RNS® System Long-term Treatment (LTT) Clinical Investigation
Phase: PHASE4
Conditions: Epilepsy
Sponsor: NeuroPace



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i. 
Protocol Synopsis 
RNS® System Long-term Treatment Clinical Investigation 
June 24, 2014 
Test Device 
RNS® System 
(NeuroPace 
RNS® System 
Premarket 
Approval Application (PMA) approved by the FDA on 
November 14, 2013) 
Indication for Use 
The RNS® System is an adjunctive therapy in reducing the 
frequency of seizures in individuals 18 years of age or older 
with partial onset seizures who have undergone diagnostic 
testing that has localized no more than 2 epileptogenic foci, 
are refractory to two or more antiepileptic medications, and 
currently have frequent and disabling seizures (motor 
partial seizures, complex partial seizures and / or 
secondarily generalized seizures). The RNS® System has 
demonstrated safety and effectiveness in patients who 
average 3 or more disabling seizures per month over the 
three most recent months (with no month with fewer than 
two seizures), and has not been evaluated in patients with 
less frequent seizures. 
Cohort 
Subjects implanted with the RNS® System who have 
completed the RNS® System Feasibility or Pivotal Clinical 
Investigations.
Primary Objectives 
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 who have 
undergone diagnostic testing that localized no more than 2 
epileptogenic foci, that are refractory to two or more 
antiepileptic medications, and currently have frequently or 
disabling seizures. 
Device Sizes 
The RNS® Neurostimulator is an implantable, battery 
powered, microprocessor controlled device that is designed 
to detect electrographic patterns  from intracranial 
electrodes and to deliver a short train of current pulses to 
the 
brain 
upon 
detection 
of 
those 
patterns. 
The 
Neurostimulator connects to up to two intracranial leads. 

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Study Design 
An open-label multi-center prospective clinical investigation. 
Data regarding safety and efficacy are collected at 6-month 
intervals beginning at enrollment, and data regarding quality 
of life are collected at yearly intervals. 
Each subject participates for 7 years following completion of 
the 
RNS® System 
Feasibility 
or 
Pivotal 
Clinical 
investigations.
Number of Subjects 
to be Enrolled 
Enrollment will be offered to all subjects completing the 
RNS® System Feasibility or Pivotal Clinical Investigations. 
Assuming that all subjects completing these investigations 
elect to enroll in the Long-term Treatment Clinical 
Investigation, the anticipated enrollment is 280. 
Number of Sites 
All sites participating in the RNS® System Feasibility and 
Pivotal Clinical Investigations 
Key Inclusion 
Criteria
Subject has completed the RNS® System Feasibility or 
Pivotal Clinical Investigation. 
Subject has elected to continue to receive responsive 
neurostimulation 
therapy 
after 
completion 
of 
the 
RNS® System Feasibility or Pivotal Clinical Investigation. 
Key Exclusion 
Criteria
Subject has active psychiatric or medical illness that, in the 
opinion of the investigator, makes it inadvisable for the 
subject to continue to receive responsive neurostimulation 
therapy with the RNS® System. 

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Primary Efficacy 
Objective, Analysis, 
and Methods 
Primary objectives: 
The primary efficacy objective is to evaluate the long-term 
efficacy of the RNS® System. 
The primary efficacy outcome variable is the average 
percentage change in the mean frequency of total disabling 
seizures relative to pre-implant baseline. (Total disabling 
seizures are defined as simple partial motor, complex 
partial, and generalized tonic-clonic seizures.) The percent 
change will be calculated for each subject over 6-month 
intervals beginning 6 months after implant of the RNS® 
System 
(during 
the 
Feasibility 
or 
Pivotal 
Clinical 
Investigations open label period) and continuing through 
completion of the Long-term Treatment Investigation. 
Wilcoxon’s signed-rank test will be used to assess the 
statistical significance of the percent change in mean 
seizure frequency from baseline at each 6-month interval. 
The sustainability of results will be assessed by fitting a 
GEE model to the 6-month periods. 
Primary Safety 
Objective, Analysis 
and Methods 
The primary safety objective is to describe the long-term 
RNS® System Serious Adverse Event (SAE) rate. The 
primary safety outcome variable is the SAE rate. 
Descriptive statistics (rate, standard deviation, 95% 
confidence interval) will be used to summarize results. 
Other Safety 
Objective
To collect data on the frequency of sudden unexplained 
death in epilepsy (SUDEP) and upon completion of the 
clinical investigation estimate the SUDEP rate. 
Secondary Efficacy 
Objectives, Analysis 
and Methods 
Responder Rate
The responder rate (defined as the proportion of subjects 
with a greater than or equal to 50% reduction in mean 
frequency of total disabling seizures compared to pre-
implant baseline) will be calculated for each 6-month 
interval beginning 6 months post-implant. 
For every 6-month interval, the responder rate will be 
determined based upon the per-subject percentage change 
in seizure frequency. McNemar’s test will be used to assess 
the statistical significance of the change in response rates 
from baseline at each 6-month interval. A linear logistic 
regression model will be used to assess the sustainability of 
the effect over time. The model will be linear in time. The 
outcome of interest is the slope over time. 

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Quality of Life (QOL)
QOLIE-89 scores (QOLIE-31-P for Spanish-speaking 
subjects) collected at each year of follow-up after 
implantation of the RNS® System will be compared to the 
QOLIE-89 (or QOLIE-31-P) at pre-implant baseline. The 
effect of treatment with the RNS® System on QOL will be 
assessed by fitting a GEE model to the yearly outcome 
assessments.
Secondary Safety 
Objectives, Analysis 
and Methods 
The frequency and rate of occurrence of all adverse events 
(AEs) will be described.

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8.3.1.
Informed Consents........................................................................8-28
8.3.2.
Seizure Data...................................................................................8-28
8.3.3.
Quality of Life Data........................................................................8-30
8.3.3.1.
Quality of Life in Epilepsy in adults (QOLIE-89 / QOLIE-31-P) .8-
30
8.4.
Collection Tools for Subject Data......................................................8-30
8.4.1.
Subject Binders .............................................................................8-30
8.4.2.
Appointment Packets....................................................................8-30
8.5.
Data Maintenance ...............................................................................8-31
8.5.1.
Required Data Fields.....................................................................8-31
8.5.2.
Data Queries ..................................................................................8-32
8.5.3.
Edits................................................................................................8-32
8.5.4.
Protocol Deviations.......................................................................8-32
8.6.
Confidentiality, Use and Disclosure of Subject Data.......................8-33
8.7.
Data Processing..................................................................................8-35
9
Monitoring Procedures...............................................................................9-36
9.1.
NeuroPace Representatives ..............................................................9-36
9.2.
Site Visits.............................................................................................9-36
9.2.1.
Study Initiation/Training Visit.......................................................9-36
9.2.2.
Interim Monitoring Visit ................................................................9-36
9.2.3.
Final/Close Out Visit......................................................................9-36
9.3.
Device Accountability.........................................................................9-37
9.4.
Monitoring Procedure.........................................................................9-37
10
Adverse Events.........................................................................................10-38
10.1.
Event Definitions ..............................................................................10-38
10.1.2.
Adverse events............................................................................10-39
10.1.2.1. Event Resolution....................................................................10-40
10.2.
Event Documentation.......................................................................10-40
10.2.1.
Deaths ..........................................................................................10-40
10.2.2.
Adverse events............................................................................10-40
10.2.2.1. Exception for Documenting an Adverse Event ...................10-40
10.3.
Event Reporting ................................................................................10-41
10.3.1.
Deaths ..........................................................................................10-41
11
Risk Benefit Analysis ...............................................................................11-42
12
Study Committees ....................................................................................12-43
12.1.
Data Monitoring Committee.............................................................12-43
12.1.1.
DMC Scope ..................................................................................12-43
12.1.1.1. SUDEP.....................................................................................12-43
12.1.2.
Member Composition..................................................................12-43
12.1.3.
Meetings.......................................................................................12-44

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Table of Figures 
Figure 1-1:  Neurostimulator mounted in a ferrule connected to depth and 
cortical strip lead ...............................................................................1-1
Figure 4-1:  Timeline for subject participation in the RNS® System Clinical 
Investigations...................................................................................4-11

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Device Description 
The NeuroPace® RNS® System includes an implantable programmable RNS® 
Neurostimulator that senses and records brain electrical activity and implantable 
NeuroPace® Leads. The Neurostimulator detects previously identified electrical 
patterns in the brain and then delivers electrical stimulation to the brain to interrupt 
those 
patterns 
before 
the 
patient 
experiences 
clinical 
seizures. 
The 
non-implantable RNS® System products include the NeuroPace® Programmer, 
Remote Monitor, Wand, PDMS (Patient Data Management System) and Magnet. 
A depiction of the implanted system is provided in Figure 1-1.
Figure 1-1:  Neurostimulator mounted in a ferrule connected to depth and 
cortical strip lead 
Depth
Lead
Strip
Lead
Neurostimulator

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1.1.
Implantable Devices 
1.1.1.
Responsive Neurostimulator
The RNS® Neurostimulator is a battery powered, microprocessor-controlled 
device that is surgically implanted in the cranium and is covered by the scalp. A 
Ferrule (a titanium tray, which is secured to the skull) mechanically supports and 
secures the Neurostimulator in the skull so that there is no direct contact of the 
Ferrule or Neurostimulator with the brain. The Neurostimulator is connected to 
one or two NeuroPace® Leads that are surgically implanted within (Depth Lead) 
or on the surface (Cortical Strip Lead) of the brain in the area of the epileptic 
seizure focus. The Neurostimulator monitors electrocorticographic (ECoG) 
activity and can be programmed to detect abnormal electrical activity (as defined 
by the physician). When detection criteria are met, the Neurostimulator delivers 
responsive stimulation to one or two epileptic foci. Detection and stimulation 
parameters can be non-invasively adjusted.
1.1.2.
Leads
The NeuroPace® Leads provide an interface through which electrical activity of 
the brain can be sensed and recorded by the RNS® Neurostimulator and through 
which responsive electrical stimulation can be delivered. Depth Leads are 
stereotactically introduced into the epileptic seizure focus in the brain and 
Cortical Strip Leads are placed on the surface of the brain near the seizure focus. 
The Leads have a flexible, silicone Lead body that encloses four insulated wires, 
and have four platinum/iridium electrodes at their distal end. The proximal end 
has four contacts designed to connect to the RNS® Neurostimulator. 
1.2.
External Devices 
1.2.1.
Programmer
The NeuroPace® Programmer communicates with the Neurostimulator using a 
Wand with a short-range wireless radiofrequency link. The physician uses the 
Programmer to program the Neurostimulator and to view electrocorticograms. In 
addition, the Programmer tests the integrity of the Neurostimulator and Leads 
and uploads data from the Neurostimulator. The Programmer can also use a 
secure Internet connection to transmit these data to the Patient Data 
Management System (PDMS) for storage and later physician review. 
1.2.2.
Remote Monitor
The NeuroPace® Remote Monitor is a home-use monitoring device that 
communicates with the Neurostimulator using a Wand with a short-range 
wireless radiofrequency link. A patient or caregiver uses the Remote Monitor to 
collect data from the Neurostimulator, and then transmits these data using a 
secure Internet connection to the PDMS. The Remote Monitor cannot be used by 
the patient to reprogram the Neurostimulator. 

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Introduction and Rationale 
2.1.
Prevalence and Incidence of Epilepsy 
Epilepsy is a common chronic neurological disorder for which available therapies 
are often not effective. Approximately 2.5 million in the United States have active 
epilepsy and 181,000 new cases of epilepsy are diagnosed each year. By 20 
years of age, 1% of the population has developed epilepsy and by 75 years of 
age, the prevalence of epilepsy reaches 3% (Begley et.al. 2000). 
2.2.
Standard Treatments 
AEDs offer hope for seizure control with minimal or no medication related 
adverse effects in about 70% of persons with epilepsy. However, approximately 
30% of persons with partial onset seizures are refractory to pharmacotherapy, or 
have clinically significant AED related adverse effects (Kwan and Brodie, 2000). 
Some of the patients are candidates for epilepsy surgery. Others are not good 
candidates for epilepsy surgery because risk is unacceptably high and potential 
benefits are unacceptably low. These patients may choose the vagus nerve 
stimulator as a palliative therapy. Subjects participating in the RNS® System 
Feasibility or Pivotal Clinical Investigations have elected this option because 
existing options are not desirable. Patients concluding participation in the 
Feasibility or Pivotal Clinical Investigations should have the option to continue 
treatment with the RNS® System therapy within the context of an open-label 
long-term treatment investigation. 
2.3.
Rationale for Developing the RNS® System 
Since many patients with partial onset seizures do not achieve the therapeutic 
goal of no seizures and no side effects with available therapies, a new treatment 
is needed. The RNS® System has been designed to provide patients with 
medically intractable epilepsy with an option for improved seizure control as well 
as excellent tolerability and safety. 
2.3.1.
Device Attributes
The RNS® System has been developed to meet the needs of patients with 
medically intractable partial onset seizures who are not candidates for epilepsy 
resective surgery or do not choose to pursue this type of surgical therapy. The 
RNS® System is intended to reduce the frequency of disabling seizures in this 
patient population and to have a safety profile that compares favorably to 
standard treatments. The RNS® System has advantages over AEDs in that it 
does not require daily patient compliance and operates independently of 
concomitant medications. Compared to the VNS, the RNS® System 
Neurostimulator is cranially implanted and therefore will not be visible. Also the 
RNS® System should not have effects on swallowing or vocal quality. Unlike 

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Cases of SUDEP have occurred during clinical trials of epilepsy therapy. The 
rate of SUDEP in a well-defined cohort of 4,700 patients (5,747 patient-years of 
exposure) included in the worldwide clinical development database of the 
antiepileptic drug lamotrigine (Leetsma et.al., 1997) was 3.5 per 1,000 patient-
years. This rate was comparable to the rate that would be expected in young 
adults with severe epilepsy. 
SUDEP rates were also examined for 791 patients followed for 1,335 person-
years from implantation of the Cyberonics Vagus Nerve Stimulator (VNS). Six 
of the 15 deaths that occurred during VNS stimulation were considered definite 
or probable SUDEP and two as possible SUDEP. The incidence of 
definite/probable SUDEP was 4.5 per 1,000 person-years and 6.0 per 1,000 
person-years for definite/probable/possible SUDEP. A subsequent 2-year 
extension of the study followed 1819 patients for 3,176.3 person-years from 
implantation and found that the SUDEP rate dropped to 1.7/1000 after the first 
2 years of use. The SUDEP rates during the first two years of VNS use were 
thus similar to those reported from clinical trials of new drugs and cohorts of 
severe epilepsy. The drop in SUDEP rates after 2 years has not been 
confirmed in other epilepsy therapy trials. 
Patients participating in the NeuroPace RNS® System Clinical Investigations 
have medically refractory partial epilepsy and would fall into the category of 
persons with the highest risk for SUDEP. The risk would thus be comparable to 
the rates described in the Dasheiff study, as well as the rates for 
definite/probable/possible SUDEP in the initial experience in the VNS trials. 
Therefore, the upper limit for the expected SUDEP rate during the NeuroPace 
RNS® System clinical investigations is considered to be 9.3 per 1000 patient 
stimulation years.
3.2.
Secondary Objectives 
3.2.1.
Secondary Efficacy Objectives and Outcome Variables
The following efficacy outcome variables will be monitored for each 6-month 
interval beginning 6 months after implantation of the RNS® System. These 
variables will be used to perform secondary analyses to evaluate the long-term 
efficacy of the RNS® System: 
Responder Rate

Proportion of subjects with greater than or equal to 50% reduction in total 
disabling seizures compared to pre-implant baseline 
Quality of Life

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. 

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3.2.2.
Secondary Safety Objectives and Outcome Variables
The following safety outcome variable will be monitored as a secondary safety 
analysis: 

The rate of occurrence of any adverse event (AE) observed during the 
Long-term Treatment Investigation.

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Study Design 
4.1.
Overview
4.1.1.
General Characteristics
The RNS® System Long-term Treatment Investigation will enroll adult subjects 
with medically refractory partial epilepsy who have completed either the 
RNS® System Feasibility or Pivotal Clinical Investigation and elect to continue 
therapy with the RNS® System. A maximum of 280 subjects may be enrolled. 
4.1.2.
Design Features
The RNS® System Long-term Treatment Investigation is an open-label multi-
center prospective clinical investigation conducted at sites that have 
participated in the RNS® System Feasibility or Pivotal Clinical Investigations. 
4.1.3.
Duration of Subject Participation
Each subject participates for 7 years following completion of the RNS® System 
Feasibility or Pivotal Clinical Investigations.  
A time line of overall subject participation in the RNS® System Clinical 
Investigations is provided in Figure 4-1.
Figure 4-1:  Timeline for subject participation in the RNS® System Clinical 
Investigations
4.2.
Management of the RNS® System 
Programming changes in detection and stimulation parameters may be made 
during the investigation to provide optimal detection and response to therapy. 
Subjects participating in the investigation may elect to keep their Remote 
Monitors. The Remote Monitors will be used as directed by that subject’s 
physician, however it is suggested that the subject interrogate the 
Neurostimulator and upload the data to the PDMS at least once a week. 

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4.3.
Concomitant Antiepileptic Medications 
(AEDs)
AED adjustments (dose/type) may be made in order to provide optimal medical 
care.

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5
Study Population 
5.1.
Eligibility Criteria 
All subjects completing the RNS® System Feasibility or Pivotal Clinical 
Investigations are potential candidates for the RNS® System Long-term 
Treatment Investigation. Subjects who do not meet all inclusion/exclusion criteria 
will not be enrolled. 
Enrollment into the investigation begins when the clinician determines that the 
subject has met the inclusion and exclusion criteria and the subject (or legal 
guardian) has signed the informed consent. Enrollment is confirmed once the 
relevant electronic case report forms (Inclusion and Exclusion Criteria and 
Consent Information) have been entered into the Patient Data Management 
System.
5.2.
Inclusion/Exclusion Criteria 
A subject must meet the inclusion/exclusion criteria in order to be enrolled and 
participate in the RNS® System Long-term Treatment Clinical Investigation. 
5.2.1.
Inclusion Criteria

Subject has completed either the RNS® System Feasibility or Pivotal 
Clinical Investigation 

Subject has an implanted RNS® System 

Subject has elected to continue to receive responsive neurostimulation 
therapy after completion of the RNS® System Feasibility or Pivotal Clinical 
Investigations

Subject is able to attend scheduled appointments for the RNS® System 
Long-term Treatment Clinical Investigation 
5.2.2.
Exclusion Criteria

Subject has active psychiatric or medical illness that, in the opinion of the 
investigator, makes it inadvisable for the subject to continue to receive 
responsive neurostimulation therapy with the RNS® System 

Subject has been diagnosed with psychogenic or non-epileptic seizures, or 
primarily generalized seizures during the RNS® System Feasibility or 
Pivotal Clinical Investigations 

Subject has been noncompliant with scheduled appointments during the 
RNS® System Feasibility or Pivotal Clinical Investigations 

Subject has been noncompliant with maintaining seizure diaries during the 
RNS® System Feasibility or Pivotal Clinical Investigation 

Informed consent cannot be obtained from subject or caregiver 

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6.3.
Protocol Appointments & Activities 
6.3.1.
Enrollment and Registration

Screen subject and discuss investigation 

Review Inclusion / Exclusion Criteria 

Determine subject’s dominant language for participation in the clinical 
investigation*

Provide the subject with the language appropriate consent for review 

Obtain signed Consent 

Register subject with NeuroPace 

Confirm subject enrollment in investigation by completing selected eCRFs 
(Consent, Inclusion / Exclusion Criteria) 

If Spanish is determined to be the subject’s dominant language, enter the 
Spanish Participation Confirmation eCRF 
*Note: Through the remainder of the trial, ensure that the subject is provided 
with the language appropriate materials and that language appropriate 
testing and data collection is performed. 
6.3.2.
Initial Office Appointment

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6.3.8.
Explant and Revision Procedures

If implant revisions (explanted devices, adjustments to implanted devices, 
device replacement) are required during this clinical investigation, complete 
the following activities: 

Complete product registration information included in the device 
packaging.

Mail the product registration form using the provided envelope. A 
copy should be filed in the subject binder. 

Return explanted devices to NeuroPace. 

Complete and file required source documents regarding the 
explant/revision procedure (Clinical Notes, Medical Records) 
6.3.9.
Conclusion/Withdrawal

Conclusion of participation occurs at the end of the Clinical Investigation. 

Withdrawal is premature conclusion, which may occur at any time (reasons 
for and timing requirements around withdrawal are identified in Section
5.3).

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7.1.2.
Safety
The Serious Adverse Event (SAE) rate will be calculated for the Long-term 
Treatment Investigation. The SAE rate is defined as the proportion of subjects 
having a serious adverse event. 

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8.2.
Required Data 
The investigation requires that a unique data set be collected for each subject.  
The data collected are categorized by type and source as described in Table
8-2:  Data for Clinical Investigation below. 

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8.3.3.
Quality of Life Data
8.3.3.1. 
Quality of Life in Epilepsy in adults (QOLIE-89 / 
QOLIE-31-P) 
The Quality of Life survey (QOLIE-89 for English-speaking subjects / QOLIE-
31-P for Spanish-speaking subjects) survey measures overall quality of life, 
emotional well-being, role limitations due to emotional problems, social 
support, social isolation, energy/fatigue, worry about seizure, medication 
effects, 
health 
discouragement, 
work/driving/social 
function, 
attention/concentration, language, memory, physical function, pain, role 
limitations due to physical problems, and health perceptions. A reference 
copy of the QOLIE-89 and QOLIE-31-P surveys are provided in Appendix 
16.4 (Devinsky et al 1995, Wiebe et al. 2001 and Cramer et al. 2003). 
8.4.
Collection Tools for Subject Data 
8.4.1.
Subject Binders
Subject binders are provided by NeuroPace to maintain the originals (or copies) 
of all source documents and all materials. This includes all source documents 
and Appointment Packets. 
8.4.2.
Appointment Packets
NeuroPace provides official copies of the Clinical Notes as part of the 
Appointment Packets to use to record subject data during office appointments.  

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8.5.
Data Maintenance 
8.5.1.
Required Data Fields
All fields indicated with an asterisk (*), either on an eCRF or a clinical note, are 
required and should not be left blank.  
x eCRFs: 
o If a required field is not applicable (n/a) or not available 
(missing), indicate such by choosing the appropriate choice 
from the drop-down list on the eCRF (e.g. “n/a”, “missing”, etc).  
o A comment should be entered at the bottom of the eCRF 
explaining the reason for the missing data. 
x Clinical Notes: 
o If a required field is not applicable (n/a) or the data point is not 
available (missing), indicate such data as “n/a” or “missing”, 
respectively.

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9.3.
Device Accountability 
Device accountability records must be maintained at each clinical site for 
investigational product only. The number of investigational devices delivered to 
and returned by the Investigator and the used investigational devices should be 
documented. At a minimum, the investigational device information listed below 
must be recorded.  Any accountability discrepancy at the end of the investigation 
will be explained in writing by the Investigator. 
 Investigational Device Model # 
 Investigational Device Serial # 
 Date of Investigational Device Receipt 
 Date of Investigational Device Use 
 How Investigational Device Used 
 Patient ID (If provided to or implanted in a subject) 
 Investigational Device Disposition if Explanted 
9.4.
Monitoring Procedure 
A standard monitoring procedure for Clinical Investigations is followed by 
NeuroPace monitors 
.

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10 Adverse Events 
10.1. Event Definitions 
For the purposes of the clinical investigation the definitions listed below will be 
used for adverse event reporting. 

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Transient phenomena that are mild, such as sensations, motor responses, or 
suspected brief afterdischarges (AD’s) on an ECOG are expected.  Generally 
these phenomena are resolved by a change in the settings for stimulation 
testing and do not need to be documented as an Adverse Event. 
Documentation is required if the transient phenomena is: 

Serious and resolved by a change in the stimulation testing settings; 

Mild or serious and not resolved by a change in the settings for stimulation 
testing.
10.3. Event Reporting 
Adverse events may required to be reported to the reviewing Institutional Review 
Board (IRB).  The minimum reporting responsibilities are as follows: 
Event Type 
Severity 
Device-Relation 
Expectedness1
Reporting Obligation 
to IRB 
Adverse
event
Mild (non-
serious) 
No 
Not applicable 
Per reviewing IRB 
processes 
Adverse
device effect 
Mild (non-
serious) 
Yes 
Anticipated 
Per reviewing IRB 
processes 
Adverse
device effect 
Mild (non-
serious) 
Yes 
Unanticipated 
Per reviewing IRB 
processes 
Adverse
event
Serious 
No  
Not applicable 
Per reviewing IRB 
processes 
Adverse
device effect 
Serious 
Yes 
Anticipated 
Per reviewing IRB 
processes 
Adverse
device effect 
Serious 
Yes 
Unanticipated 
Immediately2
1
It is necessary to define whether the device related event is: 
Anticipated (expected) that the device contributed to or caused the adverse event; or 
Unanticipated (not expected) that the device would contribute to the adverse event 
2
Serious Unanticipated Adverse Device Effects are reported to the reviewing IRB and 
NeuroPace as soon as possible but no later than ten (10) working days after first learning 
of the event. 
10.3.1. Deaths
All subject deaths occurring during the investigation should be reported to 
NeuroPace within 24 hours of first learning of the event. 

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11 Risk Benefit Analysis 
Refer to the RNS® System Clinical Summary, located at www.neuropace.com, for 
discussion of the risk benefit analysis for the FDA approved RNS® System. 

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13 Ethical Considerations 
13.1. Declaration of Helsinki 
The Clinical Investigation will be performed in accordance with the relevant parts 
of the International Conference on Harmonisation (ICH) Guidelines for Good 
Clinical Practice (GCP), the Declaration of Helsinki (Refer to Appendix 16.12),
and applicable FDA regulations. 
13.2. Institutional Review Board 
The Institutional Review Board (IRB) at each investigational site must 
administrate the Clinical Investigation in compliance with the applicable FDA 
regulations 21 CFR Part 50 for the informed consent, 21 CFR Part 56 for the 
Institutional Review Board. 
It is the Investigators’ responsibility to obtain and maintain written approval of the 
investigational protocol, the Informed Consent form, other written subject 
information, and any proposed advertising material from the appropriate IRB. The 
Investigator must submit and, where necessary, obtain approval from the IRB for 
all subsequent protocol amendments and changes to the Informed Consent form. 
A copy of the written approval, the approved versions of the documents must be 
forwarded to the NeuroPace clinical department upon receipt from the local IRB.  
The approval should include study identification and the date of approval. A list of 
the IRB members, including titles and occupations, or the IRB assurance number 
must also be provided to the NeuroPace clinical department. NeuroPace will 
provide a standard form to capture this information. 
At a minimum the Investigator should notify the IRB of deviations from the 
protocol, serious unanticipated adverse events, and data reports provided by the 
NeuroPace. The Investigator’s IRB may impose additional requirements with 
which the Investigator must comply. All correspondence with the IRB should be 
maintained in the regulatory and subject files as appropriate and copies of such 
correspondence should be forwarded to NeuroPace. 
13.3. Emergency Actions 
NeuroPace accepts the right of the Investigator to initiate emergent medical 
intervention that may not be defined in the study protocol when necessary to 
safeguard the life or physical well-being of a study subject. The Investigator must 
give notice of any emergency deviations and justification for the deviation to the 
study personnel responsible at NeuroPace and the IRB as quickly as possible 
after the episode, and in any event no later than 24 hours after the emergency. 

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13.4. Informed Consent Materials 
Consent must be provided in a manner consistent with the Institutional Review 
Board (IRB) requirements for the site performing the Clinical Investigation and in 
compliance with Food and Drug Administration (FDA) regulations, 21 CFR 
Part 50, prior to a subject’s participation in the Clinical Investigation. 
The clinical protocol procedures, the risks and potential benefits, and the rights of 
the subject must be discussed with each potential subject and/or legal guardian 
(if applicable). 
It is required by FDA regulations and Good Clinical Practices to document the 
informed consent process (either initial or subsequent consents) for all subjects 
participating in an FDA approved clinical investigation. The record of the 
informed consent process for the initial consent should document that the 
informed consent was obtained prior to participation in the study and should be 
filed in the subject’s binder. 
The consent is an important legal document that explains the research study and 
expectations for a subject participating in a research study. The potential subject, 
or legal guardian having power of attorney over health decisions must provide a 
written consent to participate in the Clinical Investigation. 
Note: The principal investigator or co-investigators are responsible for obtaining 
the initial informed consent. 
Note: Information collected on an individual subject is considered confidential 
and will be managed in accordance with the NeuroPace Privacy Policy 
.
13.5. Amending the Investigational Plan 
This investigational plan and clinical protocol are to be followed exactly. An 
official amendment from NeuroPace must be received by the clinical site and 
approved by the local IRB in order to alter any investigational information or 
activity. Administrative changes that do not affect the subject benefit/risk ratio 
may be made by NeuroPace without further approvals from the local IRB; sites 
will be notified in the event of these circumstances. 

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14 Study Administration 
14.1. Required Documents and Record Retention 
The principal investigator is responsible for implementing the Clinical 
Investigation in accordance with the investigational plan, agreements, any 
conditions of approval imposed by the Institutional Review Board (IRB) and 
applicable FDA regulations, 21 CFR Part 50 and 21 CFR Part 56. 

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14.3. Initiating the Clinical Investigation 
The following activities and materials are required to be completed prior to 
enrolling a subject in the Clinical Investigation. Note that the investigation will not 
be initiated before NeuroPace has received written approval from the FDA and a 
copy of the IRB approval letter and IRB approved Consent Form for the 
participating clinical site (as described below). An investigation Administrative 
Binder is provided to each site to organize and maintain required documents in 
order to meet regulatory compliance. 
Note: Initiation of clinical sites for participation in the LTT study is complete. 
While this section is no longer relevant to the current stage of the study, it is 
being maintained for documentation purposes. 
14.3.1. IRB Approval

Submit prepared Protocol and Consent Form to NeuroPace for review 

Submit agreed upon Protocol application and Consent Form to the IRB and 
NeuroPace 

Receive full approval for the Protocol and Consent Form from your IRB 

Submit a copy to NeuroPace and file a copy in Administrative Binder: 

IRB approval letter 

This document is prepared by the IRB and provides 
authorization to conduct the protocol and approves the 
Consent Form 

Final IRB approved version of the protocol 

Final version of the IRB approved Informed Consent Form 

The Informed Consent Form should have an IRB approval 
stamp and/or other means of designating the version or 
approval date of the specific Consent Form approved by the 
IRB.

All IRB correspondence must be filed in the Administrative Binder 

If available, a copy of the IRB Regulations and Guidelines should be filed in 
the Administrative Binder. 

The original investigational plan sent on CD must be filed in the 
Administrative Binder 
14.3.2. Signed Agreements

Clinical Investigation Agreement (and Financial Terms) 

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
Financial Disclosure Form 

Electronic Signature Agreement 

Site Signature and Delegation Log 

Protocol Signature Page (Appendix  0)
14.3.3. Good Clinical Practices (GCP)/Human Subjects 
Protection (HSP)

All site personnel participating must provide proof of GCP or HSP training 
14.3.4. Curriculum Vitaes (CV)

Each individual involved in the Clinical Investigation must provide a CV 

The CV should provide a statement of experience for that individual 

Submit each participant’s CV to NeuroPace and file a copy in the 
Administrative Binder 
14.3.5. Training Documentation

Participating site personnel are required to be trained on applicable topics 
before participating in the Clinical Investigation 

NeuroPace personnel will contact the site prior to enrollment of the first 
subject to conduct required training 

Signed training documentation must be filed in the Administrative Binder 
and a copy provided to NeuroPace 

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14.4. Conducting and Maintaining the Investigation 
The following activities and materials are required to maintain proper compliance 
during the course of the Clinical Investigation. All materials (including all 
correspondence with the IRB, NeuroPace, the monitor, another investigator, or 
the FDA) must be filed appropriately in the Administrative Binder. 
14.4.1. Demonstrate Proper Conduct of the Investigation

At a minimum, the investigator must continue to perform the following 
responsibilities in order to continue the investigation 

Comply with protocol and applicable FDA regulations 

Complete required documents and training for newly added 
investigators 

Obtain signed Informed Consent Forms before conducting any study-
specific tests or procedures 

Complete all electronic CRFs and other source documents, data 
queries and monitoring reports promptly 

Oversee the use and handling of the investigational device 

Maintain the Monitoring Visit Log 

Maintain 
investigational 
device 
accountability 
and 
tracking 
documentation as referenced in Section 9.3

Abide by the Publication Policy (see below) 

Obtain updated CVs for site personnel every 2 years and file in 
Administrative Binder 

Obtain annual IRB approval for the continuation of the Clinical 
Investigation

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14.4.2. Obtain IRB Approval for Protocol/Consent Form 
Amendments

Submit prepared Protocol and/or Consent Form Amendments to NeuroPace 
for review 

Submit agreed upon Protocol and/or Consent Form Amendments to the IRB 
and NeuroPace 

Receive full approval for the amended Protocol and/or Consent Form to the 
IRB

Submit to NeuroPace and file in Administrative Binder: 

IRB approval letter for the Amendment 

Final version of newly approved protocol 

Final version of newly approved Informed Consent Form 

The amended informed consent should have an IRB approval 
stamp and/or other means of designating version or approval 
date of the specific Consent Form approved by the IRB. 

Investigation amendments (sent on CD) must be filed in the Administrative 
Binder
14.4.3. Provide Necessary Information to the Sponsor and/or 
IRB

The principal investigator is responsible for providing written documentation 
to the IRB and Sponsor for the items below and for maintaining all such 
correspondence in the Administrative Binder: 

Adverse events* 

Withdrawal of IRB approval 

Protocol deviations* 

Annual progress reports and final report
* Refer to Section 10.3 for event reporting obligations and Section 8.5.4 for 
protocol deviation and violation reporting obligations 
14.5. Concluding the Clinical Investigation 
The principal investigator must provide any missing regulatory documents, all 
required documents for each subject enrolled and resolve  any outstanding 
queries before the Clinical Investigation may be concluded at the institution. 
14.6. Criteria for Terminating the Clinical 
Investigation
NeuroPace reserves the right to terminate the Clinical Investigation but intends 
only to exercise this right for valid scientific or administrative reasons or reasons 

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related to the protection of subjects. Investigators and associated IRBs will be 
notified in writing in the event of termination. 
Possible reasons for termination of the Clinical Investigation include: 

The discovery of an unexpected, significant, or unacceptable risk to the 
subjects enrolled in the clinical investigation. 

A decision on the part of NeuroPace to suspend or discontinue development 
of the device. 
14.7. Criteria for Terminating a Clinical 
Investigation Center 
NeuroPace reserves the right to terminate the participation of a Clinical 
Investigation center at any time for the following reasons: 

If the site is unable to obtain IRB and contract approval within four months of 
receiving investigational trial materials 

If the center has severe protocol deviations without sufficient justification 

If the Investigator fails to comply with the responsibilities of this investigational 
plan and applicable FDA regulations 
14.8. Record Retention 
The principal investigator is responsible for maintaining all required records and 
reports for a period of two years after the latter of the following two dates:  the 
date on which the investigation is terminated or complete, or the date that the 
records and reports are no longer required for purposes of supporting the 
premarket approval application submitted by the sponsor to the FDA or other 
regulatory agency. 
14.9. Publication Policy 
Because this Clinical Investigation is part of a multi-center study, the Institution 
and the Investigators agree that the first publication of the results of the Clinical 
Investigation shall be made in conjunction with the presentation of a joint, multi-
center publication of the Clinical Investigation results, with the investigators from 
all appropriate sites contributing data, analyses, and comments.  If such a multi-
center publication is not submitted within twelve (12) months after the conclusion 
of the Clinical Investigation at all sites, the Institution and/or Investigators may 
publish the results from the Institution’s site individually, subject to the 
procedures described below. 
The Principal Investigator or the Institution shall submit to NeuroPace a copy of 
any proposed publication at least thirty (30) days for manuscripts and seven (7) 
days for abstracts prior to submission for publication.  NeuroPace shall review 

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the proposed publication and may provide comments.  Any comments by 
NeuroPace shall be considered in good faith.  NeuroPace may request deletion 
of portions of the publication containing confidential information or information 
reasonably 
considered 
trade 
secret-type 
information 
regarding 
specific 
commercial applications, constructions, processes, or formulations, and the 
submitter agrees to remove such information, or may require that the 
presentation or publication be withheld for up to ninety days to allow patent 
applications to be prepared and filed. 

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15 Bibliography
“Activa Tremor Control System, Summary of Safety and Effectiveness P960009.” Medtronic, Inc., 
Minneapolis, MN. Available at: http://www.fda.gov/cdrh/pdf/p960009.pdf. Accessed 05-09-2005. 
Activa Tremor Control System, Summary of Safety and Effectiveness P970004.” Medtronic, Inc., 
Minneapolis, MN. Available at: http://www.fda.gov/cdrh/pdf/p970004.pdf. Accessed 10-11-2005. 
Annegers JF, Coan SP, Hauser WA, Leestma J.  Epilepsy, vagal nerve stimulation by the NCP 
system, all-cause mortality, and sudden, unexpected, unexplained death. Epilepsia. 2000 
May;41(5):549-53 
Annegers JF, Coan SP. SUDEP: Overview of definitions and review of incidence data. Seizure 
1999;8(6):347-352 
Annegers JF, Coan SP, Hauser WA, Leestma J, Duffell W, Tarver B. Epilepsy, vagal nerve 
stimulation by the NCP system, mortality, and sudden, unexpected, unexplained death. Epilepsia. 
1998 Feb;39(2):206-12 
Begley CE, Famulari M, Annegers JF, Lairson DR, Reynolds TF, Coan S, Dubinsky S, Newmark M, 
Leibson C, So EL, Rocca WA. “The cost of epilepsy in the United States: an estimate from 
population-based clinical and survey data.” Epilepsia. 2000; 41(3): 342-351. 
 “Code of Federal Regulations 21 CFR Part 11.” Available at: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=11&showFR=
1. Accessed 05-09-2005 
“Code of Federal Regulations 21 CFR Part 50.” Available at: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=50&showFR=
1. Accessed 05-09-2005. 
“Code of Federal Regulations 21 CFR Part 54.” Available at: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=54&showFR=
1. Accessed 05-09-2005. 
“Code of Federal Regulations 21 CFR Part 56.” Available at: 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=56&showFR=
1. Accessed 05-09-2005. 
Cramer JA, Van Hammee G, N132 Study Group. Maintenance of improvement in health-related 
quality of life during long-term treatment with levetiracetam. Epilepsy Behav 2003; 4(2):118-23. 
Dasheiff RM. Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and 
speculation on the relationship to sudden cardiac death. J Clin Neurophysiol. 1991 Apr;8(2):216-22. 
Devinsky O, Vickrey BG, Cramer J et al. “Development of the quality of life in epilepsy inventory.” 
Epilepsia. 1995; 36: 1089-1104. 

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“Guidance for Clinical Trial Sponsors on the Establishment and Operation of Clinical Trial Data 
Monitoring Committees.” Available at: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf. Accessed 05-01-
2006.
““Oversight of Clinical Investigations-A Risk-Based Approach to Monitoring.” Available at 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm2699
19.pdf. Accessed 06-10-2014 
“International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP) 
1996.” Available at: http://www.fda.gov/cder/guidance/959fnl.pdf. Accessed 05-09-2005. 
Kwan P, Brodie MJ. “Early identification of refractory epilepsy.” N. Engl. J. Med. 2000; 342: 314-
319.
Lhatoo SD, Johnson AL, Goodridge DM, MacDonald BK, Sander JW, Shorvon SD. Mortality in 
epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, 
population-based cohort. Ann Neurol. 2001 Mar; 49(3):336-44. 
Nilsson L, Ahlbom A, Farahmand B, Tomson T. Mortality in a population-based cohort of epilepsy 
surgery Patients. Epilepsia 2003 44 (4), 575-581. 
Sperling MR. Sudden unexplained death in epilepsy. Epilepsy Curr. 2001 September; 1(1): 21-23.  
“The World Medical Association Declaration of Helsinki.” Available at: 
http://www.fda.gov/oc/health/helsinki89.html. Accessed 05-09-2005. 
Wiebe S, Eliasziw M, Matijevic S. “Changes in quality of life in epilepsy: how large must they be to 
be real?” Epilepsia. 2001; 42: 113-118. 

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16 Appendices

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16.4. Quality of Life Survey  
The following surveys are found in this section: 
x QOLIE-89 (for English-speaking subjects) 
x QOLIE-31-P (for Spanish-speaking subjects) 

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RNS® System Long-term Treatment Investigational Plan 
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16.12.
WMA Declaration of Helsinki

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WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and 
amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 
1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
Note of Clarification on Paragraph 29 added by the WMA General Assembly, 
Washington 2002 
Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 
2004
A. INTRODUCTION  
1. 
The World Medical Association has developed the Declaration of Helsinki 
as a statement of ethical principles to provide guidance to physicians and 
other participants in medical research involving human subjects. Medical 
research involving human subjects includes research on identifiable 
human material or identifiable data. 
2. 
It is the duty of the physician to promote and safeguard the health of the 
people. The physician's knowledge and conscience are dedicated to the 
fulfillment of this duty. 
3. 
The Declaration of Geneva of the World Medical Association binds the 
physician with the words, "The health of my patient will be my first 
consideration," and the International Code of Medical Ethics declares that, 
"A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental 
condition of the patient."
4. 
Medical progress is based on research which ultimately must rest in part 
on experimentation involving human subjects. 
5. 
In medical research on human subjects, considerations related to the well-
being of the human subject should take precedence over the interests of 
science and society. 
6. 
The primary purpose of medical research involving human subjects is to 
improve prophylactic, diagnostic and therapeutic procedures and the 
understanding of the aetiology and pathogenesis of disease. Even the 
best proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, 
efficiency, accessibility and quality.  
7. 
In current medical practice and in medical research, most prophylactic, 
diagnostic and therapeutic procedures involve risks and burdens.

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8. 
Medical research is subject to ethical standards that promote respect for 
all human beings and protect their health and rights. Some research 
populations are vulnerable and need special protection. The particular 
needs of the economically and medically disadvantaged must be 
recognized. Special attention is also required for those who cannot give or 
refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the 
research and for those for whom the research is combined with care.  
9. 
Research Investigators should be aware of the ethical, legal and 
regulatory requirements for research on human subjects in their own 
countries as well as applicable international requirements. No national 
ethical, legal or regulatory requirement should be allowed to reduce or 
eliminate any of the protections for human subjects set forth in this 
Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
10. 
It is the duty of the physician in medical research to protect the life, health, 
privacy, and dignity of the human subject.
11. 
Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and on adequate 
laboratory and, where appropriate, animal experimentation. 
12. 
Appropriate caution must be exercised in the conduct of research which 
may affect the environment, and the welfare of animals used for research 
must be respected. 
13. 
The design and performance of each experimental procedure involving 
human subjects should be clearly formulated in an experimental protocol. 
This protocol should be submitted for consideration, comment, guidance, 
and where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the investigator, the sponsor or 
any other kind of undue influence. This independent committee should be 
in conformity with the laws and regulations of the country in which the 
research experiment is performed. The committee has the right to monitor 
ongoing trials. The researcher has the obligation to provide monitoring 
information to the committee, especially any serious adverse events. The 
researcher should also submit to the committee, for review, information 
regarding funding, sponsors, institutional affiliations, other potential 
conflicts of interest and incentives for subjects.
14. 
The research protocol should always contain a statement of the ethical 
considerations involved and should indicate that there is compliance with 
the principles enunciated in this Declaration.  
15. 
Medical research involving human subjects should be conducted only by 
scientifically qualified persons and under the supervision of a clinically 
competent medical person. The responsibility for the human subject must 
always rest with a medically qualified person and never rest on the subject 
of the research, even though the subject has given consent.  

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16. 
Every medical research project involving human subjects should be 
preceded by careful assessment of predictable risks and burdens in 
comparison with foreseeable benefits to the subject or to others. This does 
not preclude the participation of healthy volunteers in medical research. 
The design of all studies should be publicly available. 
17. 
Physicians should abstain from engaging in research projects involving 
human subjects unless they are confident that the risks involved have 
been adequately assessed and can be satisfactorily managed. Physicians 
should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial 
results.
18. 
Medical research involving human subjects should only be conducted if 
the importance of the objective outweighs the inherent risks and burdens 
to the subject. This is especially important when the human subjects are 
healthy volunteers.
19. 
Medical research is only justified if there is a reasonable likelihood that the 
populations in which the research is carried out stand to benefit from the 
results of the research.
20. 
The subjects must be volunteers and informed participants in the research 
project.
21. 
The right of research subjects to safeguard their integrity must always be 
respected. Every precaution should be taken to respect the privacy of the 
subject, the confidentiality of the patient's information and to minimize the 
impact of the study on the subject's physical and mental integrity and on 
the personality of the subject. 
22. 
In any research on human beings, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it 
may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time 
without reprisal. After ensuring that the subject has understood the 
information, the physician should then obtain the subject's freely-given 
informed consent, preferably in writing. If the consent cannot be obtained 
in writing, the non-written consent must be formally documented and 
witnessed.
23. 
When obtaining informed consent for the research project the physician 
should be particularly cautious if the subject is in a dependent relationship 
with the physician or may consent under duress. In that case the informed 
consent should be obtained by a well-informed physician who is not 
engaged in the investigation and who is completely independent of this 
relationship.  
24. 
For a research subject who is legally incompetent, physically or mentally 
incapable of giving consent or is a legally incompetent minor, the 
investigator must obtain informed consent from the legally authorized 

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representative in accordance with applicable law. These groups should 
not be included in research unless the research is necessary to promote 
the health of the population represented and this research cannot instead 
be performed on legally competent persons.
25. 
When a subject deemed legally incompetent, such as a minor child, is 
able to give assent to decisions about participation in research, the 
investigator must obtain that assent in addition to the consent of the 
legally authorized representative.
26. 
Research on individuals from whom it is not possible to obtain consent, 
including proxy or advance consent, should be done only if the 
physical/mental condition that prevents obtaining informed consent is a 
necessary characteristic of the research population. The specific reasons 
for involving research subjects with a condition that renders them unable 
to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should 
state that consent to remain in the research should be obtained as soon 
as possible from the individual or a legally authorized surrogate. 
27. 
Both authors and publishers have ethical obligations. In publication of the 
results of research, the investigators are obliged to preserve the accuracy 
of the results. Negative as well as positive results should be published or 
otherwise publicly available. Sources of funding, institutional affiliations 
and any possible conflicts of interest should be declared in the publication. 
Reports of experimentation not in accordance with the principles laid down 
in this Declaration should not be accepted for publication.
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
28. 
The physician may combine medical research with medical care, only to 
the extent that the research is justified by its potential prophylactic, 
diagnostic or therapeutic value. When medical research is combined with 
medical care, additional standards apply to protect the patients who are 
research subjects. 
29. 
The benefits, risks, burdens and effectiveness of a new method should be 
tested against those of the best current prophylactic, diagnostic, and 
therapeutic methods. This does not exclude the use of placebo, or no 
treatment, in studies where no proven prophylactic, diagnostic or 
therapeutic method exists.  
30. 
At the conclusion of the study, every patient entered into the study should 
be assured of access to the best proven prophylactic, diagnostic and 
therapeutic methods identified by the study.  
31. 
The physician should fully inform the patient which aspects of the care are 
related to the research. The refusal of a patient to participate in a study 
must never interfere with the patient-physician relationship. 
32. 
In the treatment of a patient, where proven prophylactic, diagnostic and 
therapeutic methods do not exist or have been ineffective, the physician, 
with informed consent from the patient, must be free to use unproven or 

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new prophylactic, diagnostic and therapeutic measures, if in the 
physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. Where possible, these measures should be made the 
object of research, designed to evaluate their safety and efficacy. In all 
cases, new information should be recorded and, where appropriate, 
published. The other relevant guidelines of this Declaration should be 
followed.
Note: Note of clarification on paragraph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that extreme care must be taken in making 
use of a placebo-controlled trial and that in general this methodology should only be 
used in the absence of existing proven therapy. However, a placebo-controlled trial 
may be ethically acceptable, even if proven therapy is available, under the following 
circumstances:
– Where for compelling and scientifically sound methodological reasons its use is 
necessary to determine the efficacy or safety of a prophylactic, diagnostic or 
therapeutic method; or  
– Where a prophylactic, diagnostic or therapeutic method is being investigated for a 
minor condition and the patients who receive placebo will not be subject to any 
additional risk of serious or irreversible harm.
All other provisions of the Declaration of Helsinki must be adhered to, especially the 
need for appropriate ethical and scientific review. 
Note: Note of clarification on paragraph 30 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that it is necessary during the study planning 
process to identify post-trial access by study participants to prophylactic, diagnostic 
and therapeutic procedures identified as beneficial in the study or access to other 
appropriate care. Post-trial access arrangements or other care must be described in 
the study protocol so the ethical review committee may consider such arrangements 
during its review. 
The Declaration of Helsinki (Document 17.C) is an official policy document of the 
World Medical Association, the global representative body for physicians. It was first 
adopted in 1964 (Helsinki, Finland) and revised in 1975 (Tokyo, Japan), 1983 
(Venice, Italy), 1989 (Hong Kong), 1996 (Somerset-West, South Africa) and 2000 
(Edinburgh, Scotland). Note of clarification on Paragraph 29 added by the WMA 
General Assembly, Washington 2002. 
9.10.2004

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16.14.
Table – Abbreviations 

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Abbreviation
Full Word or Phrase 
AD
After discharge 
AE
Adverse Event
AED
Antiepileptic Drug (or antiseizure medication) 
ANOVA
Analysis of variance
CFR
Code of Federal Regulations 
CRF
Case Report Form 
CT
Computerized Tomography
DMC
Data Monitoring Committee 
ECoGs
Electrocorticograms
eCRF
Electronic Case Report Form 
EOS
End of Service 
FDA
Food and Drug Administration 
GTC
Generalized tonic clonic (seizure) 
HIPAA
Health Insurance Portability and Accountability Act 
IRB
Institutional Review Board 
PMA
Pre-market Approval Application 
PDMS
Patient Data Management System 
QOLIE
Quality of Life in Epilepsy 
SAE
Serious Adverse Event 
SUDEP
Sudden Unexplained Death in Epilepsy 
VNS
Vagus Nerve Stimulator 

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16.15.
Table – Definitions 

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Term or Phrase 
Definition
Adverse Event 
A negative change in the subject‘s physical or mental health as 
experienced by the subject or observed by the clinician during any 
part of the Clinical Investigation. 
AED Toxicity 
Side effects caused by intolerance to an antiepileptic drug. In 
most instances these side effects are referable to the central 
nervous system and may include difficulty with memory or 
concentration, negative change in mood, visual blurring or 
diplopia, or problems with fine motor movements, balance or 
coordination. AED toxicity generally arises when serum 
concentrations are inappropriately high, although some individuals 
may be susceptible even at low serum concentrations.  
Anticipated Adverse Event A device-related adverse event noted in the Investigation Plan as 
potentially caused or contributed to by the study device. 
Asthenia
Weakness, lack of energy or strength 
Ataxia
The inability to coordinate muscle movements 
Clustering
Refers to a series of seizures in a short period of time, such as 
hours or a day. If seizures arise frequently in succession, the 
patient may have difficulty differentiating each individual seizure 
for purposes of seizure counting.  
Complex Partial Seizures 
A clinically evident seizure that arises in a focus or region of the 
brain. The seizure, by definition, is associated with loss of 
awareness but does not include generalized tonic, clonic, 
myoclonic or tonic-clonic movements. The patient may display 
‘automatic’ behaviors (automatisms) such as lip smacking, 
chewing, vocalization, picking or aimless wandering. The patient 
will not recall any events occurring during the seizure. 
Device Related Adverse 
Event
The event is definitively or potentially related to a NeuroPace 
investigational device. 
Diathermy
Diathermy is the use of electrical currents to heat tissue for 
medical or surgical purposes 
Diplopia
A visual disorder characterized by double vision. 
Disabling Seizures 
Motor simple partial seizures or complex partial seizures with or 
without secondarily generalized seizures. 
Dysarthria
A speech disorder due to weakness or incoordination of speech 
muscles.  Speech is slow, weak or imprecise. 
Dysesthesia
Altered sensations such as a feeling of burning, electric shock or 
pins and needles. 
Dyskinesia
Difficulty or distortion in performing voluntary movements 
Dysphasia
Characterized by a complete or partial loss of the ability to 
understand, speak, read or write. 
Edema
Soft tissue swelling 

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Electroconvulsive therapy  Electroconvulsive therapy is a treatment for mental disorders that 
works by producing unconsciousness and convulsions through 
the use of an electric current 
Emotional Lability 
Severe mood swings, characterized by uncontrollable laughing or 
crying.
Epidural Hematoma 
Mass of clotted blood in the space between the skull and the 
brain.
Epilepsy
Epilepsy is a common neurological disorder that produces 
seizures.
Extra-Temporal Lobe 
Epilepsy
Epilepsy beginning in a focal or regional area of the brain that 
does not include the temporal lobe. Such epilepsies are 
categorized as localization-related epilepsies of the frontal, 
parietal or occipital lobes. 
Gait Difficulties 
Disturbance in walking that could arise as a consequence of 
motor, sensory or coordination deficits 
Generalized Tonic-Clonic 
Seizure
A seizure involving the entire body, usually characterized by 
muscle rigidity, rhythmic muscle contractions and loss of 
consciousness. 
Hematoma 
An abnormal collection of blood in which the blood is usually 
clotted or partially clotted. 
Hemorrhagic Stroke 
A disturbance in the function of the brain caused by bleeding from 
cranial vessels. The stroke may cause transient or permanent 
neurological symptoms. 
Intracranial Hemorrhage 
Bleeding from cranial vessels into the skull. Bleeding may be 
intraparenchymal (within the brain substance, subdural (beneath 
the dura mater) or extradural (above the dura mater). 
Intractable Epilepsy 
Difficult to treat epilepsy in which the subject continues to have 
seizures despite treatment. 
Ischemic Stroke 
Injury to the brain caused by a reduction in blood flow in 
intracranial or extracranial blood vessels supplying the brain. 
Neurological symptoms may be transient or permanent and are 
referable to the area of brain deprived of blood flow. 
Lithotripsy
Lithotripsy is a treatment used to treat kidney and gall stones. 
This procedure involves the use of shock waves to crush stones 
in the urinary system into small enough pieces to wash out. 
Mild (non-serious) Adverse 
Event
Minor in nature or behavior; acute and self-limited or transient; no 
need for invasive medical or procedural intervention to alleviate 
the adverse event or any adverse event that is not serious 
Non-Epileptic Seizure 
A period of seizure-like activity that is characterized by a loss of or 
change in physical function without a problem in the central 
nervous system but usually related to a mental health problem. 
Not Device Related 
Adverse Event 
The event is not related to a NeuroPace device. 

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Term or Phrase 
Definition
Paresthesia 
Numbness and tingling sensations that can occur anywhere in a 
person’s body, but are often felt in the hands, feet, arms or legs. 
Primary Generalized 
Seizure
A seizure that begins with a widespread electrical discharge that 
involves both sides of the brain at the same time. 
Secondarily Generalized 
Seizures
Partial seizures that evolve into generalized seizures most often 
with tonic-clonic convulsions. 
Seizure
Seizures are a disturbance in the normal electrical activity of the 
brain.
Seizure Onset Zone 
The area of the brain (cerebral cortex) that contains the abnormal, 
epileptogenic tissue that causes seizures 
Serious Adverse Event 
Significant risks or consequences to the subject's acute or long-
term health; serious injury or death; hospital admission or invasive 
medical intervention required to alleviate the adverse event. 
Sham
A surgical intervention designed to prevent a subject from 
determining the treatment group to which he/she has been 
assigned during a blinded trial. Both blinded groups receive the 
same surgical intervention; however the device in one blinded 
group is inactive (sham) and the device in the other blinded group 
is active.
Simple Partial Motor 
Seizure
A seizure beginning in a focal or regional area of the brain that 
causes transient neurological motor symptoms. By definition, the 
patient retains full awareness during this type of seizure.  
Simple Partial Sensory 
Seizure
A seizure beginning in a focal or regional area of the brain that 
causes transient neurological sensory symptoms. By definition, 
the patient retains full awareness during this type of seizure. 
Status Epilepticus 
Continuous seizure lasting longer than 30 minutes or a cluster of 
seizures in which subject does not regain baseline awareness. 
Sub-dural Hematoma 
A collection of blood between the dura and the surface of the 
brain.
Sub-galeal
A space between the scalp and the skull. 
Temporal Lobe Epilepsy 
A recurrent, unprovoked seizure disorder arising because of 
epileptogenic tissue within the temporal lobe of the brain. 
Thrombophlebitis
Inflammation of a vein that occurs when a blood clot forms. 
Tonic-Clonic Seizures 
Seizures that involve bilateral involuntary movements of the arms 
and legs that begin with stiffening (extension, tonic) and are 
followed by a series of bending movements (flexion, clonic). 
Consciousness is lost during generalized tonic clonic seizures 
although some patients with frontal lobe onset tonic-clonic 
seizures will retain awareness. 
Tremor
Involuntary movements, usually fine in amplitude and often 
principally involving the arms and hands. Tremor is typically 
persistent, although it may wax and wane.  
Unanticipated Adverse 
Event
A device-related adverse event not noted in the Investigation Plan 
as potentially caused or contributed to by the study device.