RNS System LGS Feasibility Study

Study Overview
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Brief Summary
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To generate preliminary safety and effectiveness data for brain-responsive neurostimulation of thalamocortical networks as an adjunctive therapy in reducing the frequency of generalized seizures in individuals 12 years of age or older with Lennox Gastaut Syndrome (LGS) who are refractory to antiseizure medications. The intent is to determine the feasibility and the optimal design of a subsequent pivotal study in order to expand the indication for use for the RNS System as a treatment for patients with medically intractable LGS.

Detailed Description
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This study is a prospective two-stage single-blind feasibility cross-over study designed to provide early safety and preliminary evidence of effectiveness for combined bilateral brain-responsive neurostimulation of thalamocortical networks for the treatment of generalized seizures in patients with LGS. Twenty participants will be treated with the RNS System across six Comprehensive Epilepsy Centers in the U.S. Enrollment will be staged in two cohorts of 10. Once all 10 participants of the first cohort complete Treatment Block 1 and the interim analysis criteria are met, the next cohort of 10 participants will be enrolled. The research study comprises six study periods: Baseline Period Implant (surgery) Post-Op Period Blinded Evaluation Period (which is made up of 3 treatment blocks, one of which is a sham stimulation) Open Label Period Long Term Follow-Up Period Two neurostimulators will be placed: one in the parieto-temporal skull on the left, and the second in the homologous region on the right. Depth leads will target the bilateral CM. Cortical strip or depth leads will target the prefrontal cortex. Each neurostimulator will be connected to two ipsilateral leads: one in the prefrontal cortex and one in the CM. A total of two neurostimulators and four leads will be implanted. During the Blinded Evaluation Period, the participant will move through 3 different treatment blocks (Treatment Block1, Treatment Block 2, and Treatment Block 3) in a random order. Two of the blocks will have active stimulation treatment and one of the blocks will have no (sham) stimulation treatment. The participant and caregiver will be blinded to the treatment condition. Condition A - active treatment of high frequency short burst stimulation Condition B - active treatment of low frequency long burst stimulation Sham - no stimulation treatment After completing the Blinded Evaluation Period the participant will transition to the 1-year Open Label Period and have study appointments every 3 months. After completing the 1-year Open Label Period the participant will transition to the Long Term Follow-up Period. The Long-Term Follow-up Period may last up to 2 years with appointments every 3 months until the participant complete this research or this research study ends.

Official Title
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RNS System Feasibility Study of Thalamocortical Brain-Responsive Neurostimulation for the Treatment of Lennox-Gastaut Syndrome

Conditions
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Epilepsy, Lennox Gastaut Syndrome, Lennox-Gastaut Syndrome, Intractable, Seizures, Seizures, Generalized

Intervention / Treatment
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* Device: RNS System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is 15 years of age or older for first cohort; 12 years of age or older for second cohort. Note that age requirements for eligibility differ by cohort, as follows: the age limit for Cohort 1 is 15 years of age and above and the age limit for Cohort 2 may decrease to 12 years, pending a DSMB letter of recommendation, based on review of interim data analysis and concurrence with NINDS. Participant has medically intractable epilepsy defined as failure to achieve acceptable seizure control without unacceptable medication related side effects despite trials of 2 or more antiseizure medications. Participant had an average of ≥ 5 drop seizures per month in the 2 months preceding enrollment. A drop seizure is defined as an epileptic seizure (atonic, tonic, tonic-clonic, or myoclonic) involving the entire body, trunk, or head that leads or could lead to a fall, injury, or slumping in a chair. Participant's seizures are non-localized. Participant's scalp recorded EEG has features of LGS, such as multifocal spike, slow spike and wave discharges, and paroxysmal fast activity. Participant must (a) have a stable antiseizure medication (ASM) regimen for the 2 months preceding enrollment and (b) be willing to remain on the stable regimen, as medically able, through the Blinded Evaluation Period; rescue medication for acute seizure clusters are permitted. A stable ASM regimen is defined as no introduction or discontinuation of an ASM, and no change in an ASM dose of more than 25%. Participant is not on a therapeutic diet for epilepsy, or if participant is on a therapeutic diet for epilepsy must (a) have a stable diet for the 2 months preceding enrollment and (b) be willing to remain on the stable diet, as medically able, through the Blinded Evaluation Period. Participant does not have a vagus nerve stimulator (VNS), or if participant does have a VNS must (a) have had the VNS off for the 2 months preceding enrollment and (b) be willing to remain with the VNS off through the Blinded Evaluation Period. Participant is a male, or is a female of childbearing potential who is surgically sterile, 2 years postmenopausal, or practices a reliable method of contraception (hormonal, barrier method or abstention). Participant is willing to give informed consent (or assent, if a minor); if the participant assents or is not able to give informed consent, parent/legal guardian is willing to give informed consent. Participant is able to maintain a seizure log alone or with the assistance of a competent individual. Participant is able to attend study appointments in accordance with the study schedule. Exclusion Criteria: Participant is participating in a therapeutic investigational drug or device study (including other RNS System studies). Participant is currently implanted with an electronic medical device that delivers electrical energy to the brain. Participant is currently implanted with an RNS Neurostimulator or NeuroPace Leads. Participant requires procedures that are contraindicated based on current RNS System labeling. Participant is pregnant. Participant has a diagnosed unstable psychiatric disorder or any attempt or expressed intent of suicide over the preceding 6 months. In the opinion of the investigator, the participant has a clinically significant or unstable medical condition [including alcohol, opioid, recreational cannabis (not for therapeutic purposes) or other drug use disorder] or a progressive central nervous system disease. Participant is taking any anticoagulants. In the opinion of the investigator, participant is an unsuitable candidate for this procedure. Participant has been diagnosed with psychogenic or non-epileptic seizures in the preceding year. Participant has experienced unprovoked status epilepticus in the preceding year. Participant has had therapeutic surgery to treat epilepsy in the preceding 3 months. Participants who have had epilepsy surgery more than 3 months prior to enrollment are eligible. Note: For contraindications, refer to current physician labeling (manuals) for the RNS System available at the NeuroPace website (www.neuropace.com).

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Condition A<br>high-frequency short bursts (HFSB: 100 Hz, 160 µs pulse width, 200 msec burst) | Device: RNS System<br>* The RNS System provides closed loop responsive brain stimulation. The Neurostimulator monitors the electrical activity of the brain to detect abnormal activity that could lead to a seizure. If abnormal activity is detected, the neurostimulator delivers electrical stimulation to the brain through the leads to help prevent the seizure before it occurs.<br>|
| Active Comparator: Condition B<br>low-frequency long bursts (LFLB: 5 Hz, 160 µs pulse width, 5 sec burst) | Device: RNS System<br>* The RNS System provides closed loop responsive brain stimulation. The Neurostimulator monitors the electrical activity of the brain to detect abnormal activity that could lead to a seizure. If abnormal activity is detected, the neurostimulator delivers electrical stimulation to the brain through the leads to help prevent the seizure before it occurs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Annual device-related serious adverse event (SADE) rate | The lower limit of the 95% confidence interval of the annual SADE rate at months 12 and 24 post-implant is less than 33.6% and 22.0%, respectively (twice the SADE rate of 16.8% and 11.0%, respectively, at the same time points in the RNS System pivotal study) | 12 months post-implant | 
| Safety: Annual device-related serious adverse event (SADE) rate | The lower limit of the 95% confidence interval of the annual SADE rate at months 12 and 24 post-implant is less than 33.6% and 22.0%, respectively (twice the SADE rate of 16.8% and 11.0%, respectively, at the same time points in the RNS System pivotal study) | 24 months post-implant | 
| Effectiveness: Blinded evaluation period (BEP) responder rate | The responder rate during one or both of the stimulation conditions (A or B) is ≥ 30%. The responder rate is the proportion of participants that are responders. A responder in this study is defined as a participant who has a ≥ 35% reduction in the frequency of drop seizures compared to that participant's pre-implant baseline. | 12 months post-implant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Post-op SAE rate | The lower limit of the 95% confidence interval of the SAE rate following the implant procedure (through 4 weeks post-op) is less than 24% (twice the SAE rate of 12% at the same time point in the RNS System pivotal study). | 4 weeks post-implant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medically refractory, Responsive neurostimulation, RNS System, Thalamocortical stimulation