RNS® System Pivotal Study

NCT00264810 | Completed Phase 3 Results DMC

• 1 other identifier: NP10004
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 32

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.

Conditions

Epilepsy

Keywords

Responsive Stimulation; Brain Stimulator; Epilepsy; Seizures

Outcome Measures

Primary Outcomes (3)

• 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)

Study Arms (2)

Treatment Group (stimulation ON)

ACTIVE COMPARATOR

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; Device: RNS® System responsive stimulation

Sham Group (stimulation OFF)

SHAM COMPARATOR

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

Interventions

RNS® System implantation PROCEDURE

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.

Sham Group (stimulation OFF); Treatment Group (stimulation ON)

RNS® System responsive stimulation DEVICE

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.

Treatment Group (stimulation ON)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Subject's seizures are distinct, stereotypical events that can be reliably counted.
• Subject failed treatment with a minimum of 2 anti-seizure medications.
• 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.
• 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.
• Subject is between the ages of 18 and 70 years.
• Subject has undergone diagnostic testing that has identified no more than 2 epileptogenic regions.
• Subject is male or a female of childbearing potential using a reliable method of contraception or is at least two years post-menopause.
• Subject or legal guardian is able to provide appropriate consent to participate.
• Subject can be reasonably expected to maintain a seizure diary alone or with the assistance of a competent individual.
• Subject is able to complete regular office and telephone appointments per the protocol requirements.
• Subject is willing to be implanted with the RNS® System as a treatment for his/her seizures.
• Subject is able to tolerate a neurosurgical procedure.
• 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.

You may not qualify if:

• Subject has been diagnosed with psychogenic or non-epileptic seizures in the preceding year
• Subject has been diagnosed with primarily generalized seizures.
• Subject has experienced unprovoked status epilepticus in the preceding year.
• Subject has a clinically significant or unstable medical condition (including alcohol and/or drug abuse) or a progressive central nervous system disease.
• Subject is taking chronic anticoagulants.
• 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.
• Subject is pregnant or planning on becoming pregnant in the next 2 years.
• Subject is enrolled in a therapeutic investigational drug or device trial.
• 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.)
• Subject has had therapeutic surgery to treat epilepsy in the preceding 6 months.
• Subject has had a cranial neurosurgical procedure (including endovascular procedures) other than an epilepsy surgery involving the skull or brain in the previous month.
• Subject is implanted with an electronic medical device that delivers electrical energy to the head.
• Subject is an unsuitable candidate for neurosurgery.
• Subject requires repeat MRIs in which the head is exposed to the radio frequency field.
• Subject's epileptogenic region(s) is/are located caudal to the level of the thalamus.

Sponsors & Collaborators

• NeuroPace: lead

Study Sites (32)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Mayo Clinic - Arizona

Phoenix, Arizona, 85054, United States

Location

University of Southern California

Los Angeles, California, 90033, United States

Location

California Pacific Medical Center

San Francisco, California, 94115, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06520, United States

Location

George Washington University

Washington D.C., District of Columbia, 20037, United States

Location

University of Florida at Gainesville

Gainesville, Florida, 32610, United States

Location

Mayo Clinic - Jacksonville

Jacksonville, Florida, 32224, United States

Location

Miami Children's Hospital

Miami, Florida, 33155, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Medical College of Georgia / Georgia Health Sciences University

Augusta, Georgia, 30912, United States

Location

Rush University Medical Center/ Epilepsy Center

Chicago, Illinois, 60612, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Via Christi Comprehensive Epilepsy Center

Wichita, Kansas, 67214, United States

Location

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Saint Barnabas Medical Center

Livingston, New Jersey, 07039, United States

Location

Columbia University / Columbia Presbyterian Medical Center

New York, New York, 10032, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44145, United States

Location

Oregon Health & Science University

Portland, Oregon, 97201, United States

Location

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

Swedish Medical Center

Seattle, Washington, 98122, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

Related Publications (13)

• 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.

  PMID: 9218289 BACKGROUND

• 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.

  PMID: 12378060 BACKGROUND

• 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.

  PMID: 17691324 BACKGROUND

• 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.

  PMID: 17709978 BACKGROUND

• 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.

  PMID: 11781412 BACKGROUND

• Hariz MI. Complications of deep brain stimulation surgery. Mov Disord. 2002;17 Suppl 3:S162-6. doi: 10.1002/mds.10159.

  PMID: 11948772 BACKGROUND

• 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.

  PMID: 11948774 BACKGROUND

• 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.

  PMID: 11391740 BACKGROUND

• 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.

  PMID: 12015845 BACKGROUND

• 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.

  PMID: 19199440 BACKGROUND

• 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.

  PMID: 19129963 BACKGROUND

• 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.

  PMID: 21917777 RESULT

• 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.

  PMID: 25819949 DERIVED

MeSH Terms

Conditions

Epilepsy; Seizures

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Martha Morrell, Chief Medical Officer
• Organization: NeuroPace, Inc.

mmorrell@neuropace.com

650-237-2776

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2005
• First Posted: December 13, 2005
• Study Start: December 1, 2005
• Primary Completion: October 1, 2009
• Study Completion: May 1, 2011
• Last Updated: August 28, 2013
• Results First Posted: August 28, 2013

Record last verified: 2013-08

Locations

US (32)