Stereotactic Laser Ablation for Temporal Lobe Epilepsy
Phase: NA
Conditions: Temporal Lobe Epilepsy
Sponsor: MedtronicNeuro

Stereotactic Laser Ablation for 
Temporal Lobe Epilepsy 
(SLATE) 
 
NCT02844465 
Study Protocol 
09 APRIL 2018 

 
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Stereotactic Laser Ablation 
for Temporal Lobe Epilepsy 
(SLATE) 
 
 
Clinical Investigational Plan 
Version 4.0 
09 APRIL 2018 
CIP Number: CS-05000 
IDE Number: G150255 
 
Study Sponsor: 
Medtronic Navigation, Inc.  
 
 
 
 
 

 
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Clinical Investigational Plan Signature Page  
 
The SLATE study is a prospective, single-arm, multicenter study. The study is being 
conducted to evaluate the safety and efficacy of the Visualase® MRI-Guided Laser 
Ablation System. 
 
I/we acknowledge that I/we have read, understood and agree to abide by all conditions, 
instructions and restrictions contained in the above mentioned Clinical Investigational 
Plan. I/we agree to carry out all of its items in accordance with applicable regulations, 
and in full compliance with the guidelines. 
 
 
 
Investigational Site Name 
 
 
 
First and Last Name  
Signature  
Date (dd/MMM/yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
List of Tables ................................................................................................................... 6 
List of Figures .................................................................................................................. 6 
List of Appendices ........................................................................................................... 6 
I. 
Sponsor Contact Information ............................................................................... 7 
II. 
National Principal Investigators ............................................................................ 8 
1 
Synopsis .............................................................................................................. 9 
2 
Introduction ........................................................................................................ 15 
2.1 
Study Purpose ...............................................................................................15 
2.2 
Study Description ...........................................................................................15 
3 
Background and Justification ............................................................................. 16 
3.1 
Background ....................................................................................................16 
3.2 
Clinical Rationale for the Study Design ..........................................................17 
3.3 
Justification for Human Use ...........................................................................18 
4 
System Description and Intended Use ............................................................... 18 
5 
Regulatory Compliance ...................................................................................... 22 
6 
Methods ............................................................................................................. 23 
6.1 
Study Objective ..............................................................................................23 
6.2 
Study Endpoints .............................................................................................23 
 
Primary Safety Endpoint 
23 
 
Primary Efficacy Endpoint 
23 
 
Secondary Endpoints 
23 
 
 
24 
6.3 
Subject Selection Criteria ...............................................................................25 
 
Inclusion Criteria 
25 
 
Exclusion Criteria 
26 
6.4 
Minimization of Bias .......................................................................................26 
7 
Study Procedures .............................................................................................. 27 
7.1 
Investigator / Investigational Site Selection ....................................................27 
7.2 
Site Training ...................................................................................................28 
7.3 
Site Activation ................................................................................................28 
7.4 
Equipment Requirements ...............................................................................28 
 
Visualase System 
29 
 
Visualase Procedure MRI 
29 
 
Research MRI 
29 
 
Neuro-ophthalmologic Exam 
29 
7.5 
Assessments ..................................................................................................29 
 
Seizure Classification and Diary 
29 
 
Mood Assessments 
29 
 
Quality of Life Assessments 
30 
 
Seizure Severity Assessment 
30 
 
Pain Assessment 
30 

 
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Neuropsychological Assessments 
30 
7.6 
Magnetic Resonance Imaging ........................................................................31 
7.7 
Neuro-ophthalmologic Exam ..........................................................................32 
7.8 
Data Collection ...............................................................................................32 
7.9 
Patient Informed Consent Process .................................................................34 
7.10 
Enrollment ......................................................................................................35 
7.11 
Screening .......................................................................................................35 
7.12 
Pre-Surgical Evaluation ..................................................................................36 
7.13 
Baseline Visit .................................................................................................37 
7.14 
Study Intervention: Visualase Procedure ........................................................38 
7.15 
Scheduled Follow-up Visits ............................................................................40 
 
Follow-up Visit 1: 14 ± 7 Days Post Visualase Procedure 
41 
 
Follow-up Visit 2: 3 Months (90 ± 14 Days) Post Visualase Procedure 
41 
 
Follow-up Visit 3: 6 Months (180 ± 30 Days) Post Visualase Procedure 
41 
 
Follow-up Visit 4: 12 Months (365 + 45 Days) Post Visualase Procedure 42 
 
Telephone Follow-up 
43 
7.16 
Unscheduled Follow-up Visits ........................................................................43 
7.17 
Retreatment ...................................................................................................43 
7.18 
Healthcare Services Utilization .......................................................................44 
7.19 
Study Exit .......................................................................................................44 
7.20 
Medications ....................................................................................................45 
7.21 
Role of the Sponsor Representatives .............................................................45 
8 
Investigational Device / Equipment Storage, Handling and Traceability ............. 45 
9 
Study Deviations ................................................................................................ 46 
10 
Adverse Events and Device Deficiencies ........................................................... 47 
10.1 
Adverse Event and Device Deficiency Definitions ..........................................47 
10.2 
Adverse Event and Device Deficiency Assessment ........................................51 
 
Study Reportable Adverse Events 
51 
 
Device Deficiencies 
52 
 
Adverse Event Updates and Resolution 
52 
10.3 
Adverse Event Classification and Device Deficiency Review and Reporting ..52 
10.4 
Adverse Event and Device Deficiency Reporting Requirements.....................53 
10.5 
Subject Death ................................................................................................54 
10.6 
Product Complaint Reporting .........................................................................54 
11 
Risk Analysis ..................................................................................................... 54 
11.1 
Risk Minimization ...........................................................................................55 
11.2 
Potential Benefits ...........................................................................................56 
11.3 
Risk-to-Benefit Analysis .................................................................................56 
12 
Monitoring .......................................................................................................... 56 
12.1 
Monitoring Visits .............................................................................................56 
13 
Planned Study Closure, Early Termination or Study Suspension ....................... 57 
13.1 
Planned Study Closure ..................................................................................57 

 
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13.2 
Early Termination or Suspension ...................................................................57 
 
Study-wide Termination or Suspension 
57 
 
Investigator/Site Termination or Suspension 
57 
13.3 
Procedures for Termination or Suspension ....................................................58 
 
Medtronic-initiated and Regulatory Authority-initiated 
58 
 
Investigator-initiated 
58 
 
IRB-initiated 
58 
14 
Statistical Methods and Data Analysis ............................................................... 58 
14.1 
Sample Size Determination ............................................................................58 
14.2 
General Considerations .................................................................................59 
14.3 
Analysis Populations ......................................................................................59 
 
Safety Population 
59 
 
Modified Intent to Treat (mITT) Population 
59 
 
 
60 
 
 
60 
14.4 
Primary Safety Endpoint.................................................................................60 
 
Hypothesis 
60 
 
Performance Requirements 
60 
 
Analysis Methods 
60 
14.5 
Primary Efficacy Endpoint ..............................................................................60 
 
Hypothesis 
60 
 
Performance Requirements 
61 
 
Analysis Methods 
61 
14.6 
Secondary Endpoints .....................................................................................61 
 
Secondary Endpoint #1 
61 
 
Secondary Endpoint #2 
61 
 
Secondary Endpoint #3 
62 
 
Secondary Endpoint #4 
62 
 
Secondary Endpoint #5 
63 
 
Secondary Endpoint #6 
63 
 
Secondary Endpoint #7 
63 
 
Secondary Endpoint #8 
64 
14.7 
.........................................................................................64 
14.8 
Interim Analysis ..............................................................................................65 
14.9 
Missing Data ..................................................................................................65 
14.10 
 .....................................................................................65 
15 
Data and Quality Management........................................................................... 66 
15.1 
Documentation Confidentiality and Accessibility .............................................66 
15.2 
Data Collection ...............................................................................................66 
15.3 
Study Documentation .....................................................................................66 
15.4 
Data Flow .......................................................................................................67 
15.5 
Data Transmission and Entry .........................................................................67 
15.6 
Data Edits ......................................................................................................67 
15.7 
Electronic Medical Records ............................................................................67 
16 
Required Records and Reports .......................................................................... 67 
16.1 
Investigator Records ......................................................................................67 

 
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16.2 
Investigator Reports .......................................................................................68 
16.3 
Sponsor Records ...........................................................................................69 
16.4 
Sponsor Reports ............................................................................................70 
 
 
LIST OF TABLES 
Table 1: National Principal Investigators’ Contact Information ................................ 8 
Table 2. Schedule of Events .......................................................................................14 
Table 3: System Component Information ..................................................................22 
Table 4: Data Collected at Subject Visits ...................................................................33 
Table 5: Follow-up Visit Windows ..............................................................................40 
Table 6: Adverse Event Definitions ............................................................................48 
Table 7: Adverse Event Classification Responsibilities ...........................................53 
Table 8: Investigator Reports per FDA Regulations .................................................69 
Table 9: Sponsor Reports ...........................................................................................70 
Table 10: Change History ............................................................................................85 
 
LIST OF FIGURES 
Figure 1: Study Design................................................................................................11 
Figure 2: Visualase Thermal Therapy System ...........................................................19 
Figure 3: Visualase Cooled-Laser Applicator System (VCLAS) ...............................19 
Figure 4: Temperature limits are set to protect critical structures ..........................20 
Figure 5: Visualase System software images and near real-time temperature 
information...................................................................................................................20 
Figure 6: Visualase System set up when in use with MRI ........................................21 
Figure 7: Qualifying Primary Safety Endpoint AE Flow Chart ..................................82 
 
LIST OF APPENDICES 
Appendix A: Bibliography ...........................................................................................72 
Appendix B: Clinical Research Organizations, Central Reviewers and Core Labs 76 
Appendix C: Engel Classification of Postoperative Outcome ..................................77 
Appendix D: Data Monitoring Committee (DMC) .......................................................78 
Appendix E: Foreseeable Adverse Event List ...........................................................79 
Appendix F: Qualifying Primary Safety Endpoint Adverse Events ..........................81 
Appendix G: Preliminary Publication Plan ................................................................83 
Appendix H: Other Documents ...................................................................................84 
Appendix I: Modifications to the Clinical Investigational Plan .................................85 
 
 
 
 

 
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I. 
SPONSOR CONTACT INFORMATION 
Medtronic contact information is provided below. This information is subject to change 
during the course of the clinical study. Periodic updates to study contact information will 
be sent to the sites as needed and to the FDA with annual reports; however, personnel 
changes do not necessitate a protocol amendment. 
 
Study Sponsor Contact Information: 
, Manager, Clinical Affairs 
 
 
 
 
 
  
 
Monitoring Contact Information: 
, Clinical Project Manager 
 
 
 
  
 Clinical Research Specialist 
 
 
 
 
 
  

 
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II. 
NATIONAL PRINCIPAL INVESTIGATORS 
Table 1: National Principal Investigators’ Contact Information 
Committee Member  
Contact information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1 SYNOPSIS 
Title 
Stereotactic Laser Ablation for Temporal Lobe Epilepsy (SLATE) 
Protocol Number: CS-05000 
IDE Number: G150255 
Purpose 
The purpose of this study is to evaluate the safety and efficacy of the Visualase® MRI-
Guided Laser Ablation System (Visualase System).  
Design 
Prospective, single-arm, multicenter study 
Medical Device 
The Visualase System comprises four components: a laser energy source, a cooled 
laser applicator, a circulating pump for circulating coolant through the applicator, and a 
computer workstation with magnetic resonance imaging (MRI) analysis software for 
determination and visualization of relative changes in tissue temperature during surgical 
ablation. 
All devices used in this study are FDA cleared and commercially released. Devices 
become investigational only when accessed or opened with the intent to be used within 
the context of the study.  
Objective and Endpoints 
Objective: To evaluate the safety and efficacy of the Visualase System for necrotization 
or coagulation of epileptogenic foci in patients with intractable mesial temporal lobe 
epilepsy (MTLE)  
 
Primary Safety Endpoint 
Incidence of qualifying device-, procedure-, or anesthesia-related adverse events (AEs) 
(defined in Appendix F) through 12 months following the Visualase procedure 
 
Primary Efficacy Endpoint 
Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following the 
Visualase procedure  
 
Secondary Endpoints 
1. Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following 
the Visualase procedure compared to historical control for continued medical 
therapy  
2. Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following 
the Visualase procedure, including subjects who are retreated with Visualase 
3. Within-subject change of Boston Naming Test score (English language version), 
from baseline to 12 months following the Visualase procedure 
4. Within-subject change of Rey Auditory Verbal Learning Test 5-Trial Total score 
(English language version), from baseline to 12 months following the Visualase 
procedure 

 
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5. Within-subject change of Quality of Life in Epilepsy Inventory (QOLIE-31) score 
(English language version), from baseline to 12 months following the Visualase 
procedure 
6. Within-subject change of SF-36 quality of life questionnaire Mental Component 
Score (English language version), from baseline to 12 months following the 
Visualase procedure 
7. Within-subject change of SF-36 quality of life questionnaire Physical Component 
Score (English language version), from baseline to 12 months following the 
Visualase procedure 
8. Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following 
the Visualase procedure compared to historical control for open surgical 
resection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Population 
The study subject population is adult patients with medically intractable (per the 
definition by the International League Against Epilepsy1) mesial temporal lobe epilepsy 

 
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(MTLE), with radiological and electrophysiological evidence consistent with unilateral 
focal seizure onsets. 
 
A minimum of 150 subjects will undergo the Visualase procedure and be evaluated at up 
to 25 sites in the United States. To account for attrition, up to 215 subjects may be 
enrolled.  
 
The duration of subject participation from enrollment through study exit is expected to be 
approximately 13 months.  
Treatment 
Following informed consent, subjects’ qualification for the Visualase procedure will be 
confirmed by a central review committee. Baseline assessments will also be performed 
at any time prior to the Visualase procedure.  
 
Subjects will then undergo MRI-guided laser ablation of the amygdala and hippocampus 
with the Visualase System. Subjects will be followed for 12 months following the 
Visualase procedure and assessed for adverse events, seizures, neuropsychological 
outcomes, mood, and quality of life outcomes. Figure 1 below illustrates the study 
design. Refer to Table 2 for required study visits and required assessments/procedures 
during each visit.  
 
 
Figure 1: Study Design 
Inclusion Criteria 
1. Adult subjects ≥ 18 years of age and ≤ 70 years of age at the time of enrollment   
2. History of medically refractory (or intractable) MTLE, defined per the International 
League Against Epilepsy (ILAE)1 as: failure of adequate trials of two tolerated and 
appropriately chosen and used antiepileptic drug (AED) schedules (whether as 
monotherapies or in combination) to achieve sustained seizure freedom, as 
determined by the Investigator 
3. If the subject has a vagus nerve stimulator (VNS), the subject must have failed to 
achieve sustained seizure freedom with the VNS implanted for at least 6 months 
prior to enrollment 
4. On stable antiepileptic drugs (AEDs) (and/or stable VNS setting, if applicable) for 30 
days prior to the procedure and compliant with medication use, as reported by the 
subject  
30 day 
Seizure 
exclusion 
period 
0            1             2             3             4             5             6                               12 
Visualase Procedure 
Follow Up Period 
Months Relative to Visualase Procedure 
// 

 
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5. An average of at least 1 complex partial or secondarily generalized seizure 
compatible with MTLE per month, for a minimum of the last 12 months prior to 
enrollment (i.e., at least 12 qualifying seizures in the 12 months prior to enrollment)   
6. Subject’s seizure symptoms and/or auras are compatible with MTLE  
7. Based on video EEG obtained within 24 months of enrollment, evidence of seizures 
from one temporal lobe consistent with MTLE. If the video EEG was obtained more 
than 12 months prior to enrollment, an interictal EEG done within 12 months of 
enrollment must show interictal spikes in the same distribution as seen in the 
previous video EEG monitoring. 
8. Based on MRI obtained within 24 months prior to enrollment, evidence consistent 
with mesial temporal lobe sclerosis (defined as: mesial temporal atrophy 
accompanied by either increased signal on T2-weighted image, indicative of gliosis, 
or accompanied by loss of internal architecture in the hippocampus). If there is 
evidence of a change in clinical seizure symptoms/severity or of a brain injury since 
the MRI, a repeat MRI must be obtained to confirm eligibility.  
9. Subject is willing and able to remain on stable AEDs (and stable VNS setting, if 
applicable), as directed by their treating physician, for 12 months following the 
Visualase procedure 
10. Subject is able to complete study assessments in English or Spanish language 
11. According to Investigator judgment, subject is willing and able to comply with 
protocol requirements (e.g., follow-up visit schedule, evaluations, compliance with 
AED regimen) 
Exclusion Criteria 
1. Subject is unwilling or unable to sign the study informed consent form (ICF) 
2. Subject is pregnant prior to the Visualase procedure or intends to become pregnant 
during the course of the study  
3. Subject is currently implanted with a device contraindicating MRI, including deep 
brain stimulation or responsive neurostimulator  
4. Subject has progressive brain lesions and/or tumors not associated with epileptic 
disease state 
5. Subject has a history of previous intracranial surgery for treatment of epileptic 
seizures, including intracranial resections, stereotactic radiosurgery, or deep brain 
stimulation 
6. Subject has persistent (based on medical judgment) extra-temporal or predominant 
contralateral focal interictal spikes or slowing, or generalized interictal spikes on 
EEG 
7. Subject has seizures with contralateral or extra-temporal ictal onset on EEG 
8. Subject’s aura and/or ictal behavior suggest an extra-temporal focus 

 
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9. Subject has evidence on MRI of epileptogenic extra-temporal lesions, dual 
pathology within the temporal lobe, or contralateral hippocampal increased T2 
signal changes and/or loss of internal architecture 
10. If additional testing (e.g., PET, SPECT, invasive EEG or MEG) has been performed, 
results are discordant with the seizure focus scheduled for ablation 
11. As reported by the subject or in the opinion of the Investigator, the subject is not 
compliant with AED medication requirements 
12. Subject has an IQ < 70, based on the Wechsler Abbreviated Scale of Intelligence 
(WASI or WASI-II) or Wechsler Adult Intelligence Scale Full Scale IQ or General 
Ability Index (WAIS-III or WAIS-IV FSIQ or GAI) performed within 12 months prior to 
enrollment, or after enrollment but prior to the procedure 
13. Subject has been diagnosed with dementia or other progressive neurological 
disease 
14. Subject has an unstable major psychiatric illness, psychogenic non-epileptic 
seizures, or medical illness that would contraindicate the Visualase procedure or 
affect the neuropsychological assessments 
15. Subject is currently participating in other research that may potentially interfere with 
SLATE endpoint(s), as determined by the Investigator or Sponsor 
16. Subject is allergic to gadolinium 
Clinical Procedures 
Subjects will be considered enrolled upon signing and dating the ICF and will be exited 
from the study upon completion of Follow-up Visit 4 twelve months following the 
Visualase procedure, or upon withdrawal. Required study visits and procedures are 
outlined in the Schedule of Events (Table 2) below. 
 
 

 
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Table 2. Schedule of Events 
Assessment/Procedure 
Enrollment / 
Screening 
Baseline 
Visualase Procedure 
Follow-up Visit 1   
14 days (±7days) 
Follow-up Visit 2 
 3 mos (90±14 days) 
Follow-up Visit 3 
6 mos (180±30 days) 
Follow-up Visit 4 
12 mos  
(365+45 days) 
Unscheduled Visit 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical/surgical history (including MRI 
& video EEG) 
X1 
 
 
 
 
 
 
 
Epilepsy/seizure history 
X 
 
 
 
 
 
 
 
AED & psychotropic medications 
recorded2 
X 
X 
X 
X 
X 
X 
X 
X3 
Pregnancy test 
X 
 
X4 
 
 
 
 
 
IQ test5 
X6 
 
 
 
 
 
 
 
Neurological exam, including 
oculomotor nerves & confrontation 
visual field test for AE reporting 
 
X 
 
X 
X 
X 
X 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Healthcare services utilization 
assessment 
 
 
X 
X 
X 
X 
X 
X 
Boston Naming Test 
 
X6 
 
 
 
X 
X 
 
COWA (FAS) 
 
X6 
 
 
 
X 
X 
 
Emory Semantic Fluency Tasks 
 
X6 
 
 
 
X 
X 
 
Emory Famous Faces 
Naming/Recognition 
 
X6 
 
 
 
X 
X 
 
Rey Auditory Verbal Learning Test  
 
X6,7 
 
 
 
X8 
X7 
 
WMS-IV Visual Reproduction Test 
 
X6 
 
 
 
X 
X 
 
WMS-IV Verbal Paired Associates 
 
X6 
 
 
 
 
X 
 
Beck Depression Inventory-II9 
 
X 
 
 
 
X 
X 
 
Beck Anxiety Inventory9 
 
X 
 
 
 
X 
X 
 
QOLIE-319 
 
X 
 
 
 
X 
X 
 
SF-369 
 
X 
 
 
 
X 
X 
 
Seizure Severity Questionnaire Version 
39 
 
X 
 
 
 
X10 
X10 
 
Seizure diary review11 
X 
X3 
X3 
X 
X 
X 
X 
X3 
Seizure classification13  
X 
X3 
X3 
X 
X 
X 
X 
X3 
Research MRI 
 
X 
 
 
 
X 
 
 
Visualase procedure (including pre & 
post ablation MRI scans) 
 
 
X 
 
 
 
 
 
Pain NRS 
 
 
X12 
 
 
 
 
 
Assessment of driving and 
employment/school status 
 
X 
 
 
 
 
X 
 
Neuro-ophthalmologic exam of acuity, 
fields and extraocular movements14 
 
X6 
 
 
X 
X15 
X15 
X16 

 
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AED=Antiepileptic drugs; COWA (FAS)=Controlled Oral Word Association Test; EEG= 
electroencephalogram; QOLIE-31=Quality of Life in Epilepsy Inventory; WAIS=Wechsler Adult Intelligence 
Scale; WASI=Wechsler Abbreviated Scale of Intelligence; WMS-IV=Wechsler Memory Scale 
 
1Includes past AEDs, MRI, and video EEG (and Wada test, functional MRI, MEG, PET and/or SPECT scan if 
available) 
2AEDs and their dosages should remain stable from 30 days prior to the procedure through the 12 month post 
procedure visit. 
3Assessments should be done if possible. 
4To be performed within 7 days prior to the Visualase procedure for all females of childbearing potential 
5WAIS-III or WAIS-IV (FSIQ or GAI), or WASI or WASI-II are acceptable for screening. If scores are not 
available in the medical record, one of these assessments will be administered post-consent. 
6Results of assessments performed within 12 months prior to enrollment may be used. 
7Administer Form A.  
8Administer Form GE-AB. 
9Self-reported by subjects.  
10The Seizure Severity Questionnaire is completed only by subjects who have had seizures within the 4 
weeks preceding the 6- and/or 12-month visits.  
11.The seizure diary will be provided to the subject after consent, prior to submission to the Pre-Surgical 
Evaluation Committee. Subsequent reviews shall occur at indicated timepoints. Reviews at the Baseline 
Visit, Visualase Procedure and Unscheduled Visits are encouraged, though not required. 
12The pain scale is to be completed following the Visualase procedure but prior to discharge. 
13Seizure classification will initially be conducted after consent, prior to submission to the Pre-Surgical 
Evaluation Committee, and then amended throughout the subject’s participation in the study if new seizure 
types occur. 
14Subjects who were enrolled and received treatment under a CIP version prior to 4.0 should be 
reconsented to have a neuro-ophthalmologic exam at their next scheduled study visit.  
15Any subject consenting to CIP 4.0 who has an abnormal neuro-ophthalmologic finding at any follow-up visit 
is required to have neuro-ophthalmologic exams at subsequent study follow-up visits until the finding is 
resolved or until Follow-up Visit 4, whichever occurs first.  
16If a subject consented to CIP 4.0 has symptoms of a potential vision-related adverse event prior to the 3-
month follow-up visit, a neuro-ophthalmologic exam will be performed for evaluation.  
2 INTRODUCTION 
2.1 Study Purpose 
The purpose of this study is to evaluate the safety and efficacy of the Visualase System 
for necrotization or coagulation of epileptogenic foci in patients with intractable mesial 
temporal lobe epilepsy (MTLE). To assess safety, the primary endpoint will measure the 
incidence of qualifying device-, procedure-, or anesthesia-related adverse events (AEs) 
(defined in Appendix F) through 12 months following the Visualase procedure. To 
assess efficacy, the primary endpoint will evaluate seizure freedom (defined as Engel 
Class I, Appendix C) at 12 months following the Visualase procedure.  
The cleared indication for use of the prescription-only Visualase System is “to necrotize 
or coagulate soft tissue through interstitial irradiation or thermal therapy under magnetic 
resonance imaging (MRI) guidance” for a number of surgery types, including 
neurosurgery. Based on the results of this study, the Sponsor is seeking expanded 
indications for use of the Visualase System for temporal lobe epilepsy. 
2.2 Study Description 
This is a prospective, single-arm, multicenter, investigational clinical study. The study is 
expected to be conducted at up to 25 sites located in the United States. A minimum of 
150 subjects will undergo the Visualase procedure and be evaluated. To account for 
attrition, up to 215 subjects may be enrolled. Enrollment rates across sites will be 

 
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monitored, but there is not a minimum or maximum requirement for the number of 
subjects enrolled at each site.  
Following enrollment, subjects’ qualification for the Visualase procedure will be 
confirmed by a central review committee. Baseline assessments will also be performed 
at any time prior to the Visualase procedure. Study subjects will be followed for 12 
months following the Visualase procedure. Accordingly, the expected total study duration 
is approximately 65 months, representing approximately 52 months of enrollment and 
approximately 13 months of subject participation. 
3 BACKGROUND AND JUSTIFICATION 
3.1 Background 
Epilepsy is a chronic neurological condition characterized by recurrent seizures. 
Approximately 3 million people in the United States have epilepsy,2 and it is estimated 
that at least one-third of them become medically intractable, continuing to have seizures 
regardless of the number or type of anti-epileptic drugs (AEDs) used.3 About 150,000 
new cases of epilepsy will be diagnosed in the United States each year.4 Uncontrolled 
seizures lead to a wide variety of medical consequences (e.g., trauma due to seizures, 
sudden death, depression, intermittent psychotic disorders) and significant lifestyle 
limitations and social handicaps (e.g., loss of driving privileges, difficulty getting and 
maintaining a job). Epilepsy results in an estimated annual cost of $15.5 billion in 
medical costs and lost or reduced earnings and production.5 
Perhaps the most common type of epilepsy in adults is temporal lobe epilepsy (TLE), 
which has been reported to represent about 9% of the entire population of patients with 
epilepsy6;7 and as much as 66% of all patients with localized-epilepsy seen at tertiary 
referral centers.8 Epilepsy surgery has gained an important role in the treatment of 
medically intractable epilepsy, especially TLE, over the past few decades because of the 
development of better seizure localization techniques, safer surgical techniques, and 
better surgical tools.  
Two surgical resection techniques have been commonly utilized to treat mesial temporal 
epilepsy, namely anterior temporal lobectomy with mesial temporal resection (ATL) and 
selective amygdalohippocampectomy (SAH). Schramm reviewed 53 studies in which 
various temporal lobe resections were performed for medically intractable mesial 
temporal lobe epilepsies and found consistently high rates of seizure freedom at one-
year post-operative follow-up.9 In the most referenced randomized TLE study by Wiebe 
et al, seizure freedom occurred in 58% of the group assigned to surgery versus 8% for 
the patients who continued with medical therapy only.10 A second randomized trial 
provided confirmation of these results; 73% of mesial TLE patients who underwent 
temporal lobe resection were seizure-free after 2 years compared to 0 patients with 
medical treatment.11 Despite these, and many other well-documented high rates of 
seizure-freedom following surgical resection of temporal foci, the utilization of temporal 
lobectomy has not increased from 1990 to 200812 but has decreased, according to a 
recent survey.13 Not only has surgery for epilepsy remained arguably the most 
underused of all proven effective therapies, even those patients who are referred for 
surgery wait for an average of 22 years after onset of epilepsy for that referral,14 often 
too late to prevent or reverse the disabling adverse medical, psychological and social 
consequences of recurrent seizures. Factors like prolonged recovery, surgical 
invasiveness, and potential morbidities such as neurological deficits have been 
obstacles for completion of more epilepsy surgeries. 

 
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3.2 Clinical Rationale for the Study Design 
There is growing interest from surgeons and growing demand from patients for minimally 
invasive techniques to address intractable epileptogenic foci. Vagus nerve stimulation 
and the FDA-approved responsive neurostimulation therapy15 have each been shown to 
reduce the number of seizures a patient suffers but rarely attain the goal of seizure 
freedom demonstrated with surgical resection. Surgeons have used several minimally- 
or non-invasive surgical tools and techniques including stereotactic radiosurgery (SRS)16 
and stereotactic radiofrequency (SRF) ablation17 to successfully target and destroy the 
epileptogenic targets that are otherwise resected during craniotomy, showing promise in 
producing rates of seizure freedom similar to open surgical resection. For example, 
Liscak et al noted a 78% seizure-freedom rate at 2 years using radiofrequency,17 while 
Barbaro et al demonstrated 67% seizure freedom at three years using Gamma Knife® 
radiosurgery (GKRS), which has a delayed-onset of the treatment effect.18 Although 
these methods show promise, there are morbidities associated with the procedures. 
Quigg et al provided a review of minimally invasive techniques for epilepsy and 
discussed the shortcomings of SRS and SRF. The primary shortcoming of SRS is the 
delay in therapeutic effect. Maximal seizure decrease doesn’t occur until 12-18 months 
after surgery, potentially leading patients to seek additional therapy in the interim. 
Additionally, although infrequent, the possibility of tumor generation attributed to the 
therapy has occurred. For SRF, the created lesion size is often insufficient to interrupt 
the epileptic circuit, leading to poor seizure outcomes.19 
The Visualase System is a minimally invasive tool that has also been used to destroy 
epileptogenic targets. The advantage of the Visualase procedure is three-fold: 1) it is a 
minimally-invasive procedure, 2) effects are on par with other minimally invasive 
surgeries, and 3) the procedure allows for further intervention if required. The Visualase 
System has been on the market for 8 years, with a low rate of complications. Published 
case series and case reports of a total 37 patients revealed 2 homonymous hemianopias 
(5.4%), 2 hemorrhages (5.4%, one of which was asymptomatic and did not require 
intervention), 1 transient memory impairment, and 1 transient leg weakness.20-26 In a 
recent case series, seizure-freedom rate in a comparable population was reported as 
54%.23;26 Collective work from several single-center experiences presented as abstracts 
reported that 48-50% of patients who underwent the Visualase System ablation 
procedure achieved seizure freedom (Engel Class I) through twelve months. Perhaps 
the more distinguishing feature of the Visualase System is the lack of cognitive deficit 
compared to resection.27;28 In a recently published study, patients with TLE undergoing 
either resection or laser ablation using Visualase were given a series of cognitive tests. 
No patient who underwent the laser ablation procedure had cognitive decline, compared 
to 82% of resection patients who had declines on one or more measures.29  
To build upon these early positive results, a prospective, single-arm, multicenter study 
has been designed to demonstrate the safety and efficacy of the Visualase System in 
subjects with MTLE. 
Attiah et al published a decision analysis to calculate the seizure freedom rate and late 
mortality/morbidity rate that laser ablation for temporal lobe epilepsy would need to 
demonstrate in order to provide quality of life (QOL) improvements equivalent to anterior 
temporal lobectomy (ATL).30 The meta-analysis included records of over 25,000 cases of 
ATL and the available dataset for laser ablation from a recent multi-center study. The 
results of the analysis revealed that achieving 43% Engel I outcomes and no more than 
40% late mortality/morbidity with laser ablation is needed in order to be grossly 
equivalent to ATL. Although constrained by certain analytic factors and limited to the 

 
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available data for laser ablation, this analysis provides the best current estimate for a 
success or performance threshold of laser ablation to match the well-documented long-
term effectiveness of ATL. Therefore, this study compares safety and efficacy outcomes 
of laser ablation to the threshold determined by Attiah et al.30 
Seizure control is expected to yield improvements in health-related quality of life. 
Primary and secondary endpoints of this study have been designed to evaluate these 
outcomes. Additional secondary endpoints have been designed to further evaluate the 
cognitive outcomes after the Visualase procedure.  
3.3 Justification for Human Use 
The Visualase System has been cleared by the FDA for human use in the United States 
since 2007. Peer-reviewed publications describe patients achieving seizure reduction or 
freedom with few adverse events. However, no controlled clinical trials for MTLE have 
been undertaken to investigate safety and efficacy of the device in this population.  
4 SYSTEM DESCRIPTION AND INTENDED USE 
The Visualase System (Figure 2 and 3) is 510(k) cleared and indicated for use to 
necrotize or coagulate soft tissue through interstitial irradiation or thermal therapy under 
MRI guidance in medicine and surgery in cardiovascular thoracic surgery (excluding the 
heart and the vessels in the pericardial sac), dermatology, ear-nose-throat surgery, 
neurosurgery, plastic surgery, orthopedics, pulmonology, radiology, and urology, for 
wavelengths 800nm through 1064nm. 
The Visualase System comprises four components: a cooled laser applicator, a pump for 
circulating coolant through the applicator, a laser energy source, and a computer 
workstation with MRI analysis software for determination and visualization of relative 
changes in tissue temperature during surgical ablation. A software application running 
on the workstation allows the workstation user to control the laser output and to operate 
the coolant pump from the workstation interface. 

 
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Figure 2: Visualase Thermal Therapy System 
 
 
Figure 3: Visualase Cooled-Laser Applicator System (VCLAS) 
 
The Visualase Cooled Laser Applicator System (VCLAS) consists of a Laser Diffusing 
Fiber (LDF) and a Cooling Catheter System (CCS), which provides cooling for the tissue 
and LDF in contact with the CCS. The Envision workstation and software transports and 
processes the images and displays the images on the workstation to provide 
visualization and facilitate manipulation of the data extracted by the image-processing 
tools. An example of the images and information that is displayed to aid the surgeon 
during the procedure is shown in Figure 4 and 5 below.   
 

 
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Figure 4: Temperature limits are set to protect critical structures 
 
Figure 5: Visualase System software images and near real-time temperature 
information.  
Thermal ablation of cingulated gyrus tuber: A) Pre-therapy MRI confirming placement of laser applicator into 
target tuber. B) Software estimate of thermal damage created after 90-second duration of 980nm laser at 
11.25 W. C) Immediate post-ablation contrast-enhanced T1 MRI image with enhanced border defining 
extent of thermal ablation. D) Representative thermal images and damage estimates selected from over 40 
images acquired during the ablation cycle. Images demonstrate heating up to 90s followed by immediate 
cooling after termination of laser delivery. Images courtesy of 
 
 
Critical Structure

 
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Principles of Operation 
The Visualase System utilizes the properties of light at a specified wavelength (i.e., 
980nm, but in a range that includes 800nm to 1064nm) to direct photon energy to brain 
tissue in a form that is absorbed by the surrounding cells, causing elevation of tissue 
temperature and controlled tissue damage through coagulative necrosis. For 
temperatures greater than 60oC, cell death is instantaneous. For temperatures between 
44 and 59oC, cell death is time dependent. Typically during the Visualase procedure, the 
tissue temperature is held to below 90oC to avoid tissue vaporization.31-40  
The coagulation/necrosis procedure is frequently monitored by converting changes in 
MRI images to real-time thermal maps and estimating thermal damage using an 
Arrhenius-based damage model, both of which are displayed on the workstation. This 
information helps the surgeon monitor and control the area that is receiving the photon 
energy and being ablated.  
In typical use, as per its labeling, the surgeon places the Visualase laser applicator, 
usually employing stereotactic techniques (using either frame-based or frameless 
system), into the specified target in the brain. The applicator is MRI-compatible and the 
coagulation/necrosis can be performed inside the MRI magnet (Figure 6). After securing 
the applicator, the patient is transferred to the MRI scanner, where s/he undergoes 
imaging to confirm the correct position of the laser applicator. Safety markers can be 
placed on the MRI images, which can be set by the surgeon to specify key structures in 
the brain that trigger the laser to be turned “off” upon reaching user-defined temperature 
thresholds. During the coagulation/necrosis procedure, the Visualase System processes 
images using proton resonance-frequency (PRF) shift analysis and image subtraction to 
relate the changes in the complex phase angle compared to the relative changes in 
tissue temperature. Thus, the laser thermal therapy procedure is performed under MR-
image guidance. The image data may be viewed in a number of different formats, and 
the values of data at certain selected points in the brain may be monitored and/or 
displayed over the time of treatment. After these images are acquired and a satisfactory 
necrosis/coagulation has been performed according to the surgeon, then typically a 
post-contrast enhanced T1-weighted image is acquired to define the boundary of 
thermal damage in the brain. 
 
Figure 6: Visualase System set up when in use with MRI 
 

 
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Tools & Procedures Used in Conjunction with the Visualase System 
Typical stereotactic and navigation modalities employed in general surgery and 
neurosurgery techniques may be used in conjunction with the Visualase System. Frame-
based stereotactic techniques as well as use of navigation technologies are common in 
neurosurgical procedures. Open resections and craniotomies also use such procedural 
and targeting methods to a certain extent. The Visualase System is a standalone 
tool/device and does not require integration nor are there compatibility or restriction 
concerns with current stereotactic frames and navigation systems.  
The study will be conducted using the components described in Table 3 below. The 
instructions for use of the devices used in this study are provided in their respective 
manuals. Future releases of products will be included in the study upon FDA clearance.  
Table 3: System Component Information  
Medtronic Part 
Number  
Component Description 
  
 
Sterile, single use, patient contacting, Visualase Cooled Laser 
Applicator System with 0.4mm core fiber, 3mm tip 
  
 
Sterile, single use, patient contacting, Visualase Cooled Laser 
Applicator System with 0.4mm core fiber, 10mm tip 
  
 
Sterile, single use, patient contacting, Visualase Cooled Laser 
Applicator System with 0.6mm core fiber, 15mm tip 
 
Visualase Thermal Therapy System (capital system) 
None (Component of 
 
 Laser System 
None (Component of 
 
 
 
The following optional accessory may also be used during the Visualase procedure. 
 
Medtronic Part 
Number  
Component Description 
 
 
Visualase Neuro Accessory Kit – includes: (1) titanium bone anchor, 
(1) plastic bone anchor, and (1) stiffening stylet 
  
 Visualization stylet (1) 
 
5 REGULATORY COMPLIANCE 
The study will be conducted under an FDA Investigational Device Exemption (IDE) in 
compliance with 21 CFR Parts 11, 50, 54, 56 and 812. The study will be conducted in 
compliance with international ethical and scientific quality standards, known as good 
clinical practice (GCP). GCP includes review and approval by an independent 
Institutional Review Board (IRB) before initiating a study, continuing review of an 
ongoing study by an IRB, and obtaining and documenting the freely given informed 
consent of a subject before initiating the study. 
The study will be conducted in accordance with the principles that have their origin in the 
Declaration of Helsinki. The principles of the Declaration of Helsinki have been 
implemented through the patient informed consent process, IRB approval, study training, 

 
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clinical trial registration, preclinical testing, risk-benefit assessment and publication 
policy. 
The study will be publicly registered prior to first enrollment in accordance with the 2007 
Food and Drug Administration Amendments Act (FDAAA) on http://clinicaltrials.gov (PL 
110-85, Section 810(a)). 
Approval of the Clinical Investigational Plan (CIP) is required from the following entities 
prior to any study procedures at a study site:  
• 
Medtronic  
• 
FDA 
• 
Site IRB 
Similarly, approval of subsequent revisions to the CIP is required at each study site from 
the above-mentioned entities prior to implementation of the revised CIP at that site. 
Each site’s IRB will also be required to approve any subject recruitment materials. 
Any additional requirements imposed by the site’s IRB shall be followed. 
6 METHODS 
6.1 Study Objective 
The study objective is to evaluate the safety and efficacy of the Visualase MRI-Guided 
Laser Ablation System (“Visualase System”) for necrotization or coagulation of 
epileptogenic foci in patients with intractable mesial temporal lobe epilepsy (MTLE).  
6.2 Study Endpoints 
The following endpoints will be used to evaluate the study objective. 
 Primary Safety Endpoint 
The primary safety endpoint is the incidence of qualifying device-, procedure-, or 
anesthesia-related adverse events (defined in Appendix F) through 12 months following 
the Visualase procedure.   
 Primary Efficacy Endpoint 
The primary efficacy endpoint is seizure freedom (defined as Engel Class I, Appendix C) 
at 12 months following the Visualase procedure. 
 Secondary Endpoints 
1. Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following 
the Visualase procedure compared to historical control for continued medical 
therapy  
2. Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following 
the Visualase procedure, including subjects who are retreated with Visualase 
3. Within-subject change of Boston Naming Test score (English language version), 
from baseline to 12 months following the Visualase procedure 
4. Within-subject change of Rey Auditory Verbal Learning Test 5-Trial Total score 
(English language version), from baseline to 12 months following the Visualase 
procedure 

 
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5. Within-subject change of Quality of Life in Epilepsy inventory (QOLIE-31) score 
(English language version), from baseline to 12 months following the Visualase 
procedure 
6. Within-subject change of SF-36 quality of life questionnaire Mental Component 
Score (English language version), from baseline to 12 months following the 
Visualase procedure 
7. Within-subject change of SF-36 quality of life questionnaire Physical Component 
Score (English language version), from baseline to 12 months following the 
Visualase procedure 
8. Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following 
the Visualase procedure compared to historical control for open surgical 
resection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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12.
 
6.3 Subject Selection Criteria 
Patients will be screened to ensure they meet all of the inclusion and none of the 
exclusion criteria. IRB approval of the SLATE CIP and informed consent form must be 
obtained prior to enrolling patients in the study.  
Enrollment of the subject must occur prior to any study specific procedures.  
 Inclusion Criteria 
1. Adult subjects ≥ 18 years of age and ≤ 70 years of age at the time of enrollment  
2. History of medically refractory (or intractable) MTLE, defined per the International 
League Against Epilepsy (ILAE)1 as: failure of adequate trials of two tolerated 
and appropriately chosen and used antiepileptic drug (AED) schedules (whether 
as monotherapies or in combination) to achieve sustained seizure freedom, as 
determined by the Investigator 
3. If the subject has a vagus nerve stimulator (VNS), the subject must have failed to 
achieve sustained seizure freedom with the VNS implanted for at least 6 months 
prior to enrollment 
4. On stable antiepileptic drugs (AEDs) (and/or stable VNS setting, if applicable) for 
30 days prior to the Visualase procedure and compliant with medication use, as 
reported by the subject  
5. An average of at least 1 complex partial or secondarily generalized seizure 
compatible with MTLE per month, for a minimum of the last 12 months prior to 
enrollment (i.e., at least 12 qualifying seizures in the 12 months prior to 
enrollment)  
6. Subject’s seizure symptoms and/or auras are compatible with MTLE   
7. Based on video EEG obtained within 24 months of enrollment, evidence of 
seizures from one temporal lobe consistent with MTLE. If the video EEG was 
obtained more than 12 months prior to enrollment, an interictal EEG done within 
12 months of enrollment must show interictal spikes in the same distribution as 
seen in the previous video EEG monitoring.  
8. Based on MRI obtained within 24 months prior to enrollment, evidence consistent 
with mesial temporal lobe sclerosis (defined as: mesial temporal atrophy 
accompanied by either increased signal on T2-weighted image, indicative of 
gliosis or by loss of internal architecture in the hippocampus). If there is evidence 
of a change in clinical seizure symptoms/severity or of a brain injury since the 
MRI, a repeat MRI must be obtained to confirm eligibility.  
9. Subject is willing and able to remain on stable AEDs (and stable VNS setting, if 
applicable), as directed by their treating physician, for 12 months following the 
Visualase procedure 
10. Subject is able to complete study assessments in English or Spanish language. 
11. According to Investigator judgment, subject is willing and able to comply with 
protocol requirements (e.g., follow-up visit schedule, evaluations, compliance 
with AED regimen) 

 
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 Exclusion Criteria 
1. Subject is unwilling or unable to sign the study informed consent form (ICF) 
2. Subject is pregnant prior to the Visualase procedure or intends to become 
pregnant during the course of the study 
3. Subject is currently implanted with a device contraindicating MRI, including deep 
brain stimulation or responsive neurostimulator  
4. Subject has progressive brain lesions and/or tumors not associated with epileptic 
disease state 
5. Subject has a history of previous intracranial surgery for treatment of epileptic 
seizures, including intracranial resections, stereotactic radiosurgery, or deep 
brain stimulation 
6. Subject has persistent (based on medical judgment) extra-temporal or 
predominant contralateral focal interictal spikes or slowing, or generalized 
interictal spikes on EEG 
7. Subject has seizures with contralateral or extra-temporal ictal onset on EEG 
8. Subject’s aura and/or ictal behavior suggest an extratemporal focus 
9. Subject has evidence on MRI of epileptogenic extra-temporal lesions, dual 
pathology within the temporal lobe, or contralateral hippocampal increased T2 
signal changes and/or loss of internal architecture 
10. If additional testing (e.g., PET, SPECT, invasive EEG or MEG) has been 
performed, results are discordant from the seizure focus scheduled for ablation 
11. As reported by the subject or in the opinion of the Investigator, subject is not 
compliant with AED medication requirements  
12. Subject has an IQ < 70, based on the Wechsler Abbreviated Scale of Intelligence 
(WASI or WASI-II) or Wechsler Adult Intelligence Scale Full Scale IQ or General 
Ability Index (WAIS-III or WAIS-IV FSIQ or GAI) performed within 12 months 
prior to enrollment, or after enrollment but prior to the procedure 
13. Subject has been diagnosed with dementia or other progressive neurological 
disease 
14. Subject has an unstable major psychiatric illness, psychogenic non-epileptic 
seizures, or medical illness that would contraindicate the Visualase procedure or 
affect the neuropsychological assessments 
15. Subject is currently participating in other research that may potentially interfere 
with SLATE endpoint(s), as determined by the Investigator or Sponsor 
16. Subject is allergic to gadolinium 
6.4 Minimization of Bias 
Selection of subjects, treatment of subjects, and evaluation of study data are potential 
sources of bias. Methods incorporated in the study design to minimize potential bias 
include (but are not limited to): 
1. Subjects will be screened to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to enrollment. 

 
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2. A central review of subjects’ epilepsy history, MRI and EEG will be performed to 
confirm study qualification for the Visualase procedure. 
3. Subject demographics will be collected pre-procedure in order to later assess 
possible characteristics that may influence endpoints.  
4. Subjects will serve as their own controls for selected secondary endpoints. 
5. A statistical analysis plan, which will document all pre-specified analyses and 
analysis methods, will be developed prior to analyzing data. 
6. A modified intent-to-treat analysis will be performed on the study endpoints. 
7. All study sites will use the same version of the Clinical Investigational Plan and 
Case Report Forms (CRFs). 
8. All study personnel and Medtronic personnel will be trained on their respective 
aspects of the study using standardized training materials. 
9. All study personnel will be trained on and required to follow the Clinical 
Investigational Plan. 
10. An independent Data Monitoring Committee (DMC) will be used to safeguard the 
interests of study subjects, and to act as an advisory panel ensuring continued 
scientific validity and necessity. (See Appendix D.) 
11. All study investigators will be required to meet 21 CFR Part 54, Financial 
Disclosure by Clinical Investigators. 
12. All neuropsychological assessments will be scored at a core laboratory. 
13. Volumetric analysis of tissue ablation will be conducted at a core laboratory. 
In summary, potential sources of bias that may be encountered in this clinical study have 
been considered and minimized by careful study design. 
7 STUDY PROCEDURES 
7.1 Investigator / Investigational Site Selection 
All clinical investigators managing the subject’s epilepsy must be qualified practitioners 
and experienced in the diagnosis and treatment of persons with epilepsy. All personnel 
administering neuropsychological assessments must be trained on assessment 
administration and/or licensed in psychometry. 
The role of the Principal Investigator is to implement and manage the day-to-day 
conduct of the clinical investigation as well as ensure data integrity and protection of the 
rights, safety and well-being of the subjects involved in the clinical investigation. 
The Principal Investigator must: 
• 
Be qualified by education, training, and experience to assume responsibility for 
the proper conduct of the clinical investigation 
• 
Disclose potential conflicts of interest, including financial, that interfere with the 
conduct of the clinical investigation or interpretation of results 
The Principal Investigator must be able to demonstrate that the proposed investigational 
site: 
• 
Has a sufficient number of eligible subjects needed within the recruitment period 
• 
Has one or more qualified investigators, a qualified investigational site team and 
adequate facilities for the foreseen duration of the clinical investigation 

 
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Neurosurgeons performing cases as study investigators must have prior experience with 
the study procedure. Specifically, surgeons must demonstrate experience targeting the 
hippocampus in a stereotactic surgical procedure and must have hands-on experience 
using the Visualase system. This experience can be evidenced by any of the following, 
as attested to by the participating surgeon in writing: 
1. At least 10 completed cases using the Visualase system for any target, including 
at least 5 cases for MTLE; or 
2. At least 5 completed cases using the Visualase system for any target, and 
substantial experience (5 years or more) targeting the hippocampus in other 
stereotactic procedures (e.g., electrode placement); or 
3. Surgeon has previously completed at least 3 cases using the Visualase system 
for any target. Surgeon may perform ongoing study cases only under direct 
supervision from a surgeon who meets criteria 1 and/or 2 above, until he/she has 
completed 10 cases under supervision. 
Additionally, qualification requirements include, but are not limited to sites having 
adequate facilities, infrastructure, training and experience to provide comprehensive 
treatment and care of patients with MTLE, and to conduct clinical research studies. 
7.2 Site Training 
Prior to enrolling and treating subjects, site personnel will be trained on the CIP, relevant 
standards and regulations, informed consent, and on data collection and reporting tools. 
If new members join the study site team, they will receive training on the applicable 
clinical study requirements relevant to their role before contributing to the clinical study. 
All training documentation will be maintained in the study files. 
Appropriate study personnel from each site (e.g., psychometrists/neuropsychologists) 
will be trained on administering the neuropsychological assessments per protocol.  
7.3 Site Activation  
Prior to performing study-related activities, all local regulatory requirements must be 
fulfilled, including but not limited to the following:  
• 
IRB approval of the current version of the CIP and ICF 
• 
FDA approval of the Investigational Device Exemption (IDE) application 
• 
Fully executed Clinical Trial Agreement  
• 
Financial Disclosure by Investigators  
• 
Current curriculum vitae of Investigators  
• 
Documentation of delegated tasks for all participating site staff 
• 
Documentation of study training for all participating site staff 
Additional requirements imposed by the IRB and FDA must be followed, if appropriate.  
Medtronic will provide each study site with documentation of study site/investigator 
readiness; this letter must be received prior to subject enrollment. 
7.4 Equipment Requirements 
The following equipment must be available at each site to support study activities. 

 
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 Visualase System 
The Visualase System capital equipment (computer workstation, laser energy source 
and coolant pump) must be installed and available. 
 Visualase Procedure MRI 
An MRI scanner must be available to acquire procedural scan sequences. 
 Research MRI 
A 3-Tesla MRI scanner must be available to acquire research MRI scans at baseline and 
6 months following the Visualase procedure. To maintain imaging consistency, the same 
scanner must be used for both research scans for each subject.    
 Neuro-ophthalmologic Exam  
The site must have access to a qualified specialist (for example, a neuro-
ophthalmologist or board-certified ophthalmologist) to oversee examinations of best 
corrected visual acuity, visual fields, and extraocular movements. Access to visual field 
testing using automated perimetry is required.  
7.5 Assessments 
Enrolled subjects will be required to complete all assessments. However, subjects who 
are unable to complete study assessments in English, but are able to complete 
assessments available in Spanish, will be required to complete all assessments except 
for Seizure Severity Assessment (7.5.4) and Neuropsychological Assessments (7.5.6).   
 Seizure Classification and Diary 
Each subject’s seizure types will be documented on the Seizure Classification eCRF, 
according to clinical manifestation and the subject’s own description. A study 
Investigator will then classify seizure types per the International League Against Epilepsy 
(ILAE) classification. Seizure classification will initially be conducted after consent, prior 
to submission to the Pre-Surgical Evaluation Committee for review, and then amended 
throughout the subject’s participation in the study if new seizure types occur. 
 
Subjects will be given paper-based seizure diaries to document occurrence of seizures 
after enrollment through study exit. The seizure diary will be initially provided to the 
subject after consent, prior to submission to the Pre-Surgical Evaluation Committee. 
Seizure types will be recorded for each subject in concordance with the initial Seizure 
Classification eCRF. Seizure diaries will be reviewed with the subjects and collected by 
the site at specified visits. The site will enter seizure information into the Seizure Diary 
Summary eCRF. Recorded data shall include qualifiers needed to determine Engel 
Classification per Appendix C (e.g., nocturnal seizures only or generalized convulsion 
with AED discontinuation). A new seizure diary may be issued to the subject at each visit 
if needed. 
 Mood Assessments 
Mood will be assessed using the following: 
• 
Beck Depression Inventory® II – a 21-item self-reported instrument for measuring 
the presence and severity of depression in adults and adolescents. Each of the 
21 items requires the respondent to endorse one of 4 options, scored 0 to 3, with 
increasing scores reflecting greater severity of a given depressive symptom.  

 
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• 
Beck Anxiety Inventory® – a 21-item self-reported instrument for measuring the 
severity of anxiety in adults and adolescents. Each of the 21 items requires the 
respondent to endorse one of 4 options, scored 0 to 3, with increasing scores 
reflecting greater severity of a given anxiety symptom. 
 Quality of Life Assessments 
Change in health-related quality of life (QOL) will be assessed using the following:  
• 
Quality of Life in Epilepsy-31 (QOLIE-31) -  a self-reported survey containing 
multi-item measures of quality of life, emotional well-being, role limitations, social 
support/isolation, energy/fatigue, worry about seizure, medication effects, health 
discouragement, work/driving/social function, attention/concentration, language, 
memory, physical function, pain, and health perceptions. Results of the QOLIE-
31 measures may be obtained from the Quality of Life in Epilepsy-89 (QOLIE-89) 
survey.  
• 
SF-36 Health Survey version 2 (SF-36) – a widely used measure of health-
related quality of life. The SF-36 contains 36 items that are divided into 8 different 
categories designed to evaluate the multidimensional aspects of health including: 
physical functioning, role limitations caused by physical problems, bodily pain, 
general health perceptions, vitality, social functioning, role limitations caused by 
emotional problems, and mental health. The 8 subscales can be aggregated into 
2 summary scores, physical component summary and mental component 
summary, with higher scores representing better health status. 
 Seizure Severity Assessment 
Seizure severity will be assessed using the following: 
• 
Seizure Severity Questionnaire (SSQ) Version 3 - a review of various aspects of 
seizures completed by the person who has seizures, possibly with help from 
people who have observed the seizures. There are 11 questions asking about 
events before, during, and after typical seizures. The SSQ is only required to be 
completed by subjects who have seizures within the 4 weeks preceding the 6-
month and/or 12-month visits. Subjects who are seizure free following the 
Visualase procedure are not required to complete the SSQ. 
 Pain Assessment 
Pain will be assessed using the following:  
• 
Pain Numeric Rating Scale (Pain NRS) - a unidimensional measure of pain 
intensity in adults. The subject selects a whole number (0-10 integer) that best 
reflects the intensity of their pain. The NRS is anchored by terms describing pain 
severity extremes, where 0 represents no pain and 10 represents the worst pain 
possible.41 The pain scale will be completed after the Visualase procedure but 
prior to discharge. If multiple pain scales are completed, the result of the last pain 
scale prior to discharge will be reported for the study. 
 Neuropsychological Assessments 
A neuropsychology specific manual of operations will be provided to all sites. The 
purpose of the manual will be to clearly delineate specific test administration instructions 
to specific normative databases and to otherwise standardize all procedures and 
anticipated scenarios that might occur as part of the neuropsychological assessment.  

 
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Materials for administration of the neuropsychological assessments will be provided to 
sites. 
• 
Boston Naming Test – a 60-item confrontation naming test to measure word 
retrieval performance. The subject is asked to name what they see in a picture 
book, and the time it takes for them to respond is recorded.  
• 
Controlled Oral Word Association Test (COWA) (FAS) – a measure of verbal 
fluency. Subjects are given one minute to name as many words as possible 
beginning with the letter F. The procedure is then repeated for letters A and S. 
• 
Emory Semantic Fluency Paradigm – a measure of semantic memory using 
everyday objects. Subjects are given a certain amount of time to name as many 
items in a category.  
• 
Emory Famous Faces Naming/Recognition – a measure of semantic memory 
using proper nouns (famous faces). Subjects are shown photographs of famous 
people and are given 20 seconds to identify each image.  
• 
Rey Auditory Verbal Learning Test – a test that evaluates verbal learning and 
memory (recall and recognition). Subjects are given a list of 15 unrelated words 
repeated over five different trials and asked to repeat. Another list of 15 unrelated 
words are given and repeated. The subject must then repeat the original list of 
words and then again after 30 minutes.  
• 
Wechsler Memory Scale (WMS-IV) Visual Reproduction Test - a measure of 
visual memory. Subjects are shown an image for 10 seconds and then asked to 
draw the image.  
• 
Wechsler Memory Scale (WMS-IV) Verbal Paired Associates - a measure of 
verbal memory for associated word pairs. The subject is read 10 or 14 word 
pairs. The subject is then read half the word pair and asked to respond with the 
corresponding other half of the pair. 
7.6 Magnetic Resonance Imaging 
A Research MRI manual of operations will be provided to all sites. The purpose of the 
manual will be to clearly delineate specific MR image sequences to be obtained as well 
as provide scanner specific parameters. 
The following MRI scans are to be performed: 
• 
Research scan at the Baseline visit and 6 months following the Visualase 
procedure. (Note: the subject must be scanned on the same scanner at the 
Baseline visit and at the 6-month visit.)  
o Isotropic T1 MPRAGE, sagittal plane 
o Isotropic T2, sagittal plane 
o T2-TSE/TFE, coronal plane 
o Isotropic DTI, axial plane 
• 
Procedural scans 
o Pre-ablation: volumetric T1 and/or T2 weighted sequences with 
multiplanar reformatting (MPR) to verify proper positioning through the 

 
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desired trajectory and to select appropriate imaging planes for monitoring 
during ablation 
o Ablation: per institutional standard 
o Post ablation: T1 with gadolinium contrast volumetric series in any plane 
to visualize the lesion with MPR aligned with or perpendicular to the laser 
fiber, and T2 FLAIR and DWI. Post ablation scans should be conducted 
immediately following the procedure. If this is not feasible (e.g., the 
subject required pre-ablation gadolinium for trajectory planning and 
another dose cannot be administered), the post-ablation scans may be 
completed prior to discharge. 
7.7 Neuro-ophthalmologic Exam 
A neuro-ophthalmologic exam manual will be provided to sites to delineate specific 
procedures for exams of best-corrected acuity, visual fields, and extraocular movements, 
performed under the guidance of a qualified specialist (for example, a neuro-
ophthalmologist or board-certified ophthalmologist). Visual field testing using automated 
perimetry is required.   
7.8 Data Collection 
Data will be collected using an electronic data capture system. CRF Instructions will 
include details regarding appropriately completing eCRFs and allowable data on eCRFs. 
Data collection requirements at each visit are summarized in Table 4 below. 
 
 

 
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Table 4: Data Collected at Subject Visits 
Case Report Forms 
Enrollment / 
Screening 
Baseline 
Visualase 
Procedure 
Follow-Up Visit 1 
(14 day) 
Follow-Up Visit 2 
(3 mo) 
Follow-Up Visit 3 
(6 mo) 
Follow-Up Visit 4 
(12 mo) 
Unscheduled Visit 
Site Data Collection 
Informed Consent, 
Demographics 
X 
 
 
 
 
 
 
 
Seizure Classification Form 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
Epilepsy History 
X 
 
 
 
 
 
 
 
Surgical Plan 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Medications 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
VNS Setting 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
Eligibility Criteria,  
Pregnancy Test 
X 
 
X1 
 
 
 
 
 
EEG and Additional Testing 
X 
 
 
 
 
 
 
 
MRI 
X 
X 
X 
 
 
X 
 
 
Pre-Surgical Evaluation 
Submission 
X 
 
 
 
 
 
 
 
Neurological Exam 
 
X 
 
X 
X 
X 
X 
 
Neuro-ophthalmologic Exam 
 
X4 
 
 
X4 
X4 
X4 
X4 
Neuropsych + QOL 
 
X 
 
 
 
X 
X 
 
Seizure Diary Summary, 
Seizure Log 
 
X1 
X1 
X 
X 
X 
X 
 
Visualase Procedure, 
Product Disposition  
 
 
X 
 
 
 
 
 
Procedure Steroid Log 
 
 
X1 
 
 
 
 
 
Study Visit2 
 
X2 
 
X 
X 
X 
X2 
 
NRS Pain Scale 
 
 
X3 
 
 
 
 
 
Retreatment Submission 
 
 
 
 
 
 
 
X1 
Secondary Procedure 
 
 
 
 
 
 
 
X1 
Healthcare Services 
Utilization 
 
 
X 
X1 
X1 
X1 
X1 
X1 
Study Exit 
 
X1 
X1 
X1 
X1 
X1 
X 
X1 
Adverse Event 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
Device Deficiency 
 
 
X1 
 
 
 
 
 
Protocol Deviation 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
 
 
 
 
 

 
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Case Report Forms 
Enrollment / 
Screening 
Baseline 
Visualase 
Procedure 
Follow-Up Visit 1 
(14 day) 
Follow-Up Visit 2 
(3 mo) 
Follow-Up Visit 3 
(6 mo) 
Follow-Up Visit 4 
(12 mo) 
Unscheduled Visit 
Committee/Core Lab Evaluation Data Collection 
Pre-Surgical Evaluation 
X 
 
 
 
 
 
 
 
Retreatment Evaluation 
 
 
 
 
 
 
 
X1 
Volumetric Analysis 
 
 
 
 
 
X 
 
 
Neuropsych + QOL Analysis 
 
X 
 
 
 
X 
X 
 
Neuro-ophthalmologic 
Analysis 
 
X4 
 
 
X4 
X4 
X4 
X4 
 
1If applicable, events, changes or updates should be captured on eCRFs as they occur. 
 
2Including assessment of driving and employment/school status 
 
3Pain scale will be completed after the Visualase procedure but prior to discharge. 
 
4Neuro-ophthalmologic exam data should be entered for subjects as specified in Table 2. 
 
7.9 
 
 Patient Informed Consent Process 
A patient informed consent form (ICF) is a legally effective documented confirmation of a 
subject’s voluntary agreement to participate in a particular clinical study after information 
has been given to the subject on all aspects of the clinical study that are relevant to the 
subject’s decision to participate. This process includes obtaining a signed ICF and an 
authorization to use and disclose personal health information (HIPAA release 
authorization) that has been signed and dated by the subject.  
Prior to enrolling subjects, each site’s IRB will be required to approve the ICF. The 
document(s) must be controlled (i.e., versioned and/or dated) to ensure it is clear which 
version(s) were approved by the IRB. Any adaptation of the sample consent form must 
be reviewed and approved by Medtronic prior to enrolling subjects.  
The Investigator must notify the subject of any significant new findings about the study 
that become available during the course of the study which are pertinent to the safety 
and well-being of the subject, as this could impact a subject’s willingness to participate in 
the study. If relevant, approval may be requested from subjects to confirm their 
continued participation. 
The informed consent process must be conducted by the Principal Investigator or an 
authorized designee, and the ICF and authorization to use and disclose personal health 
information must be rendered to the subject in a language he/she is able to read and 
understand. The process of subject informed consent must be conducted without using 
coercion or undue improper influence on or inducement of the subject to participate by 
the Investigator or other site personnel. The informed consent process must not waive or 
appear to waive a subject’s legal right. The language used must be as non-technical as 
possible and must be understandable to the subject and the impartial witness, where 
applicable. 
If applicable, the witness must also sign and personally date the consent form to attest 
that the information in the ICF was accurately explained and clearly understood by the 
subject, and that informed consent was freely given.   

 
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The subject must have ample time and opportunity to read and understand the ICF, to 
inquire about details of the study, and to decide whether or not to participate in the 
clinical study. All questions about the study should be answered to the satisfaction of the 
subject. 
When the subject decides to participate in the clinical study, the ICF must be signed and 
personally dated by the subject and Investigator or authorized designee. Consent by 
legally authorized representatives is not permitted, since the study requires the subject 
to complete seizure diaries and self-reported quality of life and mood assessments.  
A copy of the signed and dated ICF and the authorization to use and disclose personal 
health information must be provided to the subject.  
If consent is obtained the same day the subject begins participating in study-related 
procedures, it must be documented in the subject’s case history that consent was 
obtained prior to participation in any study-related procedures. It is best practice for the 
informed consent process to be documented in the subject’s case history, regardless of 
circumstance. 
The original of the signed ICF must be filed in the hospital/clinical chart or with the 
subject’s study documents.  
CIP 4.0 includes the addition of neuro-ophthalmologic exams. Subjects consented but 
not yet treated with Visualase prior to CIP 4.0 will be asked to reconsent to these 
exams. Subjects who refuse to consent to CIP 4.0 will be withdrawn from the study. 
Subjects treated with Visualase prior to CIP 4.0 will be asked to reconsent to have a 
neuro-ophthalmologic exam performed at their next scheduled study visit. Subjects who 
refuse to consent under CIP 4.0 will be followed under the protocol version to which 
they consented. 
7.10 Enrollment 
Upon signing the ICF, a subject is considered to be enrolled in the study. Each subject 
will be assigned a subject identification code (subject ID) that will be used on all 
documentation for the subject.  
Each investigational site must maintain a log of all the subjects enrolled in the study, 
linking subject IDs to their names or medical record numbers. 
The following activity will be completed at enrollment: 
• 
Informed consent 
7.11 Screening 
The following must be completed at screening to assess subject eligibility: 
• 
Review of demographics 
• 
Review of medical history, including MRI and video EEG (and Wada test, 
functional MRI, magnetoencephalography [MEG], positron emission tomography 
[PET] and/or single-photon emission computerized tomography [SPECT] scans if 
available) 
o If the MRI on record shows evidence of eligibility for the study but was not 
completed within the protocol-defined timeframe, the Baseline Research 
MRI scan (see Baseline Visit) may be used to confirm eligibility. 

 
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Multiplanar reformatting (MPR) may be required to achieve the planes 
appropriate for eligibility verification. 
• 
Review and documentation of epilepsy and seizure history, including seizure 
frequency during the 12 months immediately preceding enrollment, as 
ascertained by subject and family report, and/or seizure diaries from the medical 
record 
• 
Review of past and current AEDs and current concomitant psychotropic 
medications 
• 
Pregnancy test for women of childbearing potential 
If results of the following assessment performed within 12 months of enrollment are not 
in the subject’s medical record, they must be completed as part of screening: 
• 
IQ Test: Wechsler Abbreviated Scale of Intelligence® (WASI® or WASI®-II) or 
Wechsler Adult Intelligence Scale Full Scale IQ or General Ability Index (WAIS®-
III or WAIS®-IV FSIQ or GAI) 
o WASI-II materials will be provided by Medtronic as needed 
After consent and prior to evaluation by the Pre-Surgical Evaluation Committee, the 
following activities will be completed: 
• 
Subject provided a seizure diary 
• 
Seizure classification 
Subjects who sign an ICF but do not meet the eligibility criteria prior to the Visualase 
procedure, fail pre-surgical evaluation, or decline study participation will be considered 
screen failures. 
7.12   Pre-Surgical Evaluation 
The pre-surgical evaluation will consist of a central review of each subject’s epilepsy 
history, MRI, EEG and any additional testing results available (e.g., PET, SPECT, 
invasive EEG or MEG) to confirm study qualification for the Visualase procedure.  
Following consent, the site will enter subject data obtained during screening into the 
electronic database. The following data are specifically required for the pre-surgical 
evaluation for every enrolled subject (unless withdrawn prior to pre-surgical evaluation): 
• 
MRI 
o T1- and T2-weighted images including thin section coronal images 
suitable for quantitative measurement, sufficient to confirm eligibility 
criteria  
o MRI report 
• 
Video EEG 
o Printout of seizure activity from EEG 
o EEG report and video description 
• 
Additional testing, if performed (e.g., PET, SPECT, invasive EEG or MEG) 
• 
Epilepsy History and Seizure Classification Forms 
 

 
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Each subject’s data are reviewed by a central committee (Appendix B) to verify study 
qualification for the Visualase procedure based on the following criteria: 
• 
Does the submitted MRI show mesial temporal atrophy accompanied by either 
increased signal indicative of gliosis or by loss of internal architecture in the 
hippocampus? 
• 
Does the EEG evidence show seizures from one temporal lobe consistent with 
MTLE? 
• 
Is the seizure semiology consistent with MTLE? 
• 
Based on the MRI, EEG and semiology, is the laterality consistent? 
• 
If additional testing has been performed (e.g., PET, SPECT, invasive EEG or 
MEG), is it discordant from the seizure focus scheduled for ablation? 
Each subject’s data review will be assigned to one of the Committee members based on 
availability. The assigned Committee member may consult with others, though the 
assigned Committee member is individually responsible for making an evaluation 
decision. Committee members who also act as study investigators may not evaluate 
subjects enrolled by their own institution. The assigned Committee member will approve, 
disapprove or defer the subject’s continued participation in the trial. 
Subjects who are being considered for retreatment with another Visualase procedure 
(per Section 7.17) are evaluated by the committee per the same workflow as described 
above, though the supportive evidence requirements and verification criteria are 
determined on a case-by-case basis by the assigned Committee member (i.e., they are 
not pre-specified). 
7.13 Baseline Visit 
At any time after enrollment, but before the Visualase procedure, subjects will have a 
Baseline Visit to perform assessments that serve as a comparison to post Visualase 
procedure assessments. If needed, the Baseline Visit may be performed on multiple 
days, provided that all assessments are completed prior to the Visualase procedure.  
The following activities are to be performed at this visit: 
• 
Review and documentation of current AEDs and concomitant psychotropic 
medications 
o AEDs and dosages must remain stable for at least 30 days prior to the 
Visualase procedure 
• 
Neurological exam, including oculomotor nerves and confrontation visual field 
test 
• 
AE assessment 
• 
Neurocognitive assessments, administered by qualified study personnel: 
o Boston Naming Test 
o Controlled Oral Word Association Test (COWA) (FAS) 
o Emory Semantic Fluency Tasks 
o Emory Famous Faces Naming/Recognition 
o Rey Auditory Verbal Learning Test, Form A 
o Wechsler Memory Scale (WMS-IV) Visual Reproduction Test 
o Wechsler Memory Scale (WMS-IV) Verbal Paired Associates 

 
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• 
Mood and Quality of Life (QOL) surveys, completed by the subject: 
o Beck Depression Inventory II 
o Beck Anxiety Inventory 
o Quality of Life in Epilepsy Inventory (QOLIE-31) 
o SF-36 Health Survey (SF-36) 
o Seizure Severity Questionnaire (SSQ) Version 3 
• 
If available, seizure diary review and documentation of all seizures; a new diary 
may be given to subject to record future seizures 
• 
Classification of any new types of seizures reported 
• 
Research MRI scan per Section 7.6 
o MRI scans done within 12 months prior to enrollment and performed per 
Section 7.6 may be used for baseline. 
• 
Assessment of driving and employment/school status 
• 
Neuro-ophthalmologic exam (does not apply to subjects who have undergone the 
Visualase procedure prior to release of CIP 4.0) 
o Neuro-ophthalmologic exams performed within 12 months prior to 
enrollment and performed per Section 7.7 may be used for baseline 
Results of neurological exams and neurocognitive assessments performed within 12 
months prior to enrollment may be used for baseline.  
7.14 Study Intervention: Visualase Procedure 
The following activities are to be performed before the Visualase procedure: 
• 
AEDs and dosages must remain stable for 30 days prior to the Visualase 
procedure. 
• 
For females of childbearing potential, a repeat pregnancy test should be done 
within 7 days prior to the Visualase procedure to confirm the subject is still 
eligible. If the pregnancy test is positive, the subject is considered a screen 
failure and is exited from the study.  
The following activities are to be performed prior to discharge: 
• 
Visualase procedure 
• 
MRI scans before, during and after the Visualase procedure (per Section 7.6) 
• 
Review and documentation of current AEDs and concomitant psychotropic 
medications 
• 
AE assessment 
• 
Healthcare services utilization assessment 
• 
If available, review of seizure diary and documentation of all seizures; new diary 
may be given to subject to record any future seizures 
• 
Classification of any new seizure types reported 
• 
Pain scale completed after the Visualase procedure 
The procedure should be performed in accordance with the Instructions for Use (IFU) 
supplied with the device. A supplemental surgical Technique Recommendations 
document will be provided to all sites to facilitate consistent use, correct placement and 

 
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function of the device, as well as to minimize risk to subjects. The Technique 
Recommendations should be reviewed by all participating study surgeons and 
adherence to its guidance is strongly encouraged.   
As indicated in the IFU, the potential effect of laser ablation on the stability of gadolinium 
complexes such as those used in MRI contrast agents (CAs) is currently unknown. 
Physicians should therefore observe a “washout” interval of at least three (3) half-lives 
(t½ for the CA being used) between the administration of Gadolinium-based CAs and 
initiation of the laser ablation.  
The subject is positioned and stereotactic registration for intraoperative navigation and 
cranial access is accomplished. This may require application of a stereotactic head 
frame or it may be frameless via surface-based registration (e.g., facial tracing) or 
placement of scalp or bone fiducials. Other appropriate neurosurgical stereotactic 
modalities may be used in accordance with the manufacturer’s instructions. In cases 
where a head frame is used, imaging studies (CT or MRI) are then obtained and 
interpreted for usability by the surgeon, for identification of reference points and direct 
use in operative planning after the images are fused. At the surgeon's discretion, general 
anesthesia may be induced prior to application of the head frame. For all types of 
stereotactic registration, planning is performed to identify the precise entry point on the 
skull as well as to define the target and the safest trajectory through the brain to reach it, 
as follows. A target point is selected on a coronal MRI slice through the hippocampal 
head, within the center of the hippocampus from medial-to-lateral as well as dorsal-
ventral (essentially the dentate gyrus). An initial entry point is selected on a coronal MRI 
slice through the hippocampal body at approximately the level of the lateral 
mesencephalic sulcus, which again is centered in the middle of the hippocampus. This 
trajectory is then expanded to the amygdala anteriorly, and to the cortical surface 
posteriorly. The defined trajectory is then further refined a) to maximize its extent within 
the hippocampus along its length from the level of the tectal plate to the amgydala; and 
b) to avoid cerebral vasculature and, if possible, entry into the ventricle. Attention is paid 
to the location of the optic radiation and thalamus to avoid proximity. Depending on the 
registration system, trajectory and target testing may be performed on the back table 
using a phantom. 
If not previously performed, general anesthesia is induced. The subject’s head is 
prepped by shaving or parting the hair to achieve a sterile field. If a head frame is used, 
the stereotactic arc is attached to the existing stereotactic frame and the entry and target 
coordinates are input.  Alternately, for frameless access, the stereotactic arm is mounted 
onto a skull clamp on the subject's head.  The entry point is marked and, following local 
anesthesia, a scalp incision is performed and a minimally invasive twist drill craniostomy 
is made through the skull. The dura is then opened, for example using a sequence of 
sharp and blunt instruments or cautery. The pia is opened using similar techniques. With 
aid of an alignment rod, the laser anchor bolt is then placed through the twist drill 
craniostomy and secured into the skull at the correct trajectory.  
After measurements associated with the trajectory from bone anchor to target are taken, 
the laser applicator probe is then advanced to the target site and held in place by the 
anchor bolt. If using a stereotactic head frame, the arc is then removed. If using 
frameless registration, the stereotactic arm and skull clamp are removed.  
The subject is then prepared for transfer to the MRI suite to localize the laser applicator 
probe and perform the ablation of the brain tissue. During transfer, the laser application 
probe and the anchor bolt are managed to ensure the anchor bolt is secure and the 

 
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probe is not damaged. Alternately, the procedure may be performed in an MRI-equipped 
operative suite. 
The subject is positioned within the MRI machine, with continued attention to the laser 
application probe and anchor bolt. An MRI scan is performed and interpreted by the 
surgeon to localize the laser application probe, confirming that the laser application 
probe is in the correct position and assessing for any adverse events during insertion or 
transfer.  
The correct ablation parameters (power and duration) are determined by the surgeon. 
Selected MRI images are transferred to the ablation system and safety set points are 
identified on the images to define the area of ablation to prevent overheating of adjacent 
tissues and critical structures. Additional safety set points are placed on the images to 
monitor for excessive heating at the site of the laser application probe.  
A test MRI-guided laser ablation is performed. After the test laser ablation is successfully 
completed, the MRI-guided laser ablation is performed at a wattage to achieve cell 
death.  During ablation, the surgeon monitors and interprets MRI images superimposed 
on real-time thermal maps displaying the distribution of the heat, to ensure safety and 
successful target treatment. Based on the MRI information, it is frequently necessary to 
reposition the laser application probe several times and repeat the laser ablation.  
At the end of the laser ablation surgery, a final gadolinium-enhanced MRI is acquired. 
The surgeon interprets the image to assess the ablation and confirm the ablation zone. 
In the MRI suite or operating room, the laser application probe and the anchor bolt are 
removed. If a stereotactic head frame or bone fiducials were used, they are removed. 
The scalp incision site is closed by suture, staple, or glue.  The subject is transported to 
the recovery room. 
Procedures aborted prior to skin incision may be rescheduled. Procedures aborted after 
skin incision may be retreated per Section 7.17. If a procedure is aborted without plans 
to reschedule a subsequent Visualase procedure, the subject will be followed for the 
modified intent-to-treat analysis of seizures and AEs.  
7.15 Scheduled Follow-up Visits 
All follow-up visit windows will be calculated from the date of the Visualase procedure. 
Should a subject miss a visit or the visit fall outside the pre-specified window, a study 
deviation must be reported and the original follow-up schedule maintained for 
subsequent visits.  
Data analyses will include follow-up visits, regardless of whether the visit occurs within 
the window. Therefore, a late visit is preferred over a missed visit. Follow-up visit 
windows are listed in Table 5 and are based on days post-Visualase procedure.  
Table 5: Follow-up Visit Windows 
Study Follow-up 
Visit 
Window 
(Calculated days post-procedure) 
Window Start 
(days post-
procedure) 
Target 
(days post-procedure) 
Window End 
(days post-procedure) 
Follow-up Visit 1 (14 day) 
7 
14 
21 
Follow-up Visit 2 (3 month) 
76 
90 
104 
Follow-up Visit 3 (6 month) 
150 
180 
210 
Follow-up Visit 4 (12 month) 
365 
365 
410 

 
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 Follow-up Visit 1: 14 ± 7 Days Post Visualase Procedure 
The following activities are to be performed at this visit: 
• 
Documentation of any changes in AEDs and concomitant psychotropic 
medications 
• 
Neurological exam, including oculomotor nerves and confrontation visual field 
test 
• 
AE assessment 
• 
Healthcare services utilization assessment 
• 
Review of seizure diary and documentation of any seizures; new diary may be 
given to subject to record future seizures 
• 
Seizure classification of any new types of seizures 
 Follow-up Visit 2: 3 Months (90 ± 14 Days) Post Visualase Procedure  
The following activities are to be performed at this visit: 
• 
Documentation of any changes in AEDs and concomitant psychotropic 
medications 
• 
Neurological exam, including oculomotor nerves and confrontation visual field 
test 
• 
AE assessment 
• 
Healthcare services utilization assessment 
• 
Review of seizure diary and documentation of any seizures; new diary given to 
subject to record future seizures  
• 
Seizure classification of any new types of seizures 
• 
Neuro-ophthalmologic exam (for subjects consented to CIP 4.0 prior to Follow-up 
Visit 2) 
o A neuro-ophthalmologic exam performed after the Visualase procedure 
but prior to reconsent may be used if it was performed per Section 7.7 
 Follow-up Visit 3: 6 Months (180 ± 30 Days) Post Visualase Procedure  
The following activities are to be performed at this visit: 
• 
Documentation of any changes in AEDs and concomitant psychotropic 
medications 
• 
Neurological exam, including oculomotor nerves and confrontation visual field 
test 
• 
AE assessment 
• 
Healthcare services utilization assessment 
• 
Neurocognitive assessments, administered by qualified study personnel: 
o Boston Naming Test 
o Controlled Oral Word Association Test (COWA) (FAS) 
o Emory Semantic Fluency Tasks 
o Emory Famous Faces Naming/Recognition 
o Rey Auditory Verbal Learning Test, Form GE-AB 

 
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o Wechsler Memory Scale (WMS-IV) Visual Reproduction Test 
• 
Mood, Quality of Life (QOL) and Seizure Severity surveys, completed by the 
subject: 
o Beck Depression Inventory II 
o Beck Anxiety Inventory 
o Quality of Life in Epilepsy Inventory (QOLIE-31) 
o SF-36 Health Survey (SF-36) 
o Seizure Severity Questionnaire (SSQ) Version 3 
• 
Review of seizure diary and documentation of any seizures; new diary given to 
subject to record future seizures  
• 
Seizure classification of any new types of seizures 
• 
Research MRI scan per Section 7.6 
Note: the subject must be scanned on the same scanner at the Baseline visit and 
at the 6-month visit 
• 
Neuro-ophthalmologic exam (for subjects who had an abnormal finding at Follow-
up Visit 2, and for subjects consented to CIP 4.0 after Follow-up Visit 2 but prior 
to Follow-up Visit 3) 
o A neuro-ophthalmologic exam performed after the Visualase procedure 
but prior to reconsent may be used if it was performed per Section 7.7 
 Follow-up Visit 4: 12 Months (365 + 45 Days) Post Visualase Procedure 
The following activities are to be performed at this visit: 
• 
Review and documentation of current AEDs and concomitant psychotropic 
medications 
• 
Neurological exam, including oculomotor nerves and confrontation visual field 
test 
• 
AE assessment 
• 
Healthcare services utilization assessment 
• 
Neurocognitive assessments, administered by qualified study personnel: 
o Boston Naming Test 
o Controlled Oral Word Association Test (COWA) (FAS) 
o Emory Semantic Fluency Tasks 
o Emory Famous Faces Naming/Recognition 
o Rey Auditory Verbal Learning Test, Form A 
o Wechsler Memory Scale (WMS-IV) Visual Reproduction Test 
o Wechsler Memory Scale (WMS-IV) Verbal Paired Associates 
• 
Mood, Quality of Life (QOL) and Seizure Severity surveys completed by the 
subject: 
o Beck Depression Inventory II 
o Beck Anxiety Inventory 
o Quality of Life in Epilepsy Inventory (QOLIE-31) 
o SF-36 Health Survey (SF-36) 

 
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o Seizure Severity Questionnaire (SSQ) Version 3 
• 
Review of seizure diary and documentation of any seizures 
• 
Seizure classification of any new types of seizures 
• 
Assessment of driving and employment/school status 
• 
Neuro-ophthalmologic exam (for subjects who had an unresolved abnormal 
finding at a previous visit, and for subjects consented to CIP 4.0 after Follow-up 
Visit 3 but prior to Follow-up Visit 4)  
o A neuro-ophthalmologic exam performed after the Visualase procedure 
but prior to reconsent may be used if it was performed per Section 7.7 
 Telephone Follow-up 
Any subjects who are unable to return in person for an office visit during the visit window 
may be contacted by phone as a last resort. This allows for identification of any AEs that 
have occurred, review of the subject’s seizure diary, and documentation of any changes 
in medications since last contact. In this case, the seizure diary may be sent to the site 
via email, mail or fax. Details of the conversation (including the date and names of the 
person who conducted the call and with whom they spoke), and the reason for the 
inability of the visit to occur must be documented.  
NOTE: A telephone follow-up is NOT the preferred method of follow-up, and every 
attempt should be made to have the subject return to the office for the follow-up 
visit. AEs that are noted at the time of this follow-up visit will be recorded on an 
AE CRF. A deviation form must be completed for any missed assessments. 
7.16 Unscheduled Follow-up Visits 
An unscheduled visit is defined as any visit not required by this study. When an 
unscheduled follow up visit occurs, the subject must be assessed for adverse events 
and healthcare utilizations per Section 7.18. AE and Healthcare Services Utilization 
eCRFs must be completed as appropriate. The following should be completed as 
possible/necessary at the visit: 
• 
Documentation of any changes in AEDs and concomitant psychotropic 
medications 
• 
Review of seizure diary and documentation of any seizures; new diary given to 
subject to record future seizures  
• 
Seizure classification of any new types of seizures 
A neuro-ophthalmologic exam should be performed for subjects who experience 
symptoms of a potential vision-related adverse event following the Visualase procedure. 
A neuro-ophthalmologic exam performed prior to reconsent to CIP 4.0 may be used, if 
the exam was performed per Section 7.7. 
7.17 Retreatment 
Subjects who fail to achieve Engel Class I seizure freedom or whose procedure could 
not be completed as intended prior to discharge may be evaluated for retreatment. 
Retreatment is defined as a subsequent Visualase procedure after the subject’s 
discharge following the initial Visualase procedure, to treat MTLE ipsilateral to the initial 
Visualase procedure and also within the temporal lobe. If it is determined that the 
ablation of additional tissue within the original target site may improve the outcome, the 

 
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justification for retreatment and supporting evidence will be entered on an eCRF and 
submitted to the Pre-Surgical Evaluation Committee for assessment per Section 7.12. 
Justification and supporting evidence for consideration of retreatment may include, but is 
not limited to, EEG demonstrating interictal and ictal discharges from the same temporal 
lobe, MRI showing no other lesions, same type of seizure behavior and auras, and no 
evidence of extra-temporal lesions.  
If the Pre-Surgical Evaluation Committee disagrees with the recommendation for 
retreatment, the subject may continue participation in the study per their original follow-
up schedule without retreatment. Alternatively, the subject may be withdrawn from the 
study.  
If the committee agrees with the recommendation for retreatment, the subject may be 
scheduled for an additional Visualase procedure. Retreated subjects will have the same 
assessments at the same intervals as they would for an initial procedure. The new 
follow-up visit windows will be calculated based on the date of the retreatment Visualase 
procedure.  
Subjects retreated with Visualase after the subject’s discharge from the original 
Visualase procedure will be considered to have failed the primary efficacy endpoint. 
However, their data will contribute to specified secondary 
 endpoints. 
Subjects who undergo open resection after a Visualase procedure will be considered to 
have failed the primary efficacy endpoint. Seizure and AE data will be collected per the 
standard of care for the site.  
Subjects who are retreated with Visualase or undergo open resection after a Visualase 
procedure will be followed for 12 months after the secondary procedure, or until the last 
enrolled subject completes Follow-up Visit 4 (12 months), whichever occurs first.  
All subjects will be assessed for safety for the duration of their participation in this study, 
regardless of whether they are retreated. 
7.18 Healthcare Services Utilization 
To assess use of healthcare resources specifically associated with epilepsy and the 
Visualase procedure, healthcare services utilization information will be collected during 
the Visualase procedure and hospital stay, and for any AEs requiring healthcare 
resources. Healthcare services utilization related to epilepsy and/or the Visualase 
procedure includes length of hospital stay, length of stay in ICU, ER visits, AEDs and 
psychotropic medications, physician office visits, and hospital readmissions. 
7.19 Study Exit 
A study exit eCRF is required for all subjects. Prior to exiting a subject from the study, it 
is recommended to follow the subject until all ongoing device-related, anesthesia-
related, and/or procedure-related AEs are resolved or unresolved with no further actions 
planned. Upon exiting from the study, no further study data will be collected and no 
further study visits will occur for the subject. All data available through the time of the 
subject’s exit will be used for analysis.  
Subjects are urged to remain in the study as long as possible but may be exited from the 
study for any of the following situations: 
• 
Subject has completed follow-up 
• 
Subject lost to follow-up 

 
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• 
Subject death 
• 
Subject did not meet inclusion/exclusion criteria (If ineligibility is discovered 
after the Visualase procedure, the subject will still be followed through 12 
months post procedure.) 
• 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another 
geographic location)  
• 
Investigator deems withdrawal necessary (e.g., the subject enrolls in a 
confounding investigational study, the subject fails to maintain adequate study 
compliance, or it is medically necessary or in the best interest of the subject) 
The following information is required to be documented at study exit: 
• 
Reason for exit  
• 
Date of study exit 
• 
If the subject is determined to be lost to follow-up, details of a minimum of 3 
contact attempts via 2 different methods (e.g., email, phone, and/or certified 
letter) must be recorded. 
7.20 Medications 
All prescription medications for an epilepsy or psychiatric indication (including rescue 
medications as taken) will be recorded on an electronic medication log from the time of 
enrollment. Generic medication names and doses will be captured, and any changes will 
be recorded on the medication log. 
AEDs and their doses should remain stable from 30 days prior to the procedure through 
the final visit. Transient weans of AEDs prior to the Visualase procedure are permitted 
for patient safety, and intravenous doses of AEDs during the procedure are permitted. 
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator.  
AED changes will be evaluated per Section 14.3.4. 
7.21 Role of the Sponsor Representatives 
Sponsor representatives may provide support as required for the study, including: 
• 
Study training relevant to the involvement of personnel conducting study activities 
and Investigator responsibilities 
• 
Technical support during the Visualase procedure under the supervision of a study 
Investigator  
• 
Intraoperative data collection support (e.g., acquisition of system logs and files 
from the Visualase workstation) under the supervision of a study Investigator, but 
no data entry will be performed by Medtronic personnel or their representatives at 
sites 
• 
Monitoring and auditing activities 
8 INVESTIGATIONAL DEVICE / EQUIPMENT STORAGE, 
HANDLING AND TRACEABILITY 
The Visualase System comprises a laser energy source, a pump for circulating coolant 
through the applicator, a computer workstation (Visualase capital equipment), and a 

 
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cooled laser applicator system and optional neuro accessory kit (Visualase disposables). 
All components of the Visualase System are FDA-cleared for use in neurosurgical 
procedures.  
As the Visualase System is commercially released, no special receipt, storage, or 
reconciliation requirements apply. Management of Visualase System inventories by 
investigational sites will be in accordance with their respective operating policies.   
Visualase capital equipment and disposables will enter the accountability system when 
they are accessed/opened with the intent to be used within the context of the study, at 
which point they become “investigational devices.” Therefore, none of the Visualase 
capital equipment and disposables will be labelled as investigational, and the date they 
are accessed/opened with the intent to be used within the context of the study will be 
considered the date of receipt by the site.  
For each Visualase disposable opened with the intent of being used within the context of 
the study, the following information will be documented: 
• 
Model Number 
• 
Lot number 
• 
Date used/opened 
• 
Subject ID 
• 
Date returned/disposed 
• 
Final disposition 
• 
Reason for return/method of disposal 
• 
Name/initials of the person who returned or disposed the device 
• 
Quantity 
For Visualase capital equipment, the following information will be documented: 
• 
Model number 
• 
Serial number 
• 
Date installed 
• 
Date returned/disposed (if applicable) 
• 
Final disposition 
• 
Reason for return/method of disposal 
• 
Name/initials of the person who returned or disposed the device (if applicable) 
• 
Quantity 
 
Additionally, use and disposition of investigational devices will be documented and 
tracked on eCRFs.  
The Sponsor will cover the cost of investigational disposables for study procedures. 
9 STUDY DEVIATIONS 
The investigator should not deviate from the CIP, except under emergency 
circumstances to protect the rights, safety or well-being of human subjects. A study 
deviation is defined as an event within a study that did not occur according to the CIP or 
the Clinical Trial Agreement, including, but not limited to, the following: 
• 
Failure to obtain informed consent prior to participation in the study 
• 
Incorrect version of the consent form rendered to the subject 
• 
Failure to obtain IRB approval before conducting study-related activities 

 
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• 
Enrollment of subjects during lapse of IRB approval 
• 
Investigator exceeding enrollment limits specified by Sponsor or IRB 
• 
Treated subject did not meet inclusion/exclusion criteria. 
• 
Subject did not attend follow-up visit (missed visit) 
• 
Follow-up visit outside of the protocol-defined window 
• 
Unauthorized use of an investigational product in the study by a physician 
who has not signed a Trial Agreement and/or whose training was not 
documented 
• 
AE not reported by Investigator in the required regulatory timeframe 
 
If a deviation involves a failure to obtain a subject’s consent prior to use of an 
investigational device or is made to protect the life or physical well-being of a subject in 
an emergency, the deviation must be reported to the IRB as well as Medtronic within five 
(5) working days. Reporting of all other study deviations should comply with IRB policies 
and must be reported to Medtronic as soon as possible upon the site becoming aware of 
the deviation. Refer to Investigator Reports, Table 9 for deviation reporting requirements 
and timeframes for reporting to Medtronic.  
All study deviations must be reported on an eCRF regardless of whether medically 
justifiable, an inadvertent occurrence, or taken to protect the subject in an emergency. 
Medtronic is responsible for analyzing deviations, assessing their significance, and 
identifying any additional corrective and/or preventive actions (e.g., amend the CIP, 
conduct additional training, terminate the investigation). Repetitive or serious 
Investigator compliance issues may result in initiation of a corrective action plan with the 
Investigator and site, and in some cases, necessitate suspending enrollment until the 
problem is resolved or ultimately terminating the Investigator's participation in the study.  
10 ADVERSE EVENTS AND DEVICE DEFICIENCIES 
Timely, accurate, and complete reporting and analysis of safety information for clinical 
studies are crucial for the protection of subjects. Reporting and analysis of safety data 
are mandated by regulatory authorities worldwide. Medtronic has established 
procedures in conformity with worldwide regulatory requirements to ensure appropriate 
reporting of safety information. This study is conducted in accordance with these 
procedures and regulations. 
10.1 Adverse Event and Device Deficiency Definitions 
Adverse event and device deficiency definitions are provided in Table 6. Where the 
definition indicates “device”, it refers to any Visualase System component used in the 
study.  

 
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Table 6: Adverse Event Definitions 
 
General 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory 
findings) in subjects, users or other persons, whether or not 
related to the investigational medical device 
 
NOTE 1: This definition includes events related to the 
investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the 
procedures involved. 
NOTE 3: For users or other persons, this definition is restricted 
to events related to investigational medical devices. 
(ISO 14155:2011, 3.2) 
 
NOTE: The specific adverse events collected for this study are 
described in Section 10.2.1 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical 
device 
 
NOTE 1: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from an 
error use or from intentional misuse of the investigational 
medical device. (ISO 14155:2011, 3.1) 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance.  
 
NOTE: Device deficiencies include malfunctions, use errors and 
inadequate labeling (ISO 14155:2011, 3.15) 
Relatedness 
Device-Related 
An adverse event that is directly related to the use, presence 
and/or performance of the Visualase System. 
Procedure-Related 
An adverse event that is not directly related to the Visualase 
System but is directly attributable to the surgical procedure in 
which Visualase was used. 
For the purpose of determining adverse event relatedness, the 
procedure begins at first scalp incision and ends at closure of 
all scalp incisions. 
Anesthesia-Related 
An adverse event that is not directly related to the Visualase 
System, nor to the Visualase procedure, but is directly 
attributable to the anesthesia for the Visualase procedure. 
Epilepsy-Related 
An adverse event related to the subject’s epilepsy or AEDs. 
 
 

 
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Seriousness 
Serious Adverse Event (SAE) 
 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that 
either resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body 
function, or 
3) in-patient or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure 
or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality 
or birth defect 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in 
health, is not considered a serious adverse event.  
(ISO 14155:2011, 3.37) 
 
Serious Adverse Device Effect  Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
(ISO 14155:2011, 3.36)  
Unanticipated Adverse Device 
Effect (UADE) 
 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death, was not previously 
identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary 
plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or 
welfare of subjects. (21 CFR 812.3(s)) 
Duration 
Transient 
Short-lived, not permanent. For the purpose of this study, 
adverse events lasting 30 days or fewer are considered 
transient. 
Prolonged 
Continuing, persistent. For the purpose of this study, adverse 
events lasting more than 30 days but that do not meet the 
definition of permanent.  
Permanent 
Long-lasting, for a year or longer. For the purpose of this study, 
adverse events not resolved at study exit will be considered 
permanent.  
Severity 
Mild 
A type of adverse event that is usually transient and may require 
only minimal treatment or therapeutic intervention. The event 
does not generally interfere with usual activities of daily living. 
(CDISC) 
Moderate 
A type of adverse event that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research participant.  
(CDISC) 

 
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Severe 
A type of adverse event that interrupts usual activities of daily 
living, or significantly affects clinical status, or may require 
intensive therapeutic intervention. (CDISC) 
Other 
Pre-operative 
An adverse event that occurs after the informed consent has 
been signed but before the first scalp incision for the Visualase 
procedure 
Intra-operative 
An adverse event that occurs during the Visualase procedure, 
after the first scalp incision and prior to completion of all scalp 
incision closures. 
Post-operative 
An adverse event that occurs after the Visualase procedure, 
after completion of all scalp incision closures. 
Unavoidable Event 
 
(These events need not be 
reported unless the event 
worsens or is present 
outside the stated timeframe 
post procedure.) 
 
 
An event inherent to a surgical procedure that is expected to 
occur in all subjects for a projected duration according to the 
Investigator’s opinion, including, but not limited to:  
 
Event Description 
Timeframe 
(hours) Post 
Visualase 
Procedure 
Anesthesia related nausea / vomiting  
24 
Low-grade fever (<100°F or 37.8°C) 
48 
Pain at incisional/access site 
120 
Mild to moderate bruising / ecchymosis 168 (1 week) 
Sleep problems or insomnia 
72 
Back pain related to laying on table 
72 
Pain/discomfort/stiffness related to 
immobilization during procedure 
72 
Periorbital edema related to stereotactic 
frame pin placement 
72 
Headache 
168 (1 week) 
Scalp pain 
168 (1 week) 
Scalp numbness 
168 (1 week) 
Blurry vision 
336 (2 weeks) 
Mild cerebral edema 
1008 (6 
weeks) 
Death Classification 
Sudden Unexpected Death in 
Epilepsy (SUDEP) 
A sudden, unexpected death of someone with epilepsy, who was 
otherwise healthy. May be found lying face down and/or found 
dead in bed without having had a convulsive seizure. There may 
or may not be evidence of a seizure close to the time of death.  
The death is not known to be related to an accident or seizure 
emergency such as status epilepticus. If an autopsy is 
performed, no other of cause of death is found.42  

 
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10.2 Adverse Event and Device Deficiency Assessment 
 Study Reportable Adverse Events 
Adverse event definitions are provided in Table 6. To ensure all AEs that are potentially 
relevant to the SLATE study are collected, the following adverse events will be collected 
and reported to Medtronic during the study, starting from the time the subject signs the 
informed consent: 
• 
Device-related AEs 
• 
Procedure-related AEs 
• 
Anesthesia-related AEs 
• 
Epilepsy-related AEs 
• 
All SAEs 
Each AE must be recorded on a separate AE eCRF and include a description of the 
event, the diagnosis, date of event onset, the date the site became aware of the event, 
diagnostic tests and procedures performed, actions taken as a result of the event, 
relatedness and severity of the event and the outcome of the event. Subject deaths are 
also required to be reported. Refer to Section 10.5 for subject death collection and 
reporting requirements. 
Documented pre-existing conditions are not considered AEs unless the nature or 
severity of the condition has worsened. Unavoidable events listed in Table 6 need not be 
reported unless the AE worsens or is present outside the stated timeframe post-
procedure. 
Seizures are inherent to the disease state of the target population of this study and are 
expected to continue in a portion of subjects after the Visualase procedure. While all 
seizures will be reported and captured in a seizure diary, they will not be reported as 
AEs unless there is a worsening in the nature, severity or degree of incidence, according 
to the Investigator’s opinion. Following are examples of seizures that are reportable as 
AEs: 
• 
Worsening in clinical manifestations (for example, subject began having falls with 
their seizures which was not previously a component) 
• 
Seizure frequency is increased 
• 
Subject experiences a new seizure type or non-epileptic seizure 
• 
Seizure led to injury or death 
Memory and naming decline are established risks following epilepsy surgery involving 
the temporal lobe. In standard ATL resections, changes in these cognitive scores are 
expected and consequently are not considered as adverse events unless the magnitude 
of change exceeds the site investigator’s expectations.  
This study employs a rigorous battery of neuropsychological tests to better characterize 
individual change in naming and memory following laser ablation. Changes in these 
cognitive scores are expected and consequently are not considered as adverse events 
unless the magnitude of change exceeds expectations by the site investigator. 
Similarly, adverse events related to depression and anxiety will also be based on site 
investigator assessment, and a decline in mood assessment scores alone will not be 
considered an adverse event. 

 
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For AEs that require immediate reporting (see Table 9), initial reporting may be done by 
completing as much information as possible on an AE eCRF. The remainder of the AE 
eCRF must be completed as soon as possible.  
 Device Deficiencies 
Device deficiency information will be collected throughout the study and reported to 
Medtronic on a Device Deficiency eCRF. Note that device deficiencies that result in an 
adverse device effect (ADE) to the subject should be captured as an adverse event only. 
Device deficiencies that did not lead to an AE should be reported as Device Deficiencies 
only and will be evaluated by the Investigator to determine if they could have led to a 
Serious Adverse Device Effect (SADE) (i.e., if suitable action had not been taken, if 
intervention had not been made, or if the circumstances had been less fortunate). 
 Adverse Event Updates and Resolution 
For any changes in status of a previously reported AE (e.g., change in actions taken, 
change in outcome, change in relatedness or severity), an update to the original AE 
eCRF must be completed. All AEs must be followed until the AE has been resolved, is 
unresolved with no further actions planned, the subject exits the study, or until study 
closure, whichever occurs first.  
If a subject is being considered for exit from the study prior to study closure, all efforts 
should be made to continue following the subject until all unresolved procedure-related, 
anesthesia-related, or device-related AEs, as classified by the Investigator, are resolved 
or are unresolved with no further actions planned.  
At the time of study exit, all AEs with an outcome of “Unresolved, further actions or 
treatment planned” must be reviewed by the Investigator, and an update to the original 
AE must be reported. At a minimum, if there are no changes to the description, 
relatedness, severity, tests and procedures, or actions taken, the outcome must be 
updated to reflect “Unresolved at time of study closure.” 
Reportable adverse events that may be deemed transient, prolonged, or permanent in 
nature (see Appendix F) and are unresolved when the subject exits the study will be 
considered permanent.  
10.3 Adverse Event Classification and Device Deficiency Review and 
Reporting 
All AEs and device deficiencies will be reviewed by a Medtronic representative for 
completeness and accuracy and will request clarification and/or additional information 
from the Investigator when necessary.  
Adverse events will be classified according to the definitions provided in Table 6.  
Medtronic will utilize MedDRA, the Medical Dictionary for Regulatory Activities, to assign 
a MedDRA term for each AE based on the information provided by the Investigator.  
Regulatory reporting of AEs will be completed according to FDA requirements. Refer to 
Section 10.4 for a list of required Investigator and Medtronic reporting requirements and 
timeframes. It is the responsibility of the Investigator to abide by any additional AE 
reporting requirements stipulated by the IRB responsible for oversight of the study. 
Appendix E contains the Foreseeable Adverse Event List (FAL), which is a list of AEs 
related to the system or procedure that have been observed in previous relevant 

 
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(epilepsy) studies and may be experienced by subjects. This list may help to assess if an 
AE is unexpected in nature.  
For emergency contact regarding a UADE, SAE and/or SADE, contact a clinical 
study representative immediately (refer to the study contact list provided in the 
site’s study documents binder/investigator site file or refer to the contact 
information provided in this CIP). 
AEs and deaths will be classified according to the responsibilities and parameters 
outlined in Table 7 below.  
Table 7: Adverse Event Classification Responsibilities 
What is Classified?  
Who Classifies? 
Classification Parameters 
Timing of the Event 
Investigator 
Pre-operative, intra-operative or post-
operative 
Relatedness 
 
 
Investigator 
Procedure 
Anesthesia 
Device (Visualase System) 
Epilepsy 
Sponsor 
Procedure 
Anesthesia 
Device (Visualase System) 
Epilepsy 
Seriousness 
Investigator 
Serious adverse event 
Sponsor 
Serious adverse event 
Unanticipated adverse device effect  
Severity 
Investigator 
Mild, moderate, or severe 
Sponsor 
Mild, moderate, or severe 
Diagnosis 
Investigator 
Based on presenting signs and symptoms and 
other supporting data 
Sponsor 
MedDRA term assigned based on the data 
provided by Investigator 
Death Classification 
Investigator 
SUDEP 
 
10.4 Adverse Event and Device Deficiency Reporting Requirements 
Regulatory reporting of AEs will be completed according to FDA requirements. Refer to 
Table 8 for a list of required Investigator reporting requirements and timeframes, and of 
required Medtronic reporting requirements and timeframes. 
The Investigator must submit to the Sponsor and to the reviewing IRB a report of any 
UADE occurring during an investigation as soon as possible, but in no event later than 
10 working days after the Investigator first learns of the effect. Medtronic is also required 
to report these events to the FDA. It is the responsibility of the Investigator to abide by 
any additional AE reporting requirements stipulated by the IRB responsible for oversight 
of the study. 

 
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10.5 Subject Death 
The AE that led to the subject death must be documented on an Adverse Event form as 
soon as possible after the Investigator first learns of the death. A study exit eCRF must 
also be completed. 
10.6 Product Complaint Reporting 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a medical device that has been placed on the market. 
Since all device components used in the SLATE study are market-released, product 
complaint reporting is applicable. This includes when an AE is related to a market-
released device during the study. The reporting of product complaints is not part of the 
clinical study and should be performed in addition to the AE reporting requirements. 
Refer to FDA regulations (21 CFR Part 803) for reporting requirements. 
11 RISK ANALYSIS 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the life 
of a product, from the business analysis phase through development, market release, 
and post-market surveillance. The risk analysis process for the SLATE study was 
performed to ensure that the level of risk is acceptable prior to starting the clinical study. 
Possible risks of the Visualase procedure in this study include, but are not limited to, the 
foreseeable adverse events listed in Appendix E. There may be other discomforts and 
risks related to the Visualase device and/or this study that are not foreseen at this time.  
There is a possibility of risks to an unborn child. These risks are unknown. Women who 
are pregnant at the time of the procedure or plan to become pregnant during the course 
of the study are excluded from participating.
Possible additional risks associated with participation in the SLATE study include, but 
are not limited to, the following: 
• 
Ineffective treatment: 
o Risks associated with continued seizures, including injury and sudden 
unexpected death in epilepsy (SUDEP) 
• 
Neuropsychological testing: 
o Mild emotional stress 
o Embarrassment or unpleasant feelings 
o Mild emotional discomfort due to personal questions about mood or 
behavior 
• 
Research MRI: 
o Bothersome MRI machine noise 
o Feelings of claustrophobia 
o Injury if objects containing iron or metal are present in the subject or 
anywhere in the room 
• 
Research MRI contrast agent (gadolinium): 
o Discomfort 
 

 
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o Tingling or warmth in the lips 
o Metallic taste in the mouth 
o Tingling in the arm 
o Nausea 
o Headache 
o Allergic reaction to gadolinium 
• 
Visual field exam 
o Fatigue 
• 
Neuro-ophthalmologic exam dilating eye drops 
o Stinging 
o Blurry vision 
o Sensitivity to light 
o Allergic reaction 
11.1 Risk Minimization 
The Visualase System is FDA-cleared for coagulation and necrotization in Neurosurgical 
procedures. It is used in this study as an unaltered, commercially-available medical 
device that is subject to Quality System Regulations and Good Manufacturing Practices 
per 21 CFR Part 820. A risk assessment for the device has been conducted by the 
manufacturer per ISO 14971 and is included as part of the Design History File that 
supports commercial use of the device. Appropriate mitigations to the application, design 
and manufacturing process related risks have been implemented. 
While the Visualase System is cleared for use in soft tissue ablation in neurosurgical 
procedures, the specific use to treat epilepsy is considered investigational in this study. 
The following measures will be taken to further minimize the risks arising from 
participation in this study: 
• 
The Sponsor will only involve Investigators and institutions who are experienced 
with the use of the Visualase System and the surgical procedures necessary to 
treat patients with MTLE 
• 
Proper subject preoperative assessment, surgical care, and postoperative follow-
up will be maintained to minimize the risk associated with study procedures 
• 
The Visualase System will be used according to the Instructions for Use. 
Technique Recommendations for the SLATE study will be provided to all study 
surgeons. 
• 
Sponsor representatives will be present during Visualase procedures for 
technical support 
• 
An independent Data Monitoring Committee (Appendix D) will review AEs and 
aggregate clinical study data in order to make recommendations regarding study 
conduct, should safety concerns be identified 
• 
Only subjects who meet appropriate study inclusion and exclusion criteria will be 
selected 
• 
The Sponsor will only involve Investigators and institutions who are qualified by 
training and experience to conduct clinical research 

 
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11.2 Potential Benefits 
The Visualase System is indicated for use to necrotize or coagulate tissue in 
Neurosurgical procedures. Although no assurances or guarantees can be made, there is 
a reasonable expectation that laser ablation of epileptogenic foci in patients with MTLE 
may result in seizure freedom or reduction in seizure frequency or severity. Seizure 
control is expected to yield improvements in health-related quality of life and reduce the 
risks of seizure-related injury and sudden unexplained death in epilepsy. Other potential 
benefits include providing subjects with a less invasive treatment option, potentially 
reducing time to return to normal activities and the risks of open resective surgery such 
as neuropsychological defects.20-29  
The information gained from this study could result in the improved management of 
MTLE. Additionally, information collected from this study may assist in the design of new 
product(s)/therapy(ies) and/or instructions for use.  
11.3 Risk-to-Benefit Analysis 
Although there are risks affiliated with involvement in this study, as there are with any 
intracranial surgical procedure, it is believed that for properly selected subjects the 
potential benefits outweigh the risks. 
 
As the Visualase System is indicated for use in neurosurgical procedures, investigational 
sites may offer laser ablation for MTLE patients outside of this study. For patients who 
would otherwise choose laser ablation regardless of study participation, the additional 
risks of participating in this study are not materially different, and the medical benefits 
are no greater than seeking the same treatment outside of the study. 
12 MONITORING 
It is the responsibility of Medtronic to ensure proper monitoring of this clinical study. 
Trained Medtronic personnel or delegates appointed by Medtronic may perform study 
monitoring at the study site in order to ensure that the study is conducted in accordance 
with the CIP, the Clinical Trial Agreement, and applicable regulatory and local 
requirements. Medtronic, or delegates, must therefore be allowed access to the subjects’ 
medical histories (clinic and hospital records, and other source data/documentation) 
upon request as per the subject informed consent form, HIPAA release authorization, 
and Clinical Trial Agreement. The Principal Investigator should also be available during 
monitoring visits.  
12.1 Monitoring Visits 
Monitors review site regulatory and study compliance by identifying findings of non-
compliance and communicating those findings with recommendations for 
preventative/corrective actions to site personnel. Monitors may work with study 
personnel to determine appropriate corrective action recommendations and to identify 
trends within the study or at a particular site.  
Frequency of monitoring visits may be based upon subject enrollment, duration of the 
study, site study compliance, number of AEs, number of deviations, findings from 
previous monitoring visits and any suspected inconsistency in data that requires 
investigation. Regulatory documents may be reviewed at each study site. Monitoring for 
the study, including site initiation visits, interim monitoring visits, and closeout visits, will 
be done in accordance to the study-specific monitoring plan. 

 
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13 PLANNED STUDY CLOSURE, EARLY TERMINATION OR 
STUDY SUSPENSION 
13.1 Planned Study Closure 
Study closure is a process initiated by distribution of a study closure letter. Study closure 
is defined as closure of a clinical study that occurs when Medtronic and/or regulatory 
requirements have been satisfied per the CIP and/or by a decision by Medtronic or 
regulatory authority, whichever occurs first. The study closure process is complete upon 
distribution of the final report or after final payments, whichever occurs last. Ongoing IRB 
oversight is required until the overall study closure process is complete. Refer to Section 
7.19 for additional information regarding study exit procedures. Medical care may be 
provided by the treating physician per the site’s standard of care after study closure. 
13.2 Early Termination or Suspension 
Early termination of the study is defined as the closure of the clinical study that occurs 
prior to meeting defined endpoints. This is possible for the whole study or a single site. 
Study suspension is a temporary postponement of study activities related to enrollment 
and distribution of the product. This is possible for the whole study or a single site.  
 Study-wide Termination or Suspension 
Possible reasons for considering study suspension or termination of the study include 
but are not limited to: 
• 
AEs associated with the system or product under investigation which might 
endanger the safety or welfare of the subject 
• 
Observed/suspected performance is different from the product’s design intent 
• 
Decision by Medtronic or FDA  
• 
Recommendation of early termination by the DMC  
 Investigator/Site Termination or Suspension 
Possible reasons for clinical Investigator or site termination or suspension include but 
are not limited to: 
• 
Failure to obtain initial IRB approval, failure to obtain annual renewal of IRB 
approval of the study, or IRB suspension of the site or Investigator 
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement 
(e.g., failure to submit data in a timely manner, failure to follow-up on data 
queries and monitoring findings in a timely manner, etc.) or persistent non-
compliance to the clinical investigation (e.g., failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-
ups)  
• 
Fraud or fraudulent misconduct is discovered (as defined by local law and 
regulations)  
• 
Investigator request (e.g., no longer able to support the study)  

 
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13.3 Procedures for Termination or Suspension 
 Medtronic-initiated and Regulatory Authority-initiated 
• 
In the case of study suspension or termination, Medtronic will promptly inform 
the clinical Investigators and provide the reasons for termination or 
suspension. If the termination or suspension is Medtronic-initiated, Medtronic 
will also inform the FDA.  
• 
In the case of study termination, the Investigator must inform the subjects  
• 
In the case of a study suspension, subject enrollment must stop until the 
suspension is lifted by Medtronic 
• 
In the case of a study suspension, enrolled subjects should continue to be 
followed out of consideration of their safety, rights and welfare 
• 
In the case of study termination or suspension for reasons other than a 
temporary IRB approval lapse, the Investigator or Medtronic will promptly 
inform the IRB 
 Investigator-initiated 
• 
The Investigator will inform Medtronic and provide a detailed written 
explanation of the termination or suspension 
• 
The Investigator will promptly inform the institution (if required)  
• 
The Investigator will promptly inform the IRB  
• 
The Investigator will promptly inform the subjects  
• 
In the case of a study suspension, subjects enrolled should continue to be 
followed out of consideration of their safety, rights and welfare 
 IRB-initiated 
• 
The Investigator will inform Medtronic and provide a detailed written 
explanation of the termination or suspension within 5 business days 
• 
Subject enrollment must stop until the suspension is lifted 
• 
Subjects already enrolled should continue to be followed in accordance with 
IRB policy or its determination that an overriding safety concern or ethical 
issue is involved 
• 
The Investigator will inform his/her institution (if required)  
• 
The Investigator will promptly inform the subjects, with the rationale for the 
study termination or suspension 
14 STATISTICAL METHODS AND DATA ANALYSIS 
14.1 Sample Size Determination 
Subjects will be considered enrolled upon the signing of a consent form. It is anticipated 
that once enrolled, some subjects will not proceed to the Visualase procedure due to 
failure at their pre-surgical evaluation, changes in clinical status, or non-compliance to 
protocol. Based on these factors, and on previous reports of attrition in similar studies, 
the assumed attrition rate is 30%. To account for this attrition, up to 215 subjects may be 
enrolled to ensure at least 150 subjects are treated with the Visualase procedure. 

 
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The primary efficacy endpoint is the 12-month seizure-free rate. The analysis of the 
primary efficacy endpoint will include a point estimate and exact 95% confidence interval 
(CI) of the rate. The lower bound of the 95% CI of the seizure freedom rate following the 
Visualase procedure must be above 43%. Based on published and unpublished 
accounts of seizure freedom rates following laser ablation for MTLE, it is expected that 
approximately 56% of subjects who undergo the Visualase procedure will be seizure free 
through 12 months post procedure. Given these assumptions, 89% power can be 
achieved with data from 150 treated subjects.   
Certain secondary endpoint assessments will be made using subject questionnaires. 
These self-reported instruments are influenced by primary language. Validated 
translations are not available in all languages, thus enrollment will be limited to subjects 
who can complete these assessments in either English or Spanish. Further, the impact 
of grouping across translations for analysis is an important consideration. Therefore, for 
the specified secondary cognitive and QOL endpoints, the subset of only the English-
language versions will be used for analysis. To preserve adequate statistical power for 
analysis of this subset, the total Spanish language enrollment will be restricted to no 
more than 40% of the total study-wide enrollment population.   
14.2 General Considerations 
Statistical analyses will be performed using SAS Software, Version 9.4 or later. 
All statistical tests will be conducted at a two-sided alpha level of 0.05 unless otherwise 
stated. 
A Statistical Analysis Plan (SAP) will include a comprehensive description of the 
statistical methods and reports to be included in the final study report. Any change to the 
analysis methods described in the protocol will require an amendment only if it changes 
a principal feature of the protocol. Any other change to the analysis methods described 
in the protocol, and the justification for making the change, will be described in the 
clinical study report.  
14.3 Analysis Populations 
 Safety Population  
All subjects who sign a consent form (i.e., are enrolled) will be included in the safety 
population
 
 
All summaries of 
safety data will be based on the safety population.  
 Modified Intent to Treat (mITT) Population 
All subjects who enter the operating room and start the Visualase procedure (i.e., 
undergo scalp incision) will be included in the mITT analysis population. The mITT 
population will be the primary analysis population for efficacy evaluations. Missing 
primary and secondary efficacy endpoints that are testable will be imputed. Imputation 
for the specified secondary cognitive and QOL efficacy endpoints will only include the 
English language version subset. 

 
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14.4 Primary Safety Endpoint 
The primary safety endpoint is the incidence of qualifying device-, procedure-, or 
anesthesia-related adverse events (defined in Appendix F) through 12 months following 
the Visualase procedure.   
 Hypothesis 
It is hypothesized that the upper bound of the 95% confidence interval for the proportion 
of subjects experiencing any qualifying device-, procedure-, or anesthesia-related 
adverse events (per Appendix F) through 12 months following the Visualase procedure 
will be less than 40%. 
 
Null Hypothesis: 
 
πV ≥ 0.4 
Alternate Hypothesis:  
πV < 0.4 
 
Where πV is the proportion of subjects treated with Visualase experiencing any 
qualifying AE. 
 Performance Requirements 
The performance criteria of an AE rate of 40% is based on the analysis by Attiah et al.30 
 Analysis Methods 
An exact 95% confidence interval (Clopper43) will be calculated to determine if the upper 
bound of the CI for qualified AEs is less than 40%. 
14.5 Primary Efficacy Endpoint 
The primary efficacy endpoint is seizure freedom (defined as Engel Class I, Appendix C) 
at 12 months following the Visualase procedure (starting at 30 days post-procedure 
through 365 days post-procedure, to align with Engel Class I definition). 
 Hypothesis 
It is hypothesized that the lower bound of the 95% confidence interval for seizure 
freedom at 12 months following the Visualase procedure will be greater than 43%. 
 
Null Hypothesis: 
 
πV ≤ 0.43 

 
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Alternate Hypothesis:  
πV > 0.43 
 
Where πV is the proportion of subjects treated with Visualase experiencing no 
seizures. 
 
An exact 95% confidence interval will be calculated to determine if the lower bound of 
the CI for seizure freedom at 12 months following the Visualase procedure (πV) will be 
greater than 43%. 
 Performance Requirements 
The performance criterion of seizure-free percentage greater than 43% is based on the 
analysis by Attiah et al.30 
 Analysis Methods 
An exact 95% confidence interval for the percentage of subjects who are seizure free will 
be calculated. 
14.6 Secondary Endpoints 
All secondary endpoints have specific hypotheses to be tested. The hypotheses 
associated with each of these secondary endpoints will be tested in a hierarchical 
fashion. If the primary efficacy endpoint is not significant, then no secondary endpoints 
will be tested. Testing of these secondary endpoints will proceed in order using an alpha 
of 0.05 and will stop if any test fails to reach significance. 
 Secondary Endpoint #1 
Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following the 
Visualase procedure compared to historical control for continued medical therapy  
 
It is hypothesized that the seizure freedom at 12 months following the Visualase 
procedure will be superior to 8% reported in the literature for continued medical therapy. 
 
 
Null Hypothesis: 
 
πV ≤ 8% 
 
Alternate Hypothesis:  
πV > 8% 
 
 
Where πV is the proportion of subjects treated with Visualase experiencing no 
seizures. 
 
An exact 95% confidence interval for the percentage of subjects who are seizure free will 
be calculated. 
 Secondary Endpoint #2 
Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following the 
Visualase procedure, including subjects who are retreated with Visualase 
 
It is hypothesized that the lower bound of the 95% confidence interval for seizure 
freedom at 12 months following the Visualase procedure, including subjects retreated 
with Visualase (per Section 7.17), will be greater than 43%. Subjects retreated with 
Visualase will count toward the secondary efficacy endpoint based on their outcome 
after retreatment. If they have become seizure free and have reached 12 months follow-

 
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up from time of retreatment, they are counted as seizure free. Otherwise, they will count 
as not seizure free. 
 
Null Hypothesis: 
 
πV ≤ 0.43 
Alternate Hypothesis:  
πV > 0.43 
 
Where πV is the proportion of subjects treated with Visualase experiencing no 
seizures. 
 
An exact 95% confidence interval will be calculated to determine if the lower bound of 
the CI for seizure freedom at 12 months (πV) following a subject’s last Visualase 
procedure, including patients retreated with Visualase, will be greater than 43%. 
 Secondary Endpoint #3 
Within-subject change of Boston Naming Test score (English language version), 
from baseline to 12 months following the Visualase procedure 
 
It is hypothesized that the Boston Naming Test score will not decrease from baseline to 
12 months following the Visualase procedure. 
 
Null Hypothesis: 
 
μ (V-BNT - BSL-BNT) + δ ≤ 0 
Alternate Hypothesis:  
μ (V-BNT - BSL-BNT) + δ > 0 
 
Where μ (V-BNT - BSL-BNT) = mean difference in the Boston Naming Test score 
from baseline to Month 12 post Visualase. 
 
A non-inferiority test will be performed using a paired t-test, with a non-inferiority delta 
(δ) of one Reliable Change Index (RCI) of 5 points, to test the hypothesis of no 
reduction. The 5-point RCI is based on published literature.44  A two-tailed alpha of 0.05 
will be used.  
 Secondary Endpoint #4 
Within-subject change of Rey Auditory Verbal Learning Test 5-Trial Total score 
(English language version), from baseline to 12 months following the Visualase 
procedure 
 
It is hypothesized that the Rey Auditory Verbal Learning Test 5-Trial Total score will not 
decrease from baseline to 12 months following the Visualase procedure. 
 
Null Hypothesis: 
 
μ (V-RAVLT - BSL-RAVLT) + δ ≤ 0 
Alternate Hypothesis:  
μ (V-RAVLT - BSL-RAVLT) + δ > 0 
 
Where μ (V-RAVLT - BSL-RAVLT) = mean difference in the Rey Auditory Verbal 
Learning Test 5-Trial Total score from baseline to Month 12 post Visualase. 
 
A non-inferiority test will be performed using a paired t-test, with a non-inferiority delta 
(δ) of one Reliable Change Index (RCI) of 15 points, to test the hypothesis of no 
reduction. The 15-point RCI is based on published literature.44 A two-tailed alpha of 0.05 
will be used. 

 
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 Secondary Endpoint #5 
Within-subject change of the Quality of Life in Epilepsy inventory (QOLIE-31) 
score (English language version), from baseline to 12 months following the 
Visualase procedure, categorized as -1 if the decrease is clinically significant (≤ -
11.8), categorized as 0 if not clinically significant (-11.7 to +11.7), and categorized 
as +1 if the increase is clinically significant (≥11.8). 
 
It is hypothesized that the QOLIE-31 score will increase (improve) from baseline to 12 
months following the Visualase procedure. 
 
Null Hypothesis: 
 
M (V-QOLIE-31 - BSL-QOLIE-31) ≤ 0 
Alternate Hypothesis:  
M (V-QOLIE-31 - BSL-QOLIE-31) > 0 
 
Where M (V-QOLIE-31 - BSL-QOLIE-31) = sign-test statistic ([increases-
decreases]/2) in the Quality of Life in Epilepsy inventory from baseline to Month 
12 post Visualase. 
 
A sign test will be used to determine if the median categorical change is significantly 
greater than zero. The Minimally Clinically Important Difference (MCID) of 11.8 points for 
the QOLIE-31 is based on published literature.45  
 Secondary Endpoint #6 
Within-subject change of SF-36 quality of life questionnaire Mental Component 
Score (English language version), from baseline to 12 months following the 
Visualase procedure, categorized as -1 if the decrease is clinically significant (≤ -
4.58), categorized as 0 if not clinically significant (-4.57 to +4.57), and categorized 
as +1 if the increase is clinically significant (≥4.58). 
 
It is hypothesized that the SF-36 Mental Component Score (MCS) will increase 
(improve) from baseline to 12 months following the Visualase procedure. 
 
Null Hypothesis: 
 
M (V-SF-36 - BSL-SF-36-MCS) ≤ 0 
Alternate Hypothesis:  
M (V-SF-36 - BSL-SF-36-MCS) > 0 
 
Where M (V- SF-36-MCS - BSL- SF-36-MCS) = sign-test statistic ([increases-
decreases]/2) in the SF-36 quality of life questionnaire MCS from baseline to 
Month 12 post Visualase. 
 
A sign test will be used to determine if the median categorical change is significantly 
greater than zero. The MCID of 4.58 points for the SF-36-MCS is based on published 
literature.45 
 Secondary Endpoint #7 
Within-subject change of SF-36 quality of life questionnaire Physical Component 
Score (English language version), from baseline to 12 months following the 
Visualase procedure, categorized as -1 if the decrease is clinically significant (≤ -
3.02), categorized as 0 if not clinically significant (-3.01 to +3.01), and categorized 
as +1 if the increase is clinically significant (≥3.02).  
   

 
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It is hypothesized that the SF-36 Physical Component Score (PCS) will increase 
(improve) from baseline to 12 months following the Visualase procedure. 
 
Null Hypothesis: 
 
M (V-SF-36-PCS - BSL-SF-36-PCS) ≤ 0 
Alternate Hypothesis:  
M (V-SF-36-PCS - BSL-SF-36-PCS) > 0 
 
Where M (V-SF-36-PCS - BSL- SF-36-PCS) = sign-test statistic ([increases-
decreases]/2) in the SF-36 quality of life questionnaire PCS from baseline to 
Month 12 post Visualase. 
 
A sign test will be used to determine if the median categorical change is significantly 
greater than zero. The MCID of 3.02 points for the SF-36 Physical Component Score is 
based on published literature.45 
 Secondary Endpoint #8 
Seizure freedom (defined as Engel Class I, Appendix C) at 12 months following the 
Visualase procedure compared to historical control for open surgical resection 
 
It is hypothesized that the seizure freedom at 12 months following the Visualase 
procedure will not be inferior to 64% reported in the literature for open surgical resection. 
 
Null Hypothesis: 
 
π (V-SF – 64%) + δ ≤ 0 
Alternate Hypothesis:  
π (V-SF – 64%) + δ > 0 
 
Where π (V-SF – 64%) is the proportion of subjects treated with Visualase 
experiencing no seizures. 
 
An exact 95% confidence interval for the percentage of subjects who are seizure free will 
be calculated and its lower boundary compared to zero after subtraction of the historical 
open surgical resection percentage of 64% and the addition of the equivalence delta 
percentage of 10%. 
14.7 
 
 
 
 
 
 
 
 
 
 

 
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14.8 Interim Analysis 
No formal interim analysis is planned. Any unplanned interim analyses will be conducted 
under the auspices of the DMC assigned to this study. The DMC is authorized to review 
interim efficacy and safety analyses and, if necessary, to disseminate those results. The 
DMC will release interim results only if necessary to ensure patient safety. Any such 
release will be documented and described in the final study report. Study sites will not 
receive interim results unless they need to know for the safety of their patients.  
14.9 Missing Data 
Missing primary efficacy endpoint values and missing secondary endpoint values 
associated with testable hypotheses will be imputed for analysis with the mITT analysis 
population. The primary method of imputation will be by multiple imputation (SAS PROC 
MI and MIANALIZE) using the Markov chain Monte Carlo method. Details of predictor 
variables to be used in SAS PROC MI, seed number, and number of imputations to be 
performed will be provided in the SAP.
 
14.10 
 
 

 
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15 DATA AND QUALITY MANAGEMENT 
15.1 Documentation Confidentiality and Accessibility 
Documentation provided and generated as a result of this study is considered 
confidential and governed by the terms of the Confidentiality and Study Agreements. 
Access to and collection of medical records and subject data for this study is governed 
by the terms of the ICF and HIPAA release authorization. 
All records and other information about subjects participating in this study will be treated 
as confidential. Data will be transferred and processed by Medtronic or a third party 
designated by Medtronic in a key coded form, unless it’s impossible to make it 
anonymous.  
The Sponsor or a regulatory authority may audit or inspect the study site to evaluate the 
conduct of the study. The clinical Investigator(s)/institution(s) must allow study-related 
monitoring, audits, IRB review and regulatory inspection by providing direct access to 
source data/documents. 
15.2 Data Collection 
Data will be collected using an electronic data management system for clinical trials. The 
electronic data management system will be compliant with the provisions in the Code of 
Federal Regulations Title 21 Part 11 for Electronic Records. Electronic CRF data will be 
stored in a secure, password-protected database which will be backed up routinely. Data 
will be reviewed using programmed and manual data checks. Data queries will be made 
available to sites for resolution. Study management reports may be generated to monitor 
data quality and study progress, including subject compliance.  
At the end of the study, the data will be frozen and will be retained per Medtronic 
policies. The data reported on the eCRFs must be derived from source documents and 
be consistent with these source documents, and any discrepancies must be explained in 
writing. 
15.3 Study Documentation 
The Sponsor is responsible for the development, distribution, maintenance and long-
term storage of study documentation. Pre-study documentation includes the core study 
protocol, CRF templates, CRF instructions, visual aids, and other study-specific 
materials. Intra- and post-study documentation includes archived versions of study 
protocols, CRF templates, original completed CRFs, CRF instructions, visual aids, 
source documents and other study-specific materials. 

 
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The data reported on eCRFs must be derived from source documents and be consistent 
with these source documents. Any discrepancies must be explained in writing. 
15.4 Data Flow 
Investigational sites are responsible for notifying the Sponsor of new subject enrollments 
using the appropriate notification system. Notice to the Sponsor of the entry of a subject 
in the study is the indicator that data will be expected at the intervals prescribed in this 
protocol.  
15.5 Data Transmission and Entry 
Data will be entered into the database at the intervals prescribed in this CIP 
(Section 7.7). Completed eCRFs and required file uploads will be forwarded to the 
Sponsor, or their designee. 
15.6 Data Edits 
Data edits will be performed using industry recognized methods, for which an acceptable 
audit trail exists to record all data alterations. As required, all queries for data 
verification/correction will be completed by the designated study personnel and include 
approval by the Investigator. The data editing process includes, but may not be limited 
to: 
• 
Review of the CRFs will be conducted by the Sponsor, and manual edit checks 
may be added 
• 
The Data Manager will check for discrepancies that can be corrected using 
Global Rule 
• 
Automated edit checks will fire upon data entry, generating Data Clarification 
Forms (DCFs) for site verification/correction 
• 
At periodic intervals, data validation activities will be performed to assess the 
completeness and accuracy of the data 
• 
Clean and frozen data will be translated into the appropriate file type for data 
analysis 
15.7 Electronic Medical Records 
For sites using electronic medical records, the Sponsor may request that the study site 
designee print original source documents and verify that the record is a true reproduction 
of the original source document by initialling and dating the hard copy. Any 
discrepancies must be explained in writing. 
16 REQUIRED RECORDS AND REPORTS 
16.1 Investigator Records 
The Investigator is responsible for the preparation and retention of the records cited 
below. All of the records listed below, with the exception of case history records and 
CRFs, should be kept in the Investigator site file or subject study binder. CRFs must be 
maintained and signed electronically within the electronic data capture system during the 
study. The following records are subject to inspection and must be retained for a period 

 
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of two years (or longer as local law or hospital administration requires) after product 
approval or the date on which the investigation is terminated or the date that the records 
are no longer required for purposes of supporting a pre-market approval application. 
Medtronic requires notification in writing if the Investigator wishes to store study 
documents off-site or to relinquish the study data records so that mutually agreed-upon 
arrangements can be made for transfer of the data records to a suitably qualified, 
responsible person. 
• 
All correspondence between the IRB, sponsor, monitor, FDA, and the 
Investigator that pertains to the investigation, including required reports  
• 
Subject’s case history records, including:  
o Informed consent form signed and dated by subject and 
Investigator or designee 
o Observations of AEs/ADEs/device deficiencies 
o Medical history 
o Visualase procedure and follow-up data  
o Documentation of the dates and rationale for any deviation from the 
protocol 
• 
Financial disclosure  
• 
Subject log 
• 
All approved versions of the CIP, ICF, and Report of Prior Investigations 
Summary 
• 
Signed and dated Investigator agreement 
• 
Current curriculum vitae of principal investigators and key members of 
investigational site team  
• 
Documentation of delegated tasks  
• 
IRB approval documentation. Written information that the Investigator or 
other study staff, when member of the IRB, did not participate in the 
approval process 
• 
Study training records for site staff 
• 
Any other records that FDA requires to be maintained (e.g., financial 
disclosure) 
• 
Final Study Report including the statistical analysis 
16.2 Investigator Reports 
The Investigator is responsible for the preparation (review and signature) and 
submission to the sponsor of all CRFs, AEs, device deficiencies, deaths, and any 
deviations from the CIP. If any action is taken by an IRB with respect to this clinical 
study, copies of all pertinent documentation must be forwarded to Medtronic in a timely 
manner. Reports are subject to inspection and to the retention requirements as 
described above for investigator records.  
The Investigator must prepare and submit in a complete, accurate, and timely manner 
the reports listed in this section. 

 
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Table 8: Investigator Reports per FDA Regulations 
Report  
Submit to 
Description/Timing 
UADE 
Sponsor and 
IRB 
The Investigator shall submit to the sponsor and to 
the reviewing IRB a report of any UADE occurring 
during an investigation as soon as possible, but in no 
event later than 10 working days after the 
investigator first learns of the effect.  
(21 CFR 812.150(a)(1)) 
Withdrawal of IRB 
Approval (either 
suspension or 
termination) 
Sponsor 
The Investigator shall report a withdrawal of approval 
by the reviewing IRB of the investigator’s part of the 
investigation within 5 working days. 
(21 CFR 812.150(a)(2)) 
Progress Report  
Sponsor and 
IRB 
The Investigator shall submit this report to the 
sponsor and IRB at regular intervals, but in no event 
less than yearly. (21 CFR 812.150 (a)(3)).  
Study Deviations  Sponsor and 
IRB 
Notice of deviations from the CIP to protect the life or 
physical well-being of a subject in an emergency 
shall be given as soon as possible, but no later than 
5 working days after the emergency occurred. Except 
in such an emergency, prior approval by the sponsor 
is required for changes in or deviations from a plan. If 
these changes or deviations may affect the scientific 
soundness of the plan or the rights, safety or welfare 
of human subjects, FDA and IRB must also be 
notified.  
(21 CFR 812.150(a)(4)) 
Failure to Obtain 
Informed Consent  
(prior to 
investigational 
device use) 
Sponsor and 
IRB 
If an Investigator uses a device without obtaining 
informed consent, the investigator shall report such 
use within 5 working days after device use.  
(21 CFR 812.150(a)(5)) 
Final Report 
Sponsor 
and IRB 
This report shall be submitted within 3 months of 
study completion or termination of the investigation or 
the investigator’s part of the investigation. 
(21 CFR 812.150(a)(6)) 
Other 
IRB and FDA 
An Investigator shall, upon request by a reviewing 
IRB, FDA or any other regulatory agency, provide 
accurate, complete, and current information about 
any aspect of the investigation.  
(21 CFR 812.150(a)(7)) 
16.3 Sponsor Records 
Medtronic must maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation 
• 
Signed Investigator agreements, financial disclosure and current curriculum 
vitae of Principal Investigator and key members of the investigational site 
team  
• 
Delegated task list 
• 
All signed and dated CRFs submitted by Investigator, including reports of 
AEs, ADEs and device deficiencies 

 
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• 
All approved informed consent templates and other information provided to 
the subjects as well as advertisements, including translations 
• 
Copies of all IRB approval letters and relevant IRB correspondence and 
IRB voting list/roster/letter of assurance 
• 
Names of the institutions in which the clinical study will be conducted 
• 
FDA correspondence, notification and approval  
• 
Names/contact addresses of monitors 
• 
Statistical analyses and underlying supporting data 
• 
Final report of the clinical study 
• 
The CIP, Report of Prior Investigations Summary and study related reports, 
and revisions 
• 
Study training records for site personnel and Medtronic personnel involved 
in the study 
16.4 Sponsor Reports 
Medtronic must prepare and submit the following complete, accurate, and timely 
reports listed in Table 9 below. In addition to the reports listed below, Medtronic 
must, upon request of reviewing IRB or FDA, provide accurate, complete and 
current information about any aspect of the investigation.  
Table 9: Sponsor Reports 
Report  
Submit to 
Description/Constraints 
UADE 
FDA,  
IRBs, and 
Investigators 
 
A sponsor who conducts an evaluation of an 
unanticipated adverse device effect under 812.46(b) 
shall report the results of such evaluation to FDA and 
to all reviewing IRBs and participating investigators 
within 10 working days after the sponsor first 
receives notice of the effect. Thereafter the sponsor 
shall submit such additional reports concerning the 
effect as FDA requests. 
Withdrawal of IRB 
Approval 
FDA,  
IRBs, and 
Investigators 
 
A sponsor shall notify FDA and all reviewing IRBs 
and participating investigators of any withdrawal of 
approval of an investigation or a part of an 
investigation by a reviewing IRB within 5 working 
days after receipt of the withdrawal of approval 
(21 CFR 812.150(b)(2))  
Withdrawal of FDA 
Approval 
IRBs and 
Investigators 
A sponsor shall notify all reviewing IRBs and 
participating investigators of any withdrawal of FDA 
approval of the investigation, and shall do so within 5 
working days after receipt of notice of the withdrawal 
of approval.  
(21 CFR 812.150(b)(3)) 
Investigator List 
FDA 
A sponsor shall submit at 6-month intervals, a current 
list of the names and addresses of all investigators 
participating in the investigation.  
(21 CFR 812.150(b)(4)) 
Progress Reports IRBs and  
FDA 
Progress reports will be submitted at least annually. 
(21 CFR 812.150(b)(5), 812.36(f)  

 
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Report  
Submit to 
Description/Constraints 
Recall and Device 
Disposition 
FDA and  
IRBs 
A sponsor shall notify FDA and all reviewing IRBs 
any request that an investigator return, repair, or 
otherwise dispose of any units of a device. Such 
notice shall occur within 30 working days after the 
request is made and shall state why the request was 
made. 
 (21 CFR 812.150(b)(6)) 
Final Report 
FDA,  
IRBs, and 
Investigators 
The sponsor shall notify FDA within 30 working days 
of the completion or termination of the investigation. 
The sponsor shall submit a final report to the FDA, 
investigators, and all IRBs within 6 months after 
completion or termination of this study.  
(21 CFR 812.150(b)(7)) 
Failure to Obtain 
Informed Consent 
(prior to 
investigational 
device use)  
FDA 
Investigator’s report of use of investigational device 
without obtaining consent will be submitted to FDA 
within 5 working days of notification.  
(21 CFR 812.150(b)(8)) 
Study Deviation  
Investigators 
Ensure that all deviations from the Clinical 
Investigational Plan are reviewed with the 
appropriate clinical investigator(s), are reported on 
the case report forms and the final report of the 
clinical investigation.  
Site specific study deviations may be submitted to 
investigators periodically.  
Other 
IRB, FDA 
Accurate, complete, and current information about 
any aspect of the investigation.  
(21 CFR 812.150(b)(10)) 
 
Medtronic records and reports will be maintained in a password-protected 
document management system, and paper documents (where applicable) will be 
stored in secured file cabinets at Medtronic during the course of this study.  
 
After closure of the study Medtronic will archive records and reports per standard 
operating procedure. 
 
 

 
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Appendix A: Bibliography  
 
Reference List 
 
 
(1)  Kwan P, Arzimanoglou A, Berg AT et al. Definition of drug resistant epilepsy: 
Consensus proposal by the ad hoc Task Force of the ILAE Commission on 
Therapeutic Strategies. Epilepsia 2010;51:1069-1077. 
 
(2)  Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes and Consequences. 
New York, NY: Demos Press, 1990. 
 
(3)  Kwan P, Sander JW. The natural history of epilepsy: An epidemiological view. J 
Neurol Neurosurg Psychiatry 2004;75:1376-1381. 
 
(4)  Institute of Medicine (IOM). Epilepsy Across the Spectrum: Promoting Health and 
Understanding. Washington, D.C.: The National Academies Press, 2012. 
 
(5)  Centers for Disease Control and Prevention (CDC). Fast Facts on Epilepsy.  3-
12-2015.  
 
(6)  Manford M, Hart YM, Sander JWAS, Shorvon SD. National General Practice 
Study of Epilepsy (NGPSE): Partial seizure patterns in a general population. 
Neurology 1992;42:1911-1917. 
 
(7)  Manford M, Hart YM, Sander JWAS, Shorvon SD. The National General Practice 
Study of Epilepsy: The syndromic classification of the International League 
Against Epilepsy applied to epilepsy in a general population. Arch Neurol 
1992;49:801-808. 
 
(8)  Semah F, Picot M-C, Adam C et al. Is the underlying cause of epilepsy a major 
prognostic factor for recurrence? Neurology 1998;51:1256-1262. 
 
(9)  Schramm J, Lehmann TN, Zentner J et al. Randomized controlled trial of 2.5-cm 
versus 3.5-cm mesial temporal resection - Part 2: Volumetric resection extent 
and subgroup analyses. Acta Neurochir 2011;153:221-228. 
 (10)  Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of 
surgery for temporal-lobe epilepsy. New Engl J Med 2001;345:311-318. 
 (11)  Engel J, McDermott MP, Wiebe S et al. Early surgical therapy for drug-resistant 
temporal lobe epilepsy: A randomized trial. J Am Med Assoc 2012;307:922-930. 
 (12)  Engel J. Surgical treatment for epilepsy: Too little, too late? J Am Med Assoc 
2008;300:2548-2550. 
 (13)  Jehi L, Friedman D, Carlson C, Cascino G. The evolution of epilepsy between 
1991 and 2011 in nine major epilepsy centers across the United States, 
Germany, and Australia. Epilepsia 2015;56:1526-1533. 
 (14)  Berg AT, Langfitt J, Shinnar S et al. How long does it take for partial epilepsy to 
become intractable? Neurology 2003;60:186-190. 

 
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 (15)  Morrell MJ. Responsive cortical stimulation for the treatment of medically 
intractable partial epilepsy. Neurology 2011;77:1295-1304. 
 (16)  Regis J, Rey M, Bartolomei F et al. Gamma Knife Surgery in Mesial Temporal 
Lobe Epilepsy: A Prospective Multicenter Study. Epilepsia 2004;45:504-515. 
 (17)  Liscak R, Malikova H, Kalina M et al. Stereotactic radiofrequency 
amygdalohippocampectomy in the treatment of mesial temporal lobe epilepsy. 
Acta Neurochir 2010;152:1291-1298. 
 (18)  Barbaro NM, Quigg M, Broshek DK et al. A multicenter, prospective pilot study of 
gamma knife radiosurgery for mesial temporal lobe epilepsy: Seizure response, 
adverse events, and verbal memory. Ann Neurol 2009;65:167-175. 
 (19)  Quigg M, Harden C. Minimally invasive techniques for epilepsy surgery: 
stereotactic radiosurgery and other technologies. J Neurosurg 2014;121:232-
240. 
 (20)  Curry DJ, Gowda A, McNichols RJ, Wilfong AA. MR-guided stereotactic laser 
ablation of epileptogenic foci in children. Epilepsy Behav 2012;24:408-414. 
 (21)  Esquenazi Y, Kalamangalam GP, Slater JD et al. Stereotactic laser ablation of 
epileptogenic periventricular nodular heterotopia. Epilepsy Res 2014;108:547-
554. 
 (22)  Gonzalez-Martinez J, Vadera S, Mullin J et al. Robot-assisted stereotactic laser 
ablation in medically intractable epilepsy: Operative technique. Neurosurgery 
2014;10:167-172. 
 (23)  Willie JT, Laxpati NG, Drane DL et al. Real-time magnetic resonance-guided 
stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy. 
Neurosurgery 2014;74:569-584. 
 (24)  Choi H, Tovar-Spinoza Z. MRI-guided laser interstitial thermal therapy of 
intracranial tumors and epilepsy: State-of-the-art review and a case study from 
pediatrics. Photonics Lasers Med 2014;3:107-115. 
 (25)  Tovar-Spinoza Z, Carter DA, Eksioglu Y, Huckins S. Use of magnetic resonance-
guided laser thermal ablation for children with intracranial tumors and epilepsy: 
SUNY upstate medical university preliminary experience. Child's Nerv Syst 
2013;29:1730-1731. 
 (26)  Wilfong AA, Curry DJ. Hypothalamic hamartomas: Optimal approach to clinical 
evaluation and diagnosis. Epilepsia 2013;54:109-114. 
 (27)  Gross R, Willie J, Helmers S et al. Stereotactic laser amygdalohippocampotomy 
for mesial temporal lobe epilepsy: Results of multicenter experience at 6 months 
and 1 year. Epilepsy Curr 2014;14:241-242. 

 
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 (28)  Willie JT, Gross RE, Mehta A et al. Multicenter experience with minimally 
invasive stereotactic laser thermal amygdalohippocampotomy for mesial 
temporal lobe epilepsy. Epilepsia 2013;54:290. 
 (29)  Drane DL, Loring DW, Voets NL et al. Better object recognition and naming 
outcome with MRI-guided stereotactic laser amygdalohippocampotomy for 
temporal lobe epilepsy. Epilepsia 2015;56:101-113. 
 (30)  Attiah M, Paulo D, Mani R, Danish SF, Stein SC. Anterior temporal lobectomy 
compared with laser thermal hippocampectomy for mesial temporal epilepsy. 
Stereotactic Funct Neurosurg 2014;92:15. 
 (31)  Kangasniemi M, McNichols RJ, Bankson JA, Gowda A, Price RE, Hazle JD. 
Thermal therapy of canine cerebral tumors using a 980 nm diode laser with MR 
temperature-sensitive imaging feedback. Lasers Surg Med 2004;35:41-50. 
 (32)  Kangasniemi M, Stafford RJ, Price RE, Jackson EF, Hazle JD. Dynamic 
gadolinium uptake in thermally treated canine brain tissue and experimental 
cerebral tumors. Invest Radiol 2003;38:102-107. 
 (33)  McNichols RJ, Gowda A, Kangasniemi M, Bankson JA, Price RE, Hazle JD. MR 
Thermometry-Based Feedback Control of Laser Interstitial Thermal Therapy at 
980 nm. Lasers Surg Med 2004;34:48-55. 
 (34)  McNichols RJ, Kangasniemi M, Gowda A, Bankson JA, Price RE, Hazle JD. 
Technical developments for cerebral thermal treatment: Water-cooled diffusing 
laser fibre tips and temperature-sensitive MRI using intersecting image planes. 
Int J Hyperthermia 2004;20:45-56. 
 (35)  Matthew Fox. In Vitro Performance Evaluation of the VCLAS-400-12-T10-11.  8-
4-2005.  Medtronic.  
 
 (36)  Yung JP, Shetty A, Elliott A et al. Quantitative comparison of thermal dose 
models in normal canine brain. Med Phys 2010;37:5313-5321. 
 (37)  Sinha S, Hargreaves E, Patel NV, Danish SF. Assessment of irrigation dynamics 
in magnetic-resonance guided laser induced thermal therapy (MRgLITT). Lasers 
Surg Med 2015;47:273-280. 
 (38)  Nour SG, Willie JT, Gross RE. Percutaneous selective laser 
amygdalohippocampotomy (SLAH) for treatment of mesial temporal lobe 
epilepsy within an interventional MRI suite. Photonics Lasers Med 2014;3:117-
128. 
 (39)  Hawasli AH, Bandt SK, Hogan RE, Werner N, Leuthardt EC. Laser ablation as 
treatment strategy for medically refractory dominant insular epilepsy: Therapeutic 
and functional considerations. Stereotactic Funct Neurosurg 2014;92:397-404. 
 (40)  Sloan AE, Ahluwalia MS, Valerio-Pascua J et al. Results of the NeuroBlate 
system first-in-humans phase I clinical trial for recurrent glioblastoma. J 
Neurosurg 2013;118:1202-1219. 

 
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 (41)  McCaffery M, Pasero C. Pain: Clinical Manual. 2nd ed. St. Louis: Mosby, Inc, 
1999. 
 (42)  Epilepsy Foundation, Wright C, Shafer P, Sirven J. SUDEP.  2014. 11-12-2015.  
 
 (43)  Clopper C, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 1934;26:404-413. 
 (44)  Sawrie S, Chelune G, Naugle R, et al. Empirical methods for assessing 
meaningful neuropsychological change following epilepsy surgery. J Int 
Neuropsych Soc 1996;2:556-564. 
 (45)  Wiebe S, Matijevic S, Eliasziw M, Derry PA. Clinically Important Change in 
Quality of Life in Epilepsy. Journal of Neurology Neurosurgery and Psychiatry 
2002;73:116-120. 
 
 
 
 
 
 
 
 
 

 
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Appendix B: Clinical Research Organizations, Central 
Reviewers and Core Labs  
 
Clinical Research Organizations (CROs) will be used to develop and manage the study’s 
eCRF database, and to provide statistical support of data analysis. Contact information 
and duties performed are listed below.  
To standardize critical assessments during the study, in addition to site reported results, 
assessments will be made by central reviewers or core labs as listed below. 
Assessments will be conducted in accordance with the respective reviewers’/core labs’ 
charters and/or instructions. 
 
Contact Information  
Duties performed 
 
 
 
 
 
 
• Develop study electronic case report forms, 
edit checks, and study management 
reports 
• Review electronic case report forms, 
manage discrepancies, and code 
deviations 
 
 
 
 
 
• Provide statistical recommendations for 
study endpoints and analysis 
• Generate statistical reports throughout the 
study 
 
 
 
 
 
 
 
 
 
 
• Provide site training and uniform scoring on 
neuropsychological assessment battery 
• Monitor neuropsychological data quality 
• Analyze neuroimaging data by volumetric 
analysis and visual inspection 
 
 
  
 
 
 
• Review subjects’ epilepsy history, MRI, 
EEG and additional testing, if performed 
(e.g., PET, SPECT, invasive EEG or MEG)  
to confirm study qualification for the 
Visualase procedure 
• Approve, disapprove or defer the subject’s 
continued participation in the trial. 
 
Any changes or additions to the clinical research organizations, central reviewers, or 
core lab information may be provided in a separate document. 
 
 

 
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Appendix C: Engel Classification of Postoperative 
Outcomei 
 
Class I: Free of disabling seizuresa 
A. Completely seizure free since surgery 
B. Nondisabling simple partial seizures only since surgery 
C. Some disabling seizures after surgery, but free of disabling seizures for at least 2 
years 
D. Generalized convulsions with AED discontinuation only 
Class II: Rare disabling seizures (“almost seizure free”)b 
A. Initially free of disabling seizures but has rare seizures now 
B. Rare disabling seizures since surgery 
C. More than rare disabling seizures since surgery, but rare seizures for the last 2 
years 
D. Nocturnal seizures only 
Class III: Worthwhile improvementc 
A. Worthwhile seizure reduction 
B. Prolonged seizure-free intervals amounting to greater than half the followed-up 
period, but not <2 years 
Class IV: No worthwhile improvement 
A. Significant seizure reduction 
B. No appreciable change 
C. Seizures worse 
 
aExcludes early postoperative seizures (first few weeks). This exclusion is quantitatively 
defined as 30 days for this protocol. 
b“Rare” is quantitatively defined as ≤2 seizure days per year for this protocol. 
cDetermination of “worthwhile improvement” will require quantitative analysis of 
additional data such as percentage seizure reduction, cognitive function, and quality of 
life. This is defined as 80% reduction in seizures for this protocol. 
 
 
iEngel J. Outcome with respect to epileptic seizures. In Surgical Treatment of the Epilepsies, edited by J. 
Engel, Jr. Raven Press, New York. 1987 
 

 
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Appendix D: Data Monitoring Committee (DMC) 
 
Point  
Examples 
DMC will be used 
Ongoing oversight for this study will be provided by an 
independent Data Monitoring Committee (DMC).  
Who will be involved The DMC will have one statistician, at least one physician 
specializing in neurosurgery, at least one physician specializing in 
neurology, and one neuropsychologist. None of the DMC 
members are participating in the SLATE study. A chairperson from 
among those members will be identified.  
Responsibility of the 
DMC 
The DMC will be responsible for the following: 
o Monitoring subject safety through review of aggregate 
clinical study data and adverse events 
o Acting as an advisory panel on study design, study 
materials, study conduct, and subject safety issues 
o Ensuring continued scientific validity and necessity, and 
making recommendations for protocol modifications 
o Investigating root cause of missing data to minimize 
potential bias (i.e., screen failures, lost-to-follow-up, 
discontinuation from treatment) 
o Evaluating issues associated with the procedural aspects 
of the clinical trial (e.g., slow enrollment) and providing 
recommendations for their resolution 
Recommendations 
The DMC will be advisory to the sponsor. The DMC may provide 
recommendations for continuation of the study, or early 
termination due to futility or safety concerns, or early attainment of 
study objectives. 
 
NOTE: Approval to proceed with the study or discontinue the 
study must be determined by a consensus of the DMC 
 
 
A DMC charter will be developed prior to the first subject enrollment.  
The DMC will meet (via teleconference or in person) prior to the first subject enrollment 
to establish procedures for safety data review, chairman appointment, and guidelines for 
study recommendations. The DMC will meet on a periodic basis to perform data review, 
including at a minimum, all SAEs and deaths, and will meet more frequently when 
needed. DMC meetings may consist of both open and closed sessions. Medtronic 
personnel may facilitate the DMC meetings but will not have voting privileges. 
 
 

 
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Appendix E: Foreseeable Adverse Event List 
 
The information provided in this section pertains to foreseeable adverse events that may be 
observed in SLATE study subjects and may assist in identifying those events for a given 
device or therapy that are unexpected in nature. The foreseeable adverse events 
information is based on AEs reported in published literature, the FDA Manufacturer and 
User Facility Device Experience (MAUDE) database, and Medtronic complaint handling 
system. Information regarding foreseeable adverse events may be used in combination with 
device labeling, current event reporting information, and other published data to assess for 
an unexpected occurrence. 
The Visualase procedure involves surgery; therefore, standard events associated with a 
surgical procedure may be experienced (including but not limited to anesthesia 
complications, injury, infections, bleeding, exacerbation of pre-existing conditions, healing 
complications, and the unavoidable events listed in Section 10.1 of this Clinical 
Investigational Plan). Additionally, the patient population eligible for inclusion in this study 
has an underlying disease of epilepsy; therefore, standard events associated with epilepsy 
may be experienced (including but not limited to seizures, injury resulting from seizures and 
sudden unexpected death in epilepsy). However, the focus of this section is to specifically 
address in more detail, those events that are foreseeable due to the use, performance, 
and/or presence of the system under investigation.  
Potential risks associated with the Visualase procedure as well as risk minimization are 
discussed within Section 11. Treatment required for procedure- and/or device- related 
adverse events that are experienced may include medication, surgical abandonment, or 
other surgical and medical remedies.  
Observed Adverse Device Effects in Previous Clinical Studies 
There have been no previous Medtronic-sponsored clinical studies evaluating use of the 
Visualase system for treatment of temporal lobe epilepsy. 
Adverse Events in Literature & Post-market Event Reporting 
The foreseeable adverse events associated with the Visualase procedure have been 
documented in various literature articles and in post-market event reporting. The 
foreseeable adverse events may include events that are possible but have not yet been 
reported. Adverse events associated with the Visualase System include, but are not 
limited to, the following:
• Anxiety 
• Aphasia 
• Back pain 
• Blurry vision 
• Brain abscess 
• Bruising/ 
ecchymosis 
• Cerebral vascular 
accident (CVA) 
• Cerebrospinal 
fluid (CSF) 
leakage 
• Death 
• Deep venous 
thrombosis (DVT) 
• Depression 
• Device fragment 
retained in body 
• Diplopia  
• Edema 
• Emotional lability  
• Fever 
• Headache 
• Hematoma 
• Hemianopia  
• Hemiparesis 
• Hemorrhage 
• Herniation 
• Hydrocephalus 

 
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• Infection 
• Memory 
impairment / 
difficulty 
• Meningitis 
• Nausea 
• Neurologic 
deficits 
• Pain at 
incisional/access 
site 
• Pain/discomfort/ 
stiffness 
• Paralysis 
• Persistent 
vegetative state 
• Psychological/ 
psychiatric 
complications 
• Pulmonary 
embolism (PE) 
• Quadrantanopia 
• Scalp numbness 
• Scalp pain 
• Seizure 
• Sensory loss 
• Skin abrasion or 
blister 
• Sleep problems 
or insomnia 
• Superficial wound 
infection 
• Vomiting 
 
 

 
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Appendix F: Qualifying Primary Safety Endpoint 
Adverse Events 
 
Adverse events will be reported per Section 10. Study Reportable AEs will count toward 
the primary safety endpoint if they qualify as follows: 
1. Are device-, procedure-, or anesthesia-related; and 
2. Are moderate or severe; and 
3. Are permanent, for the following adverse events: anxiety, aphasia, blurry vision, 
depression, diplopia, emotional lability, hemianopia, hemiparesis, memory 
impairment/difficulty, neurologic deficits, paralysis, psychological/psychiatric 
complications, quadrantanopia, sensory loss, sleep problems or insomnia 
Note: Transient events were not included in the literature analysis referenced as 
the performance threshold for the primary safety endpoint.30 
Figure 7 is a flow-chart to determine if a Study Reportable AE qualifies for inclusion in 
the primary safety endpoint analysis. 
 

 
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Study Reportable AEs
Is the AE related to the 
device, procedure, or 
anesthesia?
Is the AE moderate or 
severe?
Yes
Is the AE on the list of 
AEs that qualify only if 
permanent? 
Yes
Is the AE permanent 
(i.e., unresolved at 
study exit)?
Yes
Qualifying primary 
safety endpoint AE
Yes
No
Not a qualifying 
primary safety 
endpoint AE
No
No
No
 
Figure 7: Qualifying Primary Safety Endpoint AE Flow Chart 
 
 

 
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Appendix G: Preliminary Publication Plan 
 
Publications from the SLATE study will be handled according to Medtronic Standard 
Operating Procedures and as indicated in the Clinical Trial Agreement. 
This study will be registered and results posted on www.clinicaltrials.gov. Medtronic, as 
the Sponsor, has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between study investigators and Medtronic 
personnel. Authorship will be established prior to the writing of the manuscript via a 
publication committee. The publication committee will develop the final publication plan 
as a separate document. As this study involves multiple sites, no individual publications 
will be allowed prior to completion of publication submission of the multicenter study 
except as agreed with Medtronic. 
 
 
  
 

 
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Appendix H: Other Documents 
 
The following Clinical Investigational Plan documents will be provided separately:  
 
• 
Device Labeling 
• 
Informed Consent Form template 
• 
List of Investigational Sites 
• 
List of Institutional Review Boards 
• 
SLATE Study Visualase Technique Recommendations 
• 
SLATE Neuroimaging Manual of Operations  
• 
SLATE Neuropsychological Manual of Operations 
• 
SLATE Neuro-ophthalmologic Manual of Operations 
 
 
 

 
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Appendix I: Modifications to the Clinical Investigational 
Plan 
 
Table 10 summarizes modifications made to the CIP. 
Table 10: Change History 
Version & Date 
Applicable Sections 
Change 
Rationale 
1.0 16 June 2016 
All 
Initial Release 
N/A 
2.0 19 July 2017 
See Summary of Changes 
version 1.0 to 2.0 
See Summary of Changes 
version 1.0 to 2.0 
See Summary of Changes 
version 1.0 to 2.0 
3.0 26 July 2017 
See Summary of Changes 
version 2.0 to 3.0 
See Summary of Changes 
version 2.0 to 3.0 
See Summary of Changes 
version 2.0 to 3.0 
4.0 09 April 2018 
See Summary of Changes 
version 3.0 to 4.0 
See Summary of Changes 
version 3.0 to 4.0 
See Summary of Changes 
version 3.0 to 4.0