RNS® System Pivotal Study

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
NeuroPace
ClinicalTrials.gov Identifier:
NCT00264810
First received: December 9, 2005
Last updated: August 23, 2013
Last verified: August 2013
  Purpose

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.


Condition Intervention Phase
Epilepsy
Procedure: RNS® System implantation
Device: RNS® System responsive stimulation
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: RNS® System Pivotal-A Clinical Investigation

Resource links provided by NLM:


Further study details as provided by NeuroPace:

Primary Outcome Measures:
  • Acute SAE Rate [ Time Frame: Initial implant through 1 month post-implant ] [ Designated as safety issue: Yes ]

    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 ] [ Designated as safety issue: Yes ]

    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) ] [ Designated as safety issue: No ]

    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.)



Enrollment: 240
Study Start Date: December 2005
Study Completion Date: May 2011
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00264810

  Show 32 Study Locations
Sponsors and Collaborators
NeuroPace
Investigators
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 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: Robert Gross, MD Emory University
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 School of Medicine
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 Hospital and Clinics
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
  More Information

Publications:

Responsible Party: NeuroPace
ClinicalTrials.gov Identifier: NCT00264810     History of Changes
Other Study ID Numbers: NP10004
Study First Received: December 9, 2005
Results First Received: August 23, 2013
Last Updated: August 23, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by NeuroPace:
Responsive Stimulation
Brain Stimulator
Epilepsy
Seizures

Additional relevant MeSH terms:
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases

ClinicalTrials.gov processed this record on October 21, 2014