the approval order are described below.

The purpose of the PAS is to characterize the safety and effectiveness of the Exablate Neuro during real-world use for bilateral pallidothalamic tractotomy of patients with advanced, idiopathic Parkinson's Disease with medication-refractory moderate to severe motor complications as an adjunct to Parkinson's disease medication treatment. The primary safety analysis will evaluate the incidence and severity of device and procedure related adverse events associated with a staged bilateral procedure using Exablate Neuro from the index procedure through 12 months. The primary effectiveness analysis will evaluate the improvement in score of the bilateral upper & lower extremity motor score from the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III OFF-Medications at 3 months post bilateral treatment on both sides, as compared to baseline 6 month post unilateral treatment. The study will also report on score and percent improvement of the first treated side, second treated side, and both sides at all follow-up timepoints. Additional measures will include the total score parts III and IV at the same time points with specific intent of capturing information on axial symptoms. The study will newly enroll a minimum number of subjects which ensures i) a statistically valid number of subjects evaluable at 3 months post-bilateral procedure, to demonstrate meeting a clinically meaningful performance goal of the improvement of the MDS-UPDRS Part III OFF-Medications at 3 months post bilateral, and ii) a minimum of 60 subjects to demonstrate generalizability of outcomes observed in the premarket study for safety and effectiveness. Patient follow-up will occur at baseline, 3 months, 6 months, and 1 year post-bilateral procedure.

The applicant's manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

#### **XV. APPROVAL SPECIFICATIONS**

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

#### **XVI. REFERENCES**

None.

---PMA P150038/S037: FDA Summary of Safety and Effectiveness Data

37 of 37

---

**Source:** [https://fda.innolitics.com/device/P150038S037](https://fda.innolitics.com/device/P150038S037)

**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