RNS® System Pivotal Study

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.

Study Overview

• Status: Completed
• Conditions: Epilepsy
• Intervention / Treatment: Procedure: RNS® System implantation; Device: RNS® System responsive stimulation

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 Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic - Arizona
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida at Gainesville
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia / Georgia Health Sciences University
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center/ Epilepsy Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Via Christi Comprehensive Epilepsy Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University / Columbia Presbyterian Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cleveland, Ohio, United States, 44145
      • Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97201
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Procedure: RNS® 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.; Device: RNS® System responsive stimulation; 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.
Sham Comparator: 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.	Procedure: RNS® 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.)	3 months pre-implant (Baseline Period) compared to months 3, 4 and 5 post-implant (Blinded Evaluation Period)

Collaborators and Investigators

• Sponsor: NeuroPace
• Investigators: Principal Investigator: Robert Gross, MD, Emory University; Principal Investigator: Gregory Barkley, MD, Johns Hopkins University; Principal Investigator: Michel Berg, MD, University of Rochester; Principal Investigator: Gregory Bergey, MD, Henry Ford Hospital; Principal Investigator: Carl Bazil, MD, Columbia University / Columbia Presbyterian Medical Center; Principal Investigator: Andrew Cole, MD, Massachusetts General Hospital; Principal Investigator: Michael Duchowny, MD, Nicklaus Children's Hospital f/k/a Miami Children's Hospital; Principal Investigator: Robert Duckrow, MD, Yale University; Principal Investigator: Jonathan Edwards, MD, Medical University of South Carolina; Principal Investigator: Stephan Eisenschenk, MD, University of Florida at Gainesville; Principal Investigator: A. James Fessler, MD, University of Rochester; Principal Investigator: Nathan Fountain, MD, University of Virginia; Principal Investigator: Eric Geller, MD, St. Barnabas Medical Center; Principal Investigator: Ryder Gwinn, MD, Swedish Medical Center; Principal Investigator: Christianne Heck, MD, University of Southern California; Principal Investigator: Barbara Jobst, MD, Dartmouth-Hitchcock Medical Center; Principal Investigator: David King-Stephens, MD, California Pacific Medical Center; Principal Investigator: James Leiphart, MD, George Washington University; Principal Investigator: W. Richard Marsh, MD, Mayo Clinic; Principal Investigator: Andrew Massey, MD, Via Christi Comprehensive Epilepsy Center; Principal Investigator: Eli Mizrahi, MD, Baylor College of Medicine; Principal Investigator: Dileep Nair, MD, The Cleveland Clinic; Principal Investigator: Cormac O'Donovan, MD, Wake Forest University Health Sciences; Principal Investigator: A. LeBron Paige, MD, University of Alabama at Birmingham; Principal Investigator: Yong Park, MD, Medical College of Georgia / Georgia Health Sciences University; Principal Investigator: Paul Rutecki, MD, University of Wisconsin, Madison; Principal Investigator: Vicenta Salanova, MD, Indiana University; Principal Investigator: Christopher Skidmore, MD, Thomas Jefferson University; Principal Investigator: Michael Smith, MD, Rush University Medical Center / Epilepsy Center; Principal Investigator: David Spencer, MD, Oregon Health and Science University; Principal Investigator: Paul Van Ness, MD, University of Texas Southwestern Medical Center; Principal Investigator: Robert Wharen, MD, Mayo Clinic; Principal Investigator: Richard Zimmerman, MD, Mayo Clinic

Publications and helpful links

General Publications

• Koller 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.
• 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.
• Beric 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.
• Fountas 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.
• Fountas 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.
• Hamer 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.
• Hariz MI. Complications of deep brain stimulation surgery. Mov Disord. 2002;17 Suppl 3:S162-6. doi: 10.1002/mds.10159.
• Joint 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.
• Oh 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.
• Tanriverdi 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.
• Wong 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.
• Morrell 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.
• Meador 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: December 9, 2005
• First Submitted That Met QC Criteria: December 9, 2005
• First Posted (Estimate): December 13, 2005

Study Record Updates

• Last Update Posted (Estimate): August 28, 2013
• Last Update Submitted That Met QC Criteria: August 23, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: Epilepsy; Seizures; Responsive Stimulation; Brain Stimulator
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy
• Other Study ID Numbers: NP10004