← Product Code [SGS](/productcode/SGS) · P960009S482

# Medtronic DBS Therapy for Dystonia (P960009S482)

_Medtronic, Inc. · SGS · Nov 22, 2025 · Neurology · APPR_

**Canonical URL:** https://fda-staging.innolitics.com/device/P960009S482

## Device Facts

- **Applicant:** Medtronic, Inc.
- **Product Code:** [SGS](/productcode/SGS.md)
- **Decision Date:** Nov 22, 2025
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Neurology
- **Attributes:** Therapeutic, Real-World Evidence, Pediatric

## Real-World Evidence

| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
| --- | --- | --- | --- | --- | --- |
| P960009S482 · Nov 22, 2025 | Medtronic DBS Therapy for Dystonia | Medtronic, Inc. | Medtronic Product Surveillance Registry (PSR); Published clinical literature (meta-analyses of prospective and retrospective studies) | The PSR and meta-analyses of published literature were used to characterize the safety profile (e.g., rates of device complications, infections, and intracranial hemorrhage) and effectiveness (e.g., BFMDRS and TWSTRS scores) of the DBS system across different dystonia types and patient populations (adults and pediatric). | Product Surveillance Registry; Meta-analysis; Retrospective studies; Real-world safety; Dystonia |

### Clinical Evidence

| Study Design | Population | Comparator | Key Endpoints |
| --- | --- | --- | --- |
| Product Surveillance Registry (PSR); Prospective, non-randomized, multi-center, global registry; Follow-up/Duration: Average device exposure 38.2 months (adults) and 35.9 months (pediatric); Study Period: 2009 - October 31, 2022 | Patients with primary dystonia (adults and pediatric); Sample Size: 308 patients; Number of Sites: Global network | Not applicable for this study | Safety (adverse events, serious adverse events, device events) and effectiveness (EQ-5D quality of life) |
| Systematic Literature Review Meta-Analysis; Meta-analysis of published literature (RCTs, prospective, and retrospective studies); Follow-up/Duration: 6 months to 10 years; Study Period: November 1, 2012, through August 31, 2024 | Adults and pediatric patients (≥12 years) with primary generalized, segmental, or cervical dystonia; Sample Size: Varies by dystonia type (e.g., 130 patients for generalized dystonia); Number of Sites: Multiple academic/clinical centers | Not applicable for this study | Safety (AE/SAE rates) and Effectiveness (BFMDRS/TWSTRS scores) |

## Indications for Use

The Activa™, Percept™ and SenSight™ Deep Brain Stimulation Therapy System is indicated for bilateral stimulation of the internal globus pallidus (GPi) using Medtronic DBS Therapy for Dystonia as an aid in the management of chronic, intractable (oral and/or injectable medication refractory) primary dystonia, including: generalized dystonia, segmental dystonia of the head and neck, and cervical dystonia (torticollis) in adult patients; and generalized dystonia in pediatric patients twelve years of age or above.

## Device Story

Implantable multi-programmable neurostimulation system; delivers electrical stimulation to internal globus pallidus (GPi) to manage primary dystonia symptoms. System components: leads/extensions (conduct stimulation to GPi), implantable neurostimulator (INS) (generates current), burr hole device (anchors lead), clinician programmer (configures therapy parameters: amplitude, rate, pulse width, cycling), patient programmer/recharger (patient-controlled therapy maintenance). Used in clinical/surgical settings; implanted by neurosurgeons; programmed by clinicians. Output: electrical pulses to brain tissue. Benefit: reduction in dystonia severity (BFMDRS/TWSTRS scores), improved quality of life, potential prevention of secondary musculoskeletal deformities in pediatric patients.

## Clinical Evidence

Evidence includes one RCT (Kupsch 2006/Volkmann 2012) for generalized/segmental dystonia (n=30 analyzed), one RCT (Volkmann 2014) for cervical dystonia (n=62), meta-analyses of literature, and Medtronic Product Surveillance Registry (PSR) data (n=308). Primary endpoints: BFMDRS motor score (generalized/segmental) and TWSTRS severity score (cervical). Results showed significant motor score improvements (e.g., ~60% improvement in generalized dystonia). Safety profile consistent with existing DBS indications; device complications (11-26%), infections (7-16%), and revisions (14-21%) reported across populations.

## Technological Characteristics

Implantable multi-programmable neurostimulation system. Components: leads, extensions, INS, burr hole device, programmers, recharger. Energy source: battery-powered INS (rechargeable or non-rechargeable). Connectivity: clinician/patient programmers. Sterilization: standard medical device methods. Software: rule-based parameter configuration (amplitude, rate, pulse width, cycling).

## Regulatory Identification

To stimulate deep brain structure to manage dystonia symptoms

## Reference Devices

- Activa SC Model 37602 Neurostimulator ([P960009](/device/P960009.md)/S092)
- Soletra Neurostimulator ([P960009](/device/P960009.md)/S009)
- Activa PC Neurostimulator ([P960009](/device/P960009.md)/S052)
- Percept PC INS ([P960009](/device/P960009.md)/S361)
- Percept RC INS ([P960009](/device/P960009.md)/S438)
- SenSight Directional Lead Kit ([P960009](/device/P960009.md)/S391)

## Submission Summary (Full Text)

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>
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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

# I. GENERAL INFORMATION

|  Device Generic Name: | Implantable multi-programmable deep brain stimulation system  |
| --- | --- |
|  Device Trade Name: | Medtronic DBS Therapy for Dystonia (including Activa™, Percept™ and SenSight™ devices)  |
|  Device Procode: | SGS  |
|  Applicant's Name and Address: | Medtronic, Inc. Medtronic Neuromodulation 7000 Central Ave., N.E. Minneapolis, MN 55432  |
|  Date(s) of Panel Recommendation: | None  |
|  Premarket Approval Application (PMA) Number: | P960009/S482  |
|  Date of FDA Notice of Approval: | November 22, 2025  |

Medtronic's Deep Brain Stimulator (DBS) System was approved for the following indications for use:

- P960009 approved on July 31, 1997: Unilateral thalamic stimulation of the ventral intermediate nucleus (VIM) using Medtronic DBS Therapy for Tremor is indicated for the suppression of tremor in the upper extremity. The system is intended for patients who are diagnosed with essential tremor or parkinsonian tremor not adequately controlled by medications and where the tremor constitutes a significant functional disability.
- P960009/S7 approved on January 14, 2002 (Modified in P960009/S229 approved on November 18, 2015): Bilateral stimulation of the internal globus pallidus (GPi) or the subthalamic nucleus (STN) using Medtronic DBS Therapy for Parkinson's Disease is indicated for adjunctive therapy in reducing some of the symptoms in individuals with levodopa-responsive Parkinson's disease of at least 4 years' duration that are not adequately controlled with medication, including motor complications of recent onset (from 4 months to 3 years) or motor complications of longer-standing duration.
- P960009/S219 approved on April 27, 2018: Bilateral stimulation of the anterior nucleus of the thalamus (ANT) using the Medtronic DBS System for Epilepsy is

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indicated as an adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial-onset seizures, with or without secondary generalization, that are refractory to three or more antiepileptic medications.

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

The SSEDs to support the indication are available on the CDRH website and are incorporated by reference here:

https://www.accessdata.fda.gov/cdrh_docs/pdf/P960009B.pdf

https://www.accessdata.fda.gov/cdrh_docs/pdf/P960009S007B.pdf

https://www.accessdata.fda.gov/cdrh_docs/pdf/P960009S219B.pdf

The current supplement (S482) was submitted to expand the indication for the Medtronic DBS System to aid in the management of chronic, intractable (oral and/or injectable medication refractory) primary dystonia symptoms for the Indications for Use specifically stated below.

## **II. INDICATIONS FOR USE**

The Activa™, Percept™ and SenSight™ Deep Brain Stimulation Therapy System is indicated for bilateral stimulation of the internal globus pallidus (GPi) using Medtronic DBS Therapy for Dystonia as an aid in the management of chronic, intractable (oral and/or injectable medication refractory) primary dystonia, including:

- generalized dystonia, segmental dystonia of the head and neck, and cervical dystonia (torticollis) in adult patients; and
- generalized dystonia in pediatric patients twelve years of age or above.

## **III. CONTRAINDICATIONS**

### General DBS contraindications

Implantation of a deep brain stimulation (DBS) system is contraindicated for these situations:

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

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

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

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

**Certain magnetic resonance imaging (MRI) procedures** - Use of a full body transmit radio frequency (RF) coil, a receive-only head coil, or a head transmit coil that extends over the chest area is contraindicated for patients with the following implanted DBS systems or system components:

- Activa SC Model 37602 Neurostimulator
- Model 64001 and Model 64002 pocket adaptors implanted with any DBS system

Tissue lesions from component heating, especially at the lead electrodes, resulting in serious and permanent injury including coma, paralysis, or death, can occur if a contraindicated MRI scan is performed on a patient with any of these DBS systems.

**Refer to the MRI guidelines for Medtronic deep brain stimulation systems**
**Instructions for use manual associated with this product for comprehensive safety information and instructions.**

**Patients unable to operate patient devices** - Patients who are unable, or do not have the necessary assistance, to properly operate the patient control device (e.g., patient programmer, therapy access controller) or a charging system (applicable to rechargeable DBS Systems only) should not use this device.

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

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# IV. WARNINGS AND PRECAUTIONS

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

# V. DEVICE DESCRIPTION

Medtronic DBS Therapy for Dystonia uses an implantable multi-programmable neurostimulation system to deliver electrical stimulation to the internal globus pallidus (GPi) of the brain. Refer to Figure 1 for a representation of a DBS system. The major components of a DBS system include:

- Leads and Extensions – Conducts electrical stimulation to the GPi as part of a DBS system. The extension connects the lead to the neurostimulator. In some cases, a pocket adaptor is also used to connect the extension to the neurostimulator
- Implantable Neurostimulator (INS) – Generates electrical current that is conducted through DBS extensions and leads to the distal lead electrodes.
- Burr Hole Device – Used to anchor the lead to the skull.
- Clinician Programmer – Used by the clinician to configure and maintain the patient’s therapy through adjustment of the available therapy parameters (amplitude, rate, pulse width, cycling, electrode configuration, etc.) and the creation of programs which consist of a specific set of values for each of the therapy parameters.
- Patient Programmer – Used by the patient to maintain their therapy within parameters configured by the clinician.
- Patient Recharger – Used by the patient to charge the battery of a rechargeable INS. A plug-in charger recharges the patient recharger.

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

Figure 1. Representation of a Bilateral DBS System

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Medtronic DBS system components within the scope of this submission have been approved by FDA through the initial submission and supplements to PMA P960009. Table 1 lists the system components and associated document control numbers for their market approval. There are no changes proposed for these devices; the only changes proposed are to the labeling concerning the indication for use.

Table 1. Medtronic DBS System Components

|  Component |   | Model | FDA Submission Number | FDA Approval or Clearance Date  |
| --- | --- | --- | --- | --- |
|  Implantable | Neurostimulators | 7426 Soletra Neurostimulator* | P960009/S009 | March 21, 2000  |
|   |   |  37601 Activa PC Neurostimulator* | P960009/S052 | April 07, 2009  |
|   |   |  37602 Activa SC Neurostimulator 37603 Activa SC Neurostimulator | P960009/S092 | January 26, 2011  |
|   |   |  B35200 Percept PC INS | P960009/S361 | June 24, 2020  |
|   |   |  B35300 Percept RC INS | P960009/S438 | January 08, 2024  |
|   |  Leads | 3387S DBS Lead Kit* 3389S DBS Lead Kit* | P960009/S036 | March 2, 2006  |
|   |   |  B33005 SenSight Directional Lead Kit B33015 SenSight Directional Lead Kit | P960009/S391 | May 25, 2021  |
|   |  Extensions | 7482 / 7482A DBS Extension* | P960009/S010 | April 12, 2000  |
|   |   |  37085 Extension Kit* | P960009/S051 | March 27, 2009  |
|   |   |  7483 DBS Extension* 37086 Extension Kit | P960009/S134 | February 3, 2012  |
|   |   |  B34000 SenSight Extension Kit | P960009/S391 | May 25, 2021  |
|   |  Implantable accessories | 3550-25 Boots Accessory Kit | P960009/S026 | October 31, 2002  |
|   |   |  64001 Pocket Adapter (1 x 4) 64002 Pocket Adapter (2 x 4) | P960009/S067 | June 8, 2009  |
|   |   |  B31060 Connector Plug | P960009/S361 | June 24, 2020  |

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|  Component |   | Model | FDA Submission Number | FDA Approval or Clearance Date  |
| --- | --- | --- | --- | --- |
|  External |  | B31000 Burr Hole Device B31020 SenSight Lead Cap Kit B31061 SenSight Connector Plug B32000 SenSight Burr Hole Device Kit | P960009/S391 | May 25, 2021  |
|   |  Implant accessories | 3550-05 Percutaneous Extension Kit | P960009 | July 31, 1997  |
|   |   |  3550-67 Screening Cable 3550-68 Screening Cable 37022 External Neurostimulator | P960009/S051 | March 27, 2009  |
|   |   |  3550-45 Torque Wrench Accessory Kit | P960009/R017 | January 25, 2010  |
|   |   |  B31010 SenSight Depth Stop and Cranial Tunneler Kit B31040 SenSight Lead Test Cable Kit B31050 SenSight Extension Test Cable Kit | P960009/S391 | May 25, 2021  |
|   |  Clinician accessories | 8840 N'Vision Clinician Programmer 8870 Software Application Card | P960009/S025 | October 31, 2002  |
|   |   |  8880T2 Communicator A610 DBS Clinician Programmer Application | P960009/S304 | May 26, 2018  |
|   |  Patient accessories | 37092 External Antenna 37642 Patient Programmer | P960009/S051 | March 27, 2009  |
|   |   |  A620 DBS Patient Programmer Application TH90 Handset and Communicator Package Kit | P960009/S333 | July 3, 2019  |
|   |   |  TH91 Handset and Communicator Package Kit | P960009/S361 | June 24, 2020  |
|   |   |  A90300 Recharger Application Software CD9000 Charging Dock | P960009/S365 | June 25, 2020  |
|   |   |  RS6230 DBS Recharging System | P960009/S438 | January 08, 2024  |

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|  Component | Model | FDA Submission Number | FDA Approval or Clearance Date  |
| --- | --- | --- | --- |
|   | WR9230 Wireless Recharger |  |   |

* Model is no longer sold, however electronic labeling (eManuals) is available on the Medtronic Manual Library website (www.medtronic.com/manuals).

## VI. ALTERNATIVE PRACTICE AND PROCEDURES

There are several other alternatives for the correction of dystonia, including oral medications, botulinum toxin, and lesioning procedures. In patients with generalized and focal isolated dystonia syndromes, anticholinergic medications have proved useful. Levodopa is effective in some patients with dopa-responsive dystonia parkinsonism. Baclofen, carbamazepine, and benzodiazepines are other agents that have been used in the treatment of dystonia either alone or in combination.¹ Botulinum toxin (BoNT) is often of limited interest in general dystonia due to the need for repeated injections covering multiple body areas. However, BoNT is the first line of treatment for patients with blepharospasm and cervical dystonia (spasmodic torticollis). Lesioning procedures (thalamotomies and pallidotomies) have been used for treatment but were discouraged in the 2006 EFNS/MDS-ES guidelines² due to their high risk of side effects, and the absence of new data maintained this decision in the EFNS 2011 update.³

## VII. MARKETING HISTORY

The Medtronic DBS Therapy for Dystonia system was approved in the US through a Humanitarian Device Exemption (HDE) under H020007 on April 15, 2003, for the following indications for use:

“The Medtronic Activa™ Dystonia Therapy is indicated for unilateral or bilateral stimulation of the internal globus pallidus (GPi) or the subthalamic nucleus (STN) to aid in the management of chronic, intractable (drug refractory) primary dystonia, including generalized and/or segmental dystonia, hemidystonia, and cervical dystonia (torticollis) in patients seven years of age or above.”

The Summary of Safety and Probable Benefit can be found at:
https://www.accessdata.fda.gov/cdrh_docs/pdf2/H020007B.pdf.

## 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 as identified in device labeling. One may reasonably expect the risks associated with the use of the DBS system for the approved indications of Parkinson’s disease (PD) and Essential Tremor (ET) to be similar in treating dystonia in adults. Additional considerations for pediatric patients that may alter potential adverse effects on

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health include smaller size with ongoing physical growth, age-related differences in neurocognitive development, and continued behavioral maturation.

Risks (potential adverse events) related to the lead, extension, or neurostimulator implant, explant, or revision procedures:

- Immediate intracranial hemorrhage or cerebral infarction which could be symptomatic, or which could result in temporary or permanent neurological injury or death
- Asymptomatic intracerebral hemorrhage or ischemia related to the DBS lead implant identified through postoperative imaging
- Complications related to anesthesia, including allergic reaction, hypotension, nausea and vomiting, headache, and other symptoms
- Complications or effects related to the device implantation or removal procedure, including lead insertion or removal difficulty, failure of the burr hole ring and cap, mechanical or electrical complications of the device, lead(s) not within target requiring replacement
- Complications or effects related to the tunneling procedure, including injury to nerve tissue (such as the spinal accessory nerve), vascular injury that may result in prolonged hospitalization, and tunneling through unintended anatomy (such as in between the ribs and entering the thoracic cavity)
- Cerebrospinal fluid leakage (also called CSF fistula)
- Pneumocephalus
- New onset seizures associated with the lead implant procedure
- General medical complications such as deep vein thrombosis, postoperative fever, and general postoperative discomfort

Risks (potential adverse events) after implantation of the lead(s), extension(s), or neurostimulator(s):

- Delayed intracranial hemorrhage or cerebral infarction which could be symptomatic, or which could result in temporary or permanent neurological injury or death
- Complications of the incision/surgical site, including inflammation, lack of healing, wound dehiscence, transient or persistent pain, seroma, or hematoma
- Infection of the incision/surgical site that could result in sepsis
- Meningitis, encephalitis, or brain abscess resulting from infection involving the brain and/or central nervous system
- Focal edema localized to the area around the lead
- Aseptic intraparenchymal cyst formation around the distal lead tip that may occur weeks to months after implant and may present as new neurological symptoms. Surgical removal of the lead may reduce the size of the cyst and the neurological symptoms caused by cyst formation.
- Erosion of the skin at the lead, extension, or neurostimulator site
- Migration or dislodgement of the lead, extension, or neurostimulator

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- Lead, extension, or neurostimulator device complications, including lead or extension fracture, neurostimulator malfunction, neurostimulator setscrews not adequately tightened, and high impedance
- Fibrosis (including tightening, tethering, or bowstringing) at the extension or neurostimulator site may develop weeks to years after implant. It can be associated with pain, disfigurement, limited head mobility, and may require surgical intervention.
- Neurological symptoms, new or exacerbation of existing symptoms which might be transient or permanent, including:
  - vision disorders: diplopia, oculomotor difficulties, or other visual field disorders.
  - speech and swallowing disorders: dysphagia, dysarthria, dysphasia, drooling.
  - motor coordination and balance disorders: akinesia, "freezing," bradykinesia, dyskinesia, paresis, asthenia, muscle spasms/rigidity, tremor, loss of balance/coordination, gait disorder, dizziness, involuntary movements, tics, chorea, dystonia, facial muscle or limb partial paralysis.
  - sensory disturbances: paresthesia, hypoesthesia, burning sensation, headache.
  - mentation impairment: attention or cognitive deficits, dysgraphia, memory disturbances, confusion, somnolence, lethargy.
  - sleep disorders: insomnia, abnormal dreams.
  - déjà vu.
- Psychiatric and behavioral disorders, new or exacerbation of existing symptoms that might be transient or permanent, including:
  - new onset or worsening depression, suicidal ideation, suicide attempt, suicide.
  - anxiety, panic, restlessness.
  - irritability, anger, aggression, agitation.
  - changes or fluctuations in mood, apathy, fatigue.
  - other behavioral manifestations: changes in eating behaviors, obsessive-compulsive disorder, abnormal behavior.
  - hyperactivity or euphoria (hypomania).
  - psychosis, delusions, hallucinations, delirium, disinhibition, perseveration, abnormal thinking.
- New onset seizures during ongoing therapy
- Allergic or immune system response to the implanted materials
- Gastrointestinal disturbances
- Cough associated with DBS
- Transient uncomfortable stimulation (jolting or shocking sensation)
- Lack of effective therapy or loss of therapeutic effect
- Weight gain or loss

In addition to the adverse events related to DBS therapy, the following potential adverse events can occur with DBS Therapy for Dystonia.

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Risks (potential adverse events) after implantation of the lead(s), extension(s), or neurostimulator(s):

- Hemiplegia or hemiparesis

**Note:** Pediatric patients may have increased risks of infections, device-related complications (for example, hardware breakage), revisions, and explants compared to adults due to continued growth, increased physical activity, and potential for longer duration of use.

**Patient brain development:** The impact of DBS on overall cognitive and neurological development and behavioral changes in pediatric patients is unknown.

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

## **IX. SUMMARY OF NON-CLINICAL STUDIES**

All components of the Medtronic DBS System for Dystonia are commercially approved as part of PMA P960009 and supplements. The preclinical testing of these components provided in the relevant PMA/PMA supplements is also applicable to the Medtronic DBS System for Dystonia. Table 1 lists the system components and associated document control numbers for their market approval. There are no physical changes proposed for these devices.

## **X. SUMMARY OF PRIMARY CLINICAL STUDIES**

These data were the basis for the PMA approval decision. A summary of the clinical data is presented below.

### **A. Study Design**

#### **1. Data Sources**

The applicant employed information from multiple data sources to establish a reasonable assurance of safety and effectiveness of the Medtronic DBS Therapy system in the US as an aid in the management of chronic, intractable (oral and/or injectable medication refractory) primary dystonia, including:

- generalized dystonia, segmental dystonia of the head and neck, and cervical dystonia (torticollis) in adult patients
- generalized dystonia in pediatric patients twelve years of age and above.

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These data sources included an analysis of a subset of clinical data purchased from a published randomized controlled trial (RCT) by Kupsch (2006)$^{4}$ and its long-term follow-up study by Volkmann (2012),$^{5}$ collectively referred to as the 'Investigator Study'$^{6}$ in this document; an additional RCT conducted by Volkmann (2014)$^{7}$; a meta-analysis of published literature; and data from the Medtronic Product Surveillance Registry (PSR).

Specially, the following clinical data sources were used:

# - • Study Specific Data

The applicant performed an analysis on a subset of clinical data from a RCT that was published in Kupsch (2006).$^{4}$ The sponsor purchased the actual clinical data for 30 out of 40 studied patients directly from the authors and performed analysis of that data. Follow-up data from the same study that was published in Volkmann (2012)$^{5}$ was also used. This data is referred to as the Investigator Study.$^{6}$ The Investigator Study$^{6}$ was used to support the safety and effectiveness of bilateral GPi DBS in primary generalized and segmental dystonia in adults. The corresponding data in the primary generalized dystonia are also considered as supportive evidence for bilateral GPi DBS in primary generalized dystonia in pediatric patients 12 years of age or above.

A RCT Study from Volkmann (2014)$^{7}$ was used to support the safety and effectiveness of bilateral GPi DBS in primary cervical dystonia in adults.

# - • Meta Analysis from Systematic Literature Review

The systematic literature review involved a comprehensive search of the MEDLINE and Embase databases, as well as PubMed ahead-of-print and in-process records, over a more than 10-year period covering November 1, 2012, through August 31, 2024. It also included a key RCT by Kupsch (2006)$^{4}$ and its long-term follow-up,$^{5}$ both published outside this period. Other relevant studies were found by cross-referencing, with an emphasis on evidence related to particular dystonia types. The focus was on primary data sources for bilateral GPi DBS in adult patients with primary generalized, segmental, and cervical dystonia, without other neurological features or pathological abnormalities and in pediatric patients 12 years of age or above with primary generalized dystonia, without other neurological features or pathological abnormalities. Published studies were included in the analysis if at least 80% of the study population aligned with the indication or individual patient data could be extracted for analysis.

# - • Medtronic Product Surveillance Registry (PSR)

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Real-world data from the PSR is summarized for patients receiving Medtronic DBS Therapy for primary dystonia. The PSR is a prospective, non-randomized, multi-center, global registry that enrolls patients on a rolling basis without specified limits on the number of patients or end dates. Patients from active PSR sites worldwide are followed prospectively in alignment with routine care practices throughout the lifetime of their devices or until they exit the registry. These data were mainly used to support safety.

2. Study Objectives

• Safety Objectives

The overall safety objective was to summarize current safety information for Medtronic DBS Therapy for Dystonia through analysis of current data from the systematic review of published scientific literature and the PSR. The analysis focused on the following therapy-relevant safety events which are already labeled as potential risks associated with DBS-related surgical procedures or with use of DBS therapy after implantation, and are commonly reported in published scientific literature for DBS Therapy for Movement Disorders:

- Hemorrhage (cerebral or intracranial, symptomatic or asymptomatic)
- Infection
- Device complications (lead migration, device failures, etc.)
- Suicide and suicide attempt

The rates of therapy-relevant safety events were pooled separately for adult and pediatric populations and summarized using descriptive statistics. Surgical interventions including system revision (e.g., device repositioning or replacement) and complete system explant were summarized.

• Effectiveness Objectives

The overall effectiveness objective was to characterize the clinical benefits related to reduction in movement symptoms. The effectiveness of the Medtronic DBS Dystonia system was demonstrated through analysis of Study Specific Data and results from a meta-analysis of the systematic review of published scientific literature. The average Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score was used in the analysis for primary generalized dystonia in both adults and pediatric patients 12 years of age or above and segmental dystonia in adults. The average Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity score was used in the analysis for primary cervical dystonia in adults. The European Quality of Life 5-Dimension Questionnaire (EQ-5D) information at baseline and follow-up in the PSR was used in the analysis for health-related quality of life for all types of dystonia in adults.

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### 3. Study Design: Study Specific Data

The Investigator Study$^{6}$ provided the main evidence to support the GPi DBS therapy in primary generalized dystonia in adults. The study contains a subset of data purchased by Medtronic from the study published in Kupsch (2006).$^{4}$ Data from long-term follow-up were also used from the study published in Volkmann (2012).$^{5}$ The main purpose of the analysis was to demonstrate the safety and effectiveness of bilateral GPi DBS in patients with primary generalized or segmental dystonia who were oral and/or injectable medication refractory. The Kupsch (2006)$^{4}$ study includes 40 patients (full study cohort), of which only 30 patients signed an Informed Consent Form agreeing to have their data released to Medtronic (MDT). As such, the results and associated conclusions from the Study Specific Data contain data from only those 30 patients. The study in Kupsch (2006)$^{4}$ was not sponsored by Medtronic.

#### Kupsch (2006)$^{4}$ RCT Study

Kupsch (2006)$^{4}$ was a two arm, double-blind, randomized and placebo-controlled study to demonstrate the safety and effectiveness of GPi stimulation in subjects with primary generalized or segmental idiopathic dystonia who were severely handicapped, in spite of optimal conservative therapy. Patients were randomized in a 1:1 manner to receive either neurostimulation or sham stimulation for the 3-month blinded phase. The subjects in both groups were given the same operation to implant stimulation electrodes in the GPi. During a 3-month follow-up period, the neurostimulation group was administered effective pallidum stimulation (frequency 130 Hz; pulse width 120 µs; amplitude 0.5 V below adverse event threshold). In the sham stimulation group, the stimulator was set at 0 volts (V) so that there would be only placebo or apparent stimulation for 3 months. Drug therapy was freely adjusted to the subjects' requirements in both groups. The groups were unblinded after 3 months and the stimulation system in the sham stimulation group was then switched to the same parameters as the neurostimulation group. This was followed by an open follow-up observation phase, with subsequent final evaluation (in comparison to the pre-operative status of both groups) after 6 months of continuous pallidum stimulation. After 6 months of follow-up, patients were assessed annually for 5 years in Volkmann (2012)$^{5}$ for the long-term device effect.

#### Study Population

The intended study population was subjects with idiopathic segmental, multifocal or generalized dystonia who benefit inadequately from drug treatment and who are seriously handicapped by the disease.

There were 8 study centers participating in the study, 7 centers in Germany and 1 center in Austria. The centers were chosen based on their experience with DBS Therapy. To participate, a center must have successfully treated 8 subjects with DBS Therapy, at least 2 with the target Globus Pallidus internus (GPi). In

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addition, centers were required to have a projected implant rate of 10 patients per year.

# Inclusion Criteria

- Presence of idiopathic multifocal segmental or generalized dystonia
- Duration of disease > 5 years
- Age between 14 and 75 years
- Relevant handicap in daily life, in spite of optimal drug therapy
- Presence of subject's written informed consent
- For adolescents between 14 and 18 years: additional written consent from parent or guardian

# Exclusion Criteria

- Mattis Score < 120
- Beck depression inventory (BDI) > 25
- Prior stereotactic brain operations
- Marked cerebral atrophy
- Raised bleeding tendency
- Reduced resistance to infection
- Relevant cerebrovascular disease
- Psychiatric disease which could impair cooperation in the study
- Other contraindications

# Study Device

Table 2 below describes the Medtronic DBS System components used in the Kupsch (2006)⁴ study.

Table 2. Description of Dystonia DBS System Components

|  Device Component | Model  |
| --- | --- |
|  Neurostimulator | Model 7424 Itrel II Neurostimulator Model 7428 Kinetra Neurostimulator  |
|  DBS Leads | Model 3387 DBS Lead Model 3389 DBS Lead  |
|  Extensions | Model 7482/7483 DBS Extension Model 37085/37086 DBS Extension with Universal Port Plug  |
|  Accessories | Model 8840 N'Vision Clinician Programmer Model 8870 N'Vision Application Card Model 7438 Access Review Therapy Controller Model 7436 Access Therapy Controller Model 37642 Patient Programmer w/ optional 37092 antenna Models 64001 and 64002 Pocket Adaptor  |

# Statistical Analysis

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In Kupsch (2006)⁴, the primary null hypothesis was an outcome of no significant difference in the change in the BFMDRS movement score (an average of the two scores recorded by observers who were unaware of the group assignments) from baseline to 3 months between patients receiving active neurostimulation and those receiving sham stimulation. Sample Size: 40 patients were needed to provide the study with 90% power to detect a 25% difference between treatment groups while allowing for an overall dropout rate of 10%, with a 5% probability of a type I error on the basis of a two-sided Mann–Whitney test. Data from all patients who underwent randomization were analyzed; missing values were imputed with the last observation carried forward.

Because not all patients were reconsented for use by Medtronic, only 30 of the 40 implanted patients are available for analysis. If the original power calculation was redone using the number of patients reconsented in each group (17 active and 13 sham), the estimated power for the primary analysis of the study remains over 80%. This reinforces the fact that 30 patients are sufficient to show significant benefit with this therapy. In the Investigator Study,⁶ missing values were not imputed with the last observation carried forward. The analyses include only those patients who were reconsented for use by Medtronic.

#### *Analyses by Dystonia Type*

Analysis of effectiveness was completed by dystonia type. This analysis represents data from 18 patients with generalized dystonia and 11 patients with segmental dystonia. One additional patient with multifocal dystonia is excluded from this subgroup analysis.

#### *Safety Objectives*

- Systematic recording of the side-effects and adverse events.
- To characterize adverse events (AEs) for all subjects, including a tabulation of the profiles of the neurostimulation and sham stimulation group subjects through the 3-month blinded phase.

#### *Primary Objectives*

To demonstrate that the improvement in the movement score in the Burke-Fahn-Marsden-Dystonia-Rating-Scale (BFMDRS) for subjects in the DBS treatment group (neurostimulation) is greater than for subjects in the control group (sham stimulation) after 3 months of therapy.

The primary endpoint was a change from baseline to three months in severity of symptoms assessed with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) movement score. Data from all of the investigational sites (30/40 patients) were pooled for analysis.

Secondary endpoints included the effect of neurostimulation on activities of daily living, the disability score on the BFMDRS, and quality of life (as assessed

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with the SF-36).

The Kupsch (2006)⁴ trial is registered with ClinicalTrials.gov, number NCT00142259.

# Volkmann (2012)⁵

Volkmann (2012)⁵ assessed the safety and effectiveness of bilateral GPi DBS in patients with primary generalized or segmental dystonia prospectively followed up for 5 years in the Kupsch (2006)⁴ trial. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the BFMDRS motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analyzed on an intention-to-treat basis.

# Volkmann J (2014)⁷

Volkmann (2014)⁷ was used as evidence to support the Medtronic DBS Dystonia system in bilateral GPi DBS therapy in primary cervical dystonia. Volkmann (2014)⁷ used a similar study design as that in Kupsch (2006).⁴ In brief, Volkmann (2014)⁷ is a two-arm, double-blind, randomized, and placebo-controlled study design to demonstrate the safety and effectiveness of bilateral GPi DBS stimulation in patients with medication-refractory cervical dystonia.

# Eligibility Criteria:

Aged 18–75 years, disease duration ≥3 years, TWSTRS severity score ≥15 points. 62 Patients were enrolled from 10 academic centers in Germany, Norway, and Austria.

# Protocol

Patients were randomized in a 1:1 manner to receive either neurostimulation or sham (amplitude 0 V) stimulation by computer-generated randomization lists with randomly permuted block lengths stratified by center. All patients, masked to treatment assignment, were implanted with a DBS device and received their assigned treatment for 3 months, during which the neurostimulation group was administered pallidum stimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0.5 V below adverse event threshold). In the sham stimulation group, the stimulator was set at 0 volts (V) so that there would be only placebo or apparent stimulation for 3 months. Drug therapy was freely adjusted to the subjects' requirements in both groups. The groups were unblinded after 3 months and the stimulation system in the sham stimulation group was then switched to the same parameters as the neurostimulation group. This was followed by an open follow-up observation phase, with subsequent final evaluation (in comparison to the pre-operative status of both groups) after 6 months of continuous pallidum

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stimulation, i.e. 6 months post-operatively in the neurostimulation group and 9 months postoperatively in the sham stimulation group.

#### Statistical Analysis:

The primary null hypothesis was an outcome of no difference in the change of the TWSTRS severity score (mean of the two observer-blinded scores) from baseline to 3 months between patients receiving active neurostimulation and those receiving sham stimulation. It was estimated that a sample size of 60 patients, i.e., 30 per group, would power the study at 80% with a 5% probability of a type I error (two-sided Mann-Whitney U test of the primary null hypothesis). This design allows detection of a 20% difference between treatment groups with respect to the primary outcome criterion (percentage change in TWSTRS severity score) assuming a standard deviation (SD) of 25%, while making provision for an overall dropout rate of 10%. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardized videos, analyzed by intention to treat. The key secondary outcome included change in TWSTRS disability. TWSTRS total score was one of the exploratory effectiveness endpoints.

This trial is registered with ClinicalTrials.gov, number NCT00148889.

#### 4. Study Design: Meta-Analyses of Literature

##### Safety

A meta-analysis was conducted to evaluate rates of therapy-relevant safety events (excluding suicide and suicide attempt because of no reported occurrence in the patient populations evaluated), system revisions, and explants in adult patients based on the type of dystonia and in pediatric patients 12 years of age or above with primary generalized dystonia. Additionally, the analysis was conducted to compare these rates between adult and pediatric patients 12 years of age or above with primary generalized dystonia.

To avoid the possibility that the quantities estimated with different study designs (e.g., randomized controlled trials, prospective studies, retrospective studies/case controls) may not represent the same target of inference (e.g., estimates from randomized trials may be for unconditional treatment effects, while estimates from observational studies may represent treatment effects conditional on covariates), meta-analyses of safety were also conducted in both adult and pediatric patients with primary dystonia stratified by study designs.

##### Effectiveness

The meta-analysis was conducted to evaluate effectiveness outcomes in adult patients with primary generalized, segmental and cervical dystonia, and in pediatric patients with primary generalized dystonia. Additionally, a comparative analysis was conducted to evaluate differences in adults versus pediatric patients 12 years of age or above with primary generalized dystonia.

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To avoid the possibility that the quantities estimated with different study designs may not represent the same target of inference, meta-analyses of effectiveness outcomes in both adult and pediatric patients were also conducted with different types of dystonia stratified by study design. Only one RCT for each dystonia type was included in the meta-analysis; therefore, only point estimate was provided for the RCT.

## Data Extraction

- For safety outcomes, the proportion of patients with safety events was extracted from the publication or calculated by dividing the reported number of events by the number of patients enrolled in the study. If the authors specifically stated a type of event did not occur the rates were reported as 0 (0%). If the authors did not comment on a type of event, not reported (NR) is shown.
- For effectiveness outcomes, the average Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score was used in the analysis for generalized dystonia and segmental dystonia. The average Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity score was used in the analysis for cervical dystonia.

## Statistical Methods

Meta-analysis of dystonia effectiveness and safety were implemented using random-effects modeling with inverse variance weighting. All analyses were completed using the 'meta' package in R software which enabled the use of both fixed-effect and random effects models, depending on the level of heterogeneity observed among the studies. The random effects model was preferred in cases of significant heterogeneity, quantified using the I² statistic and Cochran's Q-test. The precision of pooled estimates was represented by 95% confidence intervals, ensuring a comprehensive understanding of variability within and across studies.⁸,⁹

- Safety assessment: The pooled proportions of therapy-relevant safety events were calculated separately for each dystonia type with the metaprop function from the 'meta' package in R. The individual proportion from each study was logit transformed before being pooled for overall proportion estimation. A continuity correction of 0.5 was applied to studies with zero events. Confidence intervals for individual studies used the Clopper-Pearson method, and random-effects models accounted for between-study heterogeneity.¹⁰,¹¹
- Effectiveness assessment: Dystonia rating scale improvement (BFMDRS and TWSTRS) was measured as percentage change from baseline for effectiveness assessment. The pooled effect sizes were derived using the metagen function from the 'meta' package in R. Standard errors were computed from reported or imputed standard deviations to reflect score variability accurately. Confidence intervals were calculated using standard normal critical values to quantify estimate precision.

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All safety and effectiveness meta-analyses were also conducted with stratification by study designs (e.g., randomized controlled trials, prospective studies, retrospective studies/case controls) to avoid the possibility that the quantities estimated with different study designs may not represent the same target of inference. Within each stratum, a random-effects model (REML estimator with Hartung–Knapp adjustment) was applied to appropriately account for between-study variability across study designs. When only a single study was available for a design stratum, the individual study was estimated and 95% confidence interval along with a narrative discussion of precision and risk of bias.

Subgroup analyses of adult vs pediatric were performed using stratified meta-analysis based on patient population (adult vs pediatric) by utilizing the option of subgroup in *metaprop* function in R. Differences were statistically tested using the Chi-square ($\chi^2$) test for group differences, with significance defined as $p < 0.05$.$^{8-10,12}$

##### 5. Study Design: Product Surveillance Registry (PSR)

The PSR (the Registry) is sponsored by Medtronic and is comprised of a global network of hospitals, clinics and clinicians from which “real-world” product safety and patient clinical outcome information is generated. The purpose of the Registry is to provide continuing evaluation and periodic reporting of safety and effectiveness of market-released products for their intended use.

The PSR is a prospective, non-randomized, multi-center, global registry allowing new products to be easily added following market release. Patients are enrolled on a rolling basis without specified limits on the number of patients or end dates. Patients from all geographies where there are active PSR sites are followed prospectively in accordance with the routine care practices over the lifetime of their devices or upon exit from the registry. In addition to event collection, patients enrolled under the PSR protocol collect quality of life (EQ-5D) data at baseline and follow-up. The EQ-5D scoring generates an index score, with higher scores representing better health-related quality of life.

The primary objective of the PSR is continuing evaluation of safety and effectiveness of Medtronic market-released products for their intended use. Patients are followed prospectively for events related to the device, procedure, and/or therapy, as well as negative changes in behavior from baseline (e.g., depression, suicidal ideation). Events are further categorized as product performance events (PPE) or non-PPE.

The registry began as the Implantable Systems Performance Registry (ISPR) and started collecting data on deep brain stimulation (DBS) patients in 2009. Medtronic has continually worked to develop systems and processes to monitor product performance following market release more effectively and launched the

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global Product Surveillance Registry (PSR) in 2011. This analysis represents the data collected through October 31, 2022.

The PSR is registered with ClinicalTrials.gov, number NCT01524276.

# Data Collection

Patients were identified as receiving DBS for the treatment of dystonia if they met the following criteria:

- Primary purpose for device use is for symptomatic dystonia treatment
- Patients were consented
- Patients were implanted with a DBS system

Events that occurred on or after implant are included in the analysis. All device/therapy/procedure related adverse events are included in the adverse event summaries. All device events are included in the device event summaries, regardless of the associated device (i.e., neurostimulator, lead, extension).

Patients were categorized as Pediatric (21 years of age or less) or Adult (older than 21 years of age).

# B. Safety and Effectiveness Results

Safety and effectiveness outcomes are presented separately for primary generalized, segmental, and cervical dystonia in adult patients (> 21 years) and for primary generalized dystonia in pediatric patients (≥ 12 years of age but ≤ 21 years of age). These categorizations are based on the dystonia type and average age reported in each publication or age of patients enrolled in the PSR registry.

# 1. Safety Results

Safety outcomes are presented separately for primary generalized, segmental, and cervical dystonia for adult patients and for pediatric patients 12 years of age or above. Comparisons of therapy-relevant safety events between adult and pediatric patients with primary generalized dystonia by study designs are also provided below to add more detailed information on the safety profile of bilateral GPi DBS for primary generalized dystonia treatment in pediatric patients 12 years of age or above.

- Safety Outcomes for Bilateral GPi DBS in Adult Patients

# Primary Generalized Dystonia

# Study Specific Data

The analysis of safety of bilateral GPi DBS for the treatment of primary generalized dystonia in adult patients was based on data from 18 patients with generalized dystonia in the Investigator Study⁶. A summary of adverse events (AEs) is presented in Table 3 below. During the randomization period, a total

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of seven events were reported in 4 patients (neurostimulation: 2/9 and sham stimulation: 2/9) with generalized dystonia. Of the 7 events, two (neurostimulation: 1/9 and sham stimulation: 1/9) were considered serious adverse events (SAEs). During the randomization period, a total of two adverse device events (ADEs) were reported in 2 patients (neurostimulation: 1/9 and sham stimulation: 1/9) with generalized dystonia. The overall adverse event and serious adverse event occurrence rates were 22.2% and 11.1% in the 3-month blinded phase in the DBS group, and 72.2% and 55.6% in the open label phase, respectively.

Table 3. Adverse Event Summary – Generalized Dystonia in Adults

|  Event Type | Blinded Phase |   |   |   | Open Label Phase  |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Neurostimulation |   | Sham Stimulation |   | All Patients  |   |
|   |  Events | Patients % (n/N) | Events | Patients % (n/N) | Events | Patients % (n/N)  |
|  All Events | 4 | 22.2% (2/9) | 3 | 22.2% (2/9) | 29 | 72.2% (13/18)  |
|  **By seriousness**  |   |   |   |   |   |   |
|  SAE | 1 | 11.1% (1/9) | 1 | 11.1% (1/9) | 23 | 55.6% (10/18)  |
|  Non-SAE | 1 | 11.1% (1/9) | 1 | 11.1% (1/9) | 5 | 22.2% (4/18)  |
|  Not assessed | 2 | 22.2% (2/9) | 1 | 11.1% (1/9) | 1 | 5.6% (1/18)  |
|  **By relatedness**  |   |   |   |   |   |   |
|  ADE | 1 | 11.1% (1/9) | 1 | 11.1% (1/9) | 20 | 61.1% (11/18)  |
|  Non-ADE | 1 | 11.1% (1/9) | 1 | 11.1% (1/9) | 7 | 27.8% (5/18)  |
|  Not assessed | 2 | 22.2% (2/9) | 1 | 11.1% (1/9) | 2 | 11.1% (2/18)  |

Adverse events with missing date will be classified as blinded phase.

Adverse events from baseline to 5 years are summarized in Table 4 below.

Table 4. Adverse Event Summary – Baseline to 5 years

|  Event Type | Serious |   | Non-Serious |   | Not assessed |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event  |
|  Loss of effect | 5 | 27.8% (5/18) | 0 | 0% (0/18) | 0 | 0% (0/18) | 5 | 27.8% (5/18)  |
|  Subcutaneous infection | 5 | 16.7% (3/18) | 0 | 0% (0/18) | 0 | 0% (0/18) | 5 | 16.7% (3/18)  |
|  No stimulation | 4 | 22.2% (4/18) | 2 | 5.6% (1/18) | 1 | 5.6% (1/18) | 7 | 27.8% (5/18)  |
|  Dystonia | 3 | 11.1% (2/18) | 1 | 5.6% (1/18) | 0 | 0% (0/18) | 4 | 16.7% (3/18)  |
|  Other | 3 | 16.7% (3/18) | 1 | 5.6% (1/18) | 0 | 0% (0/18) | 4 | 16.7% (3/18)  |
|  Dysarthria | 2 | 11.1% (2/18) | 0 | 0% (0/18) | 0 | 0% (0/18) | 2 | 11.1% (2/18)  |
|  Electrode fracture | 1 | 5.6% (1/18) | 0 | 0% (0/18) | 0 | 0% (0/18) | 1 | 5.6% (1/18)  |
|  Sensory disturbances | 1 | 5.6% (1/18) | 1 | 5.6% (1/18) | 0 | 0% (0/18) | 2 | 11.1% (2/18)  |
|  Stimulator malfunction | 1 | 5.6% (1/18) | 0 | 0% (0/18) | 0 | 0% (0/18) | 1 | 5.6% (1/18)  |
|  NA | 0 | 0% (0/18) | 0 | 0% (0/18) | 3 | 16.7% (3/18) | 3 | 16.7% (3/18)  |

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|  Event Type | Serious |   | Non-Serious |   | Not assessed |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event  |
|  Facial weakness | 0 | 0% (0/18) | 1 | 5.6% (1/18) | 0 | 0% (0/18) | 1 | 5.6% (1/18)  |
|  Interrupted stimulation | 0 | 0% (0/18) | 1 | 5.6% (1/18) | 0 | 0% (0/18) | 1 | 5.6% (1/18)  |
|  Total | 25 | 55.6% (10/18) | 7 | 33.3% (6/18) | 4 | 16.7% (3/18) | 36 | 72.2% (13/18)  |

NA = Not available.

### *Safety Outcomes from the Publications*

In addition to the Investigator Study,$^{6}$ the analysis of safety of bilateral GPi DBS for the treatment of primary generalized dystonia in adult patients also includes data from 6 publications representing a total of 173 patients contributing safety outcomes. These 6 publications consist of 3 prospective studies,$^{13-15}$ and 3 retrospective studies.$^{16-18}$

Among the publications for generalized dystonia, dystonia severity was characterized by severe or marked disability, impaired function in performance of activities of daily living, or poor symptom control in spite of medical management.$^{6,13,14,16-19}$ Average age at surgery ranged from 22 to 38 years.$^{6,14-18}$ Duration of generalized dystonia before surgery ranged from 8 to 22 years.$^{6,14-16,18}$

Across six other published studies, the reported incidence rates for AE and SAE ranged from 25% to 58%,$^{14-18}$ and 8 to 18%,$^{14-16,18}$ respectively, over a follow-up period spanning 6 months to 7 years of follow-up in adult patients with generalized dystonia.

Table 5 lists the reported occurrence of one or more therapy-relevant safety events in adult patients with generalized dystonia in each publication.

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Table 5. Therapy-Relevant Safety Events in Adult Patients with GPi DBS for Generalized Dystonia$^{a}$

|  First author (Year) | Total pts. enrolled | Mean Age at surgery – yrs | Follow-up | Symptomatic ICH (n, %) | Asymptomatic ICH (n, %) | Infection (n, %) | Device complications (n, %) | Suicide, suicide attempt (n, %) | Device revisions (n, %) | Explants (n, %)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  **RCT (n=1)**  |   |   |   |   |   |   |   |   |   |   |
|  Investigator-Sponsored Clinical Study^{6} | 18 | DBS: 38.2 ± 12.9 Sham: 38.1 ± 8.7 | 6 mos. - 5 yrs. | 0 (0%) | 0 (0%) | 3/18 (16.7%) | 11/18 (61.1%) | NR | 10/18 (55.6%) | 4/18 (22.2%; 2 subcutaneous infections, 1 dystonia, 1 loss of effect)  |
|  **Prospective Studies (n=3)**  |   |   |   |   |   |   |   |   |   |   |
|  Coubes (2004)^{13} | 12 | NR | 42.1 ± 14.8 mos. | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | NR | NR  |
|  Valldeoriola (2010)^{14} | 24 | 30 ± 14 | 12 mos. | 1/24 (4.2%) | NR | 1/24 (4.2%) | 1/24 (4.2%; 1 fracture of the cable) | NR | 1/24 (4.2%; 1 fracture of the cable) | 2/24 (8.3%; 1 infection, 1 skin allergic reaction)  |
|  Vidailhet (2007)^{15} | 17 | 36.3^{b} (range: 22-53) | 3 yrs. | NR | NR | 1/17 (5.9%) | 2/17 (11.8%; 1 lead fractures) | NR | 1/17 (5.9%; 1 lead fracture) | 1/17 (5.9%; 1 infection)  |
|  **Retrospective Studies (n=3)**  |   |   |   |   |   |   |   |   |   |   |
|  Fitzgerald (2014)^{16} | 60 | 33.5 | 5 yrs. | NR | NR | 8/60 (13.3%) | 11/60 (18.3%, 6 lead revisions due to suboptimal placement, 3 lead fracture, 1 lead erosion, 1 wound granuloma) | NR | 8/60 (33.3%; 6 lead revisions, 2 extensions and INS replaced due to infection) | 7/60 (11.7%; 7 device removals due to infection)  |
|  Isaias (2009)^{17} | 30 | 28 ± 17 | Up to 8 yrs. | 0 (0%) | 0 (0%) | 4/30 (13.3%) | 6/30 (20%; 2 fractured extension cables, 1 scalp erosion, 1 IPG malfunction, 2 lack of benefit) | NR | 6/30 (20%) | NR  |
|  Sobstyl (2014)^{18b} | 12 | DYT-1 positive: 21.7 DYT-1 negative: 23.1 | Up to 5 yrs. | 0 (0%) | 0 (0%) | NR | 7/12 (58.3%, 7 pts. total: 4 electrode breakages, 2 unexpected rapid battery depletions, 2 erosions, 1 suboptimal lead position, 1 seroma) | NR | 7/12 (58.3%) | NR  |

$^{a}$ If the authors specifically stated a type of event did not occur the rates were reported as 0 (0%). If the authors did not comment on a type of event, not reported (NR) is shown.

$^{b}$ Estimated from individual patient data reported in the publication

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Table 6 summarizes overall results of the meta-analysis of therapy-relevant safety outcomes in adult patients with GPi DBS for Generalized Dystonia using a random effects model.

For adult patients with generalized dystonia, device complications (22%), infections (12%), and intracerebral hemorrhage (symptomatic: 3%, asymptomatic: 0%) are the main therapy-related safety events. Device revisions (19%) and explants (13%) are the most common other safety events. These rates are based on pooled data from multiple publications. Device complications and revisions are the most frequent safety events, followed by infections. Symptomatic and asymptomatic intracerebral hemorrhage (ICH) are less common. Substantial heterogeneity was observed for both device complication rates and device revision rates. The reasons for the variability may be multifactorial and influenced by experience gained over time with DBS implant surgery and differences in reporting device complications and revisions.

Table 6. Pooled Therapy-Relevant Safety Event Rates in adult patients with GPi DBS for Generalized Dystonia using Random Effects Model

|  Safety Event | Pooled Event Rate (95% CI) | No. of Publications | References  |
| --- | --- | --- | --- |
|  **Therapy-Relevant Safety Events**  |   |   |   |
|  Device complications | 22% (10-44%) | 7 | 6,13-18  |
|  Infection | 12% (8-18%) | 6 | 6,13-17  |
|  Symptomatic ICH | 3% (1-9%) | 5 | 6,13,14,17,18  |
|  Asymptomatic ICH | 0% (0-26%) | 4 | 6,13,17,18  |
|  **Other Safety Events**  |   |   |   |
|  Device revisions | 19% (8-40%) | 6 | 6,14-18  |
|  Explants | 13% (8-20%) | 4 | 6,14-16  |

### *Primary Segmental Dystonia of the Head and Neck*

#### *Study Specific Data*

The analysis of safety of bilateral GPi DBS for the treatment of primary segmental dystonia in adult patients was based on data from 11 patients with primary segmental dystonia in the Investigator Study⁶.

The analysis of safety of bilateral GPi DBS for the treatment of primary generalized dystonia in adult patients was based on data from 11 patients with segmental dystonia in the Investigator Study⁶. A summary of AEs is presented in Table 7 below. There were nine events reported in 7 patients (neurostimulation: 4/7 and sham stimulation: 3/4) with segmental dystonia, and four were considered SAEs in three patients (neurostimulation: 2/7 and sham stimulation: 1/4). During the open label phase after 6 months of continuous stimulation, 16 AEs were reported in 8 (72.7%) patients with segmental dystonia. During the randomization period, five ADEs were

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reported in 4 patients (neurostimulation: 3/7 and sham stimulation: 1/4) with segmental dystonia. The overall AE and SAE occurrence rates were reported as 57.1% and 28.6% in the 3-month blinded phase in the DBS group, and 72.7% and 63.6% in the open label phase, respectively.

Table 7. Adverse Event Summary – Segmental Dystonia in Adults

|  Event Type | Blinded Phase |   |   |   | Open Label Phase  |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Neurostimulation |   | Sham Stimulation |   | All Patients  |   |
|   |  Events | Patients % (n/N) | Events | Patients % (n/N) | Events | Patients % (n/N)  |
|  All Events | 6 | 57.1% (4/7) | 3 | 75.0% (3/4) | 16 | 72.7% (8/11)  |
|  **By seriousness**  |   |   |   |   |   |   |
|  SAE | 3 | 28.6% (2/7) | 1 | 25.0% (1/4) | 12 | 63.6% (7/11)  |
|  Non-SAE | 2 | 28.6% (2/7) | 0 | 0 % (0/4) | 3 | 27.3% (3/11)  |
|  Not assessed | 1 | 14.3% (1/7) | 2 | 50.0% (2/4) | 1 | 9.1% (1/11)  |
|  **By relatedness**  |   |   |   |   |   |   |
|  ADE | 4 | 42.9% (3/7) | 1 | 25.0% (1/4) | 13 | 54.5% (6/11)  |
|  Non-ADE | 1 | 14.3% (1/7) | 0 | 0 % (0/4) | 2 | 18.2% (2/11)  |
|  Not assessed | 1 | 14.3% (1/7) | 2 | 50.0% (2/4) | 1 | 9.1% (1/11)  |

Adverse events with missing date will be classified as blinded phase.

Adverse events from baseline to 5 years are summarized in Table 8 below.

Table 8. Adverse Event Summary - Baseline to 5 years- Segmental Dystonia

|  Event Type | Serious |   | Non-Serious |   | Not assessed |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event  |
|  Dysarthria | 6 | 18.2% (2/11) | 3 | 27.3% (3/11) | 0 | 0% (0/11) | 9 | 45.5% (5/11)  |
|  Loss of effect | 2 | 18.2% (2/11) | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 3 | 27.3% (3/11)  |
|  Other | 2 | 18.2% (2/11) | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 3 | 18.2% (2/11)  |
|  Depression | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 0 | 0% (0/11) | 1 | 9.1% (1/11)  |
|  Dystonia | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 0 | 0% (0/11) | 1 | 9.1% (1/11)  |
|  Electrode fracture | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 0 | 0% (0/11) | 1 | 9.1% (1/11)  |
|  Gait disturbances | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 0 | 0% (0/11) | 1 | 9.1% (1/11)  |
|  Interrupted stimulation | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 0 | 0% (0/11) | 1 | 9.1% (1/11)  |
|  Stimulator malfunction | 1 | 9.1% (1/11) | 0 | 0% (0/11) | 0 | 0% (0/11) | 1 | 9.1% (1/11)  |
|  NA | 0 | 0% (0/11) | 0 | 0% (0/11) | 3 | 27.3% (3/11) | 3 | 27.3% (3/11)  |
|  Rebound | 0 | 0% (0/11) | 0 | 0% (0/11) | 1 | 9.1% (1/11) | 1 | 9.1% (1/11)  |

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|  Event Type | Serious |   | Non-Serious |   | Not assessed |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event | Events | Patients (%) with an Event  |
|  Total | 16 | 72.7% (8/11) | 5 | 45.5% (5/11) | 4 | 36.4% (4/11) | 25 | 90.9% (10/11)  |

NA = Not available.

### Safety Outcomes from the Publications

In addition to the Investigator Study,⁶ the analysis of safety of bilateral GPi DBS for the treatment of segmental dystonia in adult patients also includes data from 8 published studies with a total of 101 patients contributing safety outcomes. The 8 publications consist of 2 prospective studies²⁰,²¹ and 6 retrospective studies.²²⁻²⁷

Among the publications for segmental dystonia, severity was characterized by severe symptoms, marked disability or functional impairment, or failed or discontinued medications or botulinum neurotoxin due to no or slight effect.⁶,²⁰⁻²⁷ Average age at surgery ranged from 47 to 67 years.⁶,²⁰⁻²⁷ Duration of segmental dystonia before surgery ranged from 3 to 20 years.⁶,²⁰⁻²⁷

Across eight other published studies, the reported incidence rates for AE and SAE are 8.3% to 100%,²⁰⁻²⁶ and 0 to 25%,²⁶,²⁷ respectively, over a follow-up period of 6 months to 5.6 years in adult patients with segmental dystonia of the head and neck.

Table 9 lists the reported occurrence of one or more therapy-relevant safety events in adult patients with GPi DBS for segmental dystonia in each publication.

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Table 9. Therapy-Relevant Safety Events in Adult Patients with GPi DBS for Segmental Dystonia$^{a}$

|  First author (Year) | Total pts. enrolled | Mean Age at surgery – yrs | Follow-up | Symptomatic ICH (n, %) | Asymptomatic ICH (n, %) | Infection (n, %) | Device complications (n, %) | Suicide, suicide attempt (n, %) | Device revisions (n, %) | Explants (n, %)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  **RCT (n=1)**  |   |   |   |   |   |   |   |   |   |   |
|  Investigator-Sponsored Clinical Study^{6} | 11 | DBS: 51.3 ± 12.8 Sham: 50.8 ± 15.3 | 5 yrs. | 0 (0%) | 0 (0%) | 0 (0%) | 6/11 (54.5%) | NR | 6/11 (54.5%) | 1/11 (9.1%)  |
|  **Prospective Studies (n=2)**  |   |   |   |   |   |   |   |   |   |   |
|  Blahak (2008)^{20} | 10 | 57.4 ± 15.0 | 17 mos. | 0 (0%) | 0 (0%) | 0 (0%) | 1/10 (10%: 1 small superficial skin granuloma above the stimulation lead) | NR | 0 (0%) | 0 (0%)  |
|  Ostrem (2007)^{21} | 6 | 62.6 | 6 mos. | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%)  |
|  **Retrospective Studies (n=6)**  |   |   |   |   |   |   |   |   |   |   |
|  Fu (2024)^{22} | 23 | 52.4 ± 7.4 | 38.3 mos. | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | NR | NR | NR  |
|  Horisawa (2019)^{23} | 16 | 51.4 | 66.6 ± 40.7 mos. (range 13–150) | NR | NR | 1/16 (6.3%) | 1/16 (13.5%, 1 lead breakage) | NR | NR | 1/16 (6.3%: 1 infection and lead breakage in same patient)  |
|  Reese (2011)^{24} | 12 | 64.5 ± 4.4 | 38.8 ± 21.7 mos. | 0 (0%) | 0 (0%) | 1/12 (8.3%) | 0 (0%) | NR | 1/12 (8.3%: 1 infection) | NR  |
|  Ren (2022)^{25} | 13 | 46.9 ± 7.2 | 36.6 ± 11.0 mos. (range 18–55) | 0 (0%) | 0 (0%) | 1/13 (7.7%) | NR | NR | 1/13 (7.7%: 1 pouch position changed after infection) | NR  |
|  Sharma (2020)^{26} | 4 | 66.5 (range 54 – 79)^{b} | 1 yr. | 1/4 (25%) | NR | 1/4 (25%) | 1/4 (25%: 1 lead fracture) | NR | NR | 1/4 (25%: 1 infection & lead fracture)  |
|  Tian (2021)^{27} | 6 | 61.2 (range 53 – 71)^{b} | 43.7 | 0 (0%) | 0 (0%) | 0 (0%) | NR | NR | NR | NR  |

$^{a}$ If the authors specifically stated a type of event did not occur the rates were reported as 0 (0%). If the authors did not comment on a type of event, not reported (NR) is shown.

$^{b}$ Estimated from individual patient data reported in the publication

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Table 10 summarizes overall results of the meta-analysis of therapy-relevant safety outcomes in adult patients with GPi DBS for segmental dystonia using a random effects model.

For adult patients with segmental dystonia, device complications (13%), infections (7%), and intracerebral hemorrhage (symptomatic: 6%, asymptomatic: 4%) are the main therapy-related safety events. Device revisions (14%) and explants (9%) are the most common other safety events. These rates are based on pooled data from multiple publications.

High heterogeneity was observed in device complications and device revision rates, likely influenced by clinical factors such as surgical experience and reporting practices.

Table 10. Pooled Therapy-Relevant Safety Event Rates in Adult Patients with GPi DBS for Segmental Dystonia Using Random Effects Model

|  Safety Event | Pooled Event Rate (95% CI) | No. of Publications | References  |
| --- | --- | --- | --- |
|  **Therapy-Relevant Safety Events**  |   |   |   |
|  Device complications | 13% (4-32%) | 7 | 6,20-24,26  |
|  Infection | 7% (3-15%) | 9 | 6,20-27  |
|  Symptomatic ICH | 6% (2-15%) | 8 | 6,20-22,24-27  |
|  Asymptomatic ICH | 4% (2-12%) | 7 | 6,20-22,24,25,27  |
|  **Other Safety Events**  |   |   |   |
|  Device revisions | 14% (4-41%) | 5 | 6,20,21,24,25  |
|  Explants | 9% (3-22%) | 5 | 6,20,21,23,26  |

### Cervical Dystonia

#### Study Specific Data

The analysis of safety of bilateral GPi DBS for the treatment of primary cervical dystonia in adult patients was based on primary source data from 62 patients with cervical dystonia in the Volkmann (2014)⁷ RCT. The neurostimulation group reported 5 SAEs (16%, 5/32) compared to 11 SAEs (37%, 11/30) in the sham group, with 69% (11/16) resolving without sequelae (Table 11).

Table 11. Adverse Event Summary for Cervical Dystonia in Adults (Volkmann 2014)

|  Event Type | Open Label Phase  |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Neurostimulation (n=32) |   | Sham Stimulation (n=30) |   | All Patients (n=62)  |   |
|   |  Events | Patients % (n/N) | Events | Patients % (n/N) | Events | Patients % (n/N)  |
|  SAE | 5 | 15.6% (5/32) | 11 | 36.7% (11/30) | 16 | 25.8% (16/62)  |

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|  Event Type | Open Label Phase  |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Neurostimulation (n=32) |   | Sham Stimulation (n=30) |   | All Patients (n=62)  |   |
|   |  Events | Patients % (n/N) | Events | Patients % (n/N) | Events | Patients % (n/N)  |
|  Non-SAE (AEs) | 21 | 65.6% (21/32) | 20 | 66.7% (20 /30) | 41 | 66.1% (41/62)  |

### *Safety Outcomes from the Publications*

In addition to Volkmann (2014)$^{7}$, the analysis of safety of bilateral GPi DBS for the treatment of cervical dystonia in adult patients also include data from 8 published studies with a total of 183 patients contributing safety outcomes. Among the publications on cervical dystonia, 7 studies$^{28–34}$ reported average age at surgery in the 50s to low 60s.$^{7}$ Two studies$^{35,36}$ reported an average age of surgery in the 40s, 1 study$^{26}$ in the low 70s and 1 study$^{37}$ did not report age at surgery. Volkmann (2014)$^{7}$ reported a duration of disease of 15 years. Duration of disease trended shorter in 6 studies$^{28,30,31,35–37}$ published since 2015, ranging from 3 to 6 years. One study$^{26}$ published in 2020 had a disease duration of 17 years before surgery.

Across nine other published studies, the reported incidence rates for AE and SAE were 3.8% to 80%$^{26,28–30,32–35}$ and 0 to 14.3%,$^{26,28,29,35,38}$ respectively, over a follow-up period of 1 year to 10 years in adult patients with cervical dystonia.

Table 12 lists the reported occurrence of one or more therapy-relevant safety events in adult dystonia patients with GPi DBS for cervical dystonia in each publication.

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Table 12. Therapy-Relevant Safety Events in Adult Patients with GPi DBS for Cervical Dystoniaᵃ

|  First author (Year) | Total pts. enrolled | Mean Age at surgery – yrs | Follow-up | ICH (symptomatic) (n, %) | ICH (asymptomatic) (n, %) | Infection (n, %) | Device complications (n, %) | Suicide, suicide attempt (n, %) | Device revisions (n, %) | Explants (n, %)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  **RCT of GPi for Cervical Dystonia (n=1)**  |   |   |   |   |   |   |   |   |   |   |
|  Volkmann (2014)⁷ | 62 | DBS: 57.1 ± 9.82 Sham: 56.6 ± 11.33 | 6 mos. | 1/62 (1.6%, 1 hemiparesis or stroke) | NR | 3/62 (4.8%) | 5/62 (8.1%, 1 tethering of extension cable, 2 electrode dislocations, 1 electrode misplacement, 1 IPG dislocation) | NR | 2/62 (3.2%): 2 surgical exchange of device components | 1/62 (1.6%)  |
|  **Prospective Study of GPi for Cervical Dystonia (n=1)**  |   |   |   |   |   |   |   |   |   |   |
|  Walsh RA (2013)¹⁴ | 10 | 55.5 ± 12.8 | 7.8 yrs. (range 4.9–10.7) | NR | NR | 2/10 (20%) | 1/10 (10%, 1 suboptimal lead placement) | NR | 4/10 (40%): 2 lead removals, 1 lead replacement, 1 lead repositioned | 1/10 (10%): 1 infection  |
|  **Retrospective Studies of GPi for Cervical Dystonia (n=7)**  |   |   |   |   |   |   |   |   |   |   |
|  Chung M (2015)²⁸ | 25 | 52.2 ± 9.6 | 19.9 ± 11.5 mos. | 2/25 (8.0%) | NR | 1/25 (4.0%) | 2/25 (8.0%, 1 electrode reposition, 1 extension line revision) | NR | 2/25 (8.0%): 1 electrode reposition, 1 extension line revision | NR  |
|  Contarino MF (2014)²⁹ | 15 | 56.5 ± 14.8 (range: 29–77) | 2.3 ± 0.9 mos. (range 1–4) | 1/15 (7%) | NR | NR | 5/15 (33%, 1 tight extension, 1 painful moving IPG, 1 lead fracture and contralateral lead migration, 1 electrode fixation replacement, 1 electrode repositioning) | NR | 5/15 (33%): 1 tight extension, 1 painful moving IPG, 1 lead fracture and contralateral lead migration, 1 electrode fixation replacement, 1 electrode repositioning | NR  |
|  Cui Z (2022)¹⁵ | 53 | 44.79 ± 12.88 | 40.49 ± 19.82 mos. | 2/53 (3.8%) | NR | NR | 0 (0%) | NR | NR | NR  |
|  Jacksch C (2022)¹² | 15 | 61.5 | 10 yrs. | NR | NR | 1/15 (6.7%) | 2/15 (13.3%, 2 cable tractions) | NR | 3/15 (20.0%): 2 revisions for cable traction, 1 pulse generator replacement for infection | NR  |

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|  First author (Year) | Total pts. enrolled | Mean Age at surgery – yrs | Follow- up | ICH (symptomatic) (n, %) | ICH (asymptomatic) (n, %) | Infection (n, %) | Device complications (n, %) | Suicide, suicide attempt (n, %) | Device revisions (n, %) | Explants (n, %)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Sharma (2020)^{26} | 7 | 72.6 ± 16.5 (range: 51- 98)^{b} | 1 yr. | 1/7 (14.3%) | NR | NR | 1/7 (14.3%; 1 tethering of extension wire) | NR | NR | NR  |
|  Wang X (2020)^{16} | 23 | 41.13 ± 13.49 (range: 16-70) | 19.04 ± 16.30 mos. (range 3– 74) | 0/23 (0%) | 0/23 (0%) | NR | NR | NR | 0/23 (0%) | NR  |
|  Witt JL (2013)^{13} | 28 | 56.0 ± 10.4 (range: 33-70) | 33.7 ± 25.0 mos. (range 4– 97) | NR | 3/28 (10.7%) | 1/28 (3.6%) | 2/28 (7.1%, 2 suboptimal lead placement) | NR | 3/28 (10.7%); 2 lead replacement, 1 system reimplantation | 1/28 (3.6%)  |

$^{a}$If the authors specifically stated a type of event did not occur; the rates were reported as 0 (0%). If the authors did not comment on a type of event, not reported (NR) is shown.

$^{b}$ Estimated from individual patient data reported in the publication

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Table 13 summarizes overall results of the meta-analysis of therapy-relevant safety outcomes in adult patients with GPi DBS for cervical dystonia using a random effects model.

For adult patients with cervical dystonia, device complications (11%), infections (7%), and intracerebral hemorrhage (symptomatic: 5%) are the main therapy-related safety events. Device revisions (14%) and explants (4%) are the most common other safety events. The event rates are based on pooled data from multiple publications, providing robust estimates for these outcomes.

Device complications and revisions are the most frequent safety events in cervical dystonia for adult patients with moderate to high heterogeneity, likely influenced by clinical factors such as surgical experience and reporting practices.

Table 13. Pooled Therapy-Related Safety Event Rates in Adult Patients with GPi DBS for Cervical Dystonia Using Random Effects Model

|  Safety Event | Pooled Event Rate (95% CI) | No. of Publications | References  |
| --- | --- | --- | --- |
|  **Therapy-Relevant Safety Events**  |   |   |   |
|  Device complications | 11% (6-19%) | 8 | 7,26,28,29,32-35  |
|  Infection | 7% (3-13%) | 5 | 7,28,32-34  |
|  Symptomatic ICH | 5% (2-10%) | 6 | 7,26,28,29,35,36  |
|  Asymptomatic ICH | NR | NA | NA  |
|  **Other Safety Events**  |   |   |   |
|  Device revisions | 14% (6-28%) | 7 | 7,28,29,32-34,36  |
|  Explants | 4% (1-11%) | 3 | 7,33,34  |

- Safety Outcomes for Bilateral GPi DBS in Pediatric Population with Primary Generalized Dystonia

The analysis of safety of GPi DBS for the treatment of primary generalized dystonia in pediatric patients 12 years of age or above was based on data from 12 publications evaluating 202 pediatric patients contributing safety outcomes. The published studies consist of 4 prospective13,15,39,40 and 8 retrospective studies.41-48

The published studies compared reasonably well in baseline patient characteristics. Most pediatric patients in these studies received bilateral GPi DBS for primary generalized dystonia. Dystonia severity was characterized as severe or significant disability or impairment in daily activities despite medical management.13,15,39-41,43,46-48 Average age at surgery ranged from 10

{32}

to 17 years.$^{15,39–43,45–48}$ Duration of dystonia symptoms before surgery ranged from 3 to 10 years.$^{15,39–48}$

Across 12 published studies, the reported incidence rates for AE and SAE were 0% to 100%$^{13,15,39–43,45–48}$ and 0 to 60%,$^{15,40,41,43}$ respectively, over a follow-up period of 6 months to 10 years in pediatric patients with generalized dystonia.

Table 14 lists the reported occurrence of one or more therapy-relevant safety events in pediatric dystonia patients with GPi DBS for generalized dystonia in each publication.

{33}

Table 14. Therapy-Relevant Safety Events in Pediatric Populations with GPi DBS Generalized Dystonia$^{a}$

|  First author (Year) | Total pts. enrolled | Mean Age at surgery – yrs | Follow-up | ICH (symptomatic) (n, %) | ICH (asymptomatic) (n, %) | Infection (n, %) | Device complications (n, %) | Suicide, suicide attempt (n, %) | Revisions (n, %) | Explants (n, %)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  **Prospective Studies (n=4)**  |   |   |   |   |   |   |   |   |   |   |
|  Borggraefe (2010)^{39} | 24 | 14.2 ± 3.4 (range: 9-20) | 12.0 ± 4.8 mos. | NR | NR | 3/24 (12.5%) | 9/24 (37.5%: 6 unexplained switching off the stimulator, 2 electrode migration, 1 cable perforation) | NR | 4/24 (16.7%: 3 exchanges of electrodes for infection, 1 abdominal pouch revision) | NR  |
|  Coubes (2004)^{13} | 19 | ≤ 17 | 42.1 ± 14.8 mos. | 0 (0%) | 0 (0%) | 1/19 (5.3%) | NR | NR | 1/19 (5.3%) | NR  |
|  Starr (2014)^{40} | 6 | 10.2 (range: 7-13)^{b} | 12 mos. | 0 (0%) | 0 (0%) | NR | 1/6 (16.7%: 1 open circuit on lead) | NR | NR | NR  |
|  Vidailhet (2007)^{15} | 5 | 17.2 (range: 15-19)^{b} | 3 yrs. | NR | NR | NR | NR | NR | NR | NR  |
|  **Retrospective Studies (n=8)**  |   |   |   |   |   |   |   |   |   |   |
|  Ghosh (2012)^{41} | 6 | 13.2 (range: 8-21)^{b} | 5.8 ± 1.4 yrs. (range 4-8 primary dystonia) | 0 (0%) | 0 (0%) | 0 (0%) | 2/6 (33.3%: 1 electrode dislocation, 1 extension breakage) | NR | 2/6 (33.3%: 1 electrode dislocation, 1 extension breakage) | NR  |
|  Haridas (2011)^{42} | 22 | 13.4 ± 2.7 (range: 9-21) | 2 yrs. | 0 (0%) | 0 (0%) | 3/22 (13.6%) | 5/22 (22.7%: 2 desire to improve clinical response, 1 lead fracture, 1 extension cable fracture, 1 suboptimal lead position) | NR | 8/22 (36.4%: 3 infections, 2 desire to improve clinical response, 1 lead fracture, 1 suboptimal lead position, 1 extension cable fracture) | NR  |
|  Krause (2016)^{43} | 8 | 12.5 ± 3.5 (range: 7-17) | 58.5 ± 18.0 mos. (range 20-156) | NR | NR | NR | 2/8 (25%: 1 IPG dislocation, 1 electrode revision) | NR | 2/8 (25%: 1 IPG dislocation, 1 bilateral | NR  |

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|  First author (Year) | Total pts. enrolled | Mean Age at surgery – yrs | Follow-up | ICH (symptomatic) (n, %) | ICH (asymptomatic) (n, %) | Infection (n, %) | Device complications (n, %) | Suicide, suicide attempt (n, %) | Revisions (n, %) | Explants (n, %)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  |  |  |  |  |  |  |  | electrode revision) |   |
|  Lumsden (2013)^{44} | 70 (63 after excluding 7 patients) | 12.8 (range: 4.6-17.5)^{b} | 12 mos. | NR | NR | 5/70 (7.1%) | NR | NR | NR | 5/70 (7.1%; removal of part of the implanted stimulating system within first 6 mos. following surgery)  |
|  Markun (2012)^{45} | 14 | 15.5 ± 5.7 (range: 10-27) | 32.2±17.9 (7-77) mos. | NR | 1/14 (7.1%) | NR | 3/14 (21.4%; 2 lead extender fractures, 1 lead repositioning) | NR | 3/14 (21.4%; 2 lead extender fractures, 1 lead repositioning) | NR  |
|  Marotta (2020)^{48} | 9 | 16.0 (range: 14-17) | 13 mos. | NR | 1/9 (11.1%) | NR | 0 (0%) | NR | 0 (0%) | 0 (0%)  |
|  Petrossian MT (2013)^{46} | 8 | 13.3 range: (9-17)^{b} | 50.8 mos. (median 52.5 mos., range 16-84) | 0 (0%) | 0 (0%) | 2/8 (25%) | 2/8 (25%; 2 lead fractures) | NR | 0 (0%) | 1/8 (12.5%; 1 infection)  |
|  Ramezani Ghamsari M (2021)^{47} | 11 | 14.72 ± 3.71 (range: 9-20) | 8.5 ± 6.9 yrs. (range 7-10) | NR | NR | 0 (0%) | 0 (0%) | NR | NR | NR  |

$^{a}$If the authors specifically stated a type of event did not occur; the rates were reported as 0 (0%). If the authors did not comment on a type of event, not reported (NR) is shown.

$^{b}$ Estimated from individual patient data reported in the publication

{35}

Table 15 summarizes overall results of the meta-analysis of therapy-relevant safety outcomes in pediatric patients with GPi DBS for generalized dystonia using a random effects model.

For pediatric patients with generalized dystonia, device complications (26%), infections (16%), and intracerebral hemorrhage (symptomatic: 4%, asymptomatic: 6%) are the main therapy-related safety events. Device revisions (21%) and explants (20%) are the most common other safety events. The event rates are based on pooled data from multiple publications, providing robust estimates for these outcomes.

Device complications, device revisions, and explants are the most frequent safety events in pediatric patients. Clinical factors (e.g., surgical experience, reporting practices) may drive this the high device-related events.

Table 15. Pooled Therapy-Relative Safety Event Rates in Pediatric Patients with GPi DBS for Generalized Dystonia Using Random Effects Model

|  Safety Event | Pooled Event Rate (95% CI) | No. of Publications | References  |
| --- | --- | --- | --- |
|  **Therapy-Relevant Safety Events**  |   |   |   |
|  Device complications | 26% (18-35%) | 9 | 39-43,45-48  |
|  Infection | 16% (9-25%) | 7 | 13,39,41,42,44,46,47  |
|  Symptomatic ICH | 4% (1-14%) | 5 | 13,40-42,46  |
|  Asymptomatic ICH | 6% (2-14%) | 7 | 13,40-42,45,46,48  |
|  **Other Safety Events**  |   |   |   |
|  Device revisions | 21% (13-22%) | 8 | 13,39,41-43,45,46,48  |
|  Explants | 20% (7-43%) | 3 | 44,46,48  |

- Comparison of Therapy-Relevant Safety Events Between Adult and Pediatric Patients with Generalized Dystonia by Study Designs

A safety meta-analysis compared adult and pediatric patients with generalized dystonia using prospective and retrospective studies, as no randomized trials existed for pediatric patients. There were no RCTs included in the pediatric analysis; therefore, the safety meta-analysis for adult vs pediatrics by study design is limited to prospective and retrospective studies only. Summary of safety events by study design comparing adult and pediatric patients with primary generalized dystonia is provided below.

Device Complications

Figure 2 presents a forest plot and detailed comparison of device complication rates between adult and pediatric patients with generalized dystonia by study design, with data pooled from the prospective studies (a) and retrospective studies (b) using a random effects model.

{36}

Prospective Studies: Using a random effects model, the pooled device complication rate was 7% (95% CI: 3–19%) for adult patients and 34% (95% CI: 19–53%) for pediatric patients, with no heterogeneity among studies. The combined device complication rate across both dystonia types was 14% (95% CI: 5–34%), with high heterogeneity across both groups (p=0.0502).

Retrospective Studies: Using a random effects model, the pooled device complication rate was 30% (95% CI: 4–83%) for adult patients and 21% (95% CI: 14–32%) for pediatric patients. No heterogeneity was observed in pediatric studies, but high heterogeneity was observed in adult studies ( \( I^{2}=75.7\% \) ,  \( \tau^{2}=0.6925 \) , p=0.0165). The combined device complication rate was 24% (95% CI: 16–35%), with low heterogeneity across both groups (p=0.2083).

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

Figure 2. Forest Plot of Device Complication Rates in Adult and Pediatric Patients with Generalized Dystonia by Study Designs, a) Prospective, b) Retrospective.

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# Infection

Fi…

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**Source:** [https://fda-staging.innolitics.com/device/P960009S482](https://fda-staging.innolitics.com/device/P960009S482)

**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