Clinical trial NCT00264810: RNS® System Pivotal Study
Official title: RNS® System Pivotal-A Clinical Investigation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Epilepsy
Keywords: Responsive Stimulation
Brain Stimulator
Epilepsy
Seizures
Lead sponsor: NeuroPace
Sponsor class: INDUSTRY
First posted: 2005-12-13
Enrollment: 240
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The RNS® System Pivotal study is designed to assess safety and demonstrate that the RNS® System is effective as an adjunctive (add-on) therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures from no more than two foci (two areas of the brain) that are refractory (drug-resistant or hard-to-treat) to two or more antiepileptic medications. Patients continue to receive their epilepsy medications while participating in the study.

Detailed description: NeuroPace, Inc. is sponsoring an investigational device study of the RNS® System, the first closed loop responsive brain stimulator designed to treat refractory epilepsy. The RNS® System Pivotal study is a multi-center, randomized, double-blinded, sham-stimulation controlled investigation being conducted at 32 epilepsy centers throughout the United States. The study is designed to assess safety and demonstrate that the RNS® System is effective in reducing the frequency of medically uncontrolled and disabling partial onset seizures that start from one or two areas of the brain.

The RNS® Neurostimulator (a pacemaker-like device) and NeuroPace® Leads (tiny wires with electrodes) are implanted in the head. The Neurostimulator is a battery powered, microprocessor controlled device that detects and stores records of electrographic patterns (such as epileptiform, or seizure-like, activity) from the Leads within the brain. When the device detects an electrographic pattern, it responds by sending electrical stimulation through the Leads to a small part of the patient's brain to interrupt the electrographic pattern. This type of treatment is called responsive stimulation, but it is not yet known if it will work for the treatment of epilepsy. Direct brain stimulation therapy has already received approval in the United States, Europe, Canada, and Australia for the treatment of Essential Tremor and Parkinson's disease. Direct brain stimulation is not approved for the treatment of epilepsy.

Subjects participating in the RNS® System Pivotal study must met inclusion criteria, including localization of epileptogenic region(s), prior to enrolling in the study. Throughout the entire study, subjects or their caregivers must keep a seizure diary. Seizure frequency, seizure severity, and antiepileptic medications, as well as physical and emotional health will be monitored and recorded throughout the study.

Upon demonstrating the required seizure frequency and stable antiepileptic medications over 3 consecutive months of the Baseline (pre-implant) Period, subjects will qualify for RNS® System implantation. Antiepileptic medications should continue to remain stable until 6 months post-implant. The surgical procedure will be performed within one month of qualification.

The RNS® Neurostimulator is cranially implanted and connected to one or two NeuroPace® Leads implanted in the brain. The investigational team will determine the placement of the Leads based on prior localization of the epileptogenic region, according to standard localization procedures. Detection of epileptiform activity will be enabled for all subjects during the 1 month Post-Operative Stabilization Period. Subjects will be randomized 1:1 to either the Treatment or Sham group prior to starting the 1 month Stimulation Optimization Period. During this period subjects are seen on a weekly basis by the Treatment Protocol investigator. Responsive stimulation will be enabled and optimized for subjects randomized to the Treatment group. Subjects randomized to the Sham group will be seen for simulated stimulation programming in order to maintain the treatment blind.

The Blinded Evaluation Period is comprised of months 3, 4, and 5 post-implant. Subjects in the Treatment group will receive responsive stimulation and subjects in the Sham group will not. Subjects will not know whether responsive stimulation is being delivered or not. At the end of the 5th month, all subjects' transition into the Open Label Evaluation Period during which all subjects may receive responsive stimulation and antiepileptic medications may be adjusted as medically required.

Subjects will be followed for 2 years post-implant. Throughout study participation, both effectiveness and safety data will be monitored continuously, and reviewed and documented by the study investigator at study appointments scheduled every month for the first year post-implant, then every 3 months.

Eligibility 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.

Primary outcomes:
measure: Acute SAE Rate
timeFrame: Initial implant through 1 month post-implant
measure: Short-term Chronic SAE Rate
timeFrame: Initial implant through 5 months post-implant
measure: Change in Frequency of Disabling Seizures
timeFrame: 3 months pre-implant (Baseline Period) compared to months 3, 4 and 5 post-implant (Blinded Evaluation Period)
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: George Washington University
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida at Gainesville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Augusta
country: United States
facility: Medical College of Georgia / Georgia Health Sciences University
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center/ Epilepsy Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Wichita
country: United States
facility: Via Christi Comprehensive Epilepsy Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Livingston
country: United States
facility: Saint Barnabas Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University / Columbia Presbyterian Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Johns Hopkins University
name: Gregory Barkley, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Michel Berg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Henry Ford Hospital
name: Gregory Bergey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University / Columbia Presbyterian Medical Center
name: Carl Bazil, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Andrew Cole, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nicklaus Children's Hospital f/k/a Miami Children's Hospital
name: Michael Duchowny, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Robert Duckrow, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of South Carolina
name: Jonathan Edwards, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida at Gainesville
name: Stephan Eisenschenk, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: A. James Fessler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Virginia
name: Nathan Fountain, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Barnabas Medical Center
name: Eric Geller, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Robert Gross, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Swedish Medical Center
name: Ryder Gwinn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern California
name: Christianne Heck, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dartmouth-Hitchcock Medical Center
name: Barbara Jobst, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: California Pacific Medical Center
name: David King-Stephens, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: George Washington University
name: James Leiphart, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: W. Richard Marsh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Via Christi Comprehensive Epilepsy Center
name: Andrew Massey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine
name: Eli Mizrahi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Dileep Nair, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University Health Sciences
name: Cormac O'Donovan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: A. LeBron Paige, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical College of Georgia / Georgia Health Sciences University
name: Yong Park, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Paul Rutecki, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: Vicenta Salanova, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Thomas Jefferson University
name: Christopher Skidmore, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rush University Medical Center / Epilepsy Center
name: Michael Smith, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oregon Health and Science University
name: David Spencer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas Southwestern Medical Center
name: Paul Van Ness, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Robert Wharen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Richard Zimmerman, MD
role: PRINCIPAL_INVESTIGATOR
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