RNS® System Pivotal Study

Epilepsy Clinical Trial

Official title:

RNS® System Pivotal-A Clinical Investigation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00264810
• Other study ID #: NP10004
• Status: Completed
• Phase: Phase 3
• First received: December 9, 2005
• Last updated: August 23, 2013
• Start date: December 2005
• Est. completion date: May 2011

Study information

• Verified date: August 2013
• Source: NeuroPace
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical 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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 240
• Est. completion date: May 2011
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Epilepsy

Intervention

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.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Medical College of Georgia / Georgia Health Sciences University	Augusta	Georgia
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Rush University Medical Center/ Epilepsy Center	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	University of Florida at Gainesville	Gainesville	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	University of Southern California	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Miami Children's Hospital	Miami	Florida
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University / Columbia Presbyterian Medical Center	New York	New York
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Mayo Clinic - Arizona	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	California Pacific Medical Center	San Francisco	California
United States	Swedish Medical Center	Seattle	Washington
United States	George Washington University	Washington	District of Columbia
United States	Via Christi Comprehensive Epilepsy Center	Wichita	Kansas
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
NeuroPace

Country where clinical trial is conducted

United States, 

References & Publications (12)

Behrens E, Schramm J, Zentner J, König R. Surgical and neurological complications in a series of 708 epilepsy surgery procedures. Neurosurgery. 1997 Jul;41(1):1-9; discussion 9-10. — View Citation

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. — View Citation

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. Review. — View Citation

Fountas KN, Smith JR. Subdural electrode-associated complications: a 20-year experience. Stereotact Funct Neurosurg. 2007;85(6):264-72. Epub 2007 Aug 17. — View Citation

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, Lüders HO. Complications of invasive video-EEG monitoring with subdural grid electrodes. Neurology. 2002 Jan 8;58(1):97-103. — View Citation

Hariz MI. Complications of deep brain stimulation surgery. Mov Disord. 2002;17 Suppl 3:S162-6. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Primary	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	Yes
Primary	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)	No