Epilepsy
Conditions
Keywords
Responsive Stimulation, Brain Stimulator, Epilepsy, Seizures
Brief summary
The RNS® System Pivotal study is designed to assess safety and demonstrate that the RNS® System is effective as an adjunctive (add-on) therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures from no more than two foci (two areas of the brain) that are refractory (drug-resistant or hard-to-treat) to two or more antiepileptic medications. Patients continue to receive their epilepsy medications while participating in the study.
Detailed description
NeuroPace, Inc. is sponsoring an investigational device study of the RNS® System, the first closed loop responsive brain stimulator designed to treat refractory epilepsy. The RNS® System Pivotal study is a multi-center, randomized, double-blinded, sham-stimulation controlled investigation being conducted at 32 epilepsy centers throughout the United States. The study is designed to assess safety and demonstrate that the RNS® System is effective in reducing the frequency of medically uncontrolled and disabling partial onset seizures that start from one or two areas of the brain. 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 Pivotal study must met 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. Upon demonstrating the required seizure frequency and stable antiepileptic medications over 3 consecutive months of the Baseline (pre-implant) Period, subjects will qualify for RNS® System implantation. Antiepileptic medications should continue to remain stable until 6 months post-implant. The surgical procedure will be performed within one month of qualification. The RNS® Neurostimulator is cranially implanted and connected to one or two NeuroPace® Leads implanted in the brain. The investigational team will determine the placement of the Leads based on prior localization of the epileptogenic region, according to standard localization procedures. Detection of epileptiform activity will be enabled for all subjects during the 1 month Post-Operative Stabilization Period. Subjects will be randomized 1:1 to either the Treatment or Sham group prior to starting the 1 month Stimulation Optimization Period. During this period subjects are seen on a weekly basis by the Treatment Protocol investigator. Responsive stimulation will be enabled and optimized for subjects randomized to the Treatment group. Subjects randomized to the Sham group will be seen for simulated stimulation programming in order to maintain the treatment blind. The Blinded Evaluation Period is comprised of months 3, 4, and 5 post-implant. Subjects in the Treatment group will receive responsive stimulation and subjects in the Sham group will not. Subjects will not know whether responsive stimulation is being delivered or not. At the end of the 5th month, all subjects' transition into the Open Label Evaluation 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 month for the first year post-implant, then every 3 months.
Interventions
PROCEDURERNS® System implantation
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.
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.
Sponsors
NeuroPace
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
for enrollment: 1. Subject has disabling motor simple partial seizures, complex partial seizures, and/or secondarily generalized seizures. Disabling refers to seizures that are severe enough to cause injuries or significantly impair functional ability. 2. Subject's seizures are distinct, stereotypical events that can be reliably counted. 3. Subject failed treatment with a minimum of 2 anti-seizure medications. 4. Subject has remained on the same antiepileptic medication(s) over the 3 most recent consecutive months (other than acute, intermittent use of benzodiazepines). Subjects on the ketogenic diet are permitted if the diet has been stable for the preceding 3 months. 5. Subject reports having an average of 3 or more disabling motor simple partial seizures, complex partial seizures and/or secondarily generalized seizures per month over the 3 most recent consecutive months, with no month with less than 2 seizures. 6. Subject is between the ages of 18 and 70 years. 7. Subject has undergone diagnostic testing that has identified no more than 2 epileptogenic regions. 8. Subject is male or a female of childbearing potential using a reliable method of contraception or is at least two years post-menopause. 9. Subject or legal guardian is able to provide appropriate consent to participate. 10. Subject can be reasonably expected to maintain a seizure diary alone or with the assistance of a competent individual. 11. Subject is able to complete regular office and telephone appointments per the protocol requirements. 12. Subject is willing to be implanted with the RNS® System as a treatment for his/her seizures. 13. Subject is able to tolerate a neurosurgical procedure. 14. Subject is considered a good candidate to be implanted with the RNS® System. Note: A subject is still eligible to participate if antiepileptic medication(s) were temporarily discontinued for the purposes of diagnostic or medical procedures during the preceding 3 months.
Exclusion criteria
for enrollment: 1. Subject has been diagnosed with psychogenic or non-epileptic seizures in the preceding year 2. Subject has been diagnosed with primarily generalized seizures. 3. Subject has experienced unprovoked status epilepticus in the preceding year. 4. Subject has a clinically significant or unstable medical condition (including alcohol and/or drug abuse) or a progressive central nervous system disease. 5. Subject is taking chronic anticoagulants. 6. Subject has been diagnosed with active psychosis, major depression or suicidal ideation in the preceding year. Subjects with post-ictal psychiatric symptoms need not be excluded. 7. Subject is pregnant or planning on becoming pregnant in the next 2 years. 8. Subject is enrolled in a therapeutic investigational drug or device trial. 9. Subject has an implanted Vagus Nerve Stimulator (VNS) or is unwilling to have the VNS explanted. (VNS therapy must have been discontinued for at least 3 months prior to enrollment.) 10. Subject has had therapeutic surgery to treat epilepsy in the preceding 6 months. 11. Subject has had a cranial neurosurgical procedure (including endovascular procedures) other than an epilepsy surgery involving the skull or brain in the previous month. 12. Subject is implanted with an electronic medical device that delivers electrical energy to the head. 13. Subject is an unsuitable candidate for neurosurgery. 14. Subject requires repeat MRIs in which the head is exposed to the radio frequency field. 15. Subject's epileptogenic region(s) is/are located caudal to the level of the thalamus. 16. Implantation of the RNS® Neurostimulator and Lead(s) would present unacceptable risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute SAE Rate | Initial implant through 1 month post-implant | RNS® System Acute SAE Rate = the percentage of implanted subject 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 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 = 15%; upper CI = 20%). The comparator was calculated based upon the literature, therefore the number of participants analyzed is unknown/not applicable. Referenced literature are listed within the citation section (Tanriverdi et al., 2009; Wong et al., 2009; Fountas and Smith, 2007; Hamer et al., 2002; Behrens et al., 1997). Primary Safety Outcome Measure was met. |
| Short-term Chronic SAE Rate | Initial implant through 5 months post-implant | RNS® System Short-term Chronic SAE rate = the percentage of implanted subject 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 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 = 42%). The comparator was calculated based upon the literature, therefore the number of participants analyzed is unknown/not applicable. Referenced literature are listed within the citation section (Oh et al., 2002; SSED, Activa Tremor Control System P960009; Beric et al., 2001; Behrens et al., 1997; Hariz, 2002; Joint et al., 2002; Koller et al., 2001). Primary Safety Outcome Measure was met. |
| Change in Frequency of Disabling Seizures | 3 months pre-implant (Baseline Period) compared to months 3, 4 and 5 post-implant (Blinded Evaluation Period) | The outcome measure is met when a significantly greater reduction in the frequency of total disabling seizures in seen in the Treatment group when compared to the Sham group, during the Blinded Evaluation Period (BEP) relative to the Pre-Implant Period (Baseline). The outcome measure is the group-by-time interaction term in a generalized estimating equation (GEE), longitudinal regression model, where group refers to therapy allocation (Treatment or Sham), time refers to study period (Baseline or BEP), and the dependent variable is seizure frequency. The outcome measure was a statistically significant group-by-time interaction term, which would demonstrate a significantly greater reduction in seizure frequency in the Treatment group than the Sham group during BEP compared to Baseline Period. Primary Effectiveness Outcome Measure was met. (Note: Disabling seizures = motor simple partial seizures or complex partial seizures with or without secondarily generalized seizures.) |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited at Level 4 epilepsy centers, as categorized by the National Association of Epilepsy Centers (NAEC), through the United States.
Pre-assignment details
Besides continuing to meet all I/E criteria, in order to undergo initial implant and be assigned to a group (randomized), subjects were required to maintain an average of 3 or more disabling partial seizures per month and remain on the same AED regimen (except for acute, intermittent use of benzodiazepines), for 3 consecutive months (12 weeks).
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group (Stimulation ON) Group of subjects that have undergone RNS® System implantation that 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 Stimulation Optimization Period (second month post-implant) and may continue throughout the subject's participation in the study. | 97 |
| Sham Group (Stimulation OFF) 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 Open Label Period (sixth month post-implant) and may continue for the remainder of the subject's participation in the study. | 94 |
| Total | 191 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Baseline | Did not Meet/Maintain Study I/E Criteria | 1 | 2 |
| Baseline | Insufficient Seizure Frequency | 2 | 2 |
| Baseline | Other | 0 | 1 |
| Baseline | Physician Decision | 7 | 8 |
| Baseline | Subject Compliance Failure | 3 | 3 |
| Baseline | Withdrawal by Subject | 10 | 10 |
| Blinded Evaluation Period | Explant due to infection | 1 | 1 |
| Open Label Evaluation Period | Death | 3 | 2 |
| Open Label Evaluation Period | Explant due to infection | 1 | 1 |
| Open Label Evaluation Period | Pursue Other Treatment Options | 2 | 3 |
| Stimulation Optimization Period | Death | 0 | 1 |
| Stimulation Optimization Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment Group (Stimulation ON) | Sham Group (Stimulation OFF) | Total |
|---|---|---|---|
| Acute benzodiazepine use (does not include daily use) No | 67 participants | 55 participants | 122 participants |
| Acute benzodiazepine use (does not include daily use) Yes | 30 participants | 39 participants | 69 participants |
| Age, Categorical <=18 years | 4 Participants | 2 Participants | 6 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 93 Participants | 91 Participants | 184 Participants |
| Age Continuous | 34.0 years | 35.9 years | 34.9 years |
| Anatomical brain abnormality (by neuroimaging) No | 31 participants | 33 participants | 64 participants |
| Anatomical brain abnormality (by neuroimaging) Yes | 66 participants | 61 participants | 127 participants |
| Duration of epilepsy | 20.0 years | 21.0 years | 20.5 years |
| Mean seizure frequency | 33.5 seizures/month | 34.9 seizures/month | 34.2 seizures/month |
| Number of AEDs at enrollment | 2.8 number of AEDs | 2.9 number of AEDs | 2.8 number of AEDs |
| Number of seizure foci Bifocal | 48 participants | 58 participants | 106 participants |
| Number of seizure foci Unifocal | 49 participants | 36 participants | 85 participants |
| Prior EEG monitoring with intracranial electrodes No | 34 participants | 44 participants | 78 participants |
| Prior EEG monitoring with intracranial electrodes Yes | 63 participants | 50 participants | 113 participants |
| Prior therapeutic surgery for epilepsy No | 63 participants | 66 participants | 129 participants |
| Prior therapeutic surgery for epilepsy Yes | 34 participants | 28 participants | 62 participants |
| Prior vagal nerve stimulator (VNS) No | 67 participants | 60 participants | 127 participants |
| Prior vagal nerve stimulator (VNS) Yes | 30 participants | 34 participants | 64 participants |
| Seizure onset location Mesial Temporal lobe ONLY | 48 participants | 47 participants | 95 participants |
| Seizure onset location Other | 49 participants | 47 participants | 96 participants |
| Sex: Female, Male Female | 47 Participants | 44 Participants | 91 Participants |
| Sex: Female, Male Male | 50 Participants | 50 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 97 | 94 / 94 |
| serious Total, serious adverse events | 49 / 97 | 52 / 94 |
Outcome results
Primary
Acute SAE Rate
RNS® System Acute SAE Rate = the percentage of implanted subject 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 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 = 15%; upper CI = 20%). The comparator was calculated based upon the literature, therefore the number of participants analyzed is unknown/not applicable. Referenced literature are listed within the citation section (Tanriverdi et al., 2009; Wong et al., 2009; Fountas and Smith, 2007; Hamer et al., 2002; Behrens et al., 1997). Primary Safety Outcome Measure was met.
Time frame: Initial implant through 1 month post-implant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Implanted Subjects | Acute SAE Rate | 12.0 percentage of subjects with ≥ 1 SAE |
Primary
Change in Frequency of Disabling Seizures
The outcome measure is met when a significantly greater reduction in the frequency of total disabling seizures in seen in the Treatment group when compared to the Sham group, during the Blinded Evaluation Period (BEP) relative to the Pre-Implant Period (Baseline). The outcome measure is the group-by-time interaction term in a generalized estimating equation (GEE), longitudinal regression model, where group refers to therapy allocation (Treatment or Sham), time refers to study period (Baseline or BEP), and the dependent variable is seizure frequency. The outcome measure was a statistically significant group-by-time interaction term, which would demonstrate a significantly greater reduction in seizure frequency in the Treatment group than the Sham group during BEP compared to Baseline Period. Primary Effectiveness Outcome Measure was met. (Note: Disabling seizures = motor simple partial seizures or complex partial seizures with or without secondarily generalized seizures.)
Time frame: 3 months pre-implant (Baseline Period) compared to months 3, 4 and 5 post-implant (Blinded Evaluation Period)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Implanted Subjects | Change in Frequency of Disabling Seizures | -37.9 Seizure frequency % change from Baseline |
| Sham Group (Stimulation OFF) | Change in Frequency of Disabling Seizures | -17.3 Seizure frequency % change from Baseline |
Primary
Short-term Chronic SAE Rate
RNS® System Short-term Chronic SAE rate = the percentage of implanted subject 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 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 = 42%). The comparator was calculated based upon the literature, therefore the number of participants analyzed is unknown/not applicable. Referenced literature are listed within the citation section (Oh et al., 2002; SSED, Activa Tremor Control System P960009; Beric et al., 2001; Behrens et al., 1997; Hariz, 2002; Joint et al., 2002; Koller et al., 2001). Primary Safety Outcome Measure was met.
Time frame: Initial implant through 5 months post-implant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Implanted Subjects | Short-term Chronic SAE Rate | 18.3 percentage of subjects with ≥ 1 SAE |