RNS® System LTT Study

• Sponsor: NeuroPace (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00572195
• Collaborator: (none)
• Enrollment: 230
• Locations: 33
• Arm: 1
• Duration (Months): 145
• Patients Per Site: 7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The RNS® System LTT study is designed to assess the ongoing safety and to evaluate the long-term efficacy of the RNS® System as an adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures that are refractory to two or more antiepileptic medications. Candidates will continue to receive their epilepsy medications while participating in the trial.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Device: RNS® System	Phase 4

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 LTT study is an open-label multi-center prospective 7-year clinical investigation which follows completion of the RNS® System Pivotal or Feasibility study. Data regarding safety and efficacy are collected at 6-month intervals, and data regarding quality of life are collected at yearly intervals.

The study is designed to assess the ongoing safety and to evaluate the long-term efficacy of the RNS® System as an adjunctive therapy in reducing the frequency of medically uncontrolled and disabling partial onset seizures that start from one or two areas of the brain.

The RNS® System LTT study will provide additional data on the safety and efficacy of the RNS® System for 7 years following a subject's completion of the RNS® System Feasibility or Pivotal studies. Data from the RNS® System LTT study will be combined with data collected during the RNS® System Feasibility and Pivotal studies, resulting in 9 total years of post-implant follow-up data. These data will be used to calculate long-term SAE rate, percent change in seizure frequency (from pre-implant baseline), as well as the frequency of sudden unexplained death in epilepsy (SUDEP).

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 230 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: RNS® System Long-term Treatment (LTT) Clinical Investigation
• Study Start Date: Apr 1, 2006
• Actual Primary Completion Date: May 1, 2018
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Evaluation Group (stimulation ON) Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term.

Device: RNS® System; The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Serious Adverse Events (SAE) [2 years post-implant through 9 years post-implant (7 years)]

   The number of subjects having an SAE during the RNS® System LTT study.

2. Percentage Change From Baseline in Seizure Frequency [6 months post-implant through 9 years post-implant (8.5 years)]

   The average percentage change in the mean frequency of total disabling seizures relative to pre-implant baseline. The percent change will be calculated for each subject over 6-month intervals beginning 6 months after RNS® System implant and continuing through completion of the RNS® System LTT study.

Secondary Outcome Measures

1. Responder Rate [6 months post-implant through 9 years post-implant (8.5 years)]

   The proportion of subjects with greater than or equal to 50% reduction in total disabling seizures compared to pre-implant baseline.

2. QOLIE (Quality of Life in Epilepsy) [1 year post-implant through 9 years post-implant (8 years)]

   QOLIE 89 (for English-speaking subjects) or QOLIE 31 P (for Spanish speaking subjects) scores collected at each year of follow-up after implantation of the RNS® System compared to the QOLIE 89 / QOLIE 31 P at pre-implant baseline. A QOLIE overall score was obtained using a weighted average of multi-item scale scores. The QOLIE overall score was converted to a T-score, a normally distributed scale with a mean score of 50 and standard deviation (SD) of 10. Higher scores reflect a better quality of life.

3. Adverse Event Rate [6 months post-implant through 9 years post-implant (8.5 years)]

   The rate of occurrence of any adverse event (AE) observed during the Long-term Treatment Investigation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject has completed either the RNS® System Pivotal or Feasibility study

2. Subject has an implanted RNS® System

3. Subject has elected to continue to receive responsive neurostimulation therapy after completion of the RNS® System Pivotal or Feasibility study

4. Subject is able to attend scheduled appointments for the RNS® System LTT study

Exclusion Criteria:

1. Subject has active psychiatric or medical illness that makes it inadvisable for the subject to continue to receive responsive neurostimulation therapy with the RNS® System

2. Subject has been diagnosed with psychogenic or non-epileptic seizures, or primarily generalized seizures during the RNS® System Pivotal or Feasibility study

3. Subject has been noncompliant with scheduled appointments during the RNS® System Pivotal or Feasibility study

4. Subject has been noncompliant with maintaining seizure diaries during the RNS® System Pivotal or Feasibility study

5. Informed consent cannot be obtained from subject or caregiver

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic - Arizona	Phoenix	Arizona	United States	85054
2	University of Southern California	Los Angeles	California	United States	90033
3	California Pacific Medical Center	San Francisco	California	United States	94115
4	Yale University School of Medicine	New Haven	Connecticut	United States	06520
5	George Washington University	Washington	District of Columbia	United States	20037
6	University of Florida at Gainesville	Gainesville	Florida	United States	32610
7	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
8	Miami Children's Hospital	Miami	Florida	United States	33155
9	Emory University	Atlanta	Georgia	United States	30322
10	Medical College of Georgia / Georgia Regents University	Augusta	Georgia	United States	30912
11	Rush University Medical Center / Epilepsy Center	Chicago	Illinois	United States	60612
12	Indiana University	Indianapolis	Indiana	United States	46202
13	Via Christi Comprehensive Epilepsy Center	Wichita	Kansas	United States	67214
14	Louisiana State University Epilepsy Center of Excellence	New Orleans	Louisiana	United States	70112
15	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21287
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	Henry Ford Hospital	Detroit	Michigan	United States	48202
18	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
19	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
20	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
21	Weill Medical College of Cornell University	New York	New York	United States	10021
22	Columbia University / Columbia Presbyterian Medical Center	New York	New York	United States	10032
23	University of Rochester	Rochester	New York	United States	14642
24	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
25	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
26	Oregon Health & Science University	Portland	Oregon	United States	97201
27	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
28	Medical University of South Carolina	Charleston	South Carolina	United States	29425
29	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
30	Baylor College of Medicine	Houston	Texas	United States	77030
31	University of Virginia	Charlottesville	Virginia	United States	22908
32	Swedish Medical Center	Seattle	Washington	United States	98122
33	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• NeuroPace

Investigators

• Study Director: Martha J Morrell, MD, NeuroPace, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 24, 2014

More Information

Publications

• Heck CN, King-Stephens D, Massey AD, Nair DR, Jobst BC, Barkley GL, Salanova V, Cole AJ, Smith MC, Gwinn RP, Skidmore C, Van Ness PC, Bergey GK, Park YD, Miller I, Geller E, Rutecki PA, Zimmerman R, Spencer DC, Goldman A, Edwards JC, Leiphart JW, Wharen RE, Fessler J, Fountain NB, Worrell GA, Gross RE, Eisenschenk S, Duckrow RB, Hirsch LJ, Bazil C, O'Donovan CA, Sun FT, Courtney TA, Seale CG, Morrell MJ. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. 2014 Mar;55(3):432-41. doi: 10.1111/epi.12534. Epub 2014 Feb 22.
• 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.

• Responsible Party: NeuroPace
• ClinicalTrials.gov Identifier: NCT00572195
• Other Study ID Numbers: NP10005; P100026
• First Posted: Dec 12, 2007
• Last Update Posted: Jun 26, 2019
• Last Verified: May 1, 2019

• Keywords provided by NeuroPace: Epilepsy; Responsive neurostimulation; RNS System; NeuroPace; Brain stimulation; Seizures
• Additional relevant MeSH terms: Epilepsy

Study Results

Participant Flow

Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Period Title: Overall Study
STARTED	230
COMPLETED	162
NOT COMPLETED	68

Baseline Characteristics

Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Overall Participants	230
Age (Count of Participants)
<=18 years	6 2.6%
Between 18 and 65 years	223 97%
>=65 years	1 0.4%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	34.2 (11.4)
Sex: Female, Male (Count of Participants)
Female	115 50%
Male	115 50%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United States	230 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Serious Adverse Events (SAE)
Description	The number of subjects having an SAE during the RNS® System LTT study.
Time Frame	2 years post-implant through 9 years post-implant (7 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Measure Participants	230
Count of Participants [Participants]	177 77%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evaluation Group (Stimulation ON)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Wilson score interval
	Estimated Value	77
	Confidence Interval	(2-Sided) 95%; 71.1 to 81.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The value is for all serious adverse events, regardless of device relation.
Other Statistical Analysis		95% confidence interval estimated using the Wilson score interval

2. Primary Outcome

Title	Percentage Change From Baseline in Seizure Frequency
Description	The average percentage change in the mean frequency of total disabling seizures relative to pre-implant baseline. The percent change will be calculated for each subject over 6-month intervals beginning 6 months after RNS® System implant and continuing through completion of the RNS® System LTT study.
Time Frame	6 months post-implant through 9 years post-implant (8.5 years)

Outcome Measure Data

Analysis Population Description

N represents the number of subjects who have data during that period.

Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Measure Participants	230
6-12 Months	-31.5
12-18 Months	-46.2
18-24 Months	-46.7
24-30 Months	-50.3
30-36 Months	-58.3
36-42 Months	-61.1
42-48 Months	-61.7
48-54 Months	-60.5
54-60 Months	-63.1
60-66 Months	-65.4
66-72 Months	-67.7
72-78 Months	-71.0
78-84 Months	-72.8
84-90 Months	-69.7
90-96 Months	-73.1
96-102 Months	-72.1
102-108 Months	-74.5
108-114 Months	-85.9
114-120 Months	-77.7
120-126 Months	-94.1
126-132 Months	-86.1
132-138 Months	-95.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evaluation Group (Stimulation ON)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	For all 6-month periods, from 6 months through 9 years post-implant, p <0.05.
	Method	Wilcoxon Signed Rank Test
	Comments

3. Secondary Outcome

Title	Responder Rate
Description	The proportion of subjects with greater than or equal to 50% reduction in total disabling seizures compared to pre-implant baseline.
Time Frame	6 months post-implant through 9 years post-implant (8.5 years)

Outcome Measure Data

Analysis Population Description

N represents the number of subjects who have data during that period.

Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Measure Participants	230
6-12 Months	33.2
12-18 Months	46.7
18-24 Months	47.6
24-30 Months	50.2
30-36 Months	56.4
36-42 Months	57.8
42-48 Months	61.2
48-54 Months	60.2
54-60 Months	61.1
60-66 Months	58.4
66-72 Months	67.0
72-78 Months	66.9
78-84 Months	65.7
84-90 Months	64.9
90-96 Months	70.2
96-102 Months	68.5
102-108 Months	70.9
108-114 Months	74.5
114-120 Months	66.7
120-126 Months	75.0
126-132 Months	83.3
132-138 Months	100.0

4. Secondary Outcome

Title	QOLIE (Quality of Life in Epilepsy)
Description	QOLIE 89 (for English-speaking subjects) or QOLIE 31 P (for Spanish speaking subjects) scores collected at each year of follow-up after implantation of the RNS® System compared to the QOLIE 89 / QOLIE 31 P at pre-implant baseline. A QOLIE overall score was obtained using a weighted average of multi-item scale scores. The QOLIE overall score was converted to a T-score, a normally distributed scale with a mean score of 50 and standard deviation (SD) of 10. Higher scores reflect a better quality of life.
Time Frame	1 year post-implant through 9 years post-implant (8 years)

Outcome Measure Data

Analysis Population Description

N represents the number of subjects who have data during that period.

Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Measure Participants	230
Baseline	46.1 (9.7)
Year 1	49.2 (10.5)
Year 2	49.3 (10.3)
Year 3	48.8 (10.4)
Year 4	48.1 (10.6)
Year 5	48.4 (10.9)
Year 6	48.4 (11.7)
Year 7	47.4 (11.0)
Year 8	47.9 (11.3)
Year 9	47.2 (11.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Evaluation Group (Stimulation ON)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Generalized estimating equation (GEE)
	Comments
Method of Estimation	Estimation Parameter	GEE estimated intercept
	Estimated Value	48.0
	Confidence Interval	(2-Sided) 95%; 46.8 to 49.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Evaluation Group (Stimulation ON)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6729
	Comments
	Method	Generalized estimating equation (GEE)
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Adverse Event Rate
Description	The rate of occurrence of any adverse event (AE) observed during the Long-term Treatment Investigation.
Time Frame	6 months post-implant through 9 years post-implant (8.5 years)

Outcome Measure Data

Analysis Population Description

N represents the number of subjects who have data during that period.

Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
Measure Participants	230
Count of Participants [Participants]	228 99.1%

Adverse Events

Time Frame	6 months post-implant through 9 years post-implant (8.5 years)
Arm/Group Title	Evaluation Group (Stimulation ON)
Arm/Group Description	Group of subjects that have an RNS® System implanted, completed the RNS® System Pivotal or Feasibility study, and elected to continue to receive RNS® System responsive stimulation for the long term. RNS® System: The previously implanted RNS® System is programmed to provide responsive stimulation. Upon detecting electrographic patterns, previously identified by the neurologist or neurosurgeon as abnormal, the Neurostimulator provides brief pulses of electrical stimulation through the Leads to interrupt those patterns. Patients with epilepsy treated with responsive direct-brain stimulation with the RNS System typically receive less than 6 minutes of stimulation a day.
All Cause Mortality
	Evaluation Group (Stimulation ON)
	Affected / at Risk (%)	# Events
Total	9/230 (3.9%)
Serious Adverse Events
	Evaluation Group (Stimulation ON)
	Affected / at Risk (%)	# Events
Total	177/230 (77%)
Blood and lymphatic system disorders
Acute myeloid leukaemia	1/230 (0.4%)	1
Cardiac disorders
Arrhthmia supraventricular	1/230 (0.4%)	1
Atrial fibrillation	1/230 (0.4%)	1
Atrial flutter	1/230 (0.4%)	1
Cardiac syncope	1/230 (0.4%)	1
Gastrointestinal disorders
Haemorrhoids	3/230 (1.3%)	3
Abdominal pain	2/230 (0.9%)	2
Gastroenteritis	2/230 (0.9%)	2
Intestinal obstruction	2/230 (0.9%)	2
Vomiting	1/230 (0.4%)	1
Pancreatitis	1/230 (0.4%)	1
Rectal discharge	1/230 (0.4%)	1
Rectal prolapse	1/230 (0.4%)	1
Tooth impacted	1/230 (0.4%)	1
Toothache	1/230 (0.4%)	1
Abdominal adhesions	1/230 (0.4%)	1
Clostridium difficile colitis	1/230 (0.4%)	1
Diarrhoea haemorrhagic	1/230 (0.4%)	1
Gastrointestinal haemorrhage	1/230 (0.4%)	1
General disorders
Death	9/230 (3.9%)	9
Adverse drug reaction	5/230 (2.2%)	5
Hernia	4/230 (1.7%)	4
Non-cardiac chest pain	3/230 (1.3%)	3
Implant site discharge	1/230 (0.4%)	1
Submandibular mass	1/230 (0.4%)	1
Chest pain	1/230 (0.4%)	1
Fatigue	1/230 (0.4%)	1
Feeling cold	1/230 (0.4%)	1
Hepatobiliary disorders
Cholecystitis	3/230 (1.3%)	3
Cholelithiasis	2/230 (0.9%)	2
Bile duct stone	1/230 (0.4%)	1
Immune system disorders
Drug hypersensitivity	2/230 (0.9%)	2
Infections and infestations
Implant site infection	26/230 (11.3%)	29
Urinary tract infection	4/230 (1.7%)	4
Upper respiratory tract infection	2/230 (0.9%)	3
Implant site infection (dts)	2/230 (0.9%)	2
Viral infection	1/230 (0.4%)	1
Incision site cellulitis	1/230 (0.4%)	1
Neutropenic infection	1/230 (0.4%)	1
Tonsillitis	1/230 (0.4%)	1
Tooth infection	1/230 (0.4%)	1
Abdominal sepsis	1/230 (0.4%)	1
Ear infection	1/230 (0.4%)	1
Gastroenteritis viral	1/230 (0.4%)	1
Injury, poisoning and procedural complications
Therapeutic agent toxicity	19/230 (8.3%)	22
Implant site erosion	8/230 (3.5%)	10
Device lead damage	5/230 (2.2%)	5
Device lead revision	4/230 (1.7%)	4
Lumbar vertebral fracture (dts)	3/230 (1.3%)	3
Hip fracture	3/230 (1.3%)	3
Skin laceration (dts)	3/230 (1.3%)	6
Ankle fracture	3/230 (1.3%)	3
Wound dehiscence	3/230 (1.3%)	4
Head injury (dts)	2/230 (0.9%)	2
Hip fracture (dts)	2/230 (0.9%)	2
Intracranial hypotension	2/230 (0.9%)	2
Jaw fracture (dts)	2/230 (0.9%)	2
Lower limb fracture	2/230 (0.9%)	2
Multiple injuries	2/230 (0.9%)	2
Road traffic accident	2/230 (0.9%)	2
Road traffic accident (dts)	2/230 (0.9%)	2
Subdural haematoma (dts)	2/230 (0.9%)	2
Thermal burn (dts)	2/230 (0.9%)	2
Traumatic intracranial haemorrhage (dts)	2/230 (0.9%)	2
Wrist fracture (dts)	1/230 (0.4%)	1
Premature battery depletion (GB-2570)	1/230 (0.4%)	1
Premature battery depletion (RE-CR2450N)	1/230 (0.4%)	1
Device protrusion	1/230 (0.4%)	1
Device electrical finding	1/230 (0.4%)	1
Device malfunction	1/230 (0.4%)	1
Suture related complication	1/230 (0.4%)	1
Procedural vomiting	1/230 (0.4%)	1
Jaw fracture	1/230 (0.4%)	1
Joint injury	1/230 (0.4%)	1
Limb injury	1/230 (0.4%)	1
Lower limb fracture (dts)	1/230 (0.4%)	1
Pelvic fracture (dts)	1/230 (0.4%)	1
Post lumbar puncture syndrome	1/230 (0.4%)	1
Postoperative respiratory distress	1/230 (0.4%)	1
Seroma	1/230 (0.4%)	1
Skeletal injury (dts)	1/230 (0.4%)	1
Snake bite	1/230 (0.4%)	1
Spinal fracture (dts)	1/230 (0.4%)	1
Ankle fracture (dts)	1/230 (0.4%)	1
Arthropod bite	1/230 (0.4%)	1
Clavicle fracture	1/230 (0.4%)	1
Clavicle fracture (dts)	1/230 (0.4%)	1
Contusion	1/230 (0.4%)	1
Contusion (dts)	1/230 (0.4%)	1
Face injury (dts)	1/230 (0.4%)	1
Facial bones fracture (dts)	1/230 (0.4%)	1
Fall	1/230 (0.4%)	1
Fall (dts)	1/230 (0.4%)	1
Foreign body trauma	1/230 (0.4%)	1
Fractured skull depressed	1/230 (0.4%)	1
Hand fracture (dts)	1/230 (0.4%)	1
Investigations
EEG monitoring	44/230 (19.1%)	63
Medical observation	5/230 (2.2%)	6
Angiogram cerebral	4/230 (1.7%)	5
Investigation	3/230 (1.3%)	3
Lumbar puncture	1/230 (0.4%)	1
Platelet count decreased	1/230 (0.4%)	1
Anticonvulsant drug level below therapeutic	1/230 (0.4%)	1
Metabolism and nutrition disorders
Dehydration	2/230 (0.9%)	2
Electrolyte imbalance	2/230 (0.9%)	2
Hyponatraemia	1/230 (0.4%)	1
Diabetes mellitus	1/230 (0.4%)	1
Hypoglycaemic coma	1/230 (0.4%)	1
Hypokalaemia	1/230 (0.4%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	4/230 (1.7%)	4
Back pain	2/230 (0.9%)	2
Intervertebral disc disorder	1/230 (0.4%)	1
Intervertebral disc protrusion	1/230 (0.4%)	1
Menicus lesion	1/230 (0.4%)	1
Musculoskeletal pain	1/230 (0.4%)	1
Rhabdomyolysis	1/230 (0.4%)	1
Tendon disorder	1/230 (0.4%)	1
Arthritis	1/230 (0.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	2/230 (0.9%)	2
Breast cancer	2/230 (0.9%)	2
Thyroid cancer	2/230 (0.9%)	2
Melanocytic naevus	1/230 (0.4%)	1
Metastatic melanoma	1/230 (0.4%)	1
Multiple myeloma	1/230 (0.4%)	1
Pancreatic carcinoma	1/230 (0.4%)	1
Renal cell carcinoma state unspecified	1/230 (0.4%)	1
Squamous cell carcinoma	1/230 (0.4%)	1
Adenoma benign	1/230 (0.4%)	1
Gastrinoma	1/230 (0.4%)	1
Nervous system disorders
Tonic-clonic seizures increased	12/230 (5.2%)	14
Complex partial seizures increased	10/230 (4.3%)	13
Pneumonia	9/230 (3.9%)	9
Convulsive status epilepticus	8/230 (3.5%)	10
Postictal state	6/230 (2.6%)	6
Nonconvulsive status epilepticus	5/230 (2.2%)	9
Tonic-clonic seizures exacerbated	5/230 (2.2%)	5
Complex partial seizures exacerbated	4/230 (1.7%)	4
Cerebral haemorrhage	4/230 (1.7%)	4
Migraine	3/230 (1.3%)	3
Appendicitis	2/230 (0.9%)	2
Carpal tunnel syndrome	2/230 (0.9%)	2
Headache	2/230 (0.9%)	3
Paraesthesia	2/230 (0.9%)	2
Postictal paralysis	2/230 (0.9%)	2
Status epilepticus	2/230 (0.9%)	2
Facial paresis	1/230 (0.4%)	1
Complex partial seizures	1/230 (0.4%)	1
Stitch abscess	1/230 (0.4%)	1
Simple partial seizures increased (sensory)	1/230 (0.4%)	1
Intraventricular haemorrhage (dts)	1/230 (0.4%)	1
Memory impairment	1/230 (0.4%)	1
Neuralgia	1/230 (0.4%)	1
Neuromyelitis optica	1/230 (0.4%)	1
Paraparesis	1/230 (0.4%)	1
Pilonidal cyst	1/230 (0.4%)	1
Pyelonephritis	1/230 (0.4%)	1
Radiculopathy	1/230 (0.4%)	1
Sepsis	1/230 (0.4%)	1
Simple partial seizures increased (motor)	1/230 (0.4%)	1
Syncope	1/230 (0.4%)	1
Tonic-clonic seizures	1/230 (0.4%)	1
Aphasia	1/230 (0.4%)	1
Ataxia	1/230 (0.4%)	1
Confusional state	1/230 (0.4%)	1
Diverticulitis	1/230 (0.4%)	1
Dizziness	1/230 (0.4%)	1
Drug withdrawal headache	1/230 (0.4%)	1
Dyskinesia	1/230 (0.4%)	1
Product Issues
Live birth	4/230 (1.7%)	4
Psychiatric disorders
Suicide attempt	6/230 (2.6%)	7
Depression suicidal	6/230 (2.6%)	6
Psychotic disorder	5/230 (2.2%)	5
Depression	3/230 (1.3%)	4
Acute psychosis	2/230 (0.9%)	2
Suicidal ideation	2/230 (0.9%)	2
Agitation	1/230 (0.4%)	1
Somatic delusion	1/230 (0.4%)	1
Suicidal behavior	1/230 (0.4%)	1
Abnormal behaviour	1/230 (0.4%)	1
Alcohol abuse	1/230 (0.4%)	1
Alcohol withdrawal syndrome	1/230 (0.4%)	1
Anxiety	1/230 (0.4%)	1
Conversion disorders	1/230 (0.4%)	1
Drug dependence	1/230 (0.4%)	1
Epileptic psychosis	1/230 (0.4%)	1
Renal and urinary disorders
Nephrolithiasis	5/230 (2.2%)	7
Urinary retention	1/230 (0.4%)	1
Focal segmental glomerulosclerosis	1/230 (0.4%)	1
Haematuria	1/230 (0.4%)	1
Reproductive system and breast disorders
Ovarian cyst	3/230 (1.3%)	4
Adenomyosis	2/230 (0.9%)	2
Menorrhagia	1/230 (0.4%)	1
Menstrual disorder	1/230 (0.4%)	1
Pelvic congestion	1/230 (0.4%)	1
Breast enlargement	1/230 (0.4%)	1
Breast mass	1/230 (0.4%)	1
Cervical cyst	1/230 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/230 (0.9%)	2
Hypoxia	1/230 (0.4%)	1
Nasal congestion	1/230 (0.4%)	1
Pneumonia aspiration	1/230 (0.4%)	1
Pulmonary embolism	1/230 (0.4%)	1
Tracheal obstruction	1/230 (0.4%)	1
Aspiration (dts)	1/230 (0.4%)	1
Asthma	1/230 (0.4%)	1
Atelectasis	1/230 (0.4%)	1
Bronchitis	1/230 (0.4%)	1
Skin and subcutaneous tissue disorders
Dermal cyst	2/230 (0.9%)	2
Keloid scar	1/230 (0.4%)	1
Skin erosion	1/230 (0.4%)	1
Social circumstances
Victim of crime	1/230 (0.4%)	1
Surgical and medical procedures
Brain lobectomy	11/230 (4.8%)	12
Medical device removal	9/230 (3.9%)	9
Hospitalisation	7/230 (3%)	9
Cranioplasty	3/230 (1.3%)	3
Breast cosmetic surgery	2/230 (0.9%)	2
Tracheostomy	1/230 (0.4%)	1
Vasectomy reversal	1/230 (0.4%)	1
Medical device implantation (LR)	1/230 (0.4%)	1
Medical device removal (LR)	1/230 (0.4%)	1
Tooth extraction	1/230 (0.4%)	1
Breast reconstruction	1/230 (0.4%)	1
Colostomy	1/230 (0.4%)	1
Endodontic procedure	1/230 (0.4%)	1
Vascular disorders
Subarachnoid haemorrhage (dts)	1/230 (0.4%)	1
Arteriovenous fistula	1/230 (0.4%)	1
Hypertension	1/230 (0.4%)	1
Other (Not Including Serious) Adverse Events
	Evaluation Group (Stimulation ON)
	Affected / at Risk (%)	# Events
Total	228/230 (99.1%)
Blood and lymphatic system disorders
Anaemia	6/230 (2.6%)	6
Eye disorders
Vision blurred	6/230 (2.6%)	6
Gastrointestinal disorders
Diarrhoea	18/230 (7.8%)	19
Vomiting	18/230 (7.8%)	20
Abdominal pain	13/230 (5.7%)	14
Constipation	10/230 (4.3%)	10
Toothache	8/230 (3.5%)	9
Gastrooesophageal reflux disease	7/230 (3%)	7
Haemorrhoids	6/230 (2.6%)	6
General disorders
Adverse drug reaction	71/230 (30.9%)	113
Implant site pain	69/230 (30%)	103
Procedural pain	24/230 (10.4%)	27
Death	9/230 (3.9%)	9
Non-cardiac chest pain	8/230 (3.5%)	9
Device interaction	7/230 (3%)	7
Fatigue	6/230 (2.6%)	6
Hernia	6/230 (2.6%)	6
Oedema peripheral	6/230 (2.6%)	6
Chest pain	6/230 (2.6%)	7
Immune system disorders
Drug hypersensitivity	14/230 (6.1%)	18
Seasonal allergy	14/230 (6.1%)	14
Hypersensitivity	7/230 (3%)	9
Infections and infestations
Nasopharyngitis	42/230 (18.3%)	63
Influenza	33/230 (14.3%)	40
Upper respiratory tract infection	30/230 (13%)	40
Implant site infection	29/230 (12.6%)	34
Urinary tract infection	29/230 (12.6%)	42
Pneumonia	13/230 (5.7%)	16
Ear infection	11/230 (4.8%)	14
Tooth infection	9/230 (3.9%)	9
Pharyngitis	8/230 (3.5%)	9
Injury, poisoning and procedural complications
Therapeutic agent toxicity	115/230 (50%)	226
Skin laceration (dts)	41/230 (17.8%)	81
Contusion (dts)	31/230 (13.5%)	65
Joint injury	22/230 (9.6%)	26
Joint injury (dts)	18/230 (7.8%)	24
Head injury (dts)	17/230 (7.4%)	25
Procedural headache	16/230 (7%)	16
Multiple injuries (dts)	16/230 (7%)	38
Contusion	13/230 (5.7%)	14
Skin laceration	13/230 (5.7%)	14
Head injury	13/230 (5.7%)	16
Road traffic accident	13/230 (5.7%)	16
Excoriation (dts)	10/230 (4.3%)	35
Fall (dts)	9/230 (3.9%)	14
Thermal burn (dts)	9/230 (3.9%)	10
Limb injury	9/230 (3.9%)	9
Implant site erosion	8/230 (3.5%)	10
Limb injury (dts)	8/230 (3.5%)	9
Clavicle fracture (dts)	6/230 (2.6%)	8
Fall	6/230 (2.6%)	6
Muscle strain	6/230 (2.6%)	6
Procedural nausea	6/230 (2.6%)	8
Road traffic accident (dts)	6/230 (2.6%)	6
Investigations
EEG monitoring	44/230 (19.1%)	64
Vitamin D abnormal	18/230 (7.8%)	18
Metabolism and nutrition disorders
Hypokalaemia	10/230 (4.3%)	13
Hypercholesterolaemia	9/230 (3.9%)	9
Musculoskeletal and connective tissue disorders
Back pain	17/230 (7.4%)	19
Musculoskeletal pain	14/230 (6.1%)	14
Arthralgia	12/230 (5.2%)	13
Pain in extremity	8/230 (3.5%)	8
Nervous system disorders
Headache	40/230 (17.4%)	51
Complex partial seizures increased	25/230 (10.9%)	40
Sinusitis	25/230 (10.9%)	30
Tonic-clonic seizures increased	20/230 (8.7%)	25
Tonic-clonic seizures exacerbated	17/230 (7.4%)	19
Complex partial seizures exacerbated	16/230 (7%)	20
Insomnia	16/230 (7%)	18
Simple partial seizures (motor)	15/230 (6.5%)	22
Postictal state	15/230 (6.5%)	15
Complex partial seizures	13/230 (5.7%)	22
Gastroenteritis	13/230 (5.7%)	14
Paraesthesia	12/230 (5.2%)	12
Dizziness	11/230 (4.8%)	12
Temor	11/230 (4.8%)	12
Photopsia	11/230 (4.8%)	15
Simple partial seizures (sensory)	11/230 (4.8%)	14
Memory impairment	11/230 (4.8%)	12
Dysaesthesia	10/230 (4.3%)	11
Migraine	9/230 (3.9%)	10
Convulsive status epilepticus	8/230 (3.5%)	10
Hypoaesthesia	8/230 (3.5%)	10
Simple partial seizures increased (sensory)	8/230 (3.5%)	10
Nonconvulsive status epilepticus	7/230 (3%)	11
Syncope	7/230 (3%)	7
Simple partial seizures increased (motor)	6/230 (2.6%)	9
Sleep apnea	6/230 (2.6%)	6
Psychiatric disorders
Depression	28/230 (12.2%)	30
Anxiety	13/230 (5.7%)	13
Agitation	9/230 (3.9%)	9
Depression suicidal	7/230 (3%)	7
Psychotic disorder	7/230 (3%)	7
Conversion disorders	6/230 (2.6%)	6
Suicide attempt	6/230 (2.6%)	8
Renal and urinary disorders
Nephrolithiasis	12/230 (5.2%)	17
Respiratory, thoracic and mediastinal disorders
Bronchitis	21/230 (9.1%)	25
Cough	13/230 (5.7%)	14
Skin and subcutaneous tissue disorders
Rash	22/230 (9.6%)	29
Surgical and medical procedures
Brain lobectomy	11/230 (4.8%)	12
Medical device removal	9/230 (3.9%)	9
Hospitalisation	7/230 (3%)	9
Tooth extraction	7/230 (3%)	7
Vascular disorders
Hypertension	14/230 (6.1%)	15

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Each Investigator and Institution agree that the 1st publication of study results shall be a joint, multi-center publication. Each Investigator, Coordinator, and Institution agree to submit publications to the RNS® System Study Publication Committee for review prior to submission for publication (at least 30 days for manuscripts and at least 7 days for abstracts) to assure that publication does not compromise the scientific integrity of the study or contain confidential NeuroPace information.