Phase II Trial of Seizure Prophylaxis in Brain Tumor Patients Undergoing Neurosurgical Procedure
Phase: PHASE2
Conditions: Glioma, Glioma of Brain, Brain Tumor
Sponsor: Duke University

CONFIDENTIAL 
The information contained in this document is regarded as confidential, and may not be disclosed to another party unless such disclosure is 
required to initiate the study, to conduct study-related activities, or to comply with national, state, or local laws and regulations.  Written 
authorization from the coordinating site and sponsor is required for disclosure otherwise. 
 
 
 
A Phase II Study 
Phase II Trial of Seizure Prophylaxis in Brain Tumor Patients 
Undergoing Neurosurgical Procedure 
 
 
 
 
 
 
Sponsor: 
Duke Department of Neurosurgery 
 
 
Funding Source: 
Departmental/Discretionary 
 
 
Duke IRB#: 
Pro00081334  
 
 
 
 
 
Principal Investigator 
Annick Desjardins, MD, FRCPC 
DUMC Box 3624 
Durham, NC 27710 
Tel: (919) 684-6173 
Fax: (919) 684-6674 
annick.desjardins@duke.edu 
 
 
 
 
Sub-Investigator(s) 
Patrick Codd, MD 
patrick.codd@duke.edu 
 
Peter Fecci, MD, PhD 
peter.fecci@duke.edu 
 
Allan Friedman, MD 
allan.friedman@duke.edu 
 
 
Sub-Investigator(s) Cont. 
Jennifer Kang, MD 
jennifer.kang@duke.edu 
 
Katherine B. Peters, MD, PhD 
katherine.peters@duke.edu 
 
Dina Randazzo, DO 
dina.randazzo@duke.edu 
 
John Sampson, MD, PhD 
john.sampson@duke.edu 
 
Eric Thompson, MD 
eric.thompson@duke.edu 
 
David Ashley, MBBS, FRACP, PhD 
david.ashley@duke.edu 
 
Henry Friedman, MD 
henry.friedman@duke.edu 
Statistician 
James E. Herndon II, PhD 
james.herndon@duke.edu 
 
Lead Study Coordinator 
Claudia Pamanes 
claudia.pamanes@duke.edu 
 
Regulatory Coordinator 
Beth Perry 
beth.perry@duke.edu 
 
Data Manager 
Beth Perry  
beth.perry@duke.edu 
 
 
 
Original version: 
01/26/2018 
 
Amended version 1: 
Amended version 2: 
Amended version 3: 
Amended version 4: 
03/19/2018 
01/16/2019 
04/08/2019 
08/04/2020 
CPC Modifications 

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
Version 3:  04/08/2019 
 
Duke Department of Neurosurgery 
Page 2 of 34 
CONFIDENTIAL 
1 TABLE OF CONTENTS 
2 
LIST OF ABBREVIATIONS ............................................................................................................................................ 5 
3 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY .................................................................................................... 6 
4 
STUDY SCHEMA ......................................................................................................................................................... 7 
5 
BACKGROUND AND SIGNIFICANCE ........................................................................................................................... 7 
5.1 
Study Disease .................................................................................................................................................... 7 
5.2 
Study Agents ...................................................................................................................................................... 8 
5.2.1 
Mechanism of action ................................................................................................................................ 8 
5.2.2 
Pharmacokinetics ...................................................................................................................................... 9 
5.2.3 
Formula dosing ......................................................................................................................................... 9 
5.2.4 
Drug-drug interactions ............................................................................................................................ 10 
5.2.5 
Adverse Events ....................................................................................................................................... 10 
5.2.6 
Efficacy in Epilepsy .................................................................................................................................. 10 
5.2.7 
Efficacy in Brain Tumors ......................................................................................................................... 11 
5.2.8 
Clinical Experience .................................................................................................................................. 12 
5.2.9 
Study Purpose and Rationale .................................................................................................................. 12 
6 
OBJECTIVES AND ENDPOINTS .................................................................................................................................. 14 
7 
INVESTIGATIONAL PLAN .......................................................................................................................................... 14 
7.1 
Study Design .................................................................................................................................................... 14 
7.1.1 
AED initiation .......................................................................................................................................... 15 
7.1.2 
AED titration ........................................................................................................................................... 15 
7.1.3 
Post-procedure data collection .............................................................................................................. 15 
7.1.4 
Adverse Events of Special Interest (AESI) ............................................................................................... 15 
7.1.5 
Safety Considerations ............................................................................................................................. 16 
7.1.6 
Missed Doses .......................................................................................................................................... 16 
7.1.7 
Concomitant Medications ...................................................................................................................... 16 
7.1.8 
Randomization ........................................................................................................................................ 16 
7.2 
Rationale for Selection of Dose and Treatment Duration ............................................................................... 16 
7.3 
Definition of Evaluable Subjects, On Study, and End of Study ........................................................................ 16 
7.4 
Early Study Termination .................................................................................................................................. 16 
8 
STUDY DRUGS .......................................................................................................................................................... 16 
8.1 
Names, Classification, and Mechanism of Action ............................................................................................ 16 
8.2 
Packaging and Labeling ................................................................................................................................... 17 
8.3 
Supply, Receipt, and Storage ........................................................................................................................... 17 
8.4 
Dispensing and Preparation ............................................................................................................................ 17 
9 
SUBJECT ELIGIBILITY ................................................................................................................................................ 17 

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Duke Department of Neurosurgery 
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CONFIDENTIAL 
9.1.1 
Inclusion Criteria ..................................................................................................................................... 17 
9.1.2 
Exclusion Criteria .................................................................................................................................... 17 
10 
SCREENING AND ON-STUDY TESTS AND PROCEDURES ........................................................................................... 17 
10.1 
Screening Evaluations ...................................................................................................................................... 18 
10.2 
Study Period .................................................................................................................................................... 18 
10.3 
Follow-up Period ............................................................................................................................................. 19 
10.4 
End of Study .................................................................................................................................................... 19 
10.5 
Early Withdrawal of Subject(s) ........................................................................................................................ 19 
10.5.1 
Criteria for Subject Discontinuation from the Study .............................................................................. 19 
10.5.2 
Replacement of Non-evaluable .............................................................................................................. 19 
10.6 
Study Assessments .......................................................................................................................................... 19 
10.6.1 
Medical History ....................................................................................................................................... 19 
10.6.2 
Physical Exam .......................................................................................................................................... 20 
10.6.3 
Laboratory Evaluations ........................................................................................................................... 20 
11 
SAFETY MONITORING AND REPORTING .................................................................................................................. 20 
11.1 
Adverse Events ................................................................................................................................................ 20 
11.1.1 
Reporting of AEs ..................................................................................................................................... 20 
11.2 
Serious Adverse Events ................................................................................................................................... 20 
11.2.1 
Reporting of SAEs.................................................................................................................................... 21 
11.3 
Quality Assurance Program ............................................................................................................................. 21 
12 
QUALITY CONTROL AND QUALITY ASSURANCE....................................................................................................... 21 
12.1 
Monitoring ....................................................................................................................................................... 21 
12.2 
Audits ............................................................................................................................................................... 23 
12.3 
Data Management and Processing .................................................................................................................. 23 
12.3.1 
Study Documentation ............................................................................................................................. 23 
12.3.2 
Case Report Forms .................................................................................................................................. 24 
12.3.3 
Data Management Procedures and Data Verification ............................................................................ 24 
12.3.4 
Coding ..................................................................................................................................................... 24 
12.3.5 
Study Closure .......................................................................................................................................... 24 
13 
STATISTICAL METHODS AND DATA ANALYSIS ......................................................................................................... 24 
13.1 
Analysis Sets .................................................................................................................................................... 24 
13.2 
Patient Demographics and Other Baseline Characteristics ............................................................................. 24 
13.3 
Treatments ...................................................................................................................................................... 24 
13.4 
Primary Objectives .......................................................................................................................................... 25 
13.4.1 
Variables ................................................................................................................................................. 25 
13.4.2 
Statistical Hypothesis, Model, and Method of Analysis ......................................................................... 25 
13.4.3 
Handling of missing values, censoring, and discontinuations ................................................................ 25 

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Dr. Annick Desjardins 
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Duke Department of Neurosurgery 
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13.5 
Secondary objectives ....................................................................................................................................... 26 
13.6 
Exploratory Objectives .................................................................................................................................... 26 
13.6.1 
Exploratory Objective:  Duration of Admission Stay ............................................................................... 26 
13.6.2 
Exploratory Objective:  Number of Provider Communications .............................................................. 26 
13.6.3 
Exploratory Objective:  Usage of Intraoperative AED ............................................................................. 26 
13.6.4 
Exploratory Objective:  Seizure Occurrence ........................................................................................... 26 
13.6.5 
Exploratory Objective:  Changes in AED Administration ........................................................................ 27 
13.6.6 
Exploratory Objective:  Risk Factors for Post-procedure seizure............................................................ 27 
13.7 
Interim Analysis ............................................................................................................................................... 27 
13.8 
Sample Size ...................................................................................................................................................... 28 
14 
ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ................................................................................................ 29 
14.1 
Regulatory and Ethical Compliance ................................................................................................................. 29 
14.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee ......................................................... 29 
14.3 
Informed Consent ............................................................................................................................................ 29 
14.4 
Privacy, Confidentiality, and Data Storage ...................................................................................................... 30 
14.5 
Data and Safety Monitoring ............................................................................................................................ 30 
14.6 
Protocol Amendments ..................................................................................................................................... 30 
14.7 
Records Retention ........................................................................................................................................... 30 
14.8 
Conflict of Interest ........................................................................................................................................... 30 
15 
REFERENCES ............................................................................................................................................................ 31 
 
 
 

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
Version 3:  04/08/2019 
 
Duke Department of Neurosurgery 
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CONFIDENTIAL 
2 LIST OF ABBREVIATIONS 
AE 
Adverse Events 
AED 
Anti-Epileptic Drug 
ALK 
Alkaline Phosphatase 
ATRX 
Alpha-Thalassemia/mental Retardation syndrome X-linked gene 
BID 
Twice a Day (from Latin bis in die) 
[Ca2+]I 
Intracellular calcium 
CAP 
College of American Pathologists 
CBC 
Complete Blood Count  
CBZ 
Carbamazepine 
CICR 
Calcium-induced calcium release 
CLIA 
Clinical Laboratory Improvement Act 
CNS 
Central Nervous System 
COLA 
Commission on Office Laboratory Accreditation 
CrCL 
Creatinine Clearance 
CPC 
Cancer Protocol Committee 
CRF 
Case Report Form (eCRF is for electronic CRF) 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochromes P450 
DCI 
Duke Cancer Institute 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
DUHS 
Duke University Health Systems 
DUMC 
Duke University Medical Center 
EIAED 
Enzyme Inducing AED 
EMA 
European Medicines Agency 
ESRD 
End Stage Renal Disease 
FDA 
US Food and Drug Administration 
GABA 
Gamma-Aminobutyric Acid 
GCP 
Good Clinical Practice 
GTC 
General tonic-clonic 
GTR 
Gross Total Resection 
HGG 
High Grade Glioma 
HRPP 
Human Research Protection Program 
HRQOL 
Healthcare related quality of life 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
ILAE 
International League Against Epilepsy 
IP3 
Inositol 1,4,5-triphosphate 
IRB 
Institutional Review Board 
IT 
Information Technology 
IV 
Intravenouss 
KPS 
Karnofsky Performance Score 
LCM 
Lacosamide 
LGG 
Low Grade Glioma 
LEV 
Levetiracetam 
LTG 
Lamotrigine 
MGMT 
O-6 Methylguanine-DNA Methyl Transferase 
MSR                Maximum Safe Resection (gross-total, sub-total, biopsy) 
NS-CRU 
Neurosurgery-Clinical Research Unit 
OARC 
Office of Audit, Risk and Compliance 
PBT 
Phenobarbital  

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
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Duke Department of Neurosurgery 
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CONFIDENTIAL 
PHT 
Phenytoin 
PI 
Primary InvestigatorQAP Quality Assurance Program 
QID 
Four times each Day (from Latin quater in die) 
QOL 
Quality of Life 
QOLIE 
QOL in Epilepsy 
RCA 
Research Compliance Assurance 
REDCap 
Research Electronic Data Capture™ 
RIO 
Research Integrity Office 
RDSP 
Research Data Security Plan 
RyR 
Ryanodine 
SAE 
Serious Adverse Effect 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase  
SOC 
Standard of Care 
SOCOMM 
Safety Oversight Committee 
SOPs 
Standing Operating Procedures 
STR 
Sub-total resection 
POS 
Partial Onset Seizures 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
VPA 
Valproic Acid 
 
 
3 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
Please see separate upload in eIRB. 
 

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
Version 3:  04/08/2019 
 
Duke Department of Neurosurgery 
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CONFIDENTIAL 
4 STUDY SCHEMA 
 
 
 
 
5 BACKGROUND AND SIGNIFICANCE 
5.1 Study Disease 
Seizures are a debilitating complication of brain tumors.  Aberrant and repetitive neuronal firing leads to the 
generation of seizures.   Approximately 75% of patients with low grade tumors and 25% with high grade tumors 
suffer from seizures compared to 0.5-1% of the general population 2.  Slower growing, low grade tumors are 
associated with higher epileptogenicity, while faster growing, high grade tumors are associated with seizures 
secondary to mass effect 3. Higher seizure frequency has been associated with reduced cognitive function and 
Health-Related Quality of Life (HRQOL) and strips patients of driving privileges for 6 months on average in the US, 
thus affecting daily functional activities of living 4.  While surgery can be potentially curative of tumor-related 
seizures by resecting the nidus of seizure activity, it could also cause seizures due to irritation of the cortex, 
hemorrhage at the surgical site, and cerebral hypoxia and acidosis during surgery 5.   
 
Glioma Diagnosis Suspected or 
Brain Metastasis
Consent
Randomization
Initiate AED
LCM
LEV
NO AED
~6-10 weeks
AED Taper

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
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Duke Department of Neurosurgery 
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CONFIDENTIAL 
The current guidelines recommend against peri-operative seizure prophylaxis in patients who have never had a 
seizure, and to taper Anti-Epileptic Drug (AED) therapy after the first post-procedure week 6,7.  However, these 
guidelines were based on older generation AEDs [(Phenytoin (PHT), Phenobarbitol (PBT), and Valproic Acid (VPA)] 
that were associated with significant side effects and drug-drug interactions.  Since these guidelines were 
published in 2000, and reaffirmed in 2003 and 2008, newer generation AEDs have emerged with more favorable 
side effect profiles 8.  LCM, a third generation AED and LEV, a second generation AED, are both well tolerated with 
unique mechanisms of action. 
 
Given the reduced risk of adverse event occurrence with newer AEDs, the clinical use of AEDs as prophylaxis has 
increased 9; however, there have been no updated guidelines and there is a lack of clinical trial data to reflect this 
practice. LCM is US Food and Drug Administration (FDA) approved as adjunctive and monotherapy for partial-
onset seizures and LEV is approved as adjunctive therapy 10 11. Their promising roles in brain tumor patients 
continue to be explored.   
5.2 Study Agents 
5.2.1 
Mechanism of action 
Lacosamide: LCM is a sodium channel blocker, enhancing slow inactivation, which is unique. Other sodium 
channel blocker AEDs enhance fast sodium channel inactivation 12.  The activation state of voltage-gated sodium 
channels in the cells determines the potential for neuronal excitability 12.  Sodium channels can either be in the 
resting, fast inactivated, or slow inactivated state (Figure 1A).  In the resting state, the sodium channels are closed 
and can be opened by the depolarization of the membrane potential and therefore lead to neuronal activity 13.  
Shortly after depolarization, the sodium channels shift into the fast inactivated state; they close their channels 
from inside the neuron and are unable to be activated 13.  Older generation AEDs work by prolonging this state 
(CBZ, PHT, and LTG) 13.  After the fast inactivated state, sodium channels return to their resting state 13.  However, 
in conditions of prolonged depolarization and repetitive neuronal stimulation, the sodium channels can assume a 
slow inactivated state by closing the pore inside the channel 13.  LCM works by enhancing this effect 13.  In doing 
so, LCM stabilizes hyperexcitable neuronal membranes that are most associated with seizures 13.  At the same 
time, it does not affect the ability to recover from slow inactivation; thus, it inhibits neuronal firing and reduces 
long-term sodium channel availability without affecting physiological function 13.  Chemically, it is a member of a 
series of functionalized amino acids 13.  Its chemical structure is C13H18N2O3 and its active drug substance is (R)-2-
acetamido-N-benzyl-3-methoxyproprionamide (Figure 1B) 13. 
 
A.
      B.
 
Figure 1. A. Voltage-gated sodium channels and the role of LCM 14.  
B. Chemical structure of lacosamide (C13H18N2O3)14 
 
Levetiracetam. LEV’s anti-epileptic properties have been widely studied, but a single mechanism has yet to be 
elucidated.  Its primary mechanism of action is binding to the synaptic vesicle protein SV2A, an essential 

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
Version 3:  04/08/2019 
 
Duke Department of Neurosurgery 
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CONFIDENTIAL 
presynaptic membrane protein in neuronal transmission that is expressed ubiquitously in the brain 15. By doing 
so, LEV decreases neurotransmitter release in states of epileptiform burst firing 16.   
 
LEV also inhibits calcium release from intraneuronal stores and high voltage activity (N-type) calcium channels 11.  
In regards to intraneuronal stores, LEV has been shown to inhibit the Inositol 1,4,5-triphosphate (IP3) and 
Ryanodine (RyR) receptors, two major receptors involved in calcium-induced calcium release (CICR), which 
effectively decreases intracellular calcium ([Ca2+]i) 17.  Ca2+ is part of important second messenger systems 
associated with neurotoxicity and neuronal plasticity 17.  Elevations in ([Ca2+]i) and alterations in calcium 
homeostatic mechanisms have been implicated in acquired epilepsy resulting from injury 17.  Thus, LEV’s effect on 
calcium plays a part in its anti-epileptic ability.   
 
LEV’s impact on GABAergic (transmitting or secreting gamma-aminobutyric acid) mechanisms has been both 
favored and rejected, with discoveries only applicable or studied in specific diseases, such as those related to 
mesial temporal lobe epilepsy and not necessarily tumor related epilepsy 18,19.  
 
Lastly, LEV has also been suggested to inhibit O-6 methylguanine-DNA methyltransferase (MGMT) 20.   While not 
directly related to its anti-epileptic effect, it is relevant in this population, since MGMT is a Deoxyribonucleic Acid 
(DNA) repair protein that plays a role in resistance of gliomas to alkylating agents 20.  Inhibiting MGMT thus 
inhibits malignant glioma cell proliferation, and increases sensitivity of gliomas to temozolomide, first-line 
chemotherapy for malignant gliomas 20. 
 
LEV’s chemical formula is C8H14N2O2 15.  It is the S-enantiomer of a-ethyl-2-oxo-1-pyrrolidine acetamide 15. 
5.2.2 
Pharmacokinetics 
Lacosamide. LCM’s time to peak is 1-4 hours and the half-life is 13 hours, allowing for twice daily dosing 21.  LCM 
achieves steady-state concentrations after 3 days of BID dosing 14.  It has negligible protein binding 14.  
Therapeutic drug monitoring is not routine given its predictable pharmacokinetics, except in instances of liver 
and/or kidney failure or to evaluate drug compliance 22.  Its absorption is not affected by food intake 23.  
 
Levetiracetam. LEV’s time to peak is 0.5-1 hour and the half-life is 6-8 hours 15,24.  It achieves steady-state 
concentrations after 48 hours of BID dosing 25.  LEV does not require routine drug monitoring for therapeutic 
levels because of its predictable pharmacokinetic profile and wide therapeutic margin 11,15. It has negligible 
protein binding 26.  Its absorption is not affected by food intake 15. 
 
LCM and LEV are both renally cleared 27.  Approximately 40% of LCM is excreted unchanged, 60% as an inactive 
metabolite formed by the liver (via several Cytochromes P450 (CYPP450) and CYP-independent mechanisms, 
mainly cytochrome CYP2C19), and the remainder as a polar fraction thought to be serine derivatives 10,28.  Nearly 
100% of LEV is excreted by the kidneys, approximately 66% unchanged and the rest as a metabolite formed by 
hydrolysis in the blood 29,30.   
5.2.3 
Formula dosing 
Lacosamide. LCM is available in IV, oral liquid and oral tablet formulations and has near 100% oral bioavailability 
21.  It is dosed twice a day with a usual starting dose of 50mg BID for adjunctive therapy or 100mg BID as 
monotherapy 10,21.  It can alternatively be initiated with a single loading dose of 200mg, followed by a 
maintenance dose regimen of 100mg BID approximately 12 hours later 10.  The maintenance dose can be titrated 
50mg BID over a week to a maximum dose of 400mg/day 21,31.  Discontinuation of LCM should be done gradually 
with a weekly taper of approximately 200mg a week 10. 
 
No dose adjustment of LCM is necessary in mild to moderately renally impaired patients; however, in patients 
who have creatinine clearance (CrCl) <30 ml/min and are diagnosed with end stage renal disease (ESRD), the 
maximum recommended dose is 300mg/day 32.  The maximum recommended dose for patients with mild to 
moderate hepatic impairment is 300mg/day, mainly attributed to associated renal dysfunction in patients with 

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
Version 3:  04/08/2019 
 
Duke Department of Neurosurgery 
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CONFIDENTIAL 
moderate hepatic impairment 10.  LCM has not been systematically studied in patients with severe hepatic 
impairment, and is thus not recommended for these patients 23.  
   
Levetiracetam. LEV is available in IV, oral liquid and oral tablet formulations, including extended release 15.  It has 
near 100% oral bioavailability.  It does not require slow titration during initiation of therapy 25.  LEV is usually 
dosed twice a day, unless it is the extended-release form, which is once a day.  The usual starting dose is 500-
1000mg BID, with a maximum dose up to 3000mg/day 15.  Discontinuation of LEV should be done gradually as 
prescribed by the primary physician. 
 
LEV must be renally adjusted for patients with CrCl less than or equal to 80 ml/min/1.73m2 33.  It does not need to 
be adjusted for mild-to-moderate liver impairment, but it does need to be reduced for severe liver impairment, 
mainly because often patients with severe liver dysfunction also have some renal impairment 34. 
 
5.2.4 
Drug-drug interactions 
Drug-drug interactions are relevant in patients with brain tumors, who take concomitant medications such as 
dexamethasone and chemotherapies that are metabolized via the CYP450 system.  Older generation AEDS that 
are enzyme-inducing AEDs (EIAEDs) increase clearance of chemotherapy and dexamethasone, reducing efficacy, 
while other AEDs that are enzyme inhibitors potentially increase the toxicity of chemotherapies 35,36.  In addition, 
AEDs themselves can build to toxic levels due to the drug-drug interactions, requiring more therapeutic 
monitoring of AED levels in these older generation drugs 35.  Such issues are alleviated with LCM and LEV. 
 
LCM has low potential for pharmacokinetic drug-drug interactions due to its low protein binding, which minimizes 
potential displacement of other drugs and because it does not inhibit or induce any of the CYP isoenzymes in a 
clinically relevant manner 23,37,38.  LEV also has no known significant pharmacokinetic interactions since it is not 
metabolized through the liver 13,27.  
5.2.5 
Adverse Events 
Lacosamide. LCM’s most common adverse events (AEs) based on phase IIB/III trials in partial-onset seizures were 
related to central nervous system (CNS) and gastrointestinal effects 39,40. Dizziness, headache, nausea and diplopia 
were the most common in a pooled analyses of the trials, occurring at ≥10% in all doses combined (200-
600mg/day, N=944) 41.  Other less common AEs included nystagmus, ataxia, vomiting, fatigue, somnolence, and 
headache 39 40,42.  Incidence appeared dose related, more apparent during the initial titration phase, and less 
frequent during the maintenance phase 14.  The most common AEs that led to discontinuation of the drug were 
dizziness and abnormal coordination, and these occurred at the higher dose of 600mg/day 42.  There were no 
serious safety concerns regarding hematologic or clinical chemistry values identified 42.  Moreover, another meta-
analysis of 10 randomized controlled trials of LCM for various indications determined LCM was not associated 
with any apparent adverse effect on cognition 43.   
 
Levetiracetam. LEV is well tolerated; however, it can cause behavioral AEs such as aggression, irritability, and 
anger, as well as somnolence and cognitive side effects.  Behavioral AEs reportedly occur in approximately 13% of 
patients, but up to 30% for some AEs such as irritability or anxiety 44.  It has been associated with suicidal 
tendency and has a contraindication for use in patients with past history of psychiatric illness 45. 
 
5.2.6 
Efficacy in Epilepsy 
Lacosamide. LCM was FDA approved as adjunctive therapy and monotherapy for partial-onset seizures (POS) in 
adults in 2008 and 2014, respectively 10. 
 
LCM is well known to be effective and well tolerated as an adjunctive agent for drug-resistant partial epilepsy, 
especially when combined with a non-sodium channel drug 46.  This has been demonstrated in at least three 

Seizure Prophylaxis Study 
Dr. Annick Desjardins 
Version 3:  04/08/2019 
 
Duke Department of Neurosurgery 
Page 11 of 34 
CONFIDENTIAL 
randomized controlled trials, as well as other studies 21.  More relevant to this study, it was more safe and 
efficacious to add LCM in patients who had breakthrough seizures on low dose LEV (<1500mg/day) than to 
increase the dose of LEV and thus increase the risk of behavioral side effects 47.   
 
Studies have been very supportive of LCM’s efficacy and safety as monotherapy in POS.  A retrospective review of 
66 patients across 6 centers with POS treated with LCM monotherapy revealed that 63.6% (42/66) remained 
seizure-free during follow up (up to 54 months) 48.  The patients were grouped into those who had LCM as first 
line therapy (n=18) and those who had previously been treated with an AED (n=48). No difference in efficacy 
between the two groups in terms of outcomes or tolerability was found.  Only 3/66 (4.5%) of patients had to 
discontinue therapy due to side effects, which were generally mild 48.  Another study prospectively followed 
patients who were converted to LCM monotherapy after 1-year seizure freedom on LCM add-on therapy, 
followed by withdrawal of the concomitant AED 49.  55.2% (32/58) patients were seizure free at one year from 
withdrawal of the background AED, with those who were on more than three lifetime AEDs more likely to have a 
seizure 49.  Side effects were mild to moderate in 20% (12/58) of patients 49.  This study was performed on 
patients with POS with or without generalization 49.  Other studies, including double-blind studies, have also 
supported the effectiveness and safety of conversion to LCM monotherapy after withdrawal of background AEDs 
50.  
 
In terms of generalized epilepsy, there have been studies to demonstrate LCM therapy being effective in these 
patients 51, and studies are still ongoing to verify this (NCT01969851, NCT02408549).  
Levetiracetam. LEV was FDA approved in 1999 as adjunctive therapy for POS in adults with refractory generalized 
myoclonic seizures 11.  Since then, LEV is widely used for POS, general tonic-clonic (GTC) seizures, and generalized 
myoclonic seizures based on studies demonstrating its efficacy as adjunctive and monotherapy in these patients 
39,52-60.  The 2013 International League Against Epilepsy (ILAE) updated review on epilepsy stated that LEV 
has level A evidence as a monotherapy for POS in adults and Level D evidence as a monotherapy for newly 
diagnosed or untreated GTCs 61.  This was based on trials showing non-inferiority compared to carbamezapine 
(CBZ), the prior first line therapy for POS 57. 
A recent prospective, open-label, randomized study further supported LEV monotherapy as non-inferior to CBZ in 
POS, resulting in 71 vs. 78% seizure freedom at 6 months (p=0.253). They were both well tolerated, but LEV had a 
better overall quality of life (QOL), measured by the QOL in Epilepsy (QOLIE)-10 questionnaire.  However, LEV was 
associated with more behavioral changes, such as aggression and anxiety 45,57,62. 
5.2.7 
Efficacy in Brain Tumors 
 
Seizures associated with brain tumors belong to the category of POS, either with or without secondary 
generalization 63.  Since it is relatively new, there is limited data on LCM in brain tumors. Current data supports its 
tolerability and efficacy as an add-on agent 64.  One retrospective analysis of 70 patients with primary brain 
tumors reported a decrease in seizure frequency in 66% (47/70) of patients 65.  There are currently ongoing 
randomized, double-blind, placebo-controlled trials of LCM for seizure prophylaxis in patients with high grade 
gliomas (NCT01432171), and one as adjunctive therapy to refractory epilepsy in patients with low grade glioma 
(LGG) (NCT02276053).  Its related side effects are the same as in non-brain tumor patients, mainly dizziness at 
high doses 65.  
 
LEV, on the other hand, has evidence to support its use as a first line agent in brain tumors, due to its efficacy, low 
drug-drug interactions, and tolerability 66-68.  Seizure freedom with LEV has ranged from 76-91% with seizure 
reduction by half in 100% of patients 3,67-69.  Recent studies have also shown it has a potential anti-tumor effect as 
an added benefit secondary to its role as an MGMT inhibitor, although this role has been contested with later 
analyses and is still being studied (NCT02815410) 20.  Its risk of emotional instability (aggression, depression or 
irritability) is about the same 5-13% risk as in non-brain tumor patients, with a reported 0.4% incidence of 
psychosis 4 weeks after initiating LEV 67,69.  

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5.2.8 
Clinical Experience 
In our institution’s experience, peri-operative LEV prophylaxis at a dose of 500mg BID was well tolerated among 
patients, with a 10% rate of AEs, mainly irritability, agitation and fatigue.  At that dose, there was not a 
statistically significant reduction in post-operative seizure rates (34.6% seizure rate at this dose of LEV) among 
patients with newly-diagnosed high-grade gliomas (Pro00047350 Descriptive and Cost Analysis of Post-Operative 
Anti-Epileptic Drugs in Malignant Glioma).  However, subsequent to the year studied, patients were initiated on 
1000mg BID.   
 
The goal of this study is to evaluate the impact of LCM, LEV or no AED on the re-admission rate and number of 
emergency room visits in the post-procedure period. If the use of an AED is shown to be beneficial, it is possible 
that LCM could be a preferable alternative for some patients, especially for those who do not tolerate LEV due to 
the behavioral side effects.  
5.2.9 
Study Purpose and Rationale 
The primary purpose of this study is to evaluate 30-day readmission rates and ED visits through randomizing 
subjects to “no AED” or to the 2 primary AEDs used in this patient population here at DUMC. 
 
Current guidelines recommend against peri-operative seizure prophylaxis for patients with newly diagnosed brain 
tumors; however, they were based on older generation AEDs that were associated with severe toxicities and 
drug-drug interactions.  In light of newer generation AEDs with more tolerable safety profiles, some 
neurosurgeons and neuro-oncologists prescribe AEDs to patients for prolonged periods of time after surgery, 
despite these guidelines; this has also been the practice here at DUMC.  Given the lack of recommendation for 
AED prophylaxis in the peri-operative period by the neurosurgical guidelines, which is contrary to Duke’s practice, 
and given the cost and potential side effects of AEDs, it was determined that it is now time to formally assess the 
impact and side effect profile of the use or not of AEDs. I If determined that AED is necessary, this study will also 
attempt to evaluate the side effect profile of the commonly used AED at Duke (levetiracetam) versus a newer AED 
(lacosamide).  
 
The question most relevant to Duke neurosurgeons is the rate of readmission and ED visits after a Maximum Safe 
Resection (MSR) (gross-total, sub-total or biopsy), a measurable patient outcome to their surgery.  If there is 
benefit on these rates from having an AED, that would provide support for neurosurgeons to prescribe AEDs.  If 
there is no difference in readmission rates/ED visits between those who did and did not receive an AED, then 
there would be much more support against AED prophylaxis.  If the adverse side effects of the AEDs studied are 
significant, then there will be a greater consideration of risk to benefit.   
 
The risks of seizures in the perioperative period are very small, which is supported by the current guidelines 
recommending against seizure prophylaxis in the peri-operative period  and further demonstrated by the 
incidence of peri-operative seizure of 34.6% observed in the Duke retrospective review (Pro00047350 Descriptive 
and Cost Analysis of Post-Operative Anti-Epileptic Drugs in Malignant Glioma).  Thus, variables related to seizure 
incidence from use of AEDs all are important to study, but written as exploratory variables in this protocol.  The 
data from this latter analysis may be suggestive of the impact of AED prophylaxis on seizure outcomes, but it is 
unclear at this point how significant the outcomes will be based on our knowledge of seizure rates.  The outcome 
of this study may, therefore, impact Duke practice.   
 
Overall, given the paucity of studies in the literature evaluating this question, it would have a significant 
contribution to outstanding literature and implications for standards in general, although the goal of this protocol 
is not to modify or update the general standard.   
 
The benefit of a prospective, randomized study is to remove the bias that occurs in an observational study 
because the latter allows neurosurgeons to let their own practice/biases decide whether a patient should receive 
AED treatment and which type. 
 

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LEV and LCM are newer generation AEDs with better safety and tolerability than first generation AEDs, and 
studies lean towards their effectiveness in patients with POS, which affect a great deal of patients with primary 
brain tumors.  LEV, a second generation AED, has been often used in these patients, but its side effects of 
irritability, somnolence, and rarely, psychosis, may be limiting for these patients already affected by cognitive and 
behavioral issues as a result of their tumors.  LCM is a third generation FDA-approved AED for POS, and initial 
studies have shown its effectiveness as monotherapy after patients have failed and been weaned off other AEDs.  
Its safety and tolerability has been demonstrated in brain tumor patients, but studies evaluating the efficacy of 
LCM in this population are still lacking. 
 
In this protocol, we will assess optimal seizure prophylaxis management during the post-procedure period for 
patients undergoing MSR for suspected diagnosis of new, recurrent, or transformed glioma (WHO grade I-IV) or 
brain metastasis. This will be determined by observing the impact of LCM, LEV, or no AED on whether visits to the 
emergency department (ED) or hospital re-admissions occur within 30 days after MSR.  A secondary endpoint will 
evaluate the safety and tolerability of LCM and LEV. Exploratory endpoints will evaluate admission duration for 
theMSR, number of post-procedure provider communications (telephone, email, and additional clinic encounters, 
etc.), and patient risk factors associated with post-procedure seizure. 
 
 
 

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6 OBJECTIVES AND ENDPOINTS 
  Table 1: Objectives and Endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
Assess the impact of LCM, LEV or no 
AED in patients with suspected 
glioma (WHO Gr I-IV) or brain 
metastasis on ED visits and 
readmissions within 30 days of MSR 
Percentage of patients with an ED visit 
or hospital readmission within 30 days of 
MSR 
See Section 13.4 
Secondary 
Assess the safety and tolerability 
profile of LCM and LEV 
Percentage of patients who experience 
an adverse event of special interest 
within the first 30 days after MSR 
See Section 13.5 
Exploratory 
Describe the duration of admission 
stays among patients treated 
prophylactically with LCM, LEV, or no 
AED 
Median duration of initial admission stay 
for MSR  
See Section 13.6.1 
Exploratory 
Describe the number of provider 
communications (email, telephone, 
or additional clinical visits) among 
patients treated prophylactically with 
LCM, LEV, or no AED 
Frequency distribution for the number 
of provider communications (email, 
telephone, or additional clinical visits) 
that occurred within 30 days of MSR. 
See Section 13.6.2 
Exploratory 
Describe the usage of intraoperative 
AED 
Percentage of patients requiring 
intraoperative AED 
See Section 13.6.3 
Exploratory 
Assess the impact of LCM, LEV, or no 
AED on post-procedure seizure 
occurrence 
Percentage of patients experiencing 
post-procedure seizures during the 30-
day post-operative phase. 
See Section 13.6.4 
Exploratory 
Describe the frequency of changes in 
AED dosage, type of AED, addition or 
discontinuation of AED 
The frequency of changes in dosages, 
type of AED, addition or discontinuation 
of AED that occur within 30 days of MSR 
See Section 13.6.5 
Exploratory 
Evaluate patient risk factors for post-
procedure seizure 
Statistically significant association of 
specific risk factors with rate of post-
procedure seizure during the 30-day 
post-procedure phase 
See Section 13.5.6 
 
7  INVESTIGATIONAL PLAN 
7.1 Study Design 
The protocol will assess the need for AED prophylaxis during the post-procedure period in patients undergoing MSR 
for a suspected diagnosis of glioma (WHO grade I-IV) or brain metastasis. Patients (n=232) will be consented and 
randomized at their pre-operative assessment, either at their pre-operative clinic visit or in the ED, if that is the time 
of their initial presentation prior to surgery.  There will be three arms to the study – patients will be randomized to 
LCM, LEV, or control (no AED).  Randomization will be stratified by suspected grade (LGG vs HGG).  The AED can be 
initiated anytime within 48 hours before a MSR incision.  
 
Patients already on AEDs specifically to treat seizures will be excluded. Those patients taking AEDs for any diagnosis 
other than seizures will be included (e.g. Gabapentin for neuropathic pain, Topiramate for migraine, benzodiazepines 
as sleeping aid, etc).  
 
Patients taking AEDs for seizure prophylaxis and without clear history of seizures will be included. If already on LEV 
and randomized to LCM and vice versa, patient will be cross-taper, a week prior to surgery, as follows:   
 
 
If on LCM 100mg BID and need to taper to LEV: 
 
Start LEV, reduce LCM to 100/50 x 2 days, then 50/50 x 2 days, then 50 daily x 2 days, then off  
 
 
If on LCM and need to taper off: 
 
Reduce LCM to 100/50 x 3 days, then 50/50 x 3 days, then 50 daily x 3 days, then off 

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 
If on LEV and switch to LCM: 
 
Start LCM, reduce LEV to 1000/500mg x2 days, 500/500mg x 2 days, 500 daily x 2 days, then off 
 
 
If on LEV and need to taper off: 
 
Reduce LEV to 1000/500 x 3 days, then 500/500 x 3 days, then 500 daily x 2 days, then off 
 
Patients consented less than a week prior to surgery, who were on LCM and get randomized to LEV (or vice versa), will 
start the new medication, cut their current regimen by half, and stop the day of surgery. 
 
Doses will be either LCM 100mg twice a day (BID) (Arm A), LEV 1000mg BID (Arm B), or no AED (Arm C).  If a patient is 
randomized to Arm C and undergoes tumor mapping, the patient is allowed to receive one dose of AED in the 
operating room.  If a patient is randomized to Arm A or Arm B and takes the morning dose of their AED, they do not 
need an intra-operative dose of AED. If a patient has a seizure during the post-procedure period, AEDs will be adjusted 
at the discretion of the treating physician.  However, if a patient has intolerable side effects, patients will be changed 
to a different dose of the same medicine before consideration of another AED [i.e., BID to four times a day (QID) 
dosing if patient experiences diplopia on LCM].   
 
Patients with high-grade tumors (newly-diagnosed or transformed) will be treated with standard radiation and 
temozolomide therapy per the Stupp protocol 25,70.  For these patients, an AED taper will be initiated at the first clinic 
visit after completion of radiation.  For patients with a low-grade tumor or recurrent disease of any grade, an AED 
taper will be initiated at the first scheduled post-procedure visit, approximately 6-10 weeks after the operation.  LCM 
will be tapered by 100mg a week one week at a time.  LEV will be tapered 500-1000mg one week at a time. 
7.1.1 
AED initiation  
At study enrollment, patients will be randomized to either LCM, LEV or no AED. Enrollment can occur at the pre-
operative visit before MSRor in the emergency room at the time of patient’s first presentation.  AED can be 
initiated anytime within 48 hours of the first MSR incision.   
7.1.2 
AED titration 
If a patient experiences seizure during the follow up period, AED doses will be modified per treating physician 
preferences.   
7.1.3 
Post-procedure data collection 
Approximately 6-10 weeks after the procedure (for LGG or recurrent high grade glioma or brain metastasis) or 
first visit after radiation [for newly-diagnosed or transformed high grade glioma (HGG)], the following data will be 
obtained:  admission duration for the MSR, any seizure activity, any readmissions, ED visits, and provider 
communications (telephone, email, and additional clinic encounters, etc.), as well as for tolerance of the AED by 
clinical history and neurological examination.  Reasons for readmission and ED visits will also be noted.  All of 
these data are only obtained if relevant during the 30-day post-procedure time.  Patients will be provided a 
physical calendar to document any of the above, or provided access to the Research Electronic Data Capture™ 
(REDCap™) calendar, based on the patient’s preference. 
7.1.4 
Adverse Events of Special Interest (AESI) 
The occurrence of adverse events of special interest (AESIs) will be recorded only for the 30-day post-procedure 
phase.  
 
AESIs for this study will be graded using the National Cancer Institute’s (NIH) Common Terminology Criteria for 
Adverse Events (CTCAE) v4 and are the following: any grade of seizure, dizziness, somnolence, cognitive 

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disturbance, nausea, vomiting, ataxia, nystagmus, suicidal ideation, suicide attempt, anxiety, irritability, 
depression, psychosis and personality change (e.g. aggression). 
7.1.5 
Safety Considerations 
LEV has even been associated with a greater suicide risk in those with a psychiatric history. The latter risk 
depends primarily on the psychiatry comorbidities of the patient.  The potential risk for the patient will be 
discussed in detail with the patient and family.  See Section 5.2.5 for additional AED side effects. 
7.1.6 
Missed Doses 
Missed doses will be taken as soon as remembered.  Patients will be provided a calendar to track doses taken in 
order to determine compliance.    
7.1.7 
Concomitant Medications 
Given the lack of significant drug-drug interactions with new generation AEDs, concomitant medications will not 
be limited. If needed, patients will be initiated on chemotherapy, radiation therapy and corticosteroids, per 
standard of care.  Concomitant medications will be recorded by the study team from time of enrollment and 
during the 30-day follow up.   
7.1.8 
Randomization 
Upon consent, patients will be randomized in REDCap™ to receive either LCM, LEV, or no AED.  Randomization 
will be stratified by suspected histologic grade (LGG vs HGG) based on MRI review by the treating neurosurgeon 
and/or neuro-oncologist.  A stratified permuted block randomization algorithm will be used assign patients to 
treatment arms.  
 
7.2 Rationale for Selection of Dose and Treatment Duration 
Dosing was based on standard dosing approved by FDA for each AED.  Treatment duration of approximately 6 to 
10 weeks correlates with when the patients will most likely be guaranteed follow up after surgery, an optimal 
time to evaluate whether an AED should be continued or not.  
7.3 Definition of Evaluable Subjects, On Study, and End of Study 
Any patient that has been consented and randomized to the trial will be included in all analyses with the 
exception of those deemed non-evaluable as described in Section 10.5.2. 
 
Subjects will be considered on study once they have signed the informed consent form..  Subjects will be 
considered off study when they have been evaluated approximately 6 to 10 weeks post MSR and once their 
calendar has been submitted.   
7.4 Early Study Termination 
This study can be terminated at any time for any reason by the PI-sponsor.  If this occurs, all subjects on study 
should be notified as soon as possible.  Additional procedures and/or follow up should occur in accordance with 
Section 10.3.    
8 STUDY DRUGS 
8.1 Names, Classification, and Mechanism of Action 
See Section 5.2 

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8.2 Packaging and Labeling 
Package Inserts are uploaded in eIRB Section 8.   
8.3 Supply, Receipt, and Storage  
Local Pharmacy and/or Duke Hospital Pharmacy. 
8.4 Dispensing and Preparation 
 Medications will be prescribed for subjects and obtained from the subject’s local pharmacy or mail-order 
pharmacy as per the subject’s health insurance plan.  Subjects receiving medication after hospital admission will 
have medication dispensed from Duke Hospital Pharmacy. 
9 SUBJECT ELIGIBILITY 
9.1.1 
Inclusion Criteria 
1. Patients with a suspected diagnosis of new, recurrent, or transformed glioma (WHO grade I-IV) or brain 
metastasis scheduled for MSR at DUMC; 
2. Safe for surgery per treating neurosurgeon; 
3. Due to the potential implications of the treatment on the developing CNS, all patients must be ≥ 18 years of 
age at the time of entry into the study; 
4. Laboratory Studies: 
a. Total bilirubin, Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic 
Transaminase (SGPT), Alkaline Phosphatase (ALK) ≤ 1.5 x upper limit of normal (ULN) 
b. Creatinine ≤ 1.5  
5. A signed informed consent form approved by the Duke University Institutional Review Board (IRB) will be 
required for patient enrollment into the study. Patients or their Legally Authorized Representative (LAR) must 
be able to read and understand the informed consent document and must sign the informed consent 
indicating that they are aware of the investigational nature of this study.  Treating physicians at the time the 
protocol is presented are able to determine based on their clinical judgment whether patients lack the 
capacity and require a LAR to sign the consent form. 
 
6. Patients of child bearing potential or with partners of child-bearing potential must agree to practice 
recommended contraceptive methods to prevent pregnancy during treatment and for 1 month after the last 
dose of AED for women and men. 
9.1.2 
Exclusion Criteria 
1. Pregnant or need to breast feed during the study period (Negative urine β-HCG test required), or unable to 
maintain use of contraception while on study and for 1 month after the last dose of AED; 
2. Patients already on AED(s) specifically to treat seizures will be excluded. Those patients taking AEDs for any 
diagnosis other than seizures will be included (e.g. Gabapentin for neuropathic pain, Topiramate for 
migraine, benzodiazepines as sleeping aid, etc). Patients taking AEDs for seizure prophylaxis and without 
clear history of seizures will be included; 
3. Known history of epilepsy/seizure disorder; 
4. Known history of dependency/abuse of psychopharmaceuticals, alcohol, illicit drugs or narcotics; 
5. Any significant medical or psychiatric illness that cannot be adequately controlled with appropriate therapy 
or would compromise the patient’s ability to tolerate therapy, per the discretion of the treating investigator; 
6. Known allergy to LCM or LEV. 
 
10 SCREENING AND ON-STUDY TESTS AND PROCEDURES 
 

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Table 2: Schedule of Events 
Description 
Screening at 
pre-operative 
visit up to 48 
hours prior to 
MSR 
 
First post-procedure visit (LGG) or first visit after 
radiation (HGG) 
Week 
 
6-10* 
Day 
0 
 
General Evaluations 
 
Physical Exam 
X 
X 
Neurologic Exam 
X 
X 
Evaluation as candidate for MSR 
X 
 
Adverse Events 
 
X  
Laboratory Evaluations 
 
CBC with differential 
X 
X 
CMP 
X 
X 
Urine Pregnancy Test 
 X 
 
Disease Evaluations 
 
Seizure-related readmissions, ED visits, provider 
communications, duration of admission for MSR 
 
X 
*While patients will be assessed between 6-10 weeks post-procedure, only endpoint data pertaining to the first 30 days post-procedure will be 
recorded in the source documentation and in the database. 
10.1 
Screening Evaluations 
The baseline physical and neurologic examination along with standard of care blood work will be performed and 
documented by the clinical team and verified by the study team during the pre-operative clinic (or ED) visit. All 
subject screening data is standard of care evaluations that occur for all patients being seen for possible MSR of 
suspected LGG or HGG (newly-diagnosed, recurrent, or transformed).)  An informed consent must be signed by 
the patient before any research-related procedure takes place.   
 
Pre-treatment evaluations will include the following:   
 
History and physical exam, as part of pre-operative evaluation  
 
Laboratory Evaluations: 
 
CBC with differential 
 
CMP 
 
Urine pregnancy test, if appropriate (serum pregnancy if unable to obtain urine) 
 
If a subject is found to be ineligible to participate in the study, minimal records regarding the subject and the 
reason for screen failure will be retained in the study database. 
 
The only data collected pertains to the 30-day post-procedure period, however, data may be delayed in collecting 
due to the standard of care clinic visit schedule.  
10.2 
Study Period 
Day 0 and prior (diagnosis): occurring at least within 48 hours prior to MSR 
 
Randomization 
 
Initiate AED, per Section 7.1.1 (LCM 100mg BID or LEV 1000mg BID)  
 
Characterize seizure type, if applicable, (i.e., simple partial, complex partial, or generalized) 
 
Week 0-6 
 
Management of AEDs for any seizure events or adverse events will be left at the discretion of the 
treating physician.  If side effects occur, adjusting dosing of current AED before changing AEDs is 
recommended. 
 

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Week 6-10: at the first planned post-procedure visit (LGG or brain metastasis) or first visit after radiation (HGG), 
the following study endpoint data will be collected only for the 30-day post-procedure time period 
 
Collection of calendar, if not already obtained from the REDcap database 
 
CMP and CBC with differential to assess resolution of toxicity 
 
AESI (please see Section 7.1.4)  
 
Number of readmissions, ED visits, provider communications during the 30-day post-procedure phase 
 
Number of dose adjustments, additions or discontinuations of AED(s) during the 30-day post-procedure 
phase 
 
Initiate weaning of the AED per discretion of the treating physician, for example: 
o 
LCM 100/50mg x1 week, 50/50mg x 1 week, 50mg daily x 1 week, then off 
o 
LEV 1000/500mg x1 week, 500/500mg x 1 week, 500mg daily x 1 week, then off 
10.3 
Follow-up Period 
Subjects will be followed for seizure-related healthcare encounters at the times described above (See Section 
10.2).  Adverse events will be collected and recorded for the first 30 days post-procedure (See Sections 7.1.3 and 
7.1.4 for details).  
10.4 
End of Study 
The study will be considered complete once enrollment has been met, follow-up evaluations on all subjects have 
been conducted, and data analysis is concluded.  The study may also be terminated early for any reason by the PI-
sponsor.   
 
Subjects that are lost to follow-up will be documented in the patient record and in the REDCap™ database.  In the 
REDCap™ database, the subject will be marked as “Patient Status Unknown,” along with a corresponding 
explanation, if any.  This status may also be documented on the “Off Study Form” in the REDCap™ database. 
10.5 
Early Withdrawal of Subject(s) 
10.5.1 
Criteria for Subject Discontinuation from the Study 
Subjects may voluntarily withdraw from the study at any time.  The primary investigator (PI) may also withdraw a 
subject from the study at any time based on his/her discretion.  Reasons for PI-initiated withdrawal may include, 
but is not limited to the following: 
 
- 
Non-compliance of the subject 
- 
Administrative issues 
- 
Concerns for patient safety 
10.5.2 
Replacement of Non-evaluable  
A subject who withdraws study participation between randomization and the MSR will be excluded from primary 
analysis.  An additional patient will be randomized to the study to replace that subject to meet the sample size 
requirements. 
10.6 
Study Assessments 
Study assessments listed here are obtained per standard of care and are only documented for purposes of 
eligibility assessment. 
10.6.1 
Medical History 
Standard medical history will be obtained and documented per institutional guidelines. 

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10.6.2 
Physical Exam 
Standard physical exam and neurological assessment will be conducted and documented per institutional 
guidelines. 
10.6.3 
Laboratory Evaluations 
The timing of standard laboratory assessments that will be obtained during the course of the study is given in the 
Schedule of Events Table 2 in Section 10.    A list of each evaluation and what they include is below. 
 
CBC with differential  
 
CMP  
 
Urine pregnancy test, if appropriate (serum pregnancy test if unable to obtain urine) 
 
11 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse events, as 
defined below.  At each study visit, the PI or designee must assess, through non-suggestive inquiries of the subject or 
evaluation of study assessments, whether an AE or serious adverse event (SAE) has occurred. 
11.1 Adverse Events 
An AE is any untoward medical occurrence in a subject receiving study drug and which does not necessarily have 
a causal relationship with this treatment.  An AE can therefore be any unfavorable and unintended or worsening 
sign (including an abnormal laboratory finding) or symptom temporally associated with the use of the AED, 
whether or not related to use of the AED.   
 
From the time the subject initiates AED therapy through the time the subject is off study (as defined in Section 
7.3), all AESIs must be recorded in the REDCap™ database AE electronic Case Report Form (eCRF). Adverse events 
which are not an AESI will not be collected. 
 
AESIs will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.  If 
CTCAE grading does not exist for an AESI, the severity of the AESI will be graded as mild (1), moderate (2), severe 
(3), life-threatening (4), or fatal (5). 
 
Attribution of AEs will be indicated as follows: 
- 
Definite:  The AE is clearly related to the study drug 
- 
Probably:  The AE is likely related to the study drug 
- 
Possible:  The AE may be related to the study drug 
- 
Unlikely:  The AE is doubtfully related to the study drug 
- 
Unrelated:  The AE is clearly NOT related to the study drug 
11.1.1 
Reporting of AEs 
A database of all AESI will be maintained in REDCap™. Adverse events which are not an AESI will not be collected. 
The event will be categorized by organ system, relationship to treatment, its grade of severity, and resolution. 
The PI and study statistician will periodically review the collective adverse events with the intention of identifying 
any trends or patterns in toxicity. If any such trends are identified, depending on their severity and frequency, a 
protocol amendment will be considered. 
11.2 Serious Adverse Events 
An AE is considered “serious” if in the opinion of the investigator it is one of the following outcomes: 
- 
Fatal 
- 
Life-threatening 
- 
Constitutes a congenital anomaly or birth defect 

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- 
A medically significant condition (defined as an event that compromises subject safety or may require 
medical or surgical intervention to prevent one of the three outcomes above). 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant incapacity or substantial disruption to conduct normal life functions. 
11.2.1 
Reporting of SAEs 
All serious and unexpected adverse events should be reported immediately to Dr. Annick Desjardins (pager 919-
970-7348 or her designee (919-684-8111).  Only adverse events that the Duke Sponsor-Investigator determines 
to be serious, unanticipated, and related or possibly/probably (i.e. more likely than not) related to the research 
must be reported to the Duke IRB.  Those adverse events will be submitted in the electronic IRB (eIRB) system, 
according the following guidelines: 
 
Report within 24 hours of learning about any subject’s death that was unanticipated and more likely 
related to the research than unrelated; 
 
Report within 5 business days of learning about any serious, unanticipated, and related or 
possibly/probably related adverse event; 
 
Report within 10 business day of learning about any other unanticipated problem or event that was 
more likely related to the research than unrelated. 
11.3 Quality Assurance Program  
The Neurosurgery Quality Assurance Program (QAP) ensures adequate oversight for all types of human subject 
research that are under the Duke Neurosurgery-Clinical Research Unit (NS-CRU) supervision. Oversight begins 
with an effective scientific and feasibility review process accompanied by a robust data safety and monitoring 
plan.  
 
The Duke Cancer Institute’s Safety Oversight Committee (DCI SOCOMM) in concert with the NS-CRU QAP 
Monitoring Team (see Section 12.1 for Monitoring Team description) oversees the conduct of DUHS cancer-
related, sponsor-investigator therapeutic intervention and prevention intervention studies that do not have an 
external monitoring plan, ensuring subject safety and that the protocol is conducted, recorded and reported in 
accordance with the protocol, standing operating procedures (SOPs), Good Clinical Practice (GCP), and applicable 
regulatory requirements. 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring 
This clinical research study will be monitored both internally by the PI and by the Department of Neurosurgery.  In 
terms of internal review, the PI will continuously monitor and tabulate adverse events.  Appropriate reporting to 
the Duke IRB will be made. The PI of this study will also continuously monitor the conduct, data, and safety of this 
study to ensure that: 
 
Interim analyses occur as scheduled; 
 
Stopping rules for toxicity and/or response are met; 
 
Risk/benefit ratio is not altered to the detriment of the subjects; 
 
Appropriate internal monitoring of AEs and outcomes is done; 
 
Over-accrual does not occur; 
 
Under-accrual is addressed with appropriate amendments or actions; 
 
Data are being appropriately collected in a reasonably timely manner. 
 
The data and safety monitoring responsibilities are shared amongst Investigators, Neurosurgery Oversight Team, 
Neurosurgery Research Working Group and Duke Research Compliance Assurance (RCA) team.   
 

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The studies that are higher-risk (risk level II, III and IV), prospective studies that consent subjects will be subjected 
to internal reviews. The following table (table: 1) describes the risk levels for the studies: 
 
 
Risk Level I 
Risk Level II 
Risk Level III 
Risk Level IV 
Study funding 
source 
Investigator 
Initiated Trial 
Investigator 
Initiated 
Trial 
Investigator 
Initiated 
Trial 
Investigator Initiated Trial 
Trial design 
Retrospective 
chart reviews  
 
Exempt 
data/tissue 
collection 
• Prospective 
-
Specimen and data 
collection studies 
• Single Arm study - off 
label use of approved 
drug/device 
• Single Arm study – 
Multiple 
IND 
drug 
regimen 
• Multiple arms (cohorts 
or treatments) – No 
Randomization 
• Multiple arms – simple 
randomization ph II  or 
I/II studies 
 
Multiple 
arms 
- 
with 
Randomization – single or 
double blinding 
Complexity of 
the 
study  
regimen 
No 
drug 
or 
device involved 
FDA approved drug/ 
Device 
 
Non-Significant 
Risk 
Device 
• Single drug/ IND study 
• Multiple 
drug/ 
IND 
study 
• IDE device study 
• IND 
+ 
Device 
combination study 
• Single drug/ IND study 
• Multiple drug/ IND study 
• IDE device study 
• IND + Device combination 
study 
Toxicity 
profile/Subject 
risk profile 
Low 
to 
No 
toxicity profile 
Known toxicity profile 
Potentially 
significant 
toxicity profile 
 
Expected 
high 
toxicity 
profile 
Table 1: Different Risk Levels for Investigator Initiated Trials 
 
The study risk assessment is done by the PI and the study team during the protocol development process. The 
expectation is that all Investigator Initiated perspective interventional studies have a monitoring plan written in 
the protocol. This monitoring plan will be reviewed and approved by the scientific reviewers during the scientific 
review of the study. 
 
Other types of studies that might be subjected to internal reviews are listed below: 
 
Studies being conducted by a new PI or a new study staff or both; 
 
Sponsored interventional studies for which Duke NSCRU is amongst the highest enrolling sites;  
 
Any phase III interventional studies that are close to receiving an FDA approval for the IND/IDE it is testing. 
 
Any study that does not fall under the above mentioned criteria are low-risk studies (e.g., retrospective chart 
reviews). Those studies may be monitored only for data integrity, completeness and/or maintenance of all 
applicable regulatory approvals. 
 
This study falls under the Risk Level III category.  This means that this study is more interventional in nature and 
may require a higher scrutiny. The studies that fall into this category will have the following oversight: 
 
Review of the subject chart and 100 % of the data of the first 2 subjects enrolled. 
 
Review of the Regulatory binder after the first 2 subjects are enrolled. 
 
Drug/Device accountability logs after the first 2 subjects are enrolled and have received a study intervention. 
 
Ongoing reviews will be done quarterly until the study is closed to enrollment and subjects are no longer 
receiving study interventions that are more than minimal risk, and will include: 
- 
Review of the informed consents of all subjects enrolled 
- 
Subject charts, drug/device accountability and specimen collection process of 20 % of the subjects 
enrolled on the study 
- 
Review of any major deviations or safety events 
- 
Review of the enrollment status 
 
Ongoing reviews of the regulatory binders will be performed annually. 

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Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious 
and/or unexpected toxicities, or other concerns and may be initiated upon request of  the NS-CRU QAP, DUHS 
and DCI leadership, the DCI Cancer Protocol Committee (CPC), the SOCOMM, the sponsor, the Principal 
Investigator, or the IRB.  All study documents must be made available upon request to the QAP Monitoring Team 
and other authorized regulatory authorities, including but not limited to the National Institute of Health, National 
Cancer Institute, and the FDA.  Every reasonable effort will be made to maintain confidentiality during study 
monitoring. 
12.2 Audits 
The Duke Office of Audit, Risk and Compliance (OARC) may conduct audits to evaluate compliance with the 
protocol and the principles of GCP. The PI agrees to allow the OARC auditor(s) direct access to all relevant 
documents and to allocate his/her time and the time of the study team to the OARC auditor(s) in order to discuss 
findings and any relevant issues. 
 
OARC audits are designed to protect the rights and well-being of human research subjects. OARC audits may be 
routine or directed (for cause). Routine audits are selected based upon risk metrics generally geared towards high 
subject enrollment, studies with limited oversight or monitoring, Investigator initiated Investigational Drugs or 
Devices, federally-funded studies, high degree of risk (based upon adverse events, type of study, or vulnerable 
populations), Phase I studies, or studies that involve Medicare populations. Directed audits occur at the directive 
of the IRB or an authorized Institutional Official. 
 
OARC audits examine research studies/clinical trials methodology, processes and systems to assess whether the 
research is conducted according to the protocol approved by the DUHS IRB. The primary purpose of the 
audit/review is to verify that the standards for safety of human subjects in clinical trials and the quality of data 
produced by the clinical trial research are met. The audit/review will serve as a quality assurance measure, 
internal to the institution. Additional goals of such audits are to detect both random and systemic errors 
occurring during the conduct of clinical research and to emphasize “best practices” in the research/clinical trials 
environment. 
12.3 Data Management and Processing 
12.3.1 
Study Documentation 
Study documentation includes but is not limited to source documents, case report forms, monitoring logs, 
appointment schedules, drug calendars, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the “Regulatory Binder,” which includes but 
is not limited to continuing reviews, safety events, and amendments, approved and signed informed consent 
forms, and College of American Pathologists (CAP), Commission on Office Laboratory Accreditation (COLA), and 
Clinical Laboratory Improvement Act (CLIA) laboratory certifications. 
 
Source documents are original records that contain source data, which is all information in original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial.  Source documents include but are not limited to hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries, drug calendars or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial.  When possible, the original record should be retained as the source document.  However, a photocopy is 
acceptable provided that it is a clear, legible, and an exact duplication of the original document. 

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12.3.2 
Case Report Forms  
Paper Case Report Forms (CRFs) will be created for purposes of eligibility and data collection.  The information 
from the paper CRFs will then be entered into the eCRF in REDCap™.   
 
The eCRF will be the primary data collection document for the study and is developed in conjunction with 
statistical oversight.  The eCRFs will be updated in a timely manner following acquisition of new source data.  Only 
study personnel trained for accessing and entering data in REDCap™ are permitted to make entries, changes, or 
corrections in the eCRF. 
 
An audit trail will be maintained automatically by the electronic CRF management system, REDCap™.  All users of 
this system will complete user training, as required or appropriate per institutional requirements and other 
regulations. 
12.3.3 
Data Management Procedures and Data Verification 
Access to electronic databases will be managed by the Data Manager. 
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be alerted to the 
presence of data inconsistencies.  Additionally, the data management team and the statistical team will cross-
reference the data to verify accuracy.  Missing or implausible data will be brought to the attention of the PI 
requiring appropriate responses (i.e. confirmation of data, correction of data, completion or confirmation that 
data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after resolution of 
all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
12.3.4 
Coding 
All medical terms will be coded using CTCAE v.4.  
12.3.5 
Study Closure 
Following completion of the studies, the PI will be responsible for ensuring the following activities: 
- 
Data clarification and/or resolution; 
- 
Review of site study records for completeness. 
 
13 STATISTICAL METHODS AND DATA ANALYSIS 
All statistical analysis will be performed under the direction of the statistician designated in key personnel.  Any data 
analysis carried out independently by the investigator must be approved by the statistician before publication or 
presentation. 
13.1 Analysis Sets 
All evaluable subjects will be included in efficacy and safety analyses.   
13.2 Patient Demographics and Other Baseline Characteristics 
Socio-demographic and clinical characteristics of patients enrolled onto this study will be summarized.  For 
categorical variables, frequencies and percentages will be provided.  Means with standard deviations and 
medians/percentiles will summarize non-categorical variables. 
13.3 Treatments 
The number of patients treated on each arm (LCM, LEV, or no AED) will be calculated. 

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13.4 Primary Objectives 
The primary objective of this study is to assess the impact of LCM, LEV or, no AED in patients undergoing MSR for 
suspected new, recurrent or transformed glioma (WHO Gr I-IV) or brain metastasis. The basis for making this 
assessment will be the number of ED visits or readmissions within 30 days of MSR.  
13.4.1 
Variables 
Percentage of subjects with an emergency room visit or re-hospitalization within 30 days after MSR. 
13.4.2 
Statistical Hypothesis, Model, and Method of Analysis 
Though the percentage of patients who are re-hospitalized or have an emergency room visit during the 30 days 
post-MSR will be calculated within each treatment group, the primary comparison will combine outcome 
observed within the LCM and LEV arms.  The statistical comparison will assess the impact of AED (LCM or LEV) 
relative to no AED on this endpoint. 
 
Let us define P1 and P2 as follows: 
 
P1 =  Percentage of patients treated prophylactically with AED (LCM or LEV) who are re-hospitalized 
or have an emergency room visit during the 30 days post-MSR 
 
P2 =  Percentage of patients not prophylactically treated (i.e. no AED) who are re-hospitalized or 
have an emergency room visit during the 30 days post-MSR 
 
Given that current guidelines recommend against peri-operative seizure prophylaxis, we are interested in 
showing that AED is better than No AED, or P1 < P2, or 0 < P2 – P1.  Hence, the hypothesis we will be testing is: 
 
H0:  θ ≤ 0 vs H1: θ > 0 
 
where θ = P2 – P1.   A one-tailed test using a large-sample Z test will be conducted given the directional 
hypothesis that is being posed. 
 
With stratification for suspected grade (LGG vs HGG), the Cochran-Mantel-Haenszel test statistic will compare 
patients who do and do not receive AED with respect to the proportion of patients re-hospitalized or have an 
emergency room visit during the 30 days post-MSR. 
 
An interim analysis will be conducted half way through the study to assess whether early study termination is 
appropriate.  An O’Brien-Fleming boundary will provide guidance for making that assessment.  This interim 
analysis will determine whether the hypothesis can be rejected or accepted at that time.  See section 13.7 and 
13.8 for further detail. 
 
An intent-to-treat philosophy will be used in generating statistical analyses. 
13.4.3 
Handling of missing values, censoring, and discontinuations 
Given that the length of follow-up required after brain surgery is limited to 30 days in terms of data collection, we 
anticipate there being a minimal amount of missing primary outcome data.  
 
In the event that a patient does not complete the 30 day follow-up due to death, the patient will be treated as if 
they were either re-hospitalized and/or visited the emergency room. 
 
If a subject withdraws study participation between randomization and the MSR, that subject will be excluded 
from primary analyses.  An additional patient will be randomized to the study to replace that subject to meet the 

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sample size requirements for the study.  It is not believed that the knowledge of treatment group assignment 
would influence a patient’s decision to withdraw from the study. 
13.5 Secondary objectives 
This study has one secondary objective which is to assess the safety and tolerability of LCM and LEV.   
 
Adverse events will be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
version 4.  For each type of toxicity, the maximum grade experienced by the patient will be summarized with 
frequency distributions based upon all AESIs.  Of particular interest are those adverse events of special interest 
(AESI), as defined in section 7.1.4, that occur within 30 days afterMSR. 
 
The percentage of patients experiencing any grade adverse events of special interest within 30 days of MSRwill be 
summarized in each of the 3 treatment arms, and compared using chi-square tests.  If AED is shown to have fewer 
re-hospitalizations or ED visits, then a pairwise comparison of LCM and LEV is of particular interest.  
13.6 Exploratory Objectives 
The 6 exploratory objectives include an examination of the duration of admission stay, the number of provider 
communications, use of intraoperative AED, seizure occurrence, modifications of AED administration and risk 
factors for post-MSR seizure.   
13.6.1 
Exploratory Objective:  Duration of Admission Stay 
For each patient accrued to this study, the duration of the initial admission stay for the MSR will be calculated as 
the time interval between the date of MSR and date of discharge.  A Wilcoxon rank sum test will compare the 
combined AED groups versus the no AED group with respect to the distribution for the duration of the initial 
admission stay.  Reasons for an extended initial stay greater than 2-3 days will be summarized by treatment 
group. 
13.6.2 
Exploratory Objective:  Number of Provider Communications 
The number of provider communications (email, telephone, or additional clinical visits) during the 30 days post-
MSR will be determined for each patient.  Within each group, the distribution of the total number of provider 
contacts will be summarized with a frequency distribution.  Either a Wilcoxon rank sum test or a chi-square test 
will compare AED (combined) and no AED groups.  
13.6.3 
Exploratory Objective:  Usage of Intraoperative AED 
Whether or not intraoperative AED is administered will be assessed for each patient, and the proportion of 
subjects requiring an intraoperative AED will be calculated within each group.  AED (combined) and no AED 
groups will be compared with respect to the percentage of subjects requiring an intraoperative AED with a chi-
square test. 
 
Details concerning the type and dose of AED will also be summarized descriptively. 
13.6.4 
Exploratory Objective:  Seizure Occurrence 
The percentage of patients experiencing post-MSR seizures will be assessed within each arm.  A chi-square test 
will compare AED (combined) to no AED groups relative to this outcome. 
 
In addition, the distribution of the number of seizures experiences over the 30 day period will be generated 
within each arm.  A Wilcoxon rank sum test will compare AED (combined) and no AED groups with respect to the 
number of seizures reported. 

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13.6.5 
Exploratory Objective:  Changes in AED Administration 
The frequency of changes in AED dose, type of AED, addition or discontinuation of AED will be described. 
13.6.6 
Exploratory Objective:  Risk Factors for Post-MSR seizure 
Well-known risk factors predictive of seizure will be assessed (age, frontal/temporal/parietal tumor locations, 
cortical vs. subcortical location, tumor size, low grade vs. high grade tumor, extent of resection [GTR vs. sub-total 
resection (STR) vs. biopsy] 71-77. Other potential risk factors such as tumor genetics will also be collected, such as, 
but not limited to: IDH1 mutation, TERT, ATRX, EGFRvIII. The association between each of these factors and the 
occurrence of post-MSR seizure will be examined within a logistic regression model.   
 
Depending upon the prevalence of post-MSR seizures, a multivariate logistic regression analysis may be 
conducted that examines the joint effect of these factors, as well as treatment assignment and treatment 
interactions on outcome.  To maintain validity and stability of such modeling, the number of predictors for 
consideration in a multivariable logistic model will be no more than 1 predictor for every 10 seizures. 
13.7 
Interim Analysis 
After 116 accrued patients have completed their 30 day follow-up post-MSR, an interim analysis will be 
conducted.  This analysis that is conducted halfway through the study will assess whether accrual could be 
terminated early and whether the null or alternative hypothesis could be accepted. 
 
The O’Brien-Fleming boundaries that are used in the decision-making are defined in terms of a Z-statistic.  Those 
boundaries are provided below for the interim and final analysis (SAS PROC SEQDESIGN). 
 
Stage 
Total N 
Accrued 
Total 
Assigned to 
AED Groups 
Total Assigned 
to No AED 
Group 
Reject Null  
Hypothesis * 
if: 
Accept Null 
Hypothesis ** 
if: 
1 
116 
  58 
  58 
Z > 2.31015 
Z ≤ 0.48887 
2 
232 
116 
116 
Z > 1.63351 
Z ≤ 1.63351 
*Reject null hypothesis and conclude that AED better. 
**Accept null hypothesis and conclude that AED is not better. 
 
These boundaries are presented graphically below.  The interim analysis occurs at the point on the x-axis labeled 
as (1), and the final analysis occurs at the point labeled as (2).   
 
 
 

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The standardized Z statistic presented in the boundaries above is a function of the following difference:  Percent 
of no AED patients with re-hospitalization or ED visit – Percent of AED patients with re-hospitalization or ED visit.  
The denominator of the Z statistic is a measure of the variability of this difference.   
 
 
If the observed percentage of patients with re-hospitalization or ED visits is greater within the no AED group 
than in the AED group, then the Z statistic will be positive.   
 
If the observed percentage in the no AED group is less than that in the AED group, then the Z statistic will be 
negative. 
 
If there is no difference between groups in the observed percentage of patients with re-hospitalization or ED 
visits, then the Z statistic will be 0. 
 
The dark blue region in the figure above is where one concludes that AED is better than no AED; whereas, the 
light blue region is where one concludes that AED is not better than “no AED” (i.e. they are the same or no AED is 
better).  At the time of the interim analysis, the study will be terminated if Z > 2.31013 (i.e. observed percentage 
within the no AED group is much larger than that in the AED group) and the conclusion will be that AED treatment 
is better.  Also at the time of the interim analysis, the study will be terminated if Z ≤ 0.48887 (i.e. observed 
percentage within the AED group is greater than that observed in the no AED group, or about the same with AED 
or no AED) and the conclusion will be that AED treatment is not better.  If the Z calculated at the time of the 
interim analysis is between 0.48887 and 2.31013, the remaining patients will be accrued to the study.  At the time 
of the final analysis, the threshold for decision-making is Z=1.63351. 
 
If the accrual is unbalanced at the time of the interim analysis, the boundaries stated here may need to be 
modified slightly. 
 
Though the verb “terminated” is used above in the description of the monitoring rules, these rules should be 
viewed as guidelines for the determination of whether accrual should be terminated or not.  Additional factors 
may be considered in the determination of whether accrual should continue after the interim analysis. 
13.8 
Sample Size 
Eligible subjects will be randomized to one of 3 treatment arms (LCM, LEV, or no AED) using an allocation ratio of 
1:1:2.  Randomization will be implemented using a permuted block algorithm.  Randomization will be stratified by 
suspected grade of glioma (high vs low grade) or brain metastasis.. 
 
The experience of subjects in the LCM and LEV groups will be combined to estimate the percentage of subjects 
with an ED visit or readmission within 30 days of MSR after seizure prophylaxis pre-surgery.  That outcome will be 
compared to the same outcome observed among patients in the no AED group. 
 
In designing this study, we have considered the following background information: 
 
 
In a recently conducted retrospective review of Duke’s experience with AEDs and MSR (Pro00047350 
Descriptive and Cost Analysis of Post-procedure Anti-Epileptic Drugs in Malignant Glioma), the experience of 
patients newly diagnosed with malignant glioma and without prior seizure history or AED use was examined.  
Among those patients who were prophylactically treated with LEV before MSR, 12% of subjects were re-
hospitalized or visited emergency room within 30 days post-MSR. 
 
 
Published literature indicates that the risk of post-MSR seizure in MG patients without AED prophylaxis 
ranges from 2.3% up to 35%, particularly in glioblastoma (GBM).75,77,78 
 
Therefore in designing the study we have assumed that the percentage of patients with re-hospitalization or ED 
visits within 30 days post-MSR is 12% in both the LCM and LEV groups.  We have also designed the study to detect 
an increase in re-hospitalization or ED visits to 25% within the no AED group. 
 

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Additional assumptions for the power calculations include the following: 
 
 
One-tailed test conducted so that the overall type I error rate if 0.05.  This type I error rate accounts for one 
interim analysis. 
 
Power = 80% under the alternative where the true outcome is 12% in the AE group (combined) and 25% in 
the no AED group. 
 
One interim analysis half way through the study that allows early termination with either acceptance or 
rejection of the null hypothesis. 
 
Under these conditions, there is a need to randomize and follow 232 subjects for 30 days.  An interim analysis as 
described in Section 13.7 will be conducted after 116 patients (SAS PROC SEQDESIGN). 
 
14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
14.1 Regulatory and Ethical Compliance 
This protocol was designed and will be conducted and reported in accordance with the International Conference 
on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki, 
and applicable federal, state, and local regulations. 
14.2 DUHS Institutional Review Board and DCI Cancer Protocol Committee 
The protocol, informed consent form, advertising material, and additional protocol-related documents must be 
submitted to the DUHS IRB and DCI CPC for review.  The study may be initiated only after the Principal 
Investigator has received written and dated approval from the CPC and IRB. 
 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol amendments 
and changes to the informed consent form.  The CPC should be informed about any protocol amendments that 
potentially affect research design or data analysis (i.e. amendments affecting subject population, 
inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 
 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most recent IRB 
approval.  The Principal Investigator must also obtain protocol re-approval from the CPC within 1 year of the most 
recent IRB approval, for as long as the protocol remains open to subject enrollment. 
14.3 Informed Consent 
The informed consent form must be written in a manner that is understandable to the subject population.  Prior 
to its use, the informed consent form must be approved by the IRB. 
 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose of the 
research, methods, potential risks and benefits, subject concerns, and other study-related matters.  This 
discussion will occur in a location that ensures subject privacy and in a manner that minimizes the possibility of 
coercion.  Appropriate accommodations will be made available for potential subjects who cannot read or 
understand English or are visually impaired.  Potential subjects will have the opportunity to contact the Principal 
investigator or authorized key personnel with questions, and will be given as much time as needed to make an 
informed decision about participation in the study. 
 
Before conducting any study-specific procedures, the Principal Investigator must obtain written informed consent 
from the subject or a legally acceptable representative.  The original informed consent form will be stored in a 
study-specific consent binder. A copy of the informed consent will be sent to Health Information Management 
and an additional copy of the informed consent form will be provided to the subject.   

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14.4 Privacy, Confidentiality, and Data Storage 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.  Research Data Security Plans (RDSPs) will be approved by the appropriate institutional Site Based 
Research group. 
 
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the course of 
the study.  Prospective participants will be consented in an exam room where it is just the research staff, the 
patient and his family, if desired. For all future visits, interactions with research staff (study doctor and study 
coordinators) regarding research activities will take place in a private exam room. All research related interactions 
with the participant will be conducted by qualified research staff who are directly involved in the conduct of the 
research study. 
 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and key 
accessible only by the research staff. Subjects will be identified only by a unique study number and subject 
initials.  Electronic records of subject data will be maintained using a dedicated database, REDCap™, which is 
housed in an encrypted and password-protected file on a secure network drive.  Access to electronic databases 
will be managed by the Data Manager.  The security and viability of the Information Technology (IT) infrastructure 
will be managed by Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS Human Research 
Protection Program (HRPP) policy.  Subject names or identifiers will not be used in reports, presentations at 
scientific meetings, or publications in scientific journals. 
14.5 
Data and Safety Monitoring 
Data and Safety Monitoring will be performed in accordance with the DCI Data and Safety Monitoring Plan.  For a 
more detailed description of the DSMP for this protocol, refer to Section 12. 
14.6 Protocol Amendments 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to 
implementation.  IRB approval is not required for protocol changes that occur to protect the safety of a subject 
from an immediate hazard.  However, the Principal Investigator must inform the IRB and all other applicable 
regulatory agencies of such action immediately. 
14.7 Records Retention 
The Principal Investigator will maintain study-related records for the longer of a period of: 
- at least six years after study completion (Duke policy). 
14.8 Conflict of Interest 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and local regulations 
regarding reporting and disclosure of conflict of interest.  Conflicts of interest may arise from situations in which 
financial or other personal considerations have the potential to compromise or bias professional judgment and 
objectivity.  Conflicts of interest include but are not limited to royalty or consulting fees, speaking honoraria, 
advisory board appointments, publicly-traded or privately-held equities, stock options, intellectual property, and 
gifts. 
 
The Duke University School of Medicine’s Research Integrity Office (RIO) reviews and manages research-related 
conflicts of interest.  The Principal Investigator and Sub-Investigators must report conflicts of interest annually 
and within 10 days of a change in status, and when applicable, must have a documented management plan that is 
developed in conjunction with the Duke RIO and approved by the IRB/Investigational Ethics Committee (IEC). 

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15 REFERENCES 
1 
Kandel, E. R., Schwartz, J. H. & Jessell, T. M. Principles of Neural Science.  (McGraw-Hill, 2000). 
2 
DeAngelis, L. M. Brain tumors. N Engl J Med, 114-123 (2001). 
3 
Ruda, R., Bello, L., Duffau, H. & Soffietti, R. Seizures in low-grade gliomas: natural history, pathogenesis, and 
outcome after treatments. Neuro Oncol 14 Suppl 4, iv55-64, doi:10.1093/neuonc/nos199 (2012). 
4 
M. Klein, N. H. E., H.M. van der Ploeg, et al. Epilepsy in low-grade gliomas: The impact on cognitive function 
and quality of life. Ann Neurol, 514-520 (2003). 
5 
Sankalp Gokhale, S. K., Abhishek Agrawal, Allan Friedman and David McDonagh. Levetiracetam seizure 
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