RNS® System Feasibility Study

Study Overview
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Brief Summary
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The RNS® System is intended to treat patients with medically refractory (hard to treat) epilepsy. The RNS® System Feasibility study is designed to demonstrate safety and evidence of effectiveness of the RNS® System to support the commencement of a pivotal clinical investigation.

Detailed Description
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NeuroPace, Inc. is sponsoring an investigational device feasibility study of the RNS® System, the first closed loop responsive brain stimulator designed to treat medically refractory epilepsy. The RNS® System Feasibility study is a multi-center investigation being conducted at 12 epilepsy centers through the United States. The first 4 subjects at each site are entered into an open label protocol, and subsequent subjects at that site are entered into a randomized, double-blinded, sham-stimulation controlled protocol. The study is designed to demonstrate safety and evidence of effectiveness of the RNS® System to support commencement of a pivotal clinical investigation. The RNS® Neurostimulator (a pacemaker-like device) and NeuroPace® Leads (tiny wires with electrodes) are implanted in the head. The Neurostimulator is a battery powered, microprocessor controlled device that detects and stores records of electrographic patterns (such as epileptiform, or seizure-like, activity) from the Leads within the brain. When the device detects an electrographic pattern, it responds by sending electrical stimulation through the Leads to a small part of the patient's brain to interrupt the electrographic pattern. This type of treatment is called responsive stimulation, but it is not yet known if it will work for the treatment of epilepsy. Direct brain stimulation therapy has already received approval in the United States, Europe, Canada, and Australia for the treatment of Essential Tremor and Parkinson's disease. Direct brain stimulation is not approved for the treatment of epilepsy. Subjects participating in the RNS® System Feasibility study are required to have successfully completed the non-significant risk Prospective Seizure Frequency (PSF) study, which gathers baseline(pre-implant) seizure frequency data. Subjects must also met the inclusion criteria, including localization of epileptogenic region(s), prior to enrolling in the study. Throughout the entire study, subjects or their caregivers must keep a seizure diary. Seizure frequency, seizure severity, and antiepileptic medications, as well as physical and emotional health will be monitored and recorded throughout the study. Antiepileptic medications should continue to remain stable until 5 months post-implant. Following enrollment, and prior to RNS® System implant, subjects undergo a neuropsychological evaluation. During the implant procedure, the RNS® Neurostimulator is cranially implanted and connected to one or two NeuroPace® Leads implanted in the brain. The investigational team determines the placement of the Leads based on prior localization of the epileptogenic region, according to standard localization procedures. The Evaluation Period begins once the subject is implanted with the RNS® System and continues through the 4th month. Detection of epileptiform activity is enabled for all subjects within the first post-operative month. Responsive stimulation is enabled and optimized for subjects enrolled in the open label protocol or randomized to the Treatment group. Subjects randomized to the Sham group undergo simulated stimulation programming in order to maintain the treatment blind. Randomized subjects will not know whether responsive stimulation is being delivered or not. At the beginning of the 5th month, subjects transition into the Follow up Period during which all subjects may receive responsive stimulation and antiepileptic medications may be adjusted as medically required. Subjects will be followed for 2 years post-implant. Throughout study participation, both effectiveness and safety data will be monitored continuously, and reviewed and documented by the study investigator at study appointments scheduled every 1-3 months.

Official Title
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RNS® System Feasibility Clinical Investigation

Conditions
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Epilepsy

Intervention / Treatment
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* Procedure: RNS® System implantation
* Device: RNS® System responsive stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has simple partial seizures (motor or sensory) or complex partial seizures (with motor manifestations) with or without secondarily generalized seizures Subject has seizures that are distinct, stereotypical events that can be reliably counted, in the opinion of the investigator, by the subject or caregiver Subject has seizures that are severe enough to cause injuries or significantly impair functional ability in domains including employment, psychosocial, education and mobility Subject failed treatment with a minimum of two antiseizure medications (used in appropriate doses) with adequate monitoring of compliance and the effects of treatment Subject has remained on the same antiseizure medication(s) over the preceding three (3) months (independent of dose and other than acute, intermittent use of benzodiazepines) Subject has a minimum of four (4) or more countable seizures every month over the last three (3) months, as reported from the NeuroPace sponsored Prospective Seizure Frequency Clinical Investigation Subject is ≥ 18 years old and ≤ 65 years old Subject has undergone diagnostic testing that has established the epileptiform activity onset region(s) as part of his/her standard care to determine candidacy for epilepsy surgery Subject is male, or if female is using a reliable method of contraception (hormonal, barrier method, surgical or abstention), or is at least two years postmenopause Subject or legal guardian is able to provide appropriate consent to participate Subject can be reasonably expected to maintain a seizure diary alone or with the assistance of a competent individual Subject is able to complete regular office visits and telephone appointments per the protocol requirements Subject is willing to be implanted with the RNS® System as a treatment for his/her seizures Subject is able to tolerate a neurosurgical procedure Subject is considered a good candidate to be implanted with an RNS® System Note: 1 month = 28 days Exclusion Criteria: Subject has been diagnosed with psychogenic or non-epileptic seizures in the preceding year Subject has been diagnosed with primarily generalized seizures Subject has experienced unprovoked status epilepticus in the preceding year In the opinion of the investigator, the subject has a clinically significant or unstable medical condition or a progressive central nervous system disease Subject has been diagnosed with active psychosis, severe depression or suicidal ideation in the preceding year Subject is pregnant or planning on becoming pregnant in the next year Subject is on the ketogenic diet Subject was enrolled in a therapeutic investigational drug or device study in the preceding year Subject has an implanted Vagus Nerve Stimulator (VNS) Subject has had therapeutic surgery to treat epilepsy in the preceding year Subject is implanted with an electronic medical device that delivers electrical energy to the head or body Subject is on chronic anticoagulants or, in the opinion of the investigator, subject is an unsuitable candidate for cranial surgery for any other reason Subject had a cranial neurosurgical procedure in the previous month Subject requires repeat MRIs Subject's seizure onset zone(s) is/are located below the level of the subthalamic nucleus or, in the opinion of the investigator, the necessary lead placement would present too high a risk Note: Subjects with an inactive VNS could be enrolled so long as the VNS was explanted prior to or at the same time as the RNS® System implant. Subjects who had had epilepsy surgery (resective, corpus callosotomy or ablation) greater than one year ago were still eligible.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Group<br>Group of subjects who have undergone RNS® System implantation who are randomized to receive RNS® System responsive stimulation (i.e. responsive stimulation enabled or turned ON) during the blinded Evaluation Period. Stimulation is enabled during the first month post-implant and may continue throughout the subject's participation in the study. | Procedure: RNS® System implantation<br>* Using standard neurosurgical techniques the surgical team implants the RNS® System, which includes the RNS® Neurostimulator and intracranial NeuroPace® Leads. Up to 4 Leads (Cortical Strips and/or Depth Leads) are placed in or near the epileptogenic focus/foci. The Neurostimulator is placed in the skull and connected to up to 2 Leads. At first the Neurostimulator is programmed to record brain activity (electrographic patterns). The neurologist or neurosurgeon reviews the recorded electrographic patterns and identifies abnormal (epileptiform, or seizure-like) activity. The Neurostimulator is then programmed to detect the abnormal activity.<br>Device: RNS® System responsive stimulation<br>* The RNS® System is programmed to provide responsive stimulation (stimulation is ON or enabled). Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal (epileptiform, or seizure-like) activity, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. The typical patient is treated with a cumulative total of 5 minutes of stimulation a day.<br>|
| Sham Comparator: Sham Group<br>Group of subjects that have undergone RNS® System implantation that are randomized to receive sham-stimulation (i.e. responsive stimulation disabled or turned OFF) during the blinded Evaluation Period. Stimulation is enabled after transition into the Follow-Up Period (5th month post-implant) and may continue for the remainder of the subject's participation in the study. | Procedure: RNS® System implantation<br>* Using standard neurosurgical techniques the surgical team implants the RNS® System, which includes the RNS® Neurostimulator and intracranial NeuroPace® Leads. Up to 4 Leads (Cortical Strips and/or Depth Leads) are placed in or near the epileptogenic focus/foci. The Neurostimulator is placed in the skull and connected to up to 2 Leads. At first the Neurostimulator is programmed to record brain activity (electrographic patterns). The neurologist or neurosurgeon reviews the recorded electrographic patterns and identifies abnormal (epileptiform, or seizure-like) activity. The Neurostimulator is then programmed to detect the abnormal activity.<br>|
| Other: Open Label Group<br>Group of subjects who have undergone RNS® System implantation who were not randomized or blinded to therapy status during the Evaluation Period. Stimulation may have been enabled during the first month post-implant and may have continued throughout the subject's participation in the study. | Procedure: RNS® System implantation<br>* Using standard neurosurgical techniques the surgical team implants the RNS® System, which includes the RNS® Neurostimulator and intracranial NeuroPace® Leads. Up to 4 Leads (Cortical Strips and/or Depth Leads) are placed in or near the epileptogenic focus/foci. The Neurostimulator is placed in the skull and connected to up to 2 Leads. At first the Neurostimulator is programmed to record brain activity (electrographic patterns). The neurologist or neurosurgeon reviews the recorded electrographic patterns and identifies abnormal (epileptiform, or seizure-like) activity. The Neurostimulator is then programmed to detect the abnormal activity.<br>Device: RNS® System responsive stimulation<br>* The RNS® System is programmed to provide responsive stimulation (stimulation is ON or enabled). Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal (epileptiform, or seizure-like) activity, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. The typical patient is treated with a cumulative total of 5 minutes of stimulation a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute SAE Rate | RNS® System Acute SAE Rate = the percentage of subjects having a serious adverse event (SAE) for the surgical implant procedure and the following month (28 days), whether reported as device-related or not. This outcome measure is met when the upper limit of the one-sided 95% confidence interval of the observed RNS® System Acute SAE Rate does not exceed the upper limit of the one-sided 95% confidence interval of the literature-based acute SAE rate associated with the implantation of intracranial electrodes for localization procedures and epilepsy surgery combined as documented in the literature (rate = 19%; upper CI = 28%). The comparator was calculated based upon the literature, therefore the number of participants analyzed is unknown/not applicable. The primary safety outcome measure was met. | Initial implant through 1 month post-implant | 
| Short-term Chronic SAE Rate | The RNS® System Short-term Chronic SAE rate = the percentage of implanted subjects having a serious adverse event (SAE) for the surgical implant procedure and the following 3 months (84 days), whether reported as device-related or not. This outcome measure is met when the upper limit of the one-sided 95% confidence interval of the observed RNS® System Short-term Chronic SAE Rate does not exceed the upper limit of the one-sided 95% confidence interval of the historical short-term chronic SAE rate for deep brain stimulation for movement disorders from the published literature (rate = 36%; upper CI = 46%). The comparator was calculated based upon the literature, therefore the number of participants analyzed is unknown/not applicable. The primary safety outcome measure was met. | Initial implant through 3 months post-implant | 
| Responder Rate | Percentage of subjects with a 50% or greater reduction in mean seizure frequency during the post-implant Evaluation Period (4 months or 112 days) compared to pre-implant baseline (collected during the Prospective Seizure Frequency study). The primary effectiveness endpoint would be met with an observed responder rate of 13% or more. The effectiveness endpoint was only calculated for the Treatment Population. The endpoint was used to support a Pivotal Study, not to demonstrate efficacy when compared to a control/sham group. The primary effectiveness endpoint was met. | Pre-implant baseline through 4 months post-implant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Responsive Stimulation, Brain Stimulator, Epilepsy, Seizures