EpilepsyPhase 3NCT00264810
RNS® System Pivotal Study
A Phase 3 study testing RNS® System implantation and RNS® System responsive stimulation in people with Epilepsy, run by NeuroPace at 32 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Epilepsy
- What is being tested?
- RNS® System implantation and RNS® System responsive stimulation
- Type of treatment
- Medical device, Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 240 participants
- Where
- 32 sitesUnited States
- Study dates
- Dec 2005to May 2011
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- Subject's seizures are distinct, stereotypical events that can be reliably counted.
- Subject failed treatment with a minimum of 2 anti-seizure medications.
- 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.
- 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.
- Subject is between the ages of 18 and 70 years.
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- Subject has undergone diagnostic testing that has identified no more than 2 epileptogenic regions.
- Subject is male or a female of childbearing potential using a reliable method of contraception or is at least two years post-menopause.
- 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 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 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.
Who cannot join
- 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.
- Subject has a clinically significant or unstable medical condition (including alcohol and/or drug abuse) or a progressive central nervous system disease.
- Subject is taking chronic anticoagulants.
- 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.
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- Subject is pregnant or planning on becoming pregnant in the next 2 years.
- Subject is enrolled in a therapeutic investigational drug or device trial.
- 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.)
- Subject has had therapeutic surgery to treat epilepsy in the preceding 6 months.
- Subject has had a cranial neurosurgical procedure (including endovascular procedures) other than an epilepsy surgery involving the skull or brain in the previous month.
- Subject is implanted with an electronic medical device that delivers electrical energy to the head.
- Subject is an unsuitable candidate for neurosurgery.
- Subject requires repeat MRIs in which the head is exposed to the radio frequency field.
- Subject's epileptogenic region(s) is/are located caudal to the level of the thalamus.
- Implantation of the RNS® Neurostimulator and Lead(s) would present unacceptable risk.
Trial locations and contacts
32 sites in 1 country.
32 sites in 1 country
United States32 sites
Emory University
Atlanta, Georgia, 30322
Medical College of Georgia / Georgia Health Sciences University
Augusta, Georgia, 30912
Johns Hopkins University School of Medicine
Baltimore, Maryland, 21287
University of Alabama at Birmingham
Birmingham, Alabama, 35294
Massachusetts General Hospital
Boston, Massachusetts, 02114
Medical University of South Carolina
Charleston, South Carolina, 29425
University of Virginia
Charlottesville, Virginia, 22908
Rush University Medical Center/ Epilepsy Center
Chicago, Illinois, 60612
Cleveland Clinic Foundation
Cleveland, Ohio, 44145
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Henry Ford Hospital
Detroit, Michigan, 48202
University of Florida at Gainesville
Gainesville, Florida, 32610
Baylor College of Medicine
Houston, Texas, 77030
Indiana University
Indianapolis, Indiana, 46202
Mayo Clinic - Jacksonville
Jacksonville, Florida, 32224
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, 03756
Saint Barnabas Medical Center
Livingston, New Jersey, 07039
University of Southern California
Los Angeles, California, 90033
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, 53792
Miami Children's Hospital
Miami, Florida, 33155
Yale University School of Medicine
New Haven, Connecticut, 06520
Columbia University / Columbia Presbyterian Medical Center
New York, New York, 10032
Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
Mayo Clinic - Arizona
Phoenix, Arizona, 85054
Oregon Health & Science University
Portland, Oregon, 97201
Mayo Clinic - Rochester
Rochester, Minnesota, 55905
University of Rochester
Rochester, New York, 14642
California Pacific Medical Center
San Francisco, California, 94115
Swedish Medical Center
Seattle, Washington, 98122
George Washington University
Washington D.C., District of Columbia, 20037
Via Christi Comprehensive Epilepsy Center
Wichita, Kansas, 67214
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157
About this study
Official title: RNS® System Pivotal-A Clinical Investigation
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.
Read the 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.
- Conditions
- Epilepsy
- Being tested
- RNS® System implantation, RNS® System responsive stimulation
- Keywords
- Responsive Stimulation, Brain Stimulator, Epilepsy, Seizures
- Medical subject headings
- Epilepsy, Seizures
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RNS® System implantationProcedure or surgery
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.
RNS® System responsive stimulationDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| Treatment Group (stimulation ON) | Active comparator | 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. Receives: Procedure: RNS® System implantation; Device: RNS® System responsive stimulation |
| Sham Group (stimulation OFF) | Sham comparator | 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. Receives: Procedure: RNS® System implantation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Initial implant through 1 month post-implant
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.
Measured: Initial implant through 5 months post-implant
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.)
Measured: 3 months pre-implant (Baseline Period) compared to months 3, 4 and 5 post-implant (Blinded Evaluation Period)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Dec 2005 (estimated)
- Study startDec 2005
- Primary completionOct 2009
- Study completionMay 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for EpilepsyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 240 participants (actual)
Sponsor and investigators
- Lead sponsor
- NeuroPace
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Gregory Barkley, MD, Principal investigator, Johns Hopkins UniversityMichel Berg, MD, Principal investigator, University of RochesterGregory Bergey, MD, Principal investigator, Henry Ford HospitalCarl Bazil, MD, Principal investigator, Columbia University / Columbia Presbyterian Medical CenterAndrew Cole, MD, Principal investigator, Massachusetts General HospitalMichael Duchowny, MD, Principal investigator, Nicklaus Children's Hospital f/k/a Miami Children's HospitalRobert Duckrow, MD, Principal investigator, Yale UniversityJonathan Edwards, MD, Principal investigator, Medical University of South Carolina
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00264810
- Sponsor's protocol ID
- NP10004
- Status last verified
- Aug 2013
- First submitted
- 9 Dec 2005
- Last updated
- 28 Aug 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Behrens E, Schramm J, Zentner J, Konig R. Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurgery. 1997 Jul;41(1):1-9; discussion 9-10. doi: 10.1097/00006123-199707000-00004.
PubMed 9218289Beric A, Kelly PJ, Rezai A, Sterio D, Mogilner A, Zonenshayn M, Kopell B. Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg. 2001;77(1-4):73-8. doi: 10.1159/000064600.
PubMed 12378060Fountas KN, Smith JR. A novel closed-loop stimulation system in the control of focal, medically refractory epilepsy. Acta Neurochir Suppl. 2007;97(Pt 2):357-62. doi: 10.1007/978-3-211-33081-4_41.
PubMed 17691324Fountas KN, Smith JR. Subdural electrode-associated complications: a 20-year experience. Stereotact Funct Neurosurg. 2007;85(6):264-72. doi: 10.1159/000107358. Epub 2007 Aug 17.
PubMed 17709978Hamer HM, Morris HH, Mascha EJ, Karafa MT, Bingaman WE, Bej MD, Burgess RC, Dinner DS, Foldvary NR, Hahn JF, Kotagal P, Najm I, Wyllie E, Luders HO. Complications of invasive video-EEG monitoring with subdural grid electrodes. Neurology. 2002 Jan 8;58(1):97-103. doi: 10.1212/wnl.58.1.97.
PubMed 11781412Hariz MI. Complications of deep brain stimulation surgery. Mov Disord. 2002;17 Suppl 3:S162-6. doi: 10.1002/mds.10159.
PubMed 11948772Joint C, Nandi D, Parkin S, Gregory R, Aziz T. Hardware-related problems of deep brain stimulation. Mov Disord. 2002;17 Suppl 3:S175-80. doi: 10.1002/mds.10161.
PubMed 11948774Koller WC, Lyons KE, Wilkinson SB, Troster AI, Pahwa R. Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov Disord. 2001 May;16(3):464-8. doi: 10.1002/mds.1089.
PubMed 11391740Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM. Long-term hardware-related complications of deep brain stimulation. Neurosurgery. 2002 Jun;50(6):1268-74; discussion 1274-6. doi: 10.1097/00006123-200206000-00017.
PubMed 12015845Tanriverdi T, Ajlan A, Poulin N, Olivier A. Morbidity in epilepsy surgery: an experience based on 2449 epilepsy surgery procedures from a single institution. J Neurosurg. 2009 Jun;110(6):1111-23. doi: 10.3171/2009.8.JNS08338.
PubMed 19199440Wong CH, Birkett J, Byth K, Dexter M, Somerville E, Gill D, Chaseling R, Fearnside M, Bleasel A. Risk factors for complications during intracranial electrode recording in presurgical evaluation of drug resistant partial epilepsy. Acta Neurochir (Wien). 2009 Jan;151(1):37-50. doi: 10.1007/s00701-008-0171-7. Epub 2009 Jan 8.
PubMed 19129963Morrell MJ; RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology. 2011 Sep 27;77(13):1295-304. doi: 10.1212/WNL.0b013e3182302056. Epub 2011 Sep 14.
PubMed 21917777Meador KJ, Kapur R, Loring DW, Kanner AM, Morrell MJ; RNS(R) System Pivotal Trial Investigators. Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation. Epilepsy Behav. 2015 Apr;45:242-7. doi: 10.1016/j.yebeh.2015.01.012. Epub 2015 Mar 26.
PubMed 25819949
Study at a glance
From the registry record, last updated by the sponsor on 28 Aug 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- RNS® System Pivotal-A Clinical Investigation
- ClinicalTrials.gov ID
- NCT00264810
- Acronym / sponsor ID
- NP10004
- Conditions
- Epilepsy
- Keywords
- Responsive Stimulation, Brain Stimulator, Epilepsy, Seizures
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 240 participants (actual)
- Lead sponsor
- NeuroPaceIndustry (pharma, biotech, devices)
- Study start
- Dec 2005
- Primary completion
- Oct 2009 (actual)
- Study completion
- May 2011 (actual)
- First posted
- 13 Dec 2005 (estimated)
- Results
- Posted 28 Aug 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment Group (stimulation ON) | Active comparator | Procedure: RNS® System implantation, Device: RNS® System responsive stimulationGroup 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. |
| Sham Group (stimulation OFF) | Sham comparator | Procedure: RNS® System implantationGroup 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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.
- Subject's seizures are distinct, stereotypical events that can be reliably counted.
- Subject failed treatment with a minimum of 2 anti-seizure medications.
- 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.
- 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.
Key exclusion criteria (16 listed)
- 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.
- Subject has a clinically significant or unstable medical condition (including alcohol and/or drug abuse) or a progressive central nervous system disease.
- Subject is taking chronic anticoagulants.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RNS® System implantationUsing 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. | Procedure or surgery | Sham Group (stimulation OFF), Treatment Group (stimulation ON) |
| RNS® System responsive stimulationThe 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. | Device | Treatment Group (stimulation ON) |
Primary outcome
Acute SAE Rate
Time frame: 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
Time frame: 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
Time frame: 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.)
Results and safety
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Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Aug 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 9218289Behrens E, Schramm J, Zentner J, Konig R. Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurgery. 1997 Jul;41(1):1-9; discussion 9-10. doi: 10.1097/00006123-199707000-00004.
- Background: PubMed 12378060Beric A, Kelly PJ, Rezai A, Sterio D, Mogilner A, Zonenshayn M, Kopell B. Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg. 2001;77(1-4):73-8. doi: 10.1159/000064600.
- Background: PubMed 17691324Fountas KN, Smith JR. A novel closed-loop stimulation system in the control of focal, medically refractory epilepsy. Acta Neurochir Suppl. 2007;97(Pt 2):357-62. doi: 10.1007/978-3-211-33081-4_41.
- Background: PubMed 17709978Fountas KN, Smith JR. Subdural electrode-associated complications: a 20-year experience. Stereotact Funct Neurosurg. 2007;85(6):264-72. doi: 10.1159/000107358. Epub 2007 Aug 17.
- Background: PubMed 11781412Hamer HM, Morris HH, Mascha EJ, Karafa MT, Bingaman WE, Bej MD, Burgess RC, Dinner DS, Foldvary NR, Hahn JF, Kotagal P, Najm I, Wyllie E, Luders HO. Complications of invasive video-EEG monitoring with subdural grid electrodes. Neurology. 2002 Jan 8;58(1):97-103. doi: 10.1212/wnl.58.1.97.
- Background: PubMed 11948772Hariz MI. Complications of deep brain stimulation surgery. Mov Disord. 2002;17 Suppl 3:S162-6. doi: 10.1002/mds.10159.
- Background: PubMed 11948774Joint C, Nandi D, Parkin S, Gregory R, Aziz T. Hardware-related problems of deep brain stimulation. Mov Disord. 2002;17 Suppl 3:S175-80. doi: 10.1002/mds.10161.
- Background: PubMed 11391740Koller WC, Lyons KE, Wilkinson SB, Troster AI, Pahwa R. Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov Disord. 2001 May;16(3):464-8. doi: 10.1002/mds.1089.
- Background: PubMed 12015845Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM. Long-term hardware-related complications of deep brain stimulation. Neurosurgery. 2002 Jun;50(6):1268-74; discussion 1274-6. doi: 10.1097/00006123-200206000-00017.
- Background: PubMed 19199440Tanriverdi T, Ajlan A, Poulin N, Olivier A. Morbidity in epilepsy surgery: an experience based on 2449 epilepsy surgery procedures from a single institution. J Neurosurg. 2009 Jun;110(6):1111-23. doi: 10.3171/2009.8.JNS08338.
- Background: PubMed 19129963Wong CH, Birkett J, Byth K, Dexter M, Somerville E, Gill D, Chaseling R, Fearnside M, Bleasel A. Risk factors for complications during intracranial electrode recording in presurgical evaluation of drug resistant partial epilepsy. Acta Neurochir (Wien). 2009 Jan;151(1):37-50. doi: 10.1007/s00701-008-0171-7. Epub 2009 Jan 8.
- Results publication: PubMed 21917777Morrell MJ; RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology. 2011 Sep 27;77(13):1295-304. doi: 10.1212/WNL.0b013e3182302056. Epub 2011 Sep 14.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gregory Barkley, MD principal investigator
Johns Hopkins University
Michel Berg, MD principal investigator
University of Rochester
Gregory Bergey, MD principal investigator
Henry Ford Hospital
32 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing RNS® System implantation and RNS® System responsive stimulation in people with Epilepsy, run by NeuroPace at 32 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Aug 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 32 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Aug 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Acute SAE Rate (time frame: Initial implant through 1 month post-implant). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00264810, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Aug 2013.