← Product Code MHY · P960009 # MEDTRONIC ACTIVA TREMOR CONTROL SYSTEM (P960009) _Medtronic, Inc. · MHY · Jul 31, 1997 · Neurology · APPR_ **Canonical URL:** https://fda.innolitics.com/device/P960009 ## Device Facts - **Applicant:** Medtronic, Inc. - **Product Code:** MHY - **Decision Date:** Jul 31, 1997 - **Decision:** APPR - **Device Class:** Class 3 - **Review Panel:** Neurology - **Attributes:** Therapeutic, Expedited Review ## Indications for Use Unilateral thalamic stimulation using the Medtronic® Activa™ Tremor Control System (herein after called the Activa™ System) is indicated for the suppression of tremor in the upper extremity. The system is intended for use in patients who are diagnosed with essential tremor or Parkinsonian tremor not adequately controlled by medications and where the tremor constitutes a significant functional disability. ## Device Story Implantable system delivers electrical stimulation to ventral intermediate nucleus (VIM) of thalamus to suppress upper extremity tremor. Components: quadripolar lead (Model 3387), extension (Model 7495), implantable pulse generator (IPG, Model 7424), console programmer (Model 7432), and memory module (Model 7458). Lead stereotactically implanted in VIM; IPG implanted subclavicularly/subcostally. Physician uses programmer via RF telemetry to adjust stimulation parameters (voltage, frequency, pulse width) to optimize tremor suppression and minimize side effects. System provides non-destructive, reversible alternative to thalamotomy. Benefits include improved activities of daily living and reduced tremor severity. Used in clinical settings by neurosurgeons and neurologists. ## Clinical Evidence Prospective multicenter clinical studies (US and European) evaluated 424 patients. Primary endpoints: tremor suppression (UPDRS/TRS scales) and functional improvement (ADL). Results showed statistically significant tremor suppression (p<0.0001) and improved ADL scores in both essential tremor and Parkinson's disease cohorts. Adverse events included paresthesia (33%), dysarthria (9%), and disequilibrium (5%). Bench testing and animal studies (sheep/rabbit) assessed biocompatibility and histopathological effects. ## Technological Characteristics Quadripolar lead with Pt/Ir electrodes, polyurethane sheath, and PTFE insulation. IPG is battery-powered, RF-telemetry programmable. Stimulation: 0-10.5V, 2-185Hz, 60-450µs pulse width. Burr hole cap/ring made of Gorillamid (nylon). Software-locked parameters prevent charge densities >30 µC/cm²/phase. Sterilization validated for components. ## Reference Devices - Itrel II Stimulation System ([P840001](/device/P840001.md)/S015) - PISCES Quad SCS Lead (Models 3487/3487A) - Model 7455 Memory Module ## 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 ## Medtronic® Activa™ Tremor Control System ## Table of Contents 1. General Information...1 2. Indications for Use...1 3. Contraindications...1 4. Warnings and Precautions...1 5. Device Description...1 5.1 Model 3387 DBS™ Lead...2 5.2 Model 7495 Extension...2 5.3 Model 7424 Implantable Pulse Generator (IPG)...2 5.4 Burr Hole Cap and Ring...2 5.5 Model 7458 Memory Module...2 Table 1. Stimulation Parameters...2 6. Alternative Practices or Procedures...2 7. Marketing History...3 8. Adverse Effects of the Device on Health...3 8.1 Observed Adverse Events...3 Table 2. Adverse Events and Surgical Interventions Related to the Device or Procedure...3 Table 3. Adverse Events During Stimulation (US and European Trials)...4 8.2 Potential Adverse Events...5 9. Summary of Preclinical Studies...5 9.1 Laboratory Studies...5 9.1.1 Component Testing...5 9.1.1.1 Model 7424 Implantable Pulse Generator (IPG)...5 Table 4. Model 7424 IPG Circuit Qualification Testing...5 9.1.1.2 Model 7495 Extension...6 9.1.1.3 Burr Hole Ring and Cap...6 9.1.1.4 Model 7458 Memory Module Cartridge and Software, and Model 7432 Console Programmer...6 9.1.2 Model 3387 DBS Lead...6 Table 5. Model 3387 Material Changes...6 9.1.2.1 Model 3387 Lead...6 9.1.2.2 Model 3387 Lead Stylet...6 Table 6. Model 3387 Design Qualification Testing...7 9.1.2.3 Process Qualification Tests for the Model 3387 DBS Lead...7 9.1.3 Reliability...7 9.1.4 Biocompatibility...8 9.1.5 Biostability...8 9.1.6 Other Testing...9 9.2 Animal Studies...9 9.2.1 Effectiveness...9 9.2.2 Safety...9 9.2.3 Related Human Study...9 9.2.4 Implant Protocol Description...10 9.2.4.1 Acute Phase...10 9.2.4.2 Chronic Phase...10 9.2.5 Additional Studies...11 9.2.5.1 Intracerebroventricular Polyurethane Device Study in Sheep for 3 and 12 Months...11 9.2.5.2 Polyurethane Tubing Intracranial Implants in Rabbits for 14, 32, 90, and 180 Days...11 9.2.6 Conclusions...11 10. Summary of Clinical Studies...11 10.1 Gender Bias...12 10.2 U.S. Tremor Study...13 10.2.1 Investigational Plan...13 10.2.2 Study Centers...14 Table 7. Centers for U.S. Tremor Study With Patients Enrolled By Etiology...14 10.2.3 Essential Tremor Patients...14 Table 8. Patient Demographics...14 Figure 1. Patient Flow...15 Table 9. Mean Tremor Scores...15 Table 10. Activities of Daily Living...16 Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page i {1} Table 11. Disability Assessment...16 Table 12. Mean Stimulation Parameters...16 10.2.4 Parkinson's Disease Patients...17 Table 13. Patient Demographics...17 Figure 2. Patient Flow...17 Table 14. Mean Tremor Scores...17 Table 15. Symptoms as Determined by the UPDRS Motor Exam...18 Table 16. Activities of Daily Living...18 Table 17. Disability Assessment...18 Table 18. Mean Stimulation Parameters...19 Table 19. Average Tremor Score Results for Essential Tremor Patients...19 Table 20. Average Tremor Score Results for Parkinson's Disease Patients...19 10.3 European Tremor Study...20 10.3.1 Investigational Plan...20 10.3.2 Study Centers...20 Table 21. Centers for European Tremor Study with Patients Enrolled by Etiology...20 Table 22. Patient Demographics...21 10.3.3 Essential Tremor Patients...21 Figure 3. Patient Flow...21 10.3.4 Parkinson's Disease Patients...22 Figure 4. Patient Flow...22 10.4 European Long-Term Efficacy Study...22 10.4.1 Investigational Plan...22 10.4.2 Study Centers...22 Table 23. Centers for European (Swedish) Long-Term Efficacy Study with Patients Enrolled by Etiology...23 10.4.3 Essential Tremor Patients...23 Table 24. Patient Demographics...23 Table 25. Mean Tremor Scores...23 10.4.4 Parkinson's Disease Patients...24 Table 26. Patient Demographics...24 Table 27. Mean Tremor Scores...24 10.4.5 European Basic Study...24 10.4.5.1 Investigational Plan...24 10.4.5.2 Patient Demographics...24 10.4.6 DBS For Pain Study...25 11. Conclusions Drawn from the Studies...25 11.1 Safety...25 11.2 Effectiveness...25 11.3 Risk Benefit Analysis...26 12. Panel Recommendation...26 13. FDA Decision...26 14. Approval Specifications...26 Medtronic Activa™ P960009: Summary of Safety and Effectiveness {2} # Summary of Safety and Effectiveness Data ## Medtronic® Activa™ Tremor Control System ### 1. General Information **Generic Name:** Implantable multiprogrammable quadripolar thalamic stimulation system for the treatment of tremor **Trade Name:** Medtronic® Activa™ Tremor Control System Model 3387 DBS™ Lead Model 7495 Extension Model 7424 Implantable Pulse Generator (IPG) Model 7458 Memory Module Model 7432 Console Programmer Burr Hole Ring and Cap Model 7452 Magnet Model 3625 Test Stimulator (Screened) Model 3353/3354 Lead Frame Kits and Accessories **Applicant’s Address:** Medtronic Inc., Neurological Division NeuroStimulation Business 800 53rd Avenue, N.E. Minneapolis, MN. 55421 **PMA Number:** P960009 **Date of Panel Recommendation:** March 14, 1997 **Date of Notice of Approval to Applicant:** July 31, 1997 ### 2. Indications for Use Unilateral thalamic stimulation using the Medtronic® Activa™ Tremor Control System (herein after called the Activa™ System) is indicated for the suppression of tremor in the upper extremity. The system is intended for use in patients who are diagnosed with essential tremor or Parkinsonian tremor not adequately controlled by medications and where the tremor constitutes a significant functional disability. ### 3. Contraindications Implantation of a Tremor Control System is contraindicated for: - Patients for whom test stimulation is unsuccessful or - Patients who are unable to properly operate the stimulator. ### 4. Warnings and Precautions The warnings and precautions can be found in the Activa™ System labeling. ### 5. Device Description The Activa™ System delivers electrical stimulation to the ventral intermediate nucleus (VIM) of the thalamus to suppress the tremor of the upper extremity associated with essential tremor and Parkinson’s disease. During the surgical procedure for implant, a lead is introduced into the VIM of the thalamus, and electrical stimulation is used to establish the optimal electrode position within the VIM. Stimulation is initiated, and the patient’s targeted extremity is observed for response. The optimum response of the targeted extremity determines the final position of the DBS lead within the VIM. Patients who demonstrate a reduction in tremor intraoperatively will then have a lead, extension and implantable pulse generator (IPG) implanted. The Activa™ System components (IPG, extension, and programmer) are currently commercially available for Spinal Cord Stimulation (SCS) for the treatment of chronic, intractable pain of the trunk or limbs Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 1 {3} (P840001/S015). The extension and screener are currently commercially available for Spinal Cord Stimulation (SCS) and peripheral nerve stimulation (PNS) for the treatment of chronic, intractable pain of the trunk or limbs (K903690, K881491, K924522, K884898, etc.). ## 5.1 Model 3387 DBS™ Lead This lead has four electrodes which are stereotactically introduced into the target and fixed at the skull with a burr hole cap and ring. The lead consists of a polyurethane protective sheath and four platinum/iridium electrodes at the tip of the lead. The function of the lead is to provide a conductive pathway for electrical current to the targeted nucleus. Accessories are provided which aid in the surgical procedure, lead securement, and temporary stimulation for therapy screening, e.g., Burr Hole Cap and Ring, Lead Frame Kits, and tunneling rods. ## 5.2 Model 7495 Extension The extension is an insulated set of wires connecting the DBS Lead and the implantable pulse generator (IPG). The extension is subcutaneously passed from the scalp area, where it connects to the proximal end of the DBS Lead, to the area below the clavicle, where it connects to the implantable pulse generator. ## 5.3 Model 7424 Implantable Pulse Generator (IPG) The IPG is the electrical "power source" for stimulation therapy. It is implanted subcutaneously, in the subclavicular or subcostal regions. The IPG delivers electrical stimulation pulses with a variety of parameters, modes, and polarities. These stimulation parameters can be non-invasively adjusted to optimize the treatment of tremor and minimize side effects. The adjustments are made by radio-frequency (RF) telemetry by the Model 7432 Console Programmer/ Model 7458 Memory Module Software. The IPG is battery powered and must be replaced surgically; the frequency of replacement is dependent on the amount of time that the IPG is used each day and the parameters at which the IPG is set. ## 5.4 Burr Hole Cap and Ring The cap and ring are made of Gorillamid (nylon). The ring has ridges that hold it in place in the skull. A trough is machined into the ring, and the burr hole cap holds the lead in the trough. ## 5.5 Model 7458 Memory Module The Model 7458 Memory Module Software Cartridge ("MemMod"), is similar to the MemMod used for SCS (Model 7455). However, the software code on the Model 7458 allows pulse rates of 185 Hz rather than being limited to 130 Hz as with the SCS application. Table 1 lists the maximum stimulus parameters as well as baseline parameters for tremor suppression based on a preliminary analysis of the clinical study: Table 1. Stimulation Parameters | Stimulus Parameter | Range (Max) | Tremor - Baseline | | --- | --- | --- | | Voltage (Volts) | 0 to 10.5 | 2 to 3 | | Frequency (Hertz) | 2 to 185 | > 100 | | Pulse Width (microseconds) | 60 to 450 | 60 to 90 | Although some combinations of stimulus parameters were not established as safe and effective, the device software will prevent the user from accidentally using these particular combinations. ## 6. Alternative Practices or Procedures Several medical and surgical alternatives are available for the treatment of tremor. When managing tremor, medication is usually tried first. When medication is no longer effective or produces unacceptable side effects at doses which are required to control the tremor, surgery is an alternative. The surgical ablative procedures, such as thalamotomy, used to manage tremor are considered true alternatives to electrical stimulation. Electrical stimulation differs from ablative procedures in that the goal of the surgical ablation is to produce a permanent lesion in the brain that may treat tremor. In some cases, the implantation of the lead or the mechanical presence of the lead may produce a temporary thalamotomy- Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 2 {4} like effect without stimulation, but the goal is not to produce a lesion. ## 7. Marketing History The Model 3387 DBS Lead has been sold outside the United States since 1991. From 1991, through October 31, 1996, approximately 1,566 Model 3387 Leads have been sold. The Activa™ System (also known as the Itrel II Stimulation System) has been commercially available in the United States and areas outside the United States since 1988 for Spinal Cord Stimulation (SCS) for the treatment of chronic pain. The Activa™ System has not been withdrawn from marketing for any reason relating to the safety and effectiveness of the device. ## 8. Adverse Effects of the Device on Health ### 8.1 Observed Adverse Events The most common adverse events reported in the US Tremor Trial (≥ 5% of patients) were postoperative pain, lead repositioning, stimulation not effective, paresthesia., dysarthria, disequilibrium, and paresis. Table 2 lists the adverse events attributed to the device or the procedure reported in more than one patient. Table 2. Adverse Events and Surgical Interventions Related to the Device or Procedure. Reported in ≥ 1 patient, all patients enrolled, N = 424 | Number of Patients | US Tremor 84 | EC Tremor 113 | Others * 227 | Total 424 | % | | --- | --- | --- | --- | --- | --- | | Adverse Event (AE) | Number of Patients with the AE | | | | | | ANY (one or more) adverse event | 32 | 20 | 68 | 120 | 28.3% | | Postoperative pain, stress or discomfort | 11 | 9 | 8 | 28 | 6.6% | | Lead repositioning | 5 | 4 | 17 | 26 | 6.1% | | Stimulation not effective/ Insufficient tremor control | 5 | 3 | 17 | 25 | 5.9% | | Lead migration/ dislodgment | 1 | 1 | 12 | 14 | 3.3% | | Intracranial hemorrhage | 5 | 3 | 5 | 13 | 3.1% | | DBS explantation | 4 | 1 | 7 | 12 | 2.8% | | Infection | 1 | 2 | 8 | 11 | 2.6% | | Erosion | 5 | 0 | 3 | 8 | 1.9% | | Paresthesia | 5 | 1 | 0 | 6 | 1.4% | | Component malfunction (IPG, lead, extension) | 2 | 1 | 2 | 5 | 1.2% | | Seizures | 1 | 0 | 4 | 5 | 1.2% | | Subcutaneous hematoma | 1 | 2 | 2 | 5 | 1.2% | | Electrical shocking or jolting | 1 | 0 | 3 | 4 | 0.9% | | Headaches | 2 | 1 | 1 | 4 | 0.9% | | Lead fractures | 1 | 0 | 3 | 4 | 0.9% | | Paresis | 3 | 0 | 1 | 4 | 0.9% | | Disequilibrium | 2 | 1 | 0 | 3 | 0.7% | | Allergic reaction | 0 | 0 | 2 | 2 | 0.5% | | Burr hole ring and cap failure | 0 | 1 | 1 | 2 | 0.5% | | Electrode short circuit or open circuit | 1 | 1 | 0 | 2 | 0.5% | * Basic Safety and DBS for Pain Studies Adverse events reported in one patient each included attention or cognitive deficit, cramping, diplopia, dysarthria, dysphasia, exacerbation of Parkinson's disease, facial weakness, IPG changed from cycling mode to continuous mode, insufficient oxygenation, no connection at "0" electrode, problem with lead/extension connection, broken tunneling rod, and twelfth cranial nerve palsy. Device failure was confirmed in one case, and resulted from premature IPG battery depletion due to a defective integrated circuit. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 3 12 {5} Table 3 lists the adverse events attributed to the therapy (deep brain stimulation) which occurred in more than one patient. The number and percentage of patients with adverse events (any one or more) in the US and European Tremor Trials for patients with essential tremor was 43 of 78 (55%) compared to 33 or 111 (30%) for patients with Parkinson's disease. The number and percentage of adverse events (any one or more) in the European Tremor Trial for all patients implanted bilaterally was 4 of 27 (15%) compared to 10 of 85 (12%) of patients implanted unilaterally. Table 3 combines the frequencies across diagnoses and unilateral/bilateral implants. Table 3. Adverse Events During Stimulation (US and European Trials) Reported in ≥ 1 patient, all tremor patients, N = 189) | Adverse Event | # of Events | # of Patients | % of Patients | | --- | --- | --- | --- | | ANY (one or more) adverse event | 242 | 76 | 40% | | Paresthesia | 123 | 63 | 33% | | Dysarthria | 22 | 17 | 9% | | Disequilibrium | 11 | 9 | 5% | | Paresis | 13 | 9 | 5% | | Dystonia | 17 | 6 | 3% | | Gait disorder | 5 | 5 | 3% | | Initial jolt | 8 | 5 | 3% | | Headaches | 5 | 4 | 2% | | Pain, discomfort or local stress | 7 | 4 | 2% | | Attention deficit | 3 | 3 | 2% | | Dysphasia | 3 | 3 | 2% | | Initial tingling | 3 | 3 | 2% | | Insufficient therapeutic effect | 3 | 3 | 2% | | Ataxia | 3 | 2 | 1% | | Dyskinesia | 2 | 2 | 1% | | Sensory deficits | 2 | 2 | 1% | Adverse events reported in one patient each included facial weakness, fatigue, intention coordination, loss of energy, numbness, other speech deficits, rebound, and transient heaviness in arm. Most (70%) of the therapy-related adverse events were tolerated by the patients and involved no clinical intervention. Stimulation parameters were adjusted in 22% of the cases. Other interventions included: patient education; adjustment of concomitant medications; and instructions to discontinue stimulation. Nine patients required lead repositioning to regain therapeutic effect. Five essential tremor patients had their Activa™ Systems explanted. Four patients were explanted due to loss of effectiveness. One patient was explanted due to infection. Of the 114 Parkinson's disease patients (US and Europe), disease progression was reported in ten patients, exacerbation of tremor in three patients (both occurred in one patient). These events were listed as adverse events, but attributed by the investigator to disease progression. Three suicides were reported during the clinical studies. One patient implanted in the periventricular gray in a DBS for Pain clinical trial reported suicidal ideation present at high stimulation amplitudes. The suicide ideation was resolved when the stimulation parameters were decreased. Depression was reported in two patients in the tremor clinical studies. The depression was judged by the investigators to be related to disease progression and not to the therapy and procedure. Ten patients died during the clinical studies. One patient suffered significant neurological decline resulting from a postoperative intracranial hemorrhage, and died two weeks after surgery. Two patients died from perioperative myocardial infarctions. The other seven patient deaths were judged unrelated to the therapy and procedure. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 4 {6} An autopsy report in one patient using a different lead showed histopathological changes within 2 mm of the implanted lead. There was no report of an associated change in the patient's neurologic status or the therapeutic effect of the stimulation. A total of 11 leads were explanted during the United States and European Clinical Studies. Of these leads, six were replaced once. No patients had leads removed and replaced more than once, and no leads were left in place while a second lead was implanted on the same side. The long term safety associated with leads left in place without use, multiple placement of leads in the thalamus, and lead explant is unknown. ## 8.2 Potential Adverse Events Adverse events which may potentially occur, but were not reported in the clinical studies, include: - Seroma at the IPG site - Nausea and vomiting - Aphasia - Leakage of cerebrospinal fluid - Motor problems such as incoordination or muscle spasms - Undesirable stimulation - Undesirable sensations (temporary or permanent) ## 9. Summary of Preclinical Studies Laboratory and animal testing was performed to assure conformance with design specifications. Results included testing of commercially available components of the Activa™ System, which are physically identical and which have a history of function in humans. ## 9.1 Laboratory Studies ### 9.1.1 Component Testing #### 9.1.1.1 Model 7424 Implantable Pulse Generator (IPG) A summary of qualification testing performed on the Model 7424 (P840001/S015) is provided in Table 4. Table 4. Model 7424 IPG Circuit Qualification Testing | Test | Description | Pass/Fail Criteria | units tested | | --- | --- | --- | --- | | Electrical output | check amplitude, rate, and PW with a 510W load | meets specifications. | 1 | | Rate | stability under battery, temp and load extremes | 130 Hz ± 5% | 1 | | Pulse width | stability under battery, temp and load extremes | 61 and 458 ms ± 5% | 1 | | Output pulse | waveform under battery and load extremes | 10.5 V maximum, 1 ms rise time, 5 V minimum | 3 | | Rate limit | stability under battery, temp, parameter and load extremes | 227 Hz | 3 | | Reed switch | sensitivity | Activation at 1.5 inches from 90 gauss magnet | 3 | | Crystal oscillator | stability under battery and temp extremes | ± 5% | 3 | | Battery monitor | accuracy over range of 2.0 to 3.7 V | ± 5% | 3 | | Digital IC | timing | within specification | 76 | | Voltage reference | stability under battery, and temp extremes | ± 3% | 3 | | Telemetry | timing and data content; distance from transmitter | functional at specified distance | 3 hybrids; 1 IPG | | ADC | accuracy a function of output amplitude | ± 3% | 3 | | Failure modes | test shorts to ground, shorts to supply voltage | will not cause hazardous situation | 1 | | EMC | environmental electromagnetic radiation susceptibility (including electrocautery) per proprietary protocol | per protocol | 4 | | Power on reset | assure parameters are reset on power up | correct parameters, no latchup | 3 | Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 5 {7} # 9.1.1.2 Model 7495 Extension Qualification testing of the Model 7495 Extension for SCS (P840001) included dimensional adherence, electrical characteristics, mechanical shock, vibration and coil testing. Pre-clinical testing included implanting ten leads in free roaming pigs for 12 months. These leads were then flex tested at a flex angle of 45° over a 3/16 inch bend radius. # 9.1.1.3 Burr Hole Ring and Cap To determine the ability of the burr hole ring and cap to stabilize the Model 3387 DBS Lead, three sets of five electrode samples were inserted by unqualified personnel into an agar medium. When the burr hole cap was locked into position, the deviation of the lead position was observed. Average lead movement was slightly less than 1 mm. A second test on five leads was used to observe the creep of the leads under tension. No deformation of the lead coil was observed on any of the five samples when a 0.5 lb. tensile force was applied. # 9.1.1.4 Model 7458 Memory Module Cartridge and Software, and Model 7432 Console Programmer The methods/procedures for the acceptance of software, and its specifications, for the Model 7458 are the same as those for the previously approved Model 7455. The Model 7458 Memory Module software testing was conducted to verify the software's response to commands and conditions programmed by the Model 7432 keyboard. Software validation and verification was also successfully completed, and the Model 7458 Software Safety Analysis was implemented and addressed. The Model 7458 Software conformed to specification and passed all the tests conducted. # 9.1.2 Model 3387 DBS Lead The Model 3387 DBS Lead is one of a "family" of helical coil designed leads. It shares common design criteria with other leads of similar structure, materials and manufacturing methods. The Models 3487/3487A PISCES Quad SCS Lead, used for the treatment of chronic intractable pain, is the core technology for this "family" of helical coil type leads. Similarities in design between the SCS and DBS leads are that they are comprised of PTFE coated quadrafilar conductors terminating in multi-electrodes (4) or inline connectors (4), are contained within a polyurethane sheath, and are of a straight cylindrical (coiled) configuration. Manufacturing processes and methods are similar but each device maintains its own distinct set of manufacturing processes and quality control inspections unique to the individual model number and the material used. The DBS and SCS leads differ in materials of construction, as presented in the Table 5. Table 5. Model 3387 Material Changes | | Model 3487A SCS Lead | Model 3387 DBS Lead | | --- | --- | --- | | Conductor Wire: | MP35N (metal alloy) | Platinum / Iridium (80/20) | | Sheath: | 55D Durometer polyurethane | 80A Durometer polyurethane | | Stylet: | 0.010" O.D.Stainless Steel PTFE coated stylet | 0.014" O.D. Tungsten Parylene C coated stylet | These material changes were implemented such that the Model 3387 DBS Lead could achieve the following design criteria: # 9.1.2.1 Model 3387 Lead The body of the lead must be pliable, in so much that it will stay in the position placed when the stylet is removed. The "memory" of either the conductor wire(s) or the outer polymer jacket (sheath) shall not cause the lead to migrate from the intended anatomical position, either immediately upon removal of the stylet or over time. # 9.1.2.2 Model 3387 Lead Stylet The stylet shall be of sufficient stiffness to direct the lead to the specific anatomical site without deviating from the insertion path, yet not inflicting damage to either the components (wire coil, coating specifically) or puncturing through the lead tip. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 6 {8} Because of the similarity in design between the Model 3387 DBS Lead and the SCS Lead, the Model 3487 and 3487A SCS Lead testing was used as a baseline for this type of helical coil design. The sponsor relied on the results of the following testing for the SCS Lead based on its similarities to the Model 3387 DBS Lead: corrosion resistance, environmental durability, chemical resistance, tensile properties and moisture resistance. Table 6 shows the testing that has been performed specifically on the Model 3387 DBS Lead. Table 6. Model 3387 Design Qualification Testing | Test | Description | Pass/Fail Criteria | Units tested | | --- | --- | --- | --- | | Polyurethane environmental stress cracking | 52 week animal implant | limited to "shallow cracks" under 70X magnification | 36 | | Dimensional measurement | correct length and spacing | within design specification | 20 | | Electrical | coil resistance, etc. | 20 to 60 Ω (ohms) | 20 | | Flex | coil flex life of 100,000 (Weibull B50), 60 degree bend over 3mm radius at 2Hz | 100,000 cycles | 10 | | Lead body static crush | insures that lead stays in place when stylet removed | 50 lbs. per nch | 20 | | Weld | pull test & visual | <70% neckdown, <0.005 height, | 20 | | Lead bend stiffness | resistance to bending | 25 grams/mm | 10 | | Lead insertion | accurate guidance into an agar medium | "deviating from intended insertion track" from 1.5 to 3.0 cm | 15 | | Stylet insertion | assess damage to insulation coating of coil | DC current > 0.01nA in saline | 20 | | Lead stabilization in burr hole ring/cap | assess burr caps ability to stabilize lead | "deviating from intended insertion track" | 15 | | | lead doesn't get crushed from strain relief | 0.5 lb. tensile | 15 | | Multiple sterilization | affect on length, tensile force, flexion | no detectable difference between sterilized and unsterilized | 22 | | Coating dimensions | Assure thickness of PTFE coating | within design specification | lot by lot | | Coil winding | Determine coil winding dimensions | Inspection per drawing specifications | 20 | | Shock and vibration | Assure that packaging will endure shipping | electrical and mechanical design specifications | 20 | | Tubing | Qualify polyurethane tubing | Biostability | 12 | | Weld and butt joint | Determine weld quality | Dimensional, Electrical and Strength | 22 | | Flex | Assure ability to withstand flexion | 100,000 cycles flexed to 60° bending | 22 | | Surface Finish | Check for visual anomalies | according to specification | 36 | ## 9.1.2.3 Process Qualification Tests for the Model 3387 DBS Lead These tests were conducted to assure that, on a limited quantity basis, the initial tooling, preliminary manufacturing processes, inspection processes, operator training outlines, and inspector training meet the dimensional, weld quality, and general workmanship required for the intended use of the Model 3387 DBS Lead. The following tests were completed to support the Process Qualification phase: - Coil winding dimensional conformance, - Lead dimensional conformance, - Workmanship requirements and conformance, - Weld requirements, and - Stylet conformance. ## 9.1.3 Reliability The estimated maximum failure rate, based on an analysis of component reliability is 0.27% per device-month. Only one electrical component failure was known to have occurred during the clinical trials, which is within bounds of the analytic prediction. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 7 {9} # 9.1.4 Biocompatibility The materials used in the Model 3387 DBS Lead, lead stylet, and burr hole ring, which come into contact with body tissues are MP35N (metal alloy), Polyetherurethane, Polyetherurethane adhesive, Polytetrafluoroethylene (PTFE), Platinum / Iridium, Tungsten, Nylon, and Parylene® C. The materials which are intended to have permanent contact with brain tissue and CSF include Polyetherurethane lead jacket, Polyetherurethane adhesive, PTFE, and the Platinum / Iridium electrodes. All other materials identified as patient contacting materials are intended to have minimal duration of contact, i.e., intraoperative, e.g., Parylene® C stylet coating and Tungsten stylet, or the contact is subcutaneous, e.g., MP35N and Nylon. MP35N metal alloy has had a long history of use as long-term neurological implant, e.g., aneurysm clips. Platinum/Iridium electrodes have had a history of use in neurological tissue, e.g., cortical and depth electrodes. There is a long history of use of Polyetherurethane from other medical devices. However, it is not known what the long-term biocompatibility of Polyetherurethane is when implanted directly in brain tissue. This type of new application often requires additional data to assure the device will not have long-term adverse effects associated with the biological response to the material. A theoretical analysis of potential breakdown products for the Polyetherurethane lead jacket included several compounds that could cause neurotoxic or carcinogenic effects. Some of these compounds have been shown in the literature to cause neurotoxicity when administered intracranially; some have not been studied with intracranial administration, but are known from the literature to cause neurotoxic or carcinogenic responses with systemic administration; while others have not been studied for neurotoxicity or carcinogenicity. Because the amounts of these compounds released from the final device over time are unknown, the device labeling includes a warning that three known neurotoxins and one known carcinogen may be breakdown products of the Polyetherurethane lead jacket, and although long term human exposure to Polyetherurethane has shown no evidence of neurotoxicity or carcinogenicity in pacemaker leads, these materials have not been previously implanted in the brain. The following biological safety tests were conducted at least in part on most of these materials in support of their biocompatibility: Tissue Culture/MEM Elution for cytotoxicity, hemolysis, USP Pyrogen Test, Modified USP Class V Plastics Test, Ames Mutagenicity Test, Modified In Vitro Chromosomal Aberration Assay, Modified In Vivo Mouse Micronucleus Test, Guinea Pig Maximization for Sensitization, and 12-Week Intramuscular Implant Test. All tests were conducted in accordance with Good Laboratory Practice. Tests not conducted on these materials and typically recommended for this type permanent duration of contact include: subchronic toxicity, chronic toxicity, and carcinogenicity testing. Additional tests performed by the sponsor intended to support the long-term contact of Polyetherurethane tubing in brain tissue include a 12 month intracerebral sheep study and 14 to 180 day intracranial rabbit study. These studies provided some information on local tissue effects of the material on brain tissue but were not designed to study the potential physiological effects of this material. In most cases, the biological safety tests identified above were not conducted on the final device, but on materials used to fabricate the final product. Not all of the tests were conducted on all of the fabrication materials, and some of the testing conditions were not optimal (e.g., extraction media, temperature and time). From the results of these tests, the FDA identified two remaining issues with Polyetherurethane when used as a permanent implant material in the brain: device potential for neurotoxicity, and carcinogenicity, which are reported to the user in the labeling. The sponsor provided to FDA a complete list of the proprietary materials used to fabricate the Polyetherurethane, in order to allow FDA to perform a risk assessment of use of this material for implantation in the brain. # 9.1.5 Biostability Biostability testing was performed on the Polyetherurethane lead jacket. No environmental stress cracking (ESC) beyond "Cosmetic ESC" (i.e., "very shallow cracks at 70X magnification) is expected to occur. All samples tested showed acceptable electrical results when compared with similar samples that had not been subjected to a biological environment. Additionally, no degradation of the PTFE insulation was found on any of the wires. The electrical current leakage testing performed on the individual wires supported evidence of the insulation integrity. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 8 {10} Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 9 ## 9.1.6 Other Testing Shelf-life and packaging validation tests, sterilization validation tests, and manufacturing validations tests were also successfully completed per recognized protocols. Expiration dating for the generator and the lead has been established and approved for 18 months and 4 years, respectively. ## 9.2 Animal Studies ### 9.2.1 Effectiveness Practically all significant evidence of the therapeutic effect of stimulating the VIM, is derived from humans. Animal models of Parkinson's Disease Tremor exist through the use of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). However, these models are antedated by the human experience which began in the 1950's. One of the methods used by clinicians to verify the target during thalamotomy procedures is electrical stimulation of the target. If stimulation suppressed the tremor, the lesion was made. Recognizing the effectiveness of the stimulation procedure itself, clinicians began to explore chronic stimulation as a therapy in humans in the mid-1980s, foregoing animal testing of effectiveness. No specific animal tests were conducted regarding the use of the Activa™ System for the treatment of tremor for the following reasons: - The stimulation principles are the same as previous generations of deep brain stimulation systems. - The implant techniques are similar to those used for the previous generations of Medtronic stimulation systems (e.g., those used for deep brain stimulation for treatment of chronic pain). - The literature contains a number of reports regarding the clinical efficacy of deep brain stimulation for the treatment of tremor. Animal testing was conducted on the Model 3387 Lead for deep brain stimulation safety. A summary of each is given below. ### 9.2.2 Safety Histopathological effects of electrical brain stimulation have been described by McCreery et al¹. They determined safe parameters from cat cerebral cortex with 30 Hz stimulation. These stimulus parameters were compared to the maximum output of the Model 7424 IPG. The Model 7424 IPG with the Model 3387 DBS Lead produced the following maximum stimulation: | Electrode Surface Area | 0.06 cm² | | --- | --- | | Pulse Duration | 450 microseconds | | Amplitude | 10.5 V, or 21.0 mA into 500 ohms | | Charge per Phase | 9.45 microCoulombs | | Charge Density | 150 microCoulombs/cm² | | Frequency | 185 Hz | These stimulus parameters are above the "damage" threshold reported by McCreery. The device labeling includes a warning identifying those parameters which result in charge densities greater than 30 microCoulombs/cm². ### 9.2.3 Related Human Study The one published autopsy from a patient who underwent thalamic stimulation for tremor relief describes small histopathological changes near the electrode. Caparros-Lefebvre et al² performed an autopsy on a patient who had undergone chronic thalamic stimulation with the predecessor to the Model 7424 IPG. They observed histopathological changes within 2 mm of the tip of the lead. These changes were attributed to the electrical stimulation. Calculations based on those of Caparros-Lefebvre reveal the following stimulus parameters: 1. Mc Creery DB, Agnew WF, Yuen TGH, Bullara L. Charge density and charge per phase as cofactors in neural injury produced by electrical stimulation, IEEE Trans. Biomed. Eng. 37:996-1001, 1990. 2. Caparros-Lefebvre D, Ruchoux MM, Blond S, et al. Long term thalamic stimulation in Parkinson’s Disease: postmortem anatomoclinical study, Neurology 44:1856-1869, 1994. {11} Electrode Surface Area 0.143 cm² Pulse Duration 150 microseconds Amplitude 1.5 V, or 3.0 mA into 500 ohms Charge per Phase 0.45 microCoulombs Charge Density 3 microCoulombs/cm² Frequency 130 Hz These stimulation parameters were within the safe limit of 30 microCoulombs/cm² of McCreery. The previous animal studies of McCreery demonstrated a potential risk from electrical stimulation. The postmortem study of Caparros-Lefebvre demonstrated that thalamic stimulation for tremor relief is capable of producing histopathological changes. ## 9.2.4 Implant Protocol Description Good Laboratory Practices (GLP) pig studies were conducted to determine acute and chronic effects of electrical stimulation on brain tissue. On each side of the brain, one lead was placed in a deep target intended to be the thalamus and another under the cortical surface. Animals were stimulated through one randomly selected cortical lead and one randomly selected thalamic lead. The contralateral cortical and thalamic leads which were not connected to a stimulator served as controls. A pathologist, who was blinded as to the stimulated electrode, examined the tissue around the electrodes for damage and made side to side comparisons indicating which, if either, of the electrodes in each pair showed greater pathology in the surrounding tissue. ## 9.2.4.1 Acute Phase This study employed acute stimulation under general anesthesia with the goal to delineate thresholds of stimulation that caused tissue damage. Ten pigs were implanted with the Model 3387 Leads (also used in the clinical trials). Each animal was given bilateral thalamic and cortical leads, and one of each bilateral lead was stimulated. The animals received stimulation for seven continuous hours under general anesthesia at the maximum commercially available voltage (10.5 volts), with eight of the pigs stimulated at 185 pps (the maximum frequency available in the Model 7458 MemMod) and two pigs stimulated at 130 pulses per second. The pulse widths ranged from 913 microseconds, which is greater than the commercially available Model 7424 IPG maximum, to nearly 2000 microseconds. These stimulus parameters gave a stimulus charge per phase ranging from 9.5 to 42.0 microCoulombs (assuming a 500 ohm load), and these exceeded the McCreery damage threshold of 2 microCoulombs (for the Model 3387 Lead surface area electrode). Over the course of the study one of the animals was eliminated because of seizures. None of the pigs displayed gross motor deficits. Histopathology results showed tissue damage from all leads (both stimulated and unstimulated). This tissue damage involved an inflammatory reaction, gliosis and neuronal degeneration, and it was seen in all animals studied. In each case the pathologist was asked to determine which side showed the most damage. Three of nine animals showed differential damage between the two sides; of these, the pathologist correctly predicted the stimulating electrode (one cortical, one thalamic). The pathologist incorrectly predicted the third stimulating thalamic electrode. ## 9.2.4.2 Chronic Phase This study used chronic stimulation at lower amplitudes to evaluate long term effects. The primary goal was to contrast the response of brain tissue around stimulated leads, with tissue around leads implanted on the contralateral side that were not stimulated. Eight animals were included in this study with Model 3387 Leads (each with two cortical and two thalamic leads), and each followed the stimulus protocol from 2 - 9 months with continuous stimulation. The stimulation parameters were: pulse width, 450 microseconds (Model 7424 IPG maximum setting), frequency, 185 pps; and the amplitude was variable depending upon what the pig could tolerate. Two animals experienced seizure as stimulus amplitudes were being adjusted. One animal developed hydrocephalus and was terminated from the study. The results are based on descriptions of the histology from five histological sections from each of the seven remaining animals. Inflammation, mineralization, gliosis and neuronal degeneration were noted to be within 2 mm along the implant tracts. Differential damage was used as a means of assessing the effects of stimulation. There were 14 lead pairs evaluated from the seven remaining pigs. Eleven lead pairs (both cortical and thalamic) were judged to show different Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 10 {12} degrees of histopathology. For 21.4% (3) of these lead pairs, there was no pathological difference found between the tissue samples exposed to stimulation and the controls (not stimulated) above the background mechanical damage caused by the lead. For the remaining 78.6% (11) lead pairs, there was a pathological difference between tissue samples. For the samples with a difference, the pathologist was able to correctly predict the stimulating lead in four sample pairs and was incorrect for seven sample pairs. It was concluded that delivering electrical stimulation through the leads at the charge densities used in this study caused no additional observable effects to brain tissue over mechanical damage caused by the lead. However, side to side comparisons of the stimulated and unstimulated leads made in this study may not be valid due to inconsistent anatomical location of the leads. ## 9.2.5 Additional Studies ### 9.2.5.1 Intracerebroventricular Polyurethane Device Study in Sheep for 3 and 12 Months Using a sheep model, samples of another polyurethane type device manufactured by Medtronic were implanted into the lateral ventricle. A summary of this study reported the following: "Six animals were implanted, with one animal terminated after 10 days due to surgical complications. The five remaining implanted animals had their intracerebroventricular pressures taken at 3 months. Two animals had elevated pressures. For these two animals, it was determined at necropsy that the device was inadvertently implanted in the thalamus instead of the lateral ventricle. Thus, the pressure readings were inaccurate. The remaining three animals did not have elevated pressures. All animals were terminated, three at 3 months and 2 at 12 months. At three months, microscopic neuropil changes ranged from minimal to mild inflammation limited to the area immediately adjacent to the device. The response observed from the device site was found to compare favorably to the tissue immediately adjacent to non-absorbable sutures used during the surgical site closure. Devices implanted for twelve months showed a minimal to mild fibrous reaction around the subcutaneous implant sites of device segments and connections, which is consistent with a 365 day implant. Inflammation was extremely minimal in all the sections and consisted mostly of histiocytes and sparse numbers of lymphocytes around suture material. No significant degeneration of the neuropil was evident adjacent to the device's tract." Since the Model 3387 DBS Lead is also comprised of Polyurethane elastomer (although without the tantalum), and is implanted in brain tissue, the results from this study are intended to further support the biocompatibility of the Model 3387 DBS Lead. ### 9.2.5.2 Polyurethane Tubing Intracranial Implants in Rabbits for 14, 32, 90, and 180 Days These studies also utilized tantalum impregnated polyurethane placed intracranially in rabbits for 14, 32, 90, and 180 days. These studies were intended to provide additional support of the biocompatibility of the polyurethane material used in the Model 3387 DBS Lead in contact with brain tissue. The test results indicated that the test material was non-irritating when compared to a USP negative control. ### 9.2.6 Conclusions The non-clinical laboratory, in-vivo (animal) studies were intended to demonstrate that the Activa™ System used with the Model 3387 DBS Lead and accessories for deep brain stimulation therapy for the treatment of tremor is safe for human use. However, these studies do not obviate the risk for the development of histopathological changes near the lead site which were seen in a postmortem study and expected from other animal studies. The studies do not completely eliminate the possibility that the materials used in direct contact with brain tissue and CSF do not have long-term physiological effects. ## 10. Summary of Clinical Studies Tremor is an involuntary, rhythmic, oscillatory movement produced by reciprocally innervated antagonistic muscles. Tremor may be classified as rest, postural, and action. Rest tremor occurs when a limb is supported against gravity; postural tremor occurs when a limb is held against gravity; and action tremor occurs during voluntary movement of a limb. Any of these tremors may be disabling. Patients may have only one of these tremors or may have a combination, depending on disease severity. Tremor is a common disabling symptom of two movement disorders, essential tremor and Parkinson's Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 11 20 {13} disease. Tremor is the only symptom of essential tremor. Generally, postural and action tremors characterize essential tremor, although in severe cases, rest tremor may be present. The tremors associated with essential tremor may produce significant functional disability including an inability to feed oneself, drink from a cup, or write. The incidence of essential tremor increases with age, but can occur at any age. Onset is often insidious, and progression may be variable. The upper extremities are often the most affected. Tremor is one of the cardinal signs of Parkinson's disease. The other symptoms are bradykinesia, rigidity, and postural instability. The characteristic rest tremor is the most common presenting sign of Parkinson's disease patients. It may be present in one or more limbs and is often asymmetric. Postural tremor is not uncommon in Parkinson's disease, and action tremors may be present in severe cases. The tremor of Parkinson's disease has a variable response to medical therapies and may be the most difficult symptom of Parkinson's disease to treat with anti-parkinsonian medications. Stereotactic neurosurgical procedures such as thalamotomy have been used to treat disabling tremor due to Parkinson's disease and essential tremor. Stimulation of the VIM of the thalamus has been proposed as a nondestructive and reversible therapy for tremor. The clinical studies conducted to demonstrate the safety, effectiveness and reliability of the Activa™ System for treating tremor of the upper extremity due to essential tremor and Parkinson's disease include the following: 1) **U.S. Tremor Study.** This multicenter prospective clinical study was designed to evaluate *the short term effectiveness* of *unilateral* stimulation of the VIM of the thalamus for the suppression of tremor associated with either essential tremor or Parkinson's disease. 2) **European Tremor Study.** This multicenter prospective clinical study was designed to assess the ability of *unilateral and bilateral* stimulation to suppress tremor associated with essential tremor and Parkinson's disease. A cohort of patients from four sites in Sweden participated in the European Long Term Efficacy Study which was a multicenter prospective randomized study designed to evaluate the *long-term effectiveness* of *unilateral* suppression of tremor associated with either essential tremor or Parkinson's disease in patients who had been implanted for more than one year. These clinical studies used the Unified Parkinson's Disease Rating Scale (UPDRS) and the Tremor Rating Scale (TRS) to assess the effect of stimulation on tremor of the upper extremity in patients with Parkinson's disease and essential tremor, respectively. Neurosurgeons used standard imaging and stereotactic techniques to implant the leads in the VIM of the thalamus with minor variations in technique. Intraoperative test stimulation was used to localize the VIM and confirm tremor suppression prior to lead implant in the VIM contralateral to the target extremity. Two additional clinical studies provided data on the safety of this device: 3) **European Basic Study.** This multicenter open-label study was designed to assess deep brain stimulation in different areas of the brain to treat various diseases or conditions. 4) **DBS for Pain Study.** This study was designed to evaluate the effect of stimulation of the periaqueductal gray or the ventroposterolateral nucleus to decrease chronic pain. ## 10.1 Gender Bias Inclusion and exclusion criteria were designed and carried out to avoid gender bias in patient enrollment. Of all patients enrolled, 254 of 454 (54%) were male. This proportion (254/210 = 1.21) of males is consistent with other therapeutic trials for movement disorders, such as Essential Tremor and Parkinsonian Tremor.³ Separate analyses of safety and effectiveness data for males and females indicated no differences between the genders; hence, the results presented in the following analyses are representative for both men and women. ³ Olanow CW, Hauser RA, Gauger L, Malapria T, Koller W, Hubble J, Bushenbark K, Lilenfeld D, Esterlitz J. The effects of deprenyl and levodopa on the progression of Parkinson’s Disease, Annals of Neurology 38(5):771-777, 1995. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 12 {14} # 10.2 U.S. Tremor Study The objective of this study was to demonstrate the safety and effectiveness of the Activa™ System for the treatment of unilateral tremor due to Parkinson's disease (PD) and essential tremor (ET) using the patient as their own control. ## 10.2.1 Investigational Plan Patients enrolled in the clinical study met the following inclusion criteria: 1. patients diagnosed with either Parkinson's disease or essential tremor, where tremor constituted a significant functional disability, and who had no other supraspinal CNS disease or injury; 2. tremor was disabling as determined by the patient and neurologist, for at least three months prior to enrollment, and both agreed tremor suppression would provide significant benefit; 3. tremor was at a level 3 or 4 in the extremity intended for treatment prior to implant as determined by a neurologist using the UPDRS or TRS; 4. a neurologist determined that functional disability due to tremor was not adequately controlled by medications for at least three months prior to implant; 5. medications for patients with Parkinson's disease were held constant for at least one month prior to study enrollment and patients with essential tremor were off all tremor medications for at least 1 month prior to study enrollment; 6. age 18 to 80 years; 7. patients or legal representative understood the therapy and gave signed informed consent; 8. patients must be available for appropriate follow-up times for the length of the study. Patients were excluded according to the following criteria: 1. patients were not surgical candidates or had clinically or medically significant disease; 2. patients had a prior thalamotomy or surgical ablation procedure; 3. patients withheld informed consent; 4. patients had demand cardiac pacemakers or medical conditions which required repeat MRIs; 5. patients had a history of dementia significantly interfering with their ability to cooperate or comply with the requirements of the study or to comprehend the informed consent; 6. patients had a history of alcohol or drug abuse; 7. patients had unpredictable fluctuations or long-term levodopa syndrome; 8. patients had Botulinum Toxin injections within the 6 months prior to enrollment. This was a prospective, controlled, multicenter clinical study with a randomized assessment at three months. Patients were implanted unilaterally and follow-up visits occurred at 1, 3, 6, 9, and 12 months. Tremor suppression with and without stimulation was compared in the absence of medications. Medication status, demographic data, and information on pre-existing conditions were collected at the preimplant assessment. Medication status, follow-up information, safety data, and stimulation parameter information were prospectively collected at follow-up visits. Patients discontinued stimulation the night before their follow-up visit. Patients with Parkinson's Disease did not take their morning dose of medications. The patient was evaluated with stimulation OFF, then with stimulation ON. The patient was evaluated again with stimulation ON after the parameters had been optimized. Therapy adverse events and system complication profiles were collected prospectively. Tremor suppression for Parkinsonian tremor was based on Question 20 on the UPDRS. Tremor is assessed on a 0 (absent) to 4 (marked in amplitude and present most of the time) scale. The primary measurement of effectiveness for essential tremor was based on Questions 5 and 6 of the TRS, depending on whether the right or left upper extremity was identified as the target extremity. In the TRS, tremor is assessed on a 0 (none) to 4 (severe) amplitude scale. Questions concerning activities of daily living and functional status from the UPDRS and TRS were used to provide supporting evidence (secondary outcome measures) for functional improvements. In addition, global assessments of disability were performed by the patient and the physician. The Wilcoxon signed rank test, a nonparametric test for paired observations, was used. Paired comparisons were made between pre-implant and stimulation OFF, between pre-implant and optimized stimulation ON, and between stimulation OFF and optimized stimulation ON at each follow-up. Comparisons for activities of daily living (ADL) scores were made between pre-implant and stimulation ON. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 13 {15} # 10.2.2 Study Centers Table 7 lists the centers who enrolled patients along with the number of patients enrolled by etiology. Between October 1993 and September 1996, 84 patients were enrolled (39 with Parkinson's disease and 45 with essential tremor.) The data from this clinical study is for unilateral stimulation only. Table 7. Centers for U.S. Tremor Study With Patients Enrolled By Etiology | Study Center | Parkinson's Disease | Essential Tremor | Total Enrollment | | --- | --- | --- | --- | | University of Kansas Medical Center, Kansas City, Kansas | 16 | 31 | 47 | | University of South Florida and Tampa General Hospital, Tampa, Florida | 3 | 2 | 5 | | New England Deaconess Hospital, Boston, Massachusetts | 3 | 1 | 4 | | Rush-Presbyterian-Study, Luke's Medical Center, Chicago, Illinois | 0 | 1 | 1 | | The Toronto Hospital, Toronto Western Division, Toronto, Canada | 9 | 6 | 15 | | The University of Minnesota and Methodist Hospital, Minneapolis, Minnesota | 1 | 0 | 1 | | Baylor College of Medicine Houston, Texas | 4 | 1 | 5. | | Vanderbilt University Medical Center Nashville, Tennessee | 2 | 1 | 3 | | The Graduate Hospital Philadelphia, Pennsylvania | 0 | 2 | 2 | | The Ohio State University Columbus, Ohio | 1 | 0 | 1 | | TOTALS | 39 | 45 | 84 | # 10.2.3 Essential Tremor Patients Table 8. Patient Demographics | Sample Size | 45 | | | | --- | --- | --- | --- | | Gender | Males: 38 (84.4%); Females: 7 (15.6%) | | | | | Mean | SD | Range | | Age at Implant (Years) | 67.1 | 11.1 | 31.3 to 79.8 | | Age at Disease Onset (Years) | 34.1 | 18.3 | 0.0 to 73.3 | | Age at Definitive Diagnosis (Years) | 57.7 | 12.1 | 26.9 to 75.0 | | Follow-up (Months) | 9.76 | 4.11 | 0.75 to 15.4 | | | | | | | Extent of Symptoms | Bilateral: 44 (97.8%) | Left: 1 (2.2%) | Right: 0 | | Target Extremity | Left Upper: 3 (6.7%) | Right Upper: 42 (93.3%) | | | Target Tremor | Action: 32 (71.1%) | Postural: 12 (26.7%) | Rest: 1 (2.2%) | Medtronic Activa™ P960009: Summary of Safety and Effectiveness {16} Figure 1. Patient Flow ![img-0.jpeg](img-0.jpeg) As seen in Table 9, tremor was suppressed at all follow-up visits when tremor scores for optimized stimulation ON were compared to stimulation OFF (p=0.0001) and when tremor scores for optimized stimulation ON were compared to preimplant tremor scores (p<0.0001). Table 9. Mean Tremor Scores | Follow-up Assessment | Pre - Implant | One Month | | Three Months | | Six Months | | Nine Months | | Twelve Months | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Stimulation Status | | OFF | ON | OFF | ON | OFF | ON | OFF | ON | OFF | ON | | N (a) | 45 | 40 | 40 | 37 | 37 | 34 | 33 | 29 | 29 | 26 | 26 | | Mean | 3.13 | 3.03 | 1.15 | 2.76 | 0.89 | 2.79 | 1.21 | 2.97 | 1.10 | 3.04 | 1.27 | | SD | 0.41 | 0.83 | 0.74 | 1.01 | 0.80 | 0.93 | 0.98 | 1.05 | 0.77 | 0.89 | 0.92 | | Range | 2 to 4 | 1 to 4 | 0 to 3 | 1 to 4 | 0 to 3 | 1 to 4 | 0 to 4 | 0 to 4 | 0 to 2 | 1 to 4 | 0 to 3 | | Difference (b) | | 0.13 | -1.98 | -0.41 | -2.30 | -0.36 | -1.94 | -0.17 | -2.03 | -0.08 | -1.84 | | p-value (c) (d) | | 0.4565 | 0.0001 | 0.0097 | 0.0001 | 0.0236 | 0.0001 | 0.2859 | 0.0001 | 0.8254 | 0.0001 | | Difference (e) | | -1.89 | | -1.92 | | -1.55 | | -1.86 | | -1.72 | | | p-value (c) | | 0.0001 | | 0.0001 | | 0.0001 | | 0.0001 | | 0.0001 | | (a) Numbers between stimulation on and stimulation off may not be identical due to missing data. (b) between stimulation status and preimplant tremor scores (c) p-values determined using Wilcoxon Signed Rank Test. (d) stimulation status (ON or OFF) score compared to preimplant score (e) between stimulation ON and OFF tremor scores As seen in Table 10, the activities of daily living were all improved at each follow-up with stimulation ON as compared to preimplant. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 15 {17} Table 10. Activities of Daily Living | ACTIVITY | Pre-implant | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month | | --- | --- | --- | --- | --- | --- | --- | | N | 45 | 42 | 38 | 36 | 29 | 26 | | Draw A | 3.09 | 1.48 | 1.55 | 1.44 | 1.24 | 1.61 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | Draw B | 3.31 | 1.90 | 1.76 | 1.91 | 1.72 | 1.96 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | Draw C | 3.13 | 1.64 | 1.39 | 1.53 | 1.38 | 1.54 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | Pouring | 3.15 | 1.35 | 1.10 | 1.55 | 1.48 | 1.54 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | Feeding food | 2.80 | 1.28 | 1.00 | 1.14 | 1.21 | 1.31 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | Liquids to mouth | 3.46 | 1.28 | 1.00 | 1.28 | 1.28 | 1.58 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | Writing | 3.22 | 1.71 | 1.61 | 1.69 | 1.59 | 1.85 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | Table 11 shows that both examiners and patients considered the disability due to tremor as decreased. Table 11. Disability Assessment | | Pre-implant | 1 month | 3 month | 6 month | 9 month | 12 month | | --- | --- | --- | --- | --- | --- | --- | | N | 44 | 42 | 38 | 36 | 29 | 26 | | Examiner | 3.11 | 1.57 | 1.34 | 1.69 | 1.65 | 1.65 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | Patient | 3.20 | 1.57 | 1.37 | 1.58 | 1.69 | 1.73 | | P-Value ON to Pre-implant | | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | Stimulation parameters used during the clinical study are presented in Table 12. Table 12. Mean Stimulation Parameters | | | Discharge | One Month | Three Months | Six Months | Nine Months | Twelve Months | | --- | --- | --- | --- | --- | --- | --- | --- | | | N: | 36 | 40 | 38 | 33 | 29 | 26 | | Amplitude (Volts) | mean: | 2.31 | 2.75 | 3.20 | 2.87 | 2.87 | 2.79 | | | SD: | 0.87 | 1.29 | 1.10 | 1.15 | 1.19 | 1.10 | | | Range: | 0.70 to 4.10 | 0.0 to 4.90 | 0.80 to 6.40 | 0.0 to 6.20 | 0.0 to 5.80 | 0.0 to 4.90 | | p-value(a) compared to discharge: | | - | 0.0008 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | | p-value(a) compared to three months: | | - | - | - | 0.2195 | 0.5689 | 0.0781 | | Pulse Width (mS) | mean: | 82.5 | 93.0 | 115.3 | 107.3 | 95.2 | 86.5 | | | SD: | 39.5 | 49.4 | 79.1 | 75.8 | 61.1 | 54.5 | | | Range: | 60 to 210 | 60 to 270 | 60 to 330 | 60 to 330 | 60 to 270 | 60 to 270 | | Frequency (pulses/second) | mean: | 151.8 | 155.8 | 162.2 | 160.8 | 154.9 | 153.3 | | | SD: | 24.6 | 29.4 | 26.7 | 27.4 | 29.1 | 32.6 | | | Range: | 100 to 185 | 100 to 185 | 100 to 185 | 100 to 185 | 100 to 185 | 90 to 185 | (a) p-values determined using Wilcoxon signed rank test. Propranolol and primidone are common medications for treating tremor due to essential tremor. During the course of the study, one patient increased his dose of primidone, one patient reinstated primidone medication, two patients decreased their dose, five patients discontinued primidone and one patient did not change his primidone dose. In the case of propranolol, three patients discontinued use, and one patient began using the medication. In addition, some patients were on other medications such as benzodiazepines that could affect tremor. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 16 {18} # 10.2.4 Parkinson's Disease Patients Table 13. Patient Demographics | Sample Size | 39 | | | | --- | --- | --- | --- | | Gender | Males: 31 (79.5%); Females: 8 (20.5%) | | | | | Mean | SD | Range | | Age at Implant (Years) | 65.3 | 10.0 | 38.2 to 79.7 | | Age at Disease Onset (Years) | 55.6 | 9.2 | 30.5 to 70.0 | | Age at Definitive Diagnosis (Years) | 57.3 | 9.5 | 33.9 to 72.0 | | Follow-up (Months) | 10.49 | 3.57 | 0.9 to 15.9 | | | | | | | Extent of Symptoms | Bilateral: 31 (79.5%) | Left: 3 (7.7.%) | Right: 5 (12.8%) | | Target Extremity | Left Upper: 12 (30.8%) | Right Upper: 27 (69.2%) | | | Target Tremor | Action: 6 (15.4%) | Postural: 10 (25.6%) | Rest: 23 (59.0%) | ![img-1.jpeg](img-1.jpeg) Figure 2. Patient Flow Tremor suppression was assessed by determining the effect of stimulation ON and OFF in Parkinson's disease patients who had foregone their morning dose of medication. Table 14 shows that tremor was suppressed at all follow-up visits when tremor scores for optimized stimulation ON were compared to stimulation OFF (p=0.0001) and when tremor scores for optimized stimulation ON were compared to preimplant (p=0.0001). Table 14. Mean Tremor Scores | Follow-up Assessment | Pre-implant | One Month | | Three Months | | Six Months | | Nine Months | | Twelve Months | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Stimulation Status | | OFF | ON | OFF | ON | OFF | ON | OFF | ON | OFF | ON | | N(a): | 39 | 30 | 31 | 30 | 30 | 28 | 29 | 24 | 24 | 24 | 23 | | Mean: | 3.38 | 2.79 | 0.90 | 3.07 | 0.63 | 2.89 | 0.69 | 3.04 | 1.00 | 2.92 | 0.78 | | SD: | 0.71 | 1.15 | 0.94 | 0.87 | 0.85 | 1.10 | 1.04 | 0.86 | 1.06 | 1.10 | 1.17 | | Range: | 1 to 4 | 0 to 4 | 0 to 3 | 1 to 4 | 0 to 3 | 0 to 4 | 0 to 3 | 1 to 4 | 0 to 4 | 0 to 4 | 0 to 4 | | Difference(b) | - | -0.55 | -2.39 | -0.27 | -2.70 | -0.43 | -2.62 | -0.29 | -2.07 | -0.33 | -2.48 | | p-value(c)(d) | - | 0.014 | 0.0001 | 0.174 | 0.0001 | 0.044 | 0.0001 | 0.303 | 0.0001 | 0.099 | 0.0001 | | Difference(e) p-value(c) | | -1.89 0.0001 | | -2.43 0.0001 | | -2.21 0.0001 | | -2.04 0.0001 | | -2.22 0.0001 | | (a) Numbers between stimulation on and stimulation off may not be identical due to missing data (b) p-values determined using Wilcoxon signed rank test (c) between stimulated status and preimplant tremor scores (d) stimulation status (ON or OFF) score compared to preimplant score (e) between stimulation ON and OFF tremor scores Medtronic Activa™ P960009: Summary of Safety and Effectiveness {19} Table 15 shows the results of optimized stimulation ON compared to preimplant for the other symptoms of Parkinson's disease. Table 15. Symptoms as Determined by the UPDRS Motor Exam | Assessment | Preimplant | 1 Month | 3 Months | 6 Months | 9 Months | 12 Months | | --- | --- | --- | --- | --- | --- | --- | | N | 39 | 31 | 30 | 30 | 24 | 23 | | Rigidity | 1.64 | 1.55 | 1.27 | 1.46 | 1.33 | 1.22 | | P-value ON to preimplant | | .7501 | .0633 | .3877 | .1447 | .0479 | | Bradykinesia | 1.97 | 1.90 | 2.00 | 1.93 | 2.13 | 2.35 | | P-value ON to preimplant | | .2734 | .8036 | .9564 | .6401 | .1001 | | Postural Stability | 0.87 | 0.77 | 0.83 | 0.83 | 0.63 | 1.00 | | P-value ON to preimplant | | .7744 | .4639 | .6720 | .7813 | .1915 | As seen in Table 16, tremor was the only activity of daily living which improved at all follow-up visits, when optimized stimulation ON was compared to preimplant. Table 16. Activities of Daily Living | ACTIVITY | Pre-implant | 1 Month | 3 Month | 6 Month | 9 Month | 12 Month | | --- | --- | --- | --- | --- | --- | --- | | N | 39 | 31 | 30 | 30 | 24 | 23 | | Writing | 2.69 | 1.81 | 2.07 | 2.34 | 2.42 | 2.26 | | P-value ON to preimplant | | .0007 | .0195 | .1971 | .6863 | .4608 | | Cut Food | 1.77 | 1.32 | 1.30 | 1.40 | 1.45 | 1.65 | | P-value ON to preimplant | | .0018 | .0579 | .4193 | .7949 | 1.0000 | | Tremor | 3.36 | 1.74 | 1.63 | 2.00 | 1.67 | 1.52 | | P-value ON to preimplant | | .0001 | .0001 | .0001 | .0001 | .0001 | | Schwab & England | 72.9 | 74.8 | 75.9 | 77.0 | 78.3 | 75.7 | | P-value ON to preimplant | | .3258 | .8968 | .9468 | .4084 | 1.000 | Table 17 shows that examiners and patients rated the disability as decreased at each follow-up visit. The Hoehn and Yahr score was significantly different at the 12 month follow-up visit (p=0.0273). Table 17. Disability Assessment | | Pre-implant | 1 Month | 3 Months | 6 Months | 9 Months | 12 Months | | --- | --- | --- | --- | --- | --- | --- | | N | 39 | 31 | 30 | 30 | 24 | 23 | | Examiner | 2.67 | 1.70 | 1.70 | 1.87 | 1.71 | 1.74 | | P-value ON to preimplant | | .0001 | 0.0004 | 0.0056 | 0.0012 | 0.0034 | | Patient | 2.82 | 1.68 | 1.70 | 1.90 | 1.71 | 1.65 | | P-value ON to preimplant | | .0001 | .0001 | .0005 | .0001 | 0.0001 | | Hoehn/Yahr | 2.13 | 2.10 | 2.17 | 2.33 | 2.21 | 2.39 | | P-value ON to preimplant | | .8242 | .3667 | .0869 | .2578 | .0273 | Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 18 {20} Stimulation parameters used during the clinical study are presented in Table 18. Table 18. Mean Stimulation Parameters | | | Discharge | One Month | Three Months | Six Months | Nine Months | Twelve Months | | --- | --- | --- | --- | --- | --- | --- | --- | | N: | | 25* | 29 | 30 | 29 | 24 | 24 | | Amplitude (Volts) | mean: | 2.08 | 2.59 | 3.01 | 3.20 | 3.18 | 3.38 | | | SD: | 1.17 | 0.99 | 1.18 | 1.19 | 0.94 | 1.11 | | | Range: | 0 to 5.0 | 0.2 to 4.5 | 0.0 to 6.0 | 0.0 to 6.0 | 1.7 to 5.5 | 1.7 to 6.0 | | p-value(a) compared to discharge: | | - | 0.0009 | 0.0001 | 0.0001 | 0.0010 | 0.0008 | | p-value(a) compared to six months: | | - | - | - | - | 0.7231 | 0.1880 | | Pulse width (mS) | mean: | 114.0 | 114.8 | 108.0 | 106.6 | 107.5 | 117.5 | | | SD: | 59.4 | 53.2 | 45.7 | 38.9 | 44.2 | 50.8 | | | Range: | 60 to 270 | 60 to 270 | 60 to 210 | 60 to 180 | 60 to 210 | 60 to 210 | | Frequency (pulses/second) | mean: | 143.8 | 157.4 | 155.0 | 156.0 | 160.2 | 165.6 | | | SD: | 45.8 | 29.9 | 34.1 | 32.3 | 24.5 | 23.8 | | | Range: | 30 to 185 | 100 to 185 | 50 to 185 | 50 to 185 | 130 to 185 | 130 to 185 | (a) p-values determined using Wilcoxon signed rank test. *Not all patients were programmed at discharge Medications commonly used to treat patients with Parkinson's disease include L-dopa and the anticholinergics. Over the course of the study, ten patients increased their L-dopa dose, seven patients began L-dopa, five patients decreased L-dopa and three patients discontinued L-dopa. In the case of the anticholinergics, six patients discontinued the medication, five patients were unchanged, and two began drug therapy. In addition, some patients were on other medications, such as benzodiazepines and dopamine agonists, that may affect tremor. The data in Tables 19 and 20 are from randomization at the three month follow-up of patients enrolled in the U.S. Tremor Study between October 1993 and January 1996. Fifty-three patients were randomized; 29 essential tremor patients and 24 Parkinson's disease patients who had foregone their morning dose of medication. Patients were randomized to two groups: (1) the treatment group, which was defined as stimulation ON, and (2) the control group, which was defined as stimulation OFF. Efficacy was measured by nonparametric comparison of average tremor scores at the three-month blinded assessment between the treatment group and the control group. Table 19. Average Tremor Score Results for Essential Tremor Patients | N | | Preimplant Baseline | Blinded 3-Month Response | Average Paired Difference | P-Values | | --- | --- | --- | --- | --- | --- | | Control: | 13 | 3.08 | 2.85 | -0.23 | 0.500 (NS) (a) | | Treatment: | 16 | 3.06 | 0.81 | -2.25 | < 0.001 | | p-Values (b) | | | < 0.001 (c) | < 0.001 (d) | | (a) Wilcoxon Signed Rank Test (paired data), "NS" = not significant at the 5% level. (b) p-values for comparisons of the stimulated group to the non-stimulated group (c) Wilcoxon Rank Sum Test (not paired data), comparing 2.85 with 0.81. (d) Wilcoxon Rank Sum Test (not paired data), comparing -0.23 with -2.25. Table 20. Average Tremor Score Results for Parkinson's Disease Patients | N | | Preimplant Baseline | Blinded 3-Month Response | Average Paired Difference | P-Values | | --- | --- | --- | --- | --- | --- | | Control: | 11 | 3.36 | 2.82 | -0.54 | 0.109 (NS) (a) | | Treatment: | 13 | 3.15 | 1.23 | -1.92 | = 0.003 | | p-Values (b) | | | 0.003 (c) | 0.018 (d) | | (a) Wilcoxon Signed Rank Test (paired data), "NS" = not significant at the 5% level. (b) p-values for comparisons of the treatment group to the control group (c) Wilcoxon Rank Sum Test (not paired data), comparing 2.82 with 1.23. (d) Wilcoxon Rank Sum Test (not paired data), comparing -0.54 with -1.92. Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 19 {21} # 10.3 European Tremor Study This clinical study was a multicenter, international study. The objective of this clinical investigation was to demonstrate the safety and effectiveness of the use of unilateral or bilateral stimulation for the suppression of tremor in patients diagnosed with Parkinson's disease or essential tremor. # 10.3.1 Investigational Plan Patients were included according to the following guidelines: 1. diagnosed with Parkinson's disease or essential tremor; 2. tremor was drug resistant; 3. the patient experienced disabling tremor most of the day while treated with anti-tremor drugs at maximal tolerated doses; 4. tremor was disabling with tremor score of 3 or greater; and 5. patient agreed to abide by the study protocol. Patients were excluded who: 1. were not good surgical candidates for thalamotomy; 2. had clinically significant brain damage as determined using MRI; and 3. had been diagnosed with any medical disorder which may interfere with the effectiveness of tremor suppression. This study was designed as a prospective, clinical investigation of the treatment of tremor using the Activa™ System. The null hypothesis was that mean tremor score decreased less than two levels on the appropriate tremor scale with stimulation as compared to pre-implant. The UPDRS was used to evaluate patients with Parkinson's Disease, and the TRS was used to evaluate essential tremor patients. Patients were assessed at 3, 6, and 12 months with stimulation ON and stimulation OFF. Medications were not discontinued prior to evaluations. The assumption was that since the tremor was not responding to the medical therapy, medications would have no effect on the evaluation since they were already at the maximum tolerable dose. Therapy adverse event and system complication profiles were collected prospectively. # 10.3.2 Study Centers One hundred and thirteen patients (38 patients with essential tremor and 75 patients with Parkinson's disease) were enrolled in this clinical investigation at 13 centers. Study enrollment ceased November 30, 1994, and one year follow-up assessments were completed by November 30, 1995. Eighty-five (28 essential tremor and 57 Parkinson's disease) patients had unilateral implants and 27 (10 essential tremor and 17 Parkinson's disease) patients had bilateral implants. The data presented is only for unilateral stimulation. Table 21. Centers for European Tremor Study with Patients Enrolled by Etiology | Study Center | Essential Tremor | Parkinson's Disease | Total Enrollment | | --- | --- | --- | --- | | Algemeines Karankenhaus der Stadt Wien and Neurologisches Krankenhaus,Vienna, Austria | 3 | 12 | 15 | | Sahlgrenska Hospital, Gothenburg, Sweden | 4 | 7 | 11 | | Joseph Fourier University of Grenoble, Grenoble, France | 10 | 23 | 33 | | Amsterdam Medical Center, Amsterdam, The Netherlands | 1 | 6 | 7 | | Heilig Hart Roselare, Roselare, Belgium | 0 | 2 | 2 | | University Hospital, Umea, Sweden | 5 | 2 | 7 | | Karolinska Hospital, Stockholm, Sweden | 5 | 5 | 10 | | Hopital Henri Mondor Creteil, France | 3 | 5 | 8 | | University Hospital, Lund, Sweden | 6 | 8 | 14 | | The National Hospital, London, United Kingdom | 0 | 1 | 1 | | Dundee Royal Infirmary, Dundee, United Kingdom | 1 | 0 | 1 | | Royal London Hospital, Whitechapel, United Kingdom | 0 | 1 | 1 | | CHU Clermont Ferrand, Chamalieres, France | 0 | 3 | 3 | | TOTALS | 38 | 75 | 113 | Medtronic Activa™ P960009: Summary of Safety and Effectiveness Page 20 {22} Table 22. Patient Demographics | | ESSENTIAL TREMOR | PARKINSON'S DISEASE | | --- | --- | --- | | Sample size | 38 | 75 | | Gender N (%) | | | | male | 25 (65.8%) | 48 (64.0%) | | female | 13 (34.2%) | 27 (36.0%) | | Age at implant (years) | | | | mean | 63.7 | 62.1 | | range | 31.0-83.3 | 29.0-77.9 | | Age at onset of disease process (years) | | | | mean | 36.8 | 51.2 | | range | 11.3-81.4 | 22.5-69.6 | | Extent of symptoms* N (%) | | | | bilateral | 34 (89.5%) | 57 (77.0%) | | unilateral | 4 (10.5%) | 17 (23.0%) | | Laterality of implant* N (%) | | | | bilateral | 10 (26.3%) | 17 (23.0%) | | right VIM | 6 (15.8%) | 23 (31.1%) | | left VIM | 22 (57.9%) | 34 (45.9%) | | Follow-up (months) | | | | mean | 12.2 | 11.9 | | range | 5.8-19.8 | 3.2-19.5 | *may not total to 113 patients due to unreported data ## 10.3.3 Essential Tremor Patients ![img-2.jpeg](img-2.jpeg) Figure 3. Patient Flow Postural tremor and action tremor were suppressed at all follow-up visits when stimulation ON was compared to stimulation OFF (p<0.0001) and when stimulation ON was compared to preimplant (p<0.0001). For essential tremor, the activities of daily living were all significantly improved with stimulation ON as compared to the preimplant baseline (p<0.001). Both the patient and examiner assessed the patients' disability due to essential tremor as significantly less with stimulation (p<0.001). Six patients were taking propranolol at preimplant. Three patients discontinued medication and one remained unchanged over the course of the clinical study. Four patients were taking primidone at the beginning of the study. Three patients discontinued the medication and one remained unchanged. In addition, some patients were on other medications that may affect tremor. Medtronic Activa™ P960009: Summary of Safety and Effectiveness {23} # 10.3.4 Parkinson's Disease Patients ![img-3.jpeg](img-3.jpeg) Figure 4. Patient Flow Rest and action/postural tremor scores for Parkinson's disease patients receiving unilateral stimulation were suppressed when stimulation ON was compared to stimulation OFF (p<0.0001) and when stimulation ON was compared to preimplant (p<0.0001). The activities of daily living were significantly improved at all follow-up visits (p<0.001). Hoehn and Yahr staging system results indicated that disability due to tremor was not significantly changed. Data was available on 45 patients at preimplant and the last follow-up visit. Thirty-three patients were on L-dopa at preimplant. Ten patients took less L-dopa, 12 patients took more L-dopa, one discontinued, five began, and seven patients did not change their dose of L-dopa. In addition, some patients were on other medications that may affect tremor. ## 10.4 European Long-Term Efficacy Study This study was designed as an addendum to the European Tremor Study that evaluated patients enrolled in the original protocol. The primary purpose was to determine the long-term (>12 months) effectiveness of unilateral thalamic stimulation for the treatment of tremor due to essential tremor and Parkinson's disease. ## 10.4.1 Investigational Plan All consecutively enrolled patients in the European Tremor Study from the four Swedish study centers were invited to participate in this trial. Thirty-six patients participated. Three patients declined to participate and two patients had died prior to initiation of this study. This study was designed as a prospective, randomized clinical trial comparing stimulation ON to stimulation OFF in patients implanted for more than one year. Both essential tremor and Parkinson's disease patients were evaluated in the same manner as patients in the 3 month randomized assessment in the U.S. Tremor Study, i.e., stimulation ON and stimulation OFF without medications. ## 10.4.2 Study Centers Table 23 lists the four centers in Sweden which participated in the study. The study was conducted in October and November of 1995. Medtronic Activa™ P960009: Summary of Safety and Effectiveness {24} Table 23. Centers for European (Swedish) Long-Term Efficacy Study with Patients Enrolled by Etiology | Study Center | Essential Tremor | Parkinson's Disease | Total Patients | | --- | --- | --- | --- | | Sahlgrenska Hospital, Gothenburg, Sweden | 4 | 5 | 9 | | University Hospital, Lund, Sweden | 6 | 6 | 12 | | Karolinska Hospital, Stockholm, Sweden | 5 | 4 | 9 | | University Hospital, Umea, Sweden | 4 | 2 | 6 | | TOTAL | 19 | 17 | 36 | ## 10.4.3 Essential Tremor Patients Table 24. Patient Demographics | Sample size: | 19 | | | | --- | --- | --- | --- | | Gender: | Males: 12 (63.2%); Females: 7 (36.8%) | | | | | Mean | SD | Range | | Age at Implant (Years): | 66.2 | 10.3 | 40.2 to 81.0 | | Age at Evaluation (Years): | 67.9 | 10.2 | 42.2 to 82.0 | | Follow-up (Months): | 20.3 | 6.0 | 11.5 to 33.8 | | | | | | | VIM Implanted: | Bilateral: 2 (10.5%) | Left: 14 (73.7%) | Right: 3 (15.8%) | | Extent of Symptoms | Bilateral: 18 (94.7%) | Right: 1 (5.3%) | | Table 25. Mean Tremor Scores | | N | Baseline (Stimulation OFF) | | Blinded Tremor Score | | Difference from Baseline (Stimulation OFF) | P-Values | | --- | --- | --- | --- | --- | --- | --- | --- | | Control Group | 11 | Mean: | 3.54 | Mean: | 3.36 | -0.18 | 0.500 (NS)^{(a)} | | | | SD: | 0.69 | SD: | 0.81 | | | | | | Range: | 2 to 4 | Range: | 2 to 4 | | | | | | | | | | | | | Treatment Group | 8 | Mean: | 3.50 | Mean: | 1.38 | -2.12 | 0.008 | | | | SD: | 0.53 | SD: | 0.92 | | | | | | Range: | 3 to 4 | Range: | 0 to 3 | | | | P-Values^{(d)} |… --- **Source:** [https://fda.innolitics.com/device/P960009](https://fda.innolitics.com/device/P960009) **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. 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