Phase II Feasibility Study to Evaluate the Efficacy and Safety of Perampanel in Seizure Patients With Primary Glial Brain Tumors
Phase: PHASE4
Conditions: Brain Tumor, Primary
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. 
PT-PhII or III v05.22.12 
 
A Phase IV Study 
 
Feasibility Study to Evaluate the Efficacy and Safety of 
Perampanel in Seizure Patients with Primary Glial Brain 
Tumors 
 
 
 
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
 
 
Funding Source: 
Eisai, Inc. 
 
 
Protocol Source: 
PI - Duke Cancer Institute 
 
 
Duke IRB#: 
Pro00055609 
 
 
IND#: 
 
IND exempt 
 
 
Principal Investigator 
Katherine B. Peters, MD PhD 
DUMC 3634 
Phone 919.684.6173 
Fax 919.684.6674 
katherine.peters@duke.edu 
 
Co-Principal Investigator(s) 
N/A 
 
Sub-Investigator(s) 
Mary Lou Affronti, DNP, RN, ANP, 
MHSc 
mary.affronti@duke.edu 
 
Annick Desjardins, MD 
annick.desjardins@duke.edu 
 
Henry S. Friedman, MD 
henry.friedman@duke.edu 
 
Dina Randazzo, DO 
Dina.randazzo@duke.edu 
 
Gordana Vlahovic, MD 
gordana.vlahovic@duke.edu 
 
Statistician 
James E. Herndon, II, PhD 
James.herndon@duke.edu 
 
Lead Study Coordinator 
Sarah Woodring 
Sarah.woodring@duke.edu  
 
Regulatory Coordinator 
Deborah Iden 
deborah.iden@duke.edu 
 
Data Manager 
Eric Lipp 
eric.lipp@duke.edu 
 
 
 
 
Original version: 
8/5/2014 
 
Amended Version 1: 
Amended Version 2: 
Amended Version 3: 
Amended Version 4: 
12/10/2014 
1/15/2015 
2/23/2015 
7/24/2015 
 

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1 
TABLE OF CONTENTS 
2 
LIST OF ABBREVIATIONS ................................................................................................. 5 
3 
PROTOCOL SYNOPSIS AND RESEARCH SUMMARY .................................................. 6 
3.1 
Purpose ............................................................................................................................. 6 
3.2 
Design and Procedure....................................................................................................... 6 
3.3 
Selection of Subjects ........................................................................................................ 6 
3.4 
Risk/Benefit Assessment .................................................................................................. 7 
3.5 
Data Analysis and Statistical Considerations ................................................................... 8 
4 
STUDY SCHEMA.................................................................................................................. 9 
5 
BACKGROUND AND SIGNIFICANCE ............................................................................ 10 
5.1 
Study Disease ................................................................................................................. 10 
5.2 
Study Agent .................................................................................................................... 10 
5.2.1 
Pre-clinical experience ............................................................................................ 10 
5.2.2 
Clinical experience .................................................................................................. 10 
5.3 
Study Purpose/Rationale ................................................................................................ 11 
6 
OBJECTIVES AND ENDPOINTS ...................................................................................... 11 
7 
INVESTIGATIONAL PLAN ............................................................................................... 12 
7.1 
Study Design .................................................................................................................. 12 
7.1.1 
Missed Doses .......................................................................................................... 12 
7.1.2 
Concomitant Medications ....................................................................................... 12 
7.1.3 
Study Drug Blinding ................................................................................................. 13 
7.1.4 
Randomization ........................................................................................................ 13 
7.2 
Rationale for Selection of Dose, Regimen, and Treatment Duration............................. 13 
7.3 
Rationale for Correlative Studies ................................................................................... 13 
7.4 
Definition of Evaluable Subjects, On Study, and End of Study .................................... 14 
7.5 
Early Study Termination ................................................................................................ 14 
8 
STUDY DRUG ..................................................................................................................... 14 
8.1 
Names, Classification, and Mechanism of Action ......................................................... 14 
8.2 
Packaging and Labeling ................................................................................................. 14 
8.3 
Supply, Receipt, and Storage ......................................................................................... 14 
8.4 
Dispensing and Preparation ............................................................................................ 15 
8.5 
Compliance and Accountability ..................................................................................... 15 
8.6 
Disposal and Destruction ............................................................................................... 15 

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9 
SUBJECT ELIGIBILITY ..................................................................................................... 15 
10 SCREENING AND ON-STUDY TESTS AND PROCEDURES ....................................... 16 
10.1 
Screening Examination ............................................................................................... 16 
10.2 
Run-In Period ............................................................................................................. 17 
10.3 
Treatment Period ........................................................................................................ 17 
10.4 
End of Treatment ........................................................................................................ 17 
10.5 
Follow-up Period ........................................................................................................ 17 
10.6 
End of Study ............................................................................................................... 17 
10.7 
Early Withdrawal of Subject(s) .................................................................................. 18 
10.7.1 
Criteria for Early Withdrawal .............................................................................. 18 
10.7.2 
Follow-up Requirements for Early Withdrawal .................................................. 18 
10.7.3 
Replacement of Early Withdrawal(s) .................................................................. 18 
10.8 
Study Assessments ..................................................................................................... 18 
10.8.1 
Medical History ................................................................................................... 18 
10.8.2 
Physical and Neurological Exam .......................................................................... 18 
10.8.3 
Laboratory Assessments ..................................................................................... 18 
10.8.4 
Quality of Life and Neurocognitive Assessments ................................................ 19 
10.8.5 
Correlative Assessments ..................................................................................... 19 
11 SAFETY MONITORING AND REPORTING.................................................................... 19 
11.1 
Adverse Events ........................................................................................................... 19 
11.1.1 
Reporting of AEs .................................................................................................. 20 
11.2 
Serious Adverse Events .............................................................................................. 20 
11.2.1 
Reporting of SAEs ................................................................................................ 20 
11.3 
Safety Oversight Committee (SOC) ........................................................................... 21 
11.4 
External Data and Safety Monitoring Board (DSMB) ............................................... 21 
12 QUALITY CONTROL AND QUALITY ASSURANCE .................................................... 21 
12.1 
Monitoring .................................................................................................................. 21 
12.2 
Audits.......................................................................................................................... 22 
12.3 
Data Management and Processing .............................................................................. 22 
12.3.1 
Study Documentation ......................................................................................... 22 
12.3.2 
Primary Data Collection Document ..................................................................... 23 
12.3.3 
Data Management Procedures and Data Verification ........................................ 23 
12.3.4 
Coding .................................................................................................................. 23 
12.3.5 
Study Closure....................................................................................................... 23 

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13 STATISTICAL METHODS AND DATA ANALYSIS ...................................................... 23 
13.1 
Analysis Sets............................................................................................................... 24 
13.2 
Patient Demographics and Other Baseline Characteristics ........................................ 24 
13.3 
Treatments .................................................................................................................. 24 
13.4 
Primary Objective ....................................................................................................... 24 
13.4.1 
Variable ............................................................................................................... 24 
13.4.2 
Statistical Hypothesis, Model, and Method of Analysis ...................................... 24 
13.5 
Secondary Objectives ................................................................................................. 24 
13.6 
Exploratory Objectives ............................................................................................... 24 
13.7 
Interim Analysis ......................................................................................................... 24 
13.8 
Sample Size Calculation ............................................................................................. 25 
14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS ............................................. 25 
14.1 
Regulatory and Ethical Compliance ........................................................................... 25 
14.2 
DUHS Institutional Review Board and DCI Cancer Protocol Committee ................. 25 
14.3 
Informed Consent ....................................................................................................... 25 
14.4 
Privacy, Confidentiality, and Data Storage ................................................................ 26 
14.5 
Data and Safety Monitoring ....................................................................................... 26 
14.6 
Protocol Amendments ................................................................................................ 26 
14.7 
Records Retention....................................................................................................... 26 
14.8 
Conflict of Interest ...................................................................................................... 26 
14.9 
Registration Procedure ............................................................................................... 27 
15 REFERENCES ..................................................................................................................... 28 
16 APPENDICES ...................................................................................................................... 29 
16.1 
Appendix A: Cytochrome P450 Drug Interaction Table ............................................ 29 
16.2 
Appendix B: Medication and Seizure Log ................................................................. 29 
 
 
 

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2 LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AED 
Anti-epileptic Drug 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BCS 
Brain Subscale 
BDI 
Beck Depression Inventory 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CPC 
Cancer Protocol Committee 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCI 
Duke Cancer Institute 
DOCR 
Duke Office of Clinical Research 
DSMB 
Data and Safety Monitoring Board 
DUHS 
Duke University Health System 
DUMC 
Duke University Medical Center 
FACT-Br 
Functional Assessment of Cancer Therapy-Brain 
FACT-Cog 
Functional Assessment of Cancer Therapy-Cognition 
FACIT-F 
Functional Assessment of Cancer Therapy-Fatigue 
FDA 
Food and Drug Administration 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IRB 
Institutional Review Board 
KPS 
Karnofsky Performance Status 
NCI 
National Cancer Institute 
p.o. 
per os/by mouth/orally 
PRO 
Patient-Reported Outcome 
PRTBTC 
Preston Robert Tisch Brain Tumor Center 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
TEAE 
Treatment-Emergent Adverse Events  
 

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3 PROTOCOL SYNOPSIS AND RESEARCH SUMMARY 
3.1 Purpose 
This is a Phase 4 single-arm study assessing the efficacy of perampanel as an adjunctive anti-epileptic drug 
(AED) in patients with primary glioma presenting refractory partial onset seizure activity. 
 
Primary Objective: 
1. To determine the efficacy of perampanel as an adjunctive AED   in patients with primary glioma 
presenting refractory partial onset seizure activity. 
 
Secondary Objective: 
1. To assess the safety and tolerability of perampanel as an adjunctive AED in patients with primary glioma 
presenting with refractory partial onset seizure activity. 
 
Exploratory Objective: 
1. To evaluate the effect that perampanel has on neurocognition and patient-reported outcomes of quality 
of life (QoL) in patients with primary glioma presenting with refractory partial onset seizure activity. 
 
Hypothesis: 
We hypothesize that the addition of perampanel as an adjunctive AED will be effective in treating patients 
with primary glioma that are presenting with refractory partial onset seizure activity on non-enzyme inducing 
anti-epileptic drug regimen.  
3.2 Design and Procedure 
This is a Phase 4 single-arm study to assess the efficacy of perampanel as an adjunct anti-epileptic in patients 
with primary glioma that are presenting refractory partial onset seizure activity (defined as 3 or more seizures 
in a 28-day period).  In this study, patients will be started on a dose of 2 mg of perampanel daily taken orally at 
bedtime for 2 weeks. At the start of week 3 Perampanel will   be titrated up in dose in 2mg increments per 
week up to 8mg daily, as long as it is well tolerated by the patient.    . The highest dose of perampanel will be 8 
mg orally at bedtime. Patients will begin the treatment period of the study starting at week 5 and will continue 
through the end of week 12. The planned treatment dose is 8mg, but the dose can be modified by the 
physician based on patient reported tolerability.  Patients will be assessed in the Brain Tumor Center Clinic 
every 8 weeks.  Study assessments will be made at enrollment, 8 weeks, 16 weeks, and 24 weeks.  
Assessments will include history and physical examination (H&P) including Karnofsky Performance Status 
(KPS), neurological examination, evaluation of seizure history, patient-reported outcomes of QoL, and 
neurocognitive testing using CNS Vital Signs®.   After a total of 16 weeks of therapy, perampanel will be 
tapered for 3 weeks and then will be discontinued, such that at week 20, patients will only be taking their 
original AED regimen. Patients will then be monitored through Week 24.  Patients will remain on their original 
AED   therapy during this treatment time and the dose of their original AED regimen at the start of the study 
will not be changed while they are on study.  If seizure control is achieved during the treatment period or if 
seizures occur during the tapering period, patients can be continued on perampanel per the discretion of the 
treating physician.  In this instance, perampanel will be prescribed by the treating physician and not provided 
within the confines of the study. Efficacy will be assessed using a log of patient-reported seizure activity.   As is 
standard procedure at the PRTBTC, patients will be given a log to record the number of seizures that occur.  
Research team members will regularly contact patients for reminders and reports from the log.  Safety will be 
assessed with the following laboratory evaluations:  complete blood count (CBC) with differential, complete 
metabolic panel (CMP), and toxicity assessment. 
3.3 Selection of Subjects 
Inclusion Criteria: 
1. Patients must be diagnosed with a primary glioma and have refractory partial onset seizure activity 
(defined as 3 or more seizures in a 28-day period) on non-enzyme inducing anti-epileptic regimen that can 

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include, but not limited to the following: levetiracetam (Keppra) or Keppra XR, lamotrigine (Lamictal) or 
Lamictal XR, gabapentin (Neurontin), tiagabine (Gabitril), topiramate (Topamax), valproic acid (Depakene) 
/ valproate (Depacon), zonisamide (Zonegran), lacosamide (Vimpat), and clonazepam (Klonopin)  
2. Adult patients (≥ 18 years old) 
3. Karnofsky ≥ 70% 
4. Hematocrit ≥ 29%, ANC ≥ 1,500 cells/L, platelets ≥ 100,000 cells/L 
5. Serum creatinine ≤ 1.5 mg/dL, serum AST and bilirubin ≤ 1.5 times the upper limit of normal 
6. If sexually active, patients will take contraceptive measures for the duration of protocol treatment and 
continue until two months after treatment.  The effectiveness of hormonal contraceptives containing 
levonorgestrel has been shown to be reduced by perampanel at a 12 mg dose.1  Therefore, alternative or 
back-up methods of contraception are recommended. 
7. 
Signed informed consent approved by the Duke Institutional Review Board 
 
Exclusion Criteria: 
1. Pregnant or breastfeeding (Both perampanel and levetiracetam are classified as Pregnancy Category C 
drugs.) 
2. Chronic excessive use of psycho-pharmaceuticals, alcohol, illicit drugs, or narcotics 
3. Inability to complete or perform measures of patient-reported outcomes or neurocognitive testing on 
the computer 
4. Known allergy to perampanel  
5. Concomitant use of known cytochrome P450 (3A4,5,7)  inducers such as carbamazepine, phenytoin, or 
oxcarbazepine (see Appendix A) 
6. Previous history of suicidal ideation, homicidal ideation, depression leading to hospitalization or mood 
disturbance leading to hospitalization. 
3.4 Risk/Benefit Assessment 
The full prescribing information for Perampanel (FYCOMPA™) includes the following boxed warning1: 
WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS 
• 
Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, 
irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA 
• 
These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, 
or concomitant use of medications associated with hostility and aggression 
• 
Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or 
changes in mood, behavior, or personality that are not typical for the patient are observed while taking 
FYCOMPA or after discontinuing FYCOMPA  
• 
Closely monitor patients particularly during the titration period and at higher doses  
• 
FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if 
symptoms are severe or are worsening 
 
The most common adverse reactions that are associated with perampanel occurring in 10% of patients or 
greater are dizziness (36%), somnolence (16%), and fatigue (10%).  Less common reactions are irritability (9%), 
falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain 
(4%).   
 
With concomitant use, perampanel, at a dose of 12 mg/day, reduced levonorgestrel exposure by 
approximately 40%. Use of perampanel with oral or implant contraceptives containing levonorgestrel may 
render them less effective. Therefore, additional non-hormonal forms of contraception are recommended 
(please see the FYCOMPA FDA-approved labeling dated 6/11/2013).1  
 
The concomitant use of known CYP enzyme inducers including carbamazepine, phenytoin, or oxcarbazepine 
with perampanel decreased the plasma levels of perampanel by approximately 50~67. The starting doses for 
perampanel should be increased in the presence of enzyme-inducing AEDs.1 When these enzyme-inducing 

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AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored 
for clinical response and tolerability. Dose adjustment of perampanel may be necessary. As noted, however, 
the decrease in the therapeutic effect seen in patients on concomitant treatment, was not affected by use of 
higher doses (8 mg to 12 mg).1  
 
Concomitant use of perampanel with other strong CYP3A inducers (e.g., rifampin, St. John’s wort) should be 
avoided.1  
 
The concomitant use of perampanel and CNS depressants including alcohol may increase CNS depression.1 A 
pharmacodynamic interaction study in healthy subjects found that the effects of perampanel on complex tasks 
such as driving ability were additive or supra-additive to the impairment effects of alcohol. Multiple dosing of 
perampanel 12 mg/day also enhanced the effects of alcohol to interfere with vigilance and alertness, and 
increased levels of anger, confusion, and depression. These effects may also be seen when perampanel is used 
in combination with other CNS depressants. Care should be taken when administering perampanel with these 
agents. Patients should limit activity until they have experience with concomitant use of CNS depressants (e.g. 
benzodiazepines, narcotics, barbiturates, sedating antihistamines).  Advise patients not to drive or operate 
machinery until they have gained sufficient experience on perampanel to gauge whether it adversely affects 
these activities.1  
3.5 Data Analysis and Statistical Considerations 
The one-arm study will assess the efficacy of perampanel for the treatment of primary brain tumor patients 
with partial onset seizures.  The basis for this assessment is the percentage of patients with a ≥ 50% seizure 
reduction during the treatment period compared with seizure frequency before initiation of perampanel (i.e. 
50% responder rate). 
 
Several recent conducted randomized studies of patients with partial-onset seizures have reported a 50% 
responder rate of approximately 20% within the standard treatment arm.2-4  Steinhoff (2009) also reports a 
50% responder rate of approximately 35% within a general population of patients with partial-onset seizures 
treated with perampanel.5 
 
This study has been designed with 90% power to detect an increase in the 50% responder rate during the 
treatment period from a benchmark of 20% to 35%.  Assuming a type I error rate of 0.1, 61 patients will be 
required.  Based on prior studies the early discontinuation rate was 16%, therefore 71 patients will be enrolled 
to compensate for patients discontinuing prior to the completion of the treatment period. 
 
 

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4 STUDY SCHEMA 
 
 
   
                                                  
 
 
 
 
 
 
Weeks 1- 4 Titration Period: Subjects will 
be started on a dose of 2 mg of 
perampanel for two weeks and will be 
titrated up in 2 mg increments to a dose 
of 8 mg, starting at week 5.     
Weeks 5-16 Treatment Period: Subjects 
will take 8 mg of perampanel for 12 
weeks. 
Weeks 17-20 Tapering Period: Subjects 
will be tapered down in dose over the 
course of 4 weeks until they are no 
longer taking any perampanel. 
Weeks 21-24 Follow-up Monitoring 
Period: Subjects will be followed for an 
additional 4 weeks. 
Patients diagnosed 
with a primary 
glioma who are 
having refractory 
partial onset 
seizures on    
current AED 
regimen 
 
Adjunctive* therapy needed 
*Patients will continue on 
their original AED regimen 
during the study. 
Consent to go on study 

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5 BACKGROUND AND SIGNIFICANCE 
5.1 Study Disease 
Of the neurological symptoms seen in brain tumor patients, seizures have remained a common occurrence.  In 
30% of patients, seizure is the presenting symptom and another 30-50% of patients develop seizures during 
the disease trajectory.   Furthermore, many patients with brain tumor experiencing seizures will continue to 
have seizures despite being on antiepileptic drug (AED).6  Even though there is a wide availability of anti-
seizure medications, patients, in particular brain tumor patients with epilepsy, can have treatment refractory 
seizures.   Therefore, there is a great need for newer AEDs with different novel mechanisms to treat seizures in 
this specific population. 
5.2 Study Agent 
Perampanel, a highly selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
(AMPA) type glutamate receptor antagonist, has shown efficacy in a randomized phase III study for refractory 
partial-onset seizures.7  For most brain tumor patients suffering from seizures, the most common type is 
partial-onset seizures, which can be either simple or complex.   The use of AMPA type glutamate receptor 
inhibition is particularly intriguing in that glutamate release appears to be responsible for epileptic activity in 
murine glioma models.8   Tissue isolated from tumor bearing mice exhibited increased glutamate release and 
presented with peritumoral hyperexcitability.9  Therefore, perampanel appears to be a viable candidate for 
seizure treatment in patients with brain tumors from both a clinical and a biological perspective.   
5.2.1 Pre-clinical experience 
Not applicable 
5.2.2 Clinical experience 
Perampanel is currently FDA-approved for the adjunctive treatment of refractory partial seizures in 
patient ≥ 12 years of age.  In a pooled analysis of three phase III studies involving 1,478 patients, 
median change in partial seizure frequency was greater with perampanel in comparison to placebo. 2   
Specifically, median change in partial seizure frequencies was as follows: perampanel 4 mg, -23.3%; 
perampanel 8 mg, -28.8%; perampanel 12 mg, -27.2%; and placebo, -12.8%.    Moreover, 50% 
responder rates were as follows:   perampanel 4 mg, 28.5%; perampanel 8 mg, 35.3%; perampanel 12 
mg, 35.0%; and placebo, 19.0%.  In this pooled analysis, perampanel was well tolerated with the most 
frequent treatment-emergent adverse events (TEAEs) being dizziness, somnolence, and headache.   Of 
note, there were no deaths reported and no clinically meaningful mean change in laboratory values, 
electrocardiography (ECG) findings, or vital signs.10  TEAEs from the pooled analysis are listed in the 
table below for perampanel dose 2 mg to 12 mg and placebo. 
 
Adverse Event, n 
(%) 
Placebo 
(n=442) 
Perampanel 2 
mg (n=180) 
Perampanel 4 
mg (n=172) 
Perampanel 8 
mg (n=431) 
Perampanel 12 
mg (n=255) 
Any TEAE 
294 (66.5) 
111 (61.7) 
111 (64.5) 
350 (81.2) 
227 (89.0) 
Dizziness 
40 (9.0) 
18 (10.0) 
28 (16.3) 
137 (31.8) 
109 (42.7) 
Somnolence 
32 (7.2) 
22 (12.2) 
16 (9.3) 
67 (15.5) 
45 (17.6) 
Headache 
50 (11.3) 
16 (8.9) 
19 (11.0) 
49 (11.4) 
34 (13.3) 
Fatigue 
21 (4.8) 
8 (4.4) 
13 (7.6) 
36 (8.4) 
31 (12.2) 
Irritability 
13 (2.9) 
7 (3.9) 
7 (4.1) 
29 (6.7) 
30 (11.8) 
Nausea 
20 (4.5) 
4 (2.2) 
5 (2.9) 
25 (5.8) 
20 (7.8) 
Fall 
15 (3.4) 
2 (1.1) 
3 (1.7) 
22 (5.1) 
26 (10.2) 
Nasopharyngitis 
18 (4.1) 
7 (3.9) 
9 (5.2) 
23 (5.3) 
11 (4.3) 
Upper respiratory 
12 (2.7) 
11 (6.1) 
6 (3.5) 
14 (3.2) 
10 (3.9) 

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tract infection 
Ataxia 
0 (0.0) 
0 (0.0) 
1 (0.6) 
14 (3.2) 
21 (8.2) 
Balance disorder 
2 (0.5) 
0 (0.0) 
0 (0.0) 
22 (5.1) 
8 (3.1) 
 
Most TEAEs were mild to moderate and appeared to be dose related.   From the pooled analyses, 
discontinuation of perampanel at 4 mg was 2.9%, at 8 mg was 7.7% , and at 12 mg was 19.2%  in 
comparison to placebo.10  Common discontinuation TEAEs were dizziness, convulsion, and somnolence.   
 
Behavioral and psychiatric TEAEs are very important to consider with AEDs as several AEDs carry boxed 
warning for serious or life-threatening psychiatric and behavioral adverse reactions.   Perampanel 
carries a similar warning to other AEDs and monitoring is recommended for serious or life-threatening 
psychiatric and behavioral adverse reactions including but not limited to suicidal ideation and homicidal 
ideation.10  In the pooled analyses, there were three serious cases of aggression and one case of suicidal 
ideation.  Perampanel is classified as a schedule III controlled substance as it causes euphoria in 
selected patients from phase III clinical trials.7  
5.3 Study Purpose/Rationale 
The new generation of AEDs that are devoid of P450 enzyme induction properties (levetiracetam, lacosamide, 
etc.) are now recommended as the AEDs of choice in primary brain tumor patients, as they do not have 
interactions with standard chemotherapeutic agents (irinotecan, topotecan, etc.) or cancer-specific targeted 
agents (dasatinib, erlotinib, etc.).11   Seizure control is an important component in the quality of life for both 
low-grade and high-grade brain tumor patients.  In fact, seizure control is the most important predictor of 
quality of life in recurrent low-grade glioma patients.12  Therefore, the study of newer AEDs in the brain tumor 
population is greatly needed.   Therefore, we seek to evaluate the efficacy of perampanel as an adjunctive AED 
for the treatment of refractory partial onset seizures in primary glial tumor (glioma) patients. 
 
6 OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Analysis 
Primary 
To determine the efficacy of 
perampanel as an adjunctive AED  in 
patients with primary glioma 
presenting refractory partial onset 
seizure activity 
Percentage of patients with  ≥50% seizure 
reduction during the treatment period 
compared with seizure frequency before 
initiation of perampanel (i.e. 50% responder 
rate) 
See Section 13.4 
Secondary 
To assess the safety and tolerability of 
perampanel as an adjunctive AED in 
patients with primary glioma 
presenting with refractory partial 
onset seizure activity 
The percentage of patients who experience a 
adverse event possibly, probably, or definitely 
attributable to perampanel treatment 
See Section 13.5 
Exploratory 
To evaluate the effect that 
perampanel has on neurocognition 
and patient-reported outcomes of 
quality of life (QoL) in patients with 
primary glioma presenting with 
refractory partial onset seizure 
activity 
Mean change from baseline for each 
neurocognitive and QoL subscale score at each 
follow-up assessment 
See Section 13.6 
 
 
 
 
 
 
 

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7 INVESTIGATIONAL PLAN 
7.1 Study Design 
This is a Phase 4 single-arm study assessing the efficacy of perampanel as an adjunct anti-epileptic drug 
(AED)in patients with primary glioma presenting refractory partial onset seizure activity (defined as 3 or more 
seizures in a 28-day period).  All primary glial tumor patients that have refractory partial onset seizures can be 
considered for this clinical trial if they meet the eligibility criteria.   This will include patients that are receiving 
active chemotherapy, which could include, but is not limited to, the following agents: temozolomide, 
bevacizumab, irinotecan, etoposide, lomustine, carboplatin.  All concomitant medications will be recorded 
during the study.  The study will enroll approximately 71 patients at the PRTBTC at Duke. 
 
Perampanel will be given according to FDA-approved guidelines over a 24-week period.  Patients will be 
started on a dose of 2 mg daily taken orally at bedtime for 2 weeks.  At the start of week 3 Perampanel will be 
titrated up in dose in 2mg increments per week up to 8mg daily, as long as it is well tolerated by the patient.   
Weeks 1 and 2, patients will take 2mg,  Week 3 they will take 4 mg, Week 4 they will take 6mg  and starting at 
week 5 they will take 8mg. Highest dose will be 8 mg orally at bedtime. Starting at week 5, patients will begin 
the treatment period, which goes from day 1 of Week 5 through day 7 of Week 16. Patients will be assessed in 
the Brain Tumor Center Clinic every 8 weeks.  Assessments will be made at enrollment, 8 weeks, 16 weeks, 
and 24 weeks.  Assessments will include history, physical examination, neurological examination, evaluation of 
seizure history, patient-reported outcomes of quality of life, and neurocognitive testing using CNS Vital Signs®.   
After a total of 16 weeks on therapy, perampanel will be tapered down.  At Week 17, patients will begin taking 
6mg of perampanel, Week 18 4mg, Week 19 2mg, and Week 20 they will no longer take perampanel. Patients 
will be considered off treatment at the end of week 20, once perampanel has cleared their system. The 
planned treatment dose is 8mg, but the dose can be modified by the physician based on patient reported 
tolerability.  Titration and taper periods will be determined by the physician in the case where patients do not 
reach the planned treatment dose of 8 mg daily. Patients will continue to take their original AED regimen after 
they stop perampanel. Patients will then be monitored through Week 24.   Patients will remain on their 
original AED regimen during this treatment time and the dose of their original AED at the start of the study will 
not be changed while they are on study.  If seizure control is achieved during the treatment period or if 
seizures occur during the tapering period, patients can be continued on perampanel per the discretion of the 
treating physician.  In this instance, perampanel will be prescribed by the treating physician and not provided 
within the confines of the study.   As is standard procedure at the PRTBTC, patients will be given a log to 
record the number of seizures that occur.  Research team members will regularly contact patients for 
reminders and reports from the log.   
7.1.1 Missed Doses 
Patients will have a dedicated clinical research nurse and coordinator who will schedule all of their 
appointments and a calendar will be provided to the patients.   If a patient misses a dose of perampanel 
medication, the PI of the study will assess each situation with the research team.  If the number of 
missed doses is less than 3, then the patient can remain on study and perampanel will continue to be 
given by the study protocol regimen.  If the patient misses more than 3 doses of perampanel, they will 
no longer remain on the clinical trial.  Patients will be given daily medication logs to record the date and 
time that they take each dose of perampanel, as well as their other AEDs..  At each study visit, they will 
be asked about all medications that they are taking. 
7.1.2 Concomitant Medications 
With concomitant use, perampanel, at a dose of 12 mg/day, reduced levonorgestrel exposure by 
approximately 40%. Use of perampanel with oral or implant contraceptives containing levonorgestrel 
may render them less effective. Therefore, additional non-hormonal forms of contraception are 
recommended (please see the FYCOMPA FDA-approved labeling dated 2/12/2014).1  
 

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The concomitant use of known CYP enzyme inducers including carbamazepine, phenytoin, or 
oxcarbazepine with perampanel decreased the plasma levels of perampanel by approximately 50~67. 
The starting doses for perampanel should be increased in the presence of enzyme-inducing AEDs.1 
When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, 
patient should be closely monitored for clinical response and tolerability. As noted, however, the 
decrease in the therapeutic effect seen in patients on concomitant treatment, was not affected by use 
of higher doses (8 mg to 12 mg).1  
 
Concomitant use of perampanel with other strong CYP3A inducers (e.g., rifampin, St. John’s wort) 
should be avoided.1  
 
The concomitant use of perampanel and CNS depressants including alcohol may increase CNS 
depression.1 A pharmacodynamic interaction study in healthy subjects found that the effects of 
perampanel on complex tasks such as driving ability were additive or supra-additive to the impairment 
effects of alcohol. Multiple dosing of perampanel 12 mg/day also enhanced the effects of alcohol to 
interfere with vigilance and alertness, and increased levels of anger, confusion, and depression. These 
effects may also be seen when perampanel is used in combination with other CNS depressants. Care 
should be taken when administering perampanel with these agents. Patients should limit activity until 
they have experience with concomitant use of CNS depressants (e.g. benzodiazepines, narcotics, 
barbiturates, sedating antihistamines).  Advise patients not to drive or operate machinery until they 
have gained sufficient experience on perampanel to gauge whether it adversely affects these activities.1 
 
Perampanel is FDA-approved as adjunctive therapy for refractory partial onset seizures, so it will be 
utilized in concert with other AEDs.    
 
If subjects are receiving chemotherapy during the study, these medications, the doses, and any 
associated serious adverse events will be recorded. 
7.1.3 Study Drug Blinding 
Not applicable. 
7.1.4 Randomization 
Not applicable. 
7.2 Rationale for Selection of Dose, Regimen, and Treatment Duration 
Please see Section 5.2.2. 
7.3 Rationale for Correlative Studies 
In order to capture fully the many aspects of QOL, we will utilize multiple questionnaires to evaluate issues of 
fatigue, cognition, and mood.   The Functional Assessment of Cancer Therapy-Brain (FACT-Br) has been used 
extensively and has been documented to identify key QOL problems for brain tumor patients.16   Other 
standardized questionnaires will include Functional Assessment of Cancer Therapy-Fatigue, Functional 
Assessment of Cancer Therapy-Cognition, and Beck Depression Inventory.   Additionally, neurocognition will 
be measured using computer-based models known as CNS Vital Signs ®.   These measurements have been 
validated and are being used extensively in our research in not only brain tumor patients, but also in patients 
with other forms of cancer.17   
 
Quality of Life will be assessed by the Functional Assessment of Cancer Therapy-Brain (FACT-BR) scale.  
The FACT-BR (version 4) contains subscales for physical (7-items), functional (7-items), emotional (6-items), 
and social/family (7-items) well-being. In addition, this instrument contains an 23-item brain cancer subscale 
(BCS) which assess symptoms commonly reported by brain cancer patients.16   Cancer-related fatigue will be 

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assessed by the 13-item Fatigue Scale using the Functional Assessment of Cancer Therapy-Fatigue (FACIT-
Fatigue) subscale, version 4. 18 Cognitive problems will be assessed using version 3 of the Functional 
Assessment of Cancer Therapy-Cognition (FACT-Cog) subscale. 19  This includes subscales for perceived 
cognitive impairments (20 items), comments from others (4 items), perceived cognitive abilities (9 items), and 
impact of quality of life (4 items).   Beck depression inventory (BDI) will be used to evaluate for underlying 
depressive symptoms.   We will use the revised version (BDI-II) and the scores will range from 0 (no 
depression) to 63 (severe depression).20  The BDI contains 21 questions in regards to mood symptoms and is 
multiple-choice and self-reported. 
 
Neurocognitive testing will include the performance on the following testing using a computerized battery CNS 
Vital Signs®.21    This battery consists of seven tests that measure verbal and visual memory, finger tapping, 
symbol digit coding, the Stroop Test, a test of shifting attention, continuous performance test.  Verbal memory 
test will assess verbal learning, memory for words, immediate recall, and delayed recall.   Visual memory tests 
will assess visual learning, memory for geometric shapes, immediate recall, and delayed recall.  Finger tapping 
test will assess motor speed and fine motor control.   Symbol digit coding test will evaluate complex attention, 
visual-perceptual speed, and information processing speed.   Stroop Test will assess executive function, simple 
and choice reaction time, speed-accuracy trade-off, information processing speed, and inhibition/disinhibition.   
Shifting attention test will assess executive function, reaction time, and information processing speed.  
Continuous performance test will assess sustained attention and choice reaction time.   Normative data is 
available for this testing through CNS Vital Signs® and patients’ performance will be compared to this 
normative data. 
7.4 Definition of Evaluable Subjects, On Study, and End of Study 
All patients who complete the treatment period will be included in the primary endpoint analysis.  All patients 
who received protocol treatment, regardless of duration, will be included in the safety analysis.   
7.5 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 10.7, which describes procedures and process for prematurely withdrawn patients. 
8 STUDY DRUG 
8.1 Names, Classification, and Mechanism of Action 
Perampanel (FYCOMPA™) is a non-competitive AMPA glutamate receptor antagonist.  Perampanel is 
described chemically as 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate. 
8.2 Packaging and Labeling 
The dose forms included in this study are packaged as follows: 
• 
2 mg Tablets: orange, round, biconvex, film-coated tablets debossed with “2” on one side and “Є 
275” on the other 
• 
4 mg Tablets: red, round, biconvex, film-coated tablets debossed with “4” on one side and “Є 277” on 
the other 
8.3 Supply, Receipt, and Storage 
2 mg tablets are supplied as follows: 
• 
Bottles of 30 NDC 62856-272-30  
• 
Bottles of 90 NDC 62856-272-90 
4 mg tablets are supplied as follows: 
• 
Bottles of 30 NDC 62856-274-30  
• 
Bottles of 90 NDC 62856-274-90 

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Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).  Study supplies of perampanel will be stored 
by ICS. 
8.4 Dispensing and Preparation 
Subjects will receive perampanel as an oral therapy and will be dispensed supplies of tablets sufficient to 
continue therapy until their next appointment. Perampanel will be self-administered by the patient.  Subjects 
will be given a Daily Medication Log on which they will record the amount of perampanel, as well as other 
AEDs that they took each day.  Subjects will be asked to bring their Logs to each study visit, during which they 
will be reviewed by a member of the study team. 
8.5 Compliance and Accountability 
Drug accountability records will be maintained for all clinical trial supplies.  All empty and partially used clinical 
trial supplies will be returned to Eisai or destroyed.   
8.6 Disposal and Destruction 
The ICS pharmacy will maintain detailed documentation of the number and identification of tablets and 
tablets that are destroyed, and copies of these documents will be provided to Eisai, upon request. 
9 SUBJECT ELIGIBILITY 
Please see Section 3.3 for a complete list of inclusion and exclusion criteria. 
 

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10 SCREENING AND ON-STUDY TESTS AND PROCEDURES 
Table 1: Study Assessment Schema 
 
Baseline  
within 4 weeks 
of initiation of 
study drug 
8 weeks 
after 
initiation of 
study drug 
16 weeks 
after 
initiation of 
study drug 
24 weeks 
after 
initiation of 
study drug 
CBC with diff  
X 
X 
X 
X 
CMP  
X 
X 
X 
X 
H&P, including 
KPS and 
concomitant 
medications 
X 
X 
X 
X 
Complete 
Neurological 
Examination 
X 
X 
X 
X 
Toxicity 
assessment 
using CTCAE v.4 
guidelines 
 
Ongoing 2 
Urine pregnancy 
test 1 
X 
 
 
 
Seizure 
History/Log 
X 3 
Ongoing 4 
QoL 
Questionnaires 
X 
X 
X 
X 
Neurocognitive 
Testing  
X 
X 
X 
X 
1 For women of childbearing potential, within 48 hours prior to initiation of study drug, if contraception not 
initiated at time of negative test result prior to that time.  Urine pregnancy test will be conducted according to 
Duke IRB and DOCR guidelines. 
2 Toxicities will be recorded from the time the subject starts study drug. 
3 Number of seizures in past 28 days 
4 Subjects will be given a seizure log to record the number of seizures that occur, as is standard procedure at the 
PRTBTC.   
10.1 Screening Examination 
The screening examination will take place within 4 weeks of initiation of study drug.  An informed consent 
must be signed by the patient before any screening procedures take place.  Subject data to be collected at the 
Screening Examination includes the following: 
 
Pre-treatment evaluations to determine eligibility will include the following:   
• 
History and physical exam, including KPS and a full neurologic assessment  
• 
Seizure history 
• 
CBC with differential, CMP, Beta-HCG if appropriate (within 48 hours of beginning study drug, if 
contraception not initiated at time of negative test result prior to that time).  Urine pregnancy test will 
be conducted according to Duke IRB and DOCR guidelines.  
• 
Quality of life measurements and neurocognitive testing, as a baseline 
 
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. 

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10.2 Run-In Period 
Not applicable. 
10.3 Treatment Period 
Day 1 
• 
Subjects will be started on a dose of 2 mg of perampanel daily taken orally at bedtime for 2 weeks. 
• 
Subjects will then be titrated up in dose in 2 mg increments each week up to 8 mg daily. Week 3  4mg 
daily, Week 4 6 mg daily and starting week 5  8 mg daily.    The highest dose of perampanel will be 8 
mg orally at bedtime.  
 
Week 8 assessments) (+ 1 week) 
• 
History and physical exam, including KPS and a full neurologic assessment, with collection of seizure 
log (subjects will keep a seizure log throughout the study) 
• 
Toxicity assessment using CTCAE v.4 guidelines (continuous throughout study) 
• 
CBC with diff 
• 
CMP  
• 
Quality of life measurements and neurocognitive testing 
 
Week 16 assessments) (+ 1 week) 
• 
After a total of 16 weeks on therapy, subjects will now be tapered off of perampanel over a period of 
4 weeks. Week 17 6mg daily, Week 18 4mg, Week 19 2mg, and at Week 20 they will no longer take 
perampanel. (  
• 
History and physical exam, including KPS and a full neurologic assessment, with collection of seizure 
log (subjects will keep a seizure log throughout the study) 
• 
Toxicity assessment using CTCAE v.4 guidelines 
• 
CBC with diff 
• 
CMP  
• 
Quality of life measurements and neurocognitive testing 
 
Week 24 assessments- End of Treatment) (+ 1 week) 
• 
History and physical exam, including KPS and a full neurologic assessment, with collection of seizure 
log (subjects will keep a seizure log throughout the study)  
• 
Toxicity assessment using CTCAE v.4 guidelines 
• 
CBC with diff 
• 
CMP  
• 
Quality of life measurements and neurocognitive testing 
• 
Toxicity assessment using CTCAE v.4 guidelines (continuous throughout study) 
10.4 End of Treatment 
The assessments obtained at the end of Week 24 will serve as the End of Treatment visit, unless the subject 
withdraws early.  If a subject withdraws from the study early, they will be asked to complete the study tests or 
procedures listed as End of Treatment. 
10.5 Follow-up Period 
There is no additional follow-up period beyond 24 weeks. 
10.6 End of Study 
The study will be considered complete once enrollment has been met, procedures 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.  In order to terminate the study with the Duke IRB, all data extraction and analysis must be complete.  

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Therefore, if any articles for publication are derived from the current study, they must be submitted and 
accepted with no further need for additional data extraction or analysis prior to termination with the IRB. 
 
Subjects that are lost to follow-up will be documented in the patient record and in the Excel database.   
10.7 Early Withdrawal of Subject(s) 
10.7.1 Criteria for Early Withdrawal 
Subjects may voluntarily withdraw from the study at any time.  The 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: 
• 
Pregnancy 
• 
Upon request of the subject 
• 
If, in the investigator’s medical judgment, further participation would be injurious to the subject’s 
health or wellbeing 
• 
Development of intolerable symptoms 
• 
Non-compliance of the subject 
• 
Development of any exclusion criteria 
10.7.2 Follow-up Requirements for Early Withdrawal 
If a subject voluntarily withdraws from the study prematurely, they will be asked to complete the 
tests/procedures that would have been conducted at their next scheduled visit.   
10.7.3 Replacement of Early Withdrawal(s) 
Not applicable. 
10.8 Study Assessments 
10.8.1 Medical History 
Standard medical history, including concomitant medications, will be obtained and documented per 
institutional guidelines. 
10.8.2 Physical and Neurological Exam 
Standard physical exam and neurological assessment will be conducted and documented per 
institutional and PRTBTC guidelines. 
10.8.3 Laboratory Assessments 
The timing of laboratory assessments that will be obtained during the course of the study is given in 
Section 10.  A list for each evaluation and what they include is below. 
• 
CBC with differential (hematocrit, hemoglobin, platelet count, white blood cell count, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
NRBC %, NRBC CT, RDW-CV, absolute lymphocyte count, percent lymphocytes, percent monocytes, 
percent neutrophils, percent eosinophils, percent basophils, absolute monocyte count, absolute 
neutrophil count, absolute eosinophil count, absolute basophil count, red blood cell count) 
• 
CMP (albumin, alanine aminotransferase, alkaline phosphatase , aspartate aminotransferase, total 
bilirubin , total protein, calcium, potassium, sodium, carbon dioxide creatinine, urea nitrogen, 
glucose, chloride) 
• 
Beta-HCG, if applicable, within 48 hours prior to start of study treatment  

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10.8.4 Quality of Life and Neurocognitive Assessments 
Patient-reported Quality of Life (QoL) outcomes will be assessed using the following standardized and 
validated questionnaires.   
• 
Functional Assessment of Cancer Therapy-Brain (FACT-BR) scale (version 4), which contains 
subscales for physical (7-items), functional (7-items), emotional (6-items), and social/family (7-
items) well-being, as well as a 23-item brain cancer subscale (BCS) that assesses symptoms 
commonly reported by brain cancer patients16 
• 
Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) subscale, version 418 
• 
Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) subscale, version 3, which 
includes subscales for perceived cognitive abilities (9 items) and impact on quality of life (4 
items)19 
• 
Beck depression inventory (BDI), revised version (BDI-II), which contains 21 questions 
regarding mood symptoms (multiple choice and self-reported).   Scores range from 0 (no 
depression) to 63 (severe depression).20
 
 
Neurocognitive testing will include the performance on the following testing using a computerized 
battery CNS Vital Signs®.21    This battery consists of seven tests that measure verbal and visual memory, 
finger tapping, symbol digit coding, the Stroop Test, a test of shifting attention, continuous 
performance test.  Verbal memory test will assess verbal learning, memory for words, immediate recall, 
and delayed recall.   Visual memory tests will assess visual learning, memory for geometric shapes, 
immediate recall, and delayed recall.  Finger tapping test will assess motor speed and fine motor 
control.   Symbol digit coding test will evaluate complex attention, visual-perceptual speed, and 
information processing speed.   Stroop Test will assess executive function, simple and choice reaction 
time, speed-accuracy trade-off, information processing speed, and inhibition/disinhibition.   Shifting 
attention test will assess executive function, reaction time, and information processing speed.  
Continuous performance test will assess sustained attention and choice reaction time.   Normative data 
is available for this testing through CNS Vital Signs® and patients’ performance will be compared to this 
normative data.      
 
Patient demographics, disease history, and concomitant medications will be obtained for all study 
participants. 
 
References for these standardized tests are provided in Section 15. 
10.8.5 Correlative Assessments 
Not applicable. 
11 SAFETY MONITORING AND REPORTING 
The PI is responsible for the identification and documentation of adverse events and serious adverse events, as 
defined below.  PI will review and sign off on all adverse events and problems as they occur and will report them to 
the IRB in accordance with HRPP policies.  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 SAE has occurred. 
 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject receiving study drug and which does 
not necessarily have a causal relationship with this treatment.  For this protocol, the definition of AE also 
includes worsening of any pre-existing medical condition.  An AE can therefore be any unfavorable and 
unintended or worsening sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of perampanel, whether or not related to use of the perampanel.  Abnormal 

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laboratory findings without clinical significance (based on the PI’s judgment) should not be recorded as AEs.  
But laboratory value changes that require therapy or adjustment in prior therapy are considered adverse 
events. 
 
From the time the subject starts the first dose of perampanel through the End of Study visit (as defined in 
Section 10.6), all AEs must be recorded in the subject medical record and adverse events case report form. 
 
AEs will be assessed according to the CTCAE version 4.0.  If CTCAE grading does not exist for an AE, the severity 
of the AE 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 
Eisai should be notified of all treatment-related adverse events on a regular basis (to be agreed upon by 
the study team and Eisai). 
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 
- 
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 
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. 
 
If an IND is held, the Sponsor-Investigator must report to the FDA, in an IND safety report, any 
suspected adverse reaction that is both serious and unexpected. Before submitting this report, 
the sponsor needs to ensure that the event meets all three of the definitions contained in the 
requirement:  

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• 
Suspected adverse reaction (i.e. there is a reasonable possibility that the drug caused the 
adverse event) 
• 
Serious  
• 
Unexpected  
If the adverse event does not meet all three of the definitions, it should not be submitted 
as an expedited IND safety report. 
 
The Sponsor-Investigator is required to report to the FDA all IND Safety reports in writing 
within 15 days (7 days for unexpected fatal or life-threatening suspected adverse reaction).  
The FDA Form 3500A can be found on the FDA website, www.fda.gov.  All other adverse 
events will be reported to the FDA in the Annual Report. 
 
All suspected adverse drug reactions (those events where a relationship to perampanel is a 
reasonable possibility) should be reported within 1 business day of the investigator’s 
awareness to ESI Safety via the email address below. 
 
SAEs will be reported to: 
Safety: 
Eisai Medical Affairs 
100 Tice Blvd. 
Woodcliff Lake, NJ 07677 
Tel: 1-888-274-2378 
Fax: -1-732-791-1111 
Email: ESI_Safety@eisai.com 
11.3 Safety Oversight Committee (SOC) 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator phase I and II, therapeutic interventional studies that do not have an independent Data Safety 
Monitoring Board (DSMB). The primary focus of the SOC is review of safety data, toxicities and new 
information that may affect subject safety or efficacy. Annual safety reviews includes but may not be limited 
to review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, reference literature, 
and interim analyses as provided by the sponsor-investigator.  The SOC in concert with the DCI 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. 
11.4 External Data and Safety Monitoring Board (DSMB) 
Not applicable. 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Monitoring 
 This clinical research study will be monitored both internally by the PI and institutionally by the Duke Cancer 
Institute (DCI).  In terms of internal review the PI will continuously monitor and tabulate adverse events.  
Appropriate reporting to the Duke University Medical Center IRB will be made.  If an unexpected frequency of 
Grade III or IV events occur, depending on their nature, action appropriate to the nature and frequency of 
these adverse events will be taken.  This may require a protocol amendment, dose de-escalation, or 

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potentially closure of the study.  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. 
 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and Safety 
Monitoring Plan.  Briefly, protocol review begins with an initial review by the Cancer Protocol Committee 
(CPC), which assesses the ethics and safety of the protocol.  Documentation of these assessments will be 
maintained.  Formal, independent monitoring will be conducted by the DCI Monitoring Team after the first 3 
subjects are enrolled, followed by annual monitoring of 1-3 subjects until the study is closed to enrollment and 
subjects are no longer receiving study interventions that are more than minimal risk.  DCI Monitoring Team 
reports and additional data/safety/toxicity reports submitted by the PI will be reviewed by the Safety 
Oversight Committee (SOC) on an annual basis.  Additional monitoring may be prompted by findings from 
monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns.  
Monitoring visits may also be initiated upon request by DUHS and DCI Leadership, CPC, SOC, a sponsor, an 
investigator, or the IRB.  
 
All study documents must be made available upon request to the DCI 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 School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct audits to evaluate 
compliance with the protocol and the principles of GCP.  The PI agrees to allow the CTQA auditor(s) direct 
access to all relevant documents and to allocate his/her time and the time of the study team to the CTQA 
auditor(s) in order to discuss findings and any relevant issues. 
 
CTQA audits are designed to protect the rights and well-being of human research subjects. CTQA 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. 
 
CTQA 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, study team correspondence with sponsors or regulatory 

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bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder,” which includes but is not limited to signed protocol and amendments, approved informed 
consent forms, FDA Form 1572, and CAP and 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’ logs 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. 
12.3.2 Primary Data Collection Document 
The Excel spreadsheet will be the primary data collection document for the study.  The spreadsheet will 
be updated in a timely manner following acquisition of new source data.  Only the PI, the study 
coordinator, the data management team, and the clinical trials manager are permitted to make entries, 
changes, or corrections in the spreadsheet. 
12.3.3 Data Management Procedures and Data Verification 
Users of the Excel spreadsheet will have access based on their specific roles in the protocol, i.e. the PI, 
the study coordinator, the data management team, and the clinical trials manager.   
 
The data management team and the statistical team will cross-reference the data to verify accuracy.  
Missing or implausible data will be highlighted for the PI requiring appropriate responses (i.e. 
confirmation of data, correction of data, completion or confirmation that data is not available, etc.). 
 
The spreadsheet will be reviewed and discussed prior to spreadsheet closure, and will be closed only 
after resolution of all remaining queries.  A record will be kept of all subsequent changes to the data. 
12.3.4 Coding 
All medical terms will be coded using CTCAE v.4.0, which has been harmonized to MedDRA (Medical 
Dictionary for Regulatory Activities) coding.  Medication will be coded according to the World Health 
Organization Drug Dictionary. 
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 
- 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories 
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. 

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13.1 Analysis Sets 
As indicated in section 7.4, subject to the availability of data, all patients who receive perampanel treatment 
will be included in safety analyses.  All patients who complete the treatment period of the study will be 
included in efficacy analyses. 
13.2 Patient Demographics and Other Baseline Characteristics 
Socio-demographic and clinical characteristics of patients receiving perampanel treatment on this study will be 
summarized.  For categorical variables, frequencies and percentages will be provided.  Means with standard 
deviations or medians/percentiles will summarize non-categorical variables. 
13.3 Treatments 
The total number of days that the patient received perampanel treatment will be determined for each patient.  
The percentage of patients who had dose modifications not consistent with the planned dosing during 
titration, treatment, and tapering will be tabulated by dosing period (i.e. titration, treatment, and tapering). 
13.4 Primary Objective 
The primary objective of this study is to assess the efficacy of perampanel as an adjunct AED to levetiracetam 
in patients with primary glioma presenting refractory partial onset seizure activity. 
13.4.1 Variable 
Efficacy will be assessed by the 50% responder rate, defined as the percentage of patients with a ≥50% 
seizure reduction during the treatment period compared with the seizure frequency before initiation of 
perampanel.  Seizure frequency during treatment perampanel will be computed as the ratio of the total 
number of seizure episodes while receiving perampanel during the treatment period and the number of 
days perampanel is administered. 
13.4.2 Statistical Hypothesis, Model, and Method of Analysis 
As described in Section 3.5 and 13.8, this study has been designed to detect an increase in the 50% 
responder rate from a benchmark of 20% to 35%.  A one-sample binomial test will test this hypothesis 
at the 0.1 level of significance. 
 
As a related secondary analysis, seizure frequency will be estimated separately for each patient within 
the titration, treatment, tapering, and follow-up phases of treatment, and the percent reduction in 
seizure frequency relative to baseline computed.  The distribution across patients within each 
treatment phase in the percent reduction will be described.  Depending upon the distribution of these 
data, means and standard deviations may be used to describe the distribution of percent reduction or 
quartiles. 
13.5 Secondary Objectives 
The percentage of patients with unacceptable adverse events that are possibly, probably, or definitely related 
to perampanel treatment will be calculated.  Unacceptable adverse events include all CTCAE Grade 4 or 5 
toxicities that are possibly, probably, or definitely related to perampanel, as well as suicidal ideation (any 
grade) or suicide attempt (Grade 3-5).   
13.6 Exploratory Objectives 
The effect of perampanel on neurocognition and patient-reported outcomes of quality of life will be explored.  
Mean changes from baseline in neurocognition and QOL subscales will be computed at each follow-up 
assessment. 
13.7 Interim Analysis 
No Interim analyses are planned. 

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13.8 Sample Size Calculation 
The one-arm study will assess the efficacy of perampanel for the treatment of primary brain tumor patients 
with partial onset seizures.  The basis for this assessment is the percentage of patients with a ≥50% seizure 
reduction during the treatment period compared with the seizure frequency before initiation of perampanel 
(i.e. 50% responder rate). 
 
Several recently conducted randomized studies of patients with partial-onset seizures have reported a 50% 
responder rate of approximately 20% within the standard treatment arm.2-4  Steinhoff (2009) also reports a 
50% responder rate of approximately 35% within a general population of patients with partial-onset seizures 
treated with perampanel.2 
 
This study has been designed with 90% power to detect an increase in the 50% responder rate during the 
treatment period from a benchmark of 20% to 35%.  Assuming a type I error rate of 0.1, 61 patients will be 
required.  Based on prior studies the early discontinuation rate was 16%, therefore 71 patients will be enrolled 
to compensate for patients discontinuing prior to the completion of the treatment period. 
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 Institutional Review Board (IRB) and DCI Cancer Protocol Committee (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. 
 

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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 with the subject’s study records, and a copy of the informed consent form will be provided to the 
subject.  The Principal Investigator is responsible for asking the subject whether the subject wishes to notify 
his/her primary care physician about participation in the study.  If the subject agrees to such notification, the 
Principal Investigator will inform the subject’s primary care physician about the subject’s participation in the 
clinical study. 
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 Excel, which is housed in an encrypted and 
password-protected file on a secure network drive.  Access to electronic databases (without edit rights) will be 
limited to the PI, the study coordinator, and the statistical team.  The security and viability of the IT 
infrastructure will be managed by the DCI and/or Duke Medicine.   
 
Upon completion of the study, research records will be archived and handled per DUHS 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 11 (Sections 11.3 and 11.4 in 
particular) and 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 two years after the date on which a New Drug Application is approved by the FDA (if an IND is 
involved) 
- at least two years after formal withdrawal of the IND associated with this protocol (if an IND is involved) 
- 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 

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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/IEC. 
14.9 Registration Procedure 
Describe how new subject registration will occur. 
 
 
 

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15 REFERENCES 
 
1. 
FDA. Highlights of Prescribing Information: FYCOMPA.   (2014).  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202834s004lbl.pdf. Accessed 05/12/2014. 
 
2. 
Steinhoff BJ, Ben-Menachem E, Ryvlin P, et al: Efficacy and safety of adjunctive perampanel for 
the treatment of refractory partial seizures: A pooled analysis of three phase III studies. Epilepsia 54:1481-9, 2013 
 
3. 
Ben-Menachem E, Biton V, Jatuzis D, et al: Efficacy and safety of oral lacosamide as adjunctive 
therapy in adults with partial-onset seizures. Epilepsia 48:1308-17, 2007 
 
4. 
Halasz P, Kalviainen R, Mazurkiewicz-Beldzinska M, et al: Adjunctive lacosamide for partial-onset 
seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia 50:443-53, 2009 
 
5. 
Steinhoff BJ, Runge U, Witte OW, et al: Substitution of anticonvulsant drugs. Ther Clin Risk 
Manag 5:449-57, 2009 
 
6. 
Glantz MJ, Cole BF, Forsyth PA, et al: Practice parameter: anticonvulsant prophylaxis in patients 
with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of 
Neurology. Neurology 54:1886-93, 2000 
 
7. 
Hanada T: The discovery and development of perampanel for the treatment of epilepsy. Expert 
Opin Drug Discov 9:449-58, 2014 
 
8. 
Campbell SL, Buckingham SC, Sontheimer H: Human glioma cells induce hyperexcitability in 
cortical networks. Epilepsia 53:1360-70, 2012 
 
9. 
Buckingham SC, Campbell SL, Haas BR, et al: Glutamate release by primary brain tumors induces 
epileptic activity. Nat Med 17:1269-74, 2011 
 
10. 
Rugg-Gunn F: Adverse effects and safety profile of perampanel: a review of pooled data. 
Epilepsia 55 Suppl 1:13-5, 2014 
 
11. 
Michelucci R: Optimizing therapy of seizures in neurosurgery. Neurology 67:S14-8, 2006 
 
12. 
Klein M: Neurocognitive functioning in adult WHO grade II gliomas: impact of old and new 
treatment modalities. Neuro Oncol 14 Suppl 4:iv17-24, 2012 
 
13. 
Rosati A, Buttolo L, Stefini R, et al: Efficacy and safety of levetiracetam in patients with glioma: a 
clinical prospective study. Arch Neurol 67:343-6, 2010 
 
14. 
Wright C, Downing J, Mungall D, et al: Clinical Pharmacology and Pharmacokinetics of 
Levetiracetam. Front Neurol 4:192, 2013 
 
15. 
Cramer JA, De Rue K, Devinsky O, et al: A systematic review of the behavioral effects of 
levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy 
Behav 4:124-32, 2003 
 
16. 
Weitzner MA, Meyers CA, Gelke CK, et al: The Functional Assessment of Cancer Therapy (FACT) 
scale. Development of a brain subscale and revalidation of the general version (FACT-G) in patients with primary 
brain tumors. Cancer 75:1151-61, 1995 
 
17. 
Jones LW, Cohen RR, Mabe SK, et al: Assessment of physical functioning in recurrent glioma: 
preliminary comparison of performance status to functional capacity testing. J Neurooncol 94:79-85, 2009 
 
18. 
Van Belle S, Paridaens R, Evers G, et al: Comparison of proposed diagnostic criteria with FACT-F 
and VAS for cancer-related fatigue: proposal for use as a screening tool. Support Care Cancer 13:246-54, 2005 
 
19. 
Jacobs SR, Jacobsen PB, Booth-Jones M, et al: Evaluation of the functional assessment of cancer 
therapy cognitive scale with hematopoietic stem cell transplant patients. J Pain Symptom Manage 33:13-23, 2007 
 
20. 
Beck AT, Steer RA, Ball R, et al: Comparison of Beck Depression Inventories -IA and -II in 
psychiatric outpatients. J Pers Assess 67:588-97, 1996 
 
21. 
Gualtieri CT, Johnson LG: Reliability and validity of a computerized neurocognitive test battery, 
CNS Vital Signs. Arch Clin Neuropsychol 21:623-43, 2006 
 
22. 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007).  http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed 2/6/2014. 

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16 APPENDICES 
16.1 
Appendix A: Cytochrome P450 Drug Interaction Table 
Please see the following website for known cytochrome P450 inducers.  The website is updated frequently as new 
information becomes available (Flockhart, 2007)22: 
 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
16.2 
Appendix B: Medication and Seizure Log 
See attached.