RNS® System Pivotal Study
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|ClinicalTrials.gov Identifier: NCT00264810|
Recruitment Status : Completed
First Posted : December 13, 2005
Results First Posted : August 28, 2013
Last Update Posted : August 28, 2013
|Condition or disease||Intervention/treatment||Phase|
|Epilepsy||Procedure: RNS® System implantation Device: RNS® System responsive stimulation||Phase 3|
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 (Clinical Trial)|
|Actual Enrollment :||240 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Outcomes Assessor)|
|Official Title:||RNS® System Pivotal-A Clinical Investigation|
|Study Start Date :||December 2005|
|Primary Completion Date :||October 2009|
|Study Completion Date :||May 2011|
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.
- 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.)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00264810
Show 32 Study Locations
|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:||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 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|