Clinical trial NCT02726074
Conditions: Epilepsy
Keywords: epilepsy partial-onset seizures secondarily generalized seizures
Sponsor: Eisai Korea Inc.
Start date: 2016-05-03; Completion date: 2018-04-26
Enrollment: 106 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-center, open-label, single-arm, phase 4 study to evaluate the efficacy of perampanel added to monotherapy for partial onset seizures with or without secondarily generalized seizures (total seizures).

Detailed description:
This multi-center, open-label, single-arm study evaluating the efficacy of perampanel added to monotherapy for partial onset seizures consists of 2 periods: Titration Period (12 weeks) and Maintenance Period (24 weeks). During the Titration Period, participants will begin receiving perampanel 2 milligrams per day (mg/day) and be up-titrated in no less than 2-week intervals in increments of 2 mg up to 12 mg according to the investigator's judgment. Upon entering the Maintenance Period, participants will receive the last dose they achieved at the end of the Titration Period and will continue receiving this dose once daily for the remainder of the study.

Arms: arm 1: During the Titration Period, participants will receive perampanel 2 milligrams per day (mg/day) and be up-titrated in no less than 2-week intervals in increments of 2 mg up to 12 mg according to the investigator's judgment. Upon entering the Maintenance Period, participants will receive the last dose they achieved at the end of the Titration Period and will continue receiving this dose once daily for the remainder of the study.
Interventions: intervention 1: Perampanel
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol  
E2007-M065-412 
 
 
Eisai 
DRAFT (V1.0): 30 Dec 2015. 
Confidential 
Page 1 of 73 
 
1 
TITLE PAGE 
 
Clinical Study Protocol 
Study 
Protocol 
Number: 
E2007-M065-412 
Study 
Protocol 
Title: 
Multicenter, open-label trial, evaluating the efficacy and safety of 
perampanel added to monotherapy in patients with partial onset 
seizures with or without secondary generalized seizures 
Sponsor: 
Eisai Korea Inc.  
10F Revessant, 6, Bongeunsa-ro 86-gil, Gangnam-gu, Seoul, 06163, 
Korea 
Investigational 
Product Name: 
E2007/Fycompa® (Perampanel) 
Indication: 
Adjunctive therapy for partial-onset seizures in ≥12 years old epilepsy 
patients with or without secondarily generalized seizures 
Phase: 
4 
Approval Date:  
V1.0 
V2.0 
V2.1 
19 Jan 2016 (original protocol) 
29 Mar 2016 (Amendment 01) 
11 Apr 2016 (Amendment 02) 
GCP Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations. All 
required study documentation will be archived as required by 
regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study. 
 
 
 


Clinical Study Protocol  
E2007-M065-412 
 
 
Eisai 
DRAFT (V1.0): 30 Dec 2015. 
Confidential 
Page 2 of 73 
 
2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.  E2007 
Name of Active Ingredient:  Perampanel 
Study Protocol Title 
Multicenter, open-label trial, evaluating the efficacy and safety of perampanel added to 
monotherapy in patients with partial onset seizures with or without secondary generalized 
seizures 
Investigators 
Samsung Medical Center : Seung-Bong Hong 
Konkuk University Medical Center : Dong-Wook Kim 
Korea University Guro Hospital : Jee-Hyun Kim 
Seoul National University Bundang Hospital : Sung-Ho Park 
Samsung Medical Center : Dae-Won Seo 
Seoul National University Hospital : Sang-Gun Lee 
Seoul National University Hospital : Ki-Young Jeong 
Asan Medical Center : Sang-Ahm Lee 
Yonsei University Severance Hospital : Kyung Huh 
Yeungnam University Medical Center : Se-Jin Lee 
Inje University Haeundae Paik Hospital : Sung- Eun Kim 
Chonnam National University Hospital : Myoung-Gyu Kim 
Chungnam National University Hospital : Jae-Moon Kim 
Sites 
Samsung Medical Center  / 81, Irwon-ro, Gangnam-gu, Seoul, Korea 
Konkuk University Medical Center Korea / 120-1, Neungdong-ro, Gwangjin-gu, Seoul, 
Korea 
Korea University Guro Hospital / 148, Gurodong-ro, Guro-gu, Seoul, Korea 
Seoul National University Bundang Hospital / 82, Gumi-ro, 173, Beon-gil, Bundang-gu, 
Seongnam-si, Gyeonggi-do, Korea 
Samsung Medical Center / 81, Irwon-ro, Gangnam-gu, Seoul, Korea 
Seoul National University Hospital / 101, Daehak-ro, Jongno-gu, Seoul, Korea 
Seoul National University Hospital / 101, Daehak-ro, Jongno-gu, Seoul, Korea 
Asan Medical Center / 88, Olympic-ro, 43-gil, Songpa-gu, Seoul, Korea 
Yonsei University Severance Hospital / 50-1, Yonsei-ro, Seodaemun-gu, Seoul, Korea 
Yeungnam University Medical Center / 170, Hyeonchung-ro, Nam-gu, Daegu, Korea 
Inje University Haeundae Paik Hospital / 875, Haeun-daero, Haeundae-gu, Busan, Korea 
Chonnam National University Hospital / 42, Jebong-ro, Dong-gu, Gwangju, Korea 
Chungnam National University / 282 Munhwa-ro, Jung-gu, Daejeon, Korea 
Study Period and Phase of Development 


Clinical Study Protocol  
E2007-M065-412 
 
 
Eisai 
DRAFT (V1.0): 30 Dec 2015. 
Confidential 
Page 3 of 73 
 
From January 2016 to April 2017, Phase 4 
Objectives 
Primary Objective 
- 
To evaluate the efficacy of perampanel added to monotherapy for partial onset seizures 
with or without secondarily generalized seizures (total seizures) as measured by 50% 
responder rate 
  
Secondary Objectives (major) 
- 
To evaluate the safety of perampanel added to monotherapy for partial onset seizures 
with or without secondarily generalized seizures  
- 
To evaluate efficacy of perampanel added to monotherapy for secondarily generalized 
tonic clonic seizure in partial onset seizures  
Study Design 
This is a multi-center, open-label, single-arm, phase 4 study. Subjects who meet all of the 
inclusion and none of the exclusion criteria will be received perampanel. 
Baseline seizure counts (frequency) data is collected by subjects or guardian/legally 
authorized representative, retrospectively. The study consists of 2 periods; titration period 
(12 weeks) and maintenance period (24 weeks). 
 
[Titration Period] 
Subjects will begin receiving perampanel 2 mg/day and be up-titrated no less than 2-week 
intervals in increments of 2 mg up to 12 mg according to the investigator’s judgment. 
Subjects experiencing intolerable adverse events (AEs) may remain on the same dose or have 
their dose reduced to the previously tolerated dose. Subjects who cannot tolerate the 4 mg 
dose will be discontinued from the study. Subjects who are taking any concomitant drug that 
shortens the half-life of perampanel (phenytoin, carbamazepine, oxcarbazepine, etc.) can be 
up-titrated by 2 mg no less than 1-week intervals, if needed. Adjustment of the concomitant 
anti-epileptic drug (AED) dose level during this period is not permitted. 
 
[Maintenance Period] 
Subjects will enter this period on the last dose they achieved at the end of the titration period 
and will continue taking this dose level once daily for the remainder of the study. According 
to the investigator’s clinical judgment, subjects experiencing intolerable AEs can have their 
dose reduced and having failure to control seizure can have their dose increased up to 12 mg. 
During the Maintenance Period, subjects whose dose has been reduced can have the dose 
increased again, as soon as the tolerability improves. Subjects who cannot tolerate 4 mg dose 
will be discontinued from the study. Adjustment of the concomitant AED dose level during 
this period is not permitted. 
 


Clinical Study Protocol  
E2007-M065-412 
 
 
Eisai 
DRAFT (V1.0): 30 Dec 2015. 
Confidential 
Page 4 of 73 
 
In the case of tapering, withdrawal will be performed four weeks after last dose of 
perampanel. 
Subjects will visit the study institution at Visit 1 (Week 0), Visit 2 (Week 6), Visit 3 (Week 
12), Visit 4 (Week 24) and Visit 5 (Week 36). 
 
 
Number of Subjects 
Male and female subjects ≥ 12 years of age who have a diagnosis of epilepsy with partial-
onset seizures with or without secondarily generalized seizures will be included in this study. 
Approximately 105 subjects will be enrolled.   
Inclusion Criteria 
1. Male or female and greater than or equal to 12 years of age  
2. Have a diagnosis of epilepsy with partial onset seizures with or without secondarily 
generalized seizures according to the International League Against Epilepsy’s 
Classification of Epileptic Seizures (1981)  
3. Need an initial add-on therapy after failure to control seizures with the first or further 
monotherapy at the optimal dose and duration  
4. Despite AED treatment within the last 8 weeks, subjects must have had ≥2 partial onset 
seizures and the interval between those seizures should be more than 24 hours prior to 
Visit 1 (Week 0).  
5. Are currently being treated with stable doses of monotherapy for 8 weeks prior to Visit 1 
(Week 0) [Standard AEDs]; Carbamazepine, phenytoin, zonisamide, phenobarbital, 
valproate, clobazam, clonazepam, primidone, gabapentin, topiramate, lamotrigine, 
levetiracetam, oxcarbazepine, pregabalin, tiagabine, felbamate, vigabatrin 
6. If antidepressants or antianxiety drugs are used, subjects on stable doses and 
administrations of antidepressants or antianxiety drugs for 8 weeks prior to Visit 1 
(Week 0)  
Exclusion Criteria 


Clinical Study Protocol  
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DRAFT (V1.0): 30 Dec 2015. 
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1. Females who are pregnant (positive β-hCG test) or breastfeeding 
2. Presence of previous history of Lennox-Gastaut syndrome 
3. Presence of nonmotor simple partial seizures only  
4. Presence of primary generalized epilepsies or seizures such as absences and/or 
myoclonic epilepsies 
5. A history of status epilepticus within 12 weeks before Visit 1 (Week 0) 
6. Subjects on antipsychotics or who have psychotic disorder(s) or unstable recurrent 
affective disorder(s) with a history of attempted suicide within 1 year before Visit 1 
(Week 0) 
7. Presence of a progressive central nervous system (CNS) disease, including degenerative 
CNS diseases and progressive tumors 
8. Concomitant use of barbiturates (except for seizure control indication and premedication 
for electroencephalogram (EEG)) and benzodiazepines (except for seizure control 
indication) within 8 weeks prior to Visit 1 (Week 0) 
9. Use of intermittent rescue benzodiazepines (i.e., 1-2 doses over a 24-hr period 
considered one-time rescue) 2 or more times in 8 weeks period prior to Visit 1 (Week 0) 
10. Moderate to severe kidney problems or patients who receive hemodialysis. (Amendment 
01) 
11. Severe liver problems. (Amendment 01) 
12. Hypersensitivity to perampanel or any substances of this drug. (Amendment 01) 
13. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption (Amendment 01) 
14. Patient who is participating in other intervention clinical trial. (Amendment 01) 
15. Patient who judged to be inadequate to participate in the study by investigator 
Study Treatment 
Test drug: E2007 (perampanel) 2 mg oral tablet(s), once daily before bedtime 
Comparator Drug (if applicable): Not applicable  
Duration of Treatment 
Titration period: 12 weeks 
Maintenance period: 24 weeks 
Concomitant Drug/Therapy 
1. Concomitant antiepilepsy drugs (AED) 
a: Only one AED can be used 
A concomitant AED must be used at the stable dose and administration between 8 
weeks prior to Visit 1 (Week 0) and the end of follow-up examination. 
 
2. Concomitant medication 
a: Prohibited concomitant drug 
The following concomitant drugs are prohibited throughout the study period (up to 


Clinical Study Protocol  
E2007-M065-412 
 
 
Eisai 
DRAFT (V1.0): 30 Dec 2015. 
Confidential 
Page 6 of 73 
 
early discontinuation visit).  
• 
The cytochrome P450 3A4 (CYP3A4)-inducing drugs and food below. If 
having been treated at enrollment, washout of these drugs is to start at the 
enrollment. 
[Rifampicin, troglitazone, barbiturates except for use as AED, modafinil, 
efavirenz, nevirapine, glucocorticoid except for topical use, pioglitazone, 
rifabutin, and food containing St. John’s Wort (Hypericum perforatum)] 
• 
Antipsychotics 
• 
Other trial drugs 
b: Restricted concomitant drug  
The dosing regimen of the following drugs must not be altered, newly introduced, or 
discontinued throughout the study (up to early discontinuation visit). 
[Antidepressants and antianxiety drugs] 
 
3. Concomitant therapy 
a: Prohibited concomitant therapy  
The following therapies must not concurrently implemented during the study. 
• 
Brain surgery 
• 
Medical device under clinical trial 
b: Restricted concomitant therapy 
A vagus nerve stimulation (VNS) is allowed, but stimulator parameters cannot be 
changed for 8 weeks prior to Visit 1 (Week 0) or thereafter during the study. A 
ketogenic diet will be allowed as long as the subject has been on this diet for 8 
weeks prior to Visit 1 (Week 0). Additionally, a ketogenic diet cannot be newly 
added or discontinued during the study. 
Assessments 
Efficacy Assessments 
Primary efficacy variable: 
50% responder rate in total seizures: 50% responders are defined as subjects who have at 
least 50% reduction in total seizure frequency during the Maintenance Period relative to the 
Baseline. 
 
Secondary efficacy variables: 
- 
75% responder rate in total seizures 
- 
100% responder rate (seizure free rate) in total seizures 
- 
The percent change in total seizure frequency in the Titration and Maintenance Period 
relative to the Baseline 
- 
50% responder rate in secondarily generalized tonic clonic seizures 


Clinical Study Protocol  
E2007-M065-412 
 
 
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DRAFT (V1.0): 30 Dec 2015. 
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- 
75% responder rate in secondarily generalized tonic clonic seizures 
- 
100% responder rate (seizure free rate) in secondarily generalized tonic clonic seizures 
- 
The percent change in secondarily generalized tonic clonic seizure frequency in the 
Titration and Maintenance Period relative to the Baseline 
 
Pharmacokinetic Assessments 
Not applicable  
 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Not applicable  
 
Safety Assessments 
Safety will be assessed by monitoring of AEs, withdrawal from treatment, clinical laboratory 
evaluations (hematology), vital signs 
 
Other Assessments 
Not applicable  
Bioanalytical Methods 
Not applicable  
Statistical Methods 
Study Endpoints 
Primary Endpoint 
50% responder rate in total seizures: The rate of subjects who have at least 50% reduction in 
seizure frequency during the Maintenance Period relative to the Baseline  
 
Secondary Endpoints 
- 
75% responder rate in total seizures 
- 
100% responder rate (seizure free rate) in total seizures 
- 
The percent change in total seizure frequency in the Titration and Maintenance Period 
relative to the Baseline 
- 
50% responder rate in secondarily generalized tonic clonic seizures 
- 
75% responder rate in secondarily generalized tonic clonic seizures 
- 
100% responder rate (seizure free rate) in secondarily generalized tonic clonic seizures 
- 
The percent change in  secondarily generalized tonic clonic seizure frequency in the 
Titration and Maintenance Period relative to the Baseline 
- 
Adverse events, Laboratory evaluation, Vital signs. 
 
Exploratory Endpoint 
Not applicable 


Clinical Study Protocol  
E2007-M065-412 
 
 
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DRAFT (V1.0): 30 Dec 2015. 
Confidential 
Page 8 of 73 
 
 
Analysis Sets 
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment. 
The Full Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 postdose primary efficacy measurement.   
The Per Protocol Set is the group of subjects who sufficiently complied with the protocol. 
Details of the evaluability criteria will be determined before database lock and will be 
specified in the Statistical Analysis Plan. 
 
Efficacy Analyses 
The efficacy analysis will be performed in the full analysis set. The per-protocol set will be 
supportive. 
This is a single-arm study having no reference arm. Therefore, formal hypothetical 
inferences are not necessary and only descriptive statistics will be given. 
 
Primary endpoint 
For 50% Responder rate in total seizures: 
- 
Number of 50% responders  
- 
50% responder rate and its 95% confidence interval (CI) will be provided. 
 
Secondary endpoint 
For 75% Responder rate in total seizures: 
- 
Number of 75% responders in total seizures 
- 
75% responder rate in total seizures and its 95% CI will be provided. 
 
For 100% Responder rate (seizure free) in total seizures: 
- 
Number of 100% responder 
- 
100% responder rate and its 95% CI will be provided. 
 
For total seizure frequency: 
- 
 Mean, standard deviation, median, minimum, maximum and 95% CI will be provided. 
 
For 50% Responder rate in secondarily generalized tonic clonic seizures: 
- 
Number of 50% responders 
- 
50% responder rate and its 95% CI will be provided. 
 
For 75% Responder rate in secondarily generalized tonic clonic seizures: 
- 
Number of 75% responders in total seizures 
- 
75% responder rate in total seizures and its 95% CI will be provided. 


Clinical Study Protocol  
E2007-M065-412 
 
 
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Page 9 of 73 
 
 
For 100% responder rate (seizure free) in  secondarily generalized tonic clonic seizure: 
- 
Number of 100% responders 
- 
100% responder rate and its 95% CI will be provided. 
 
For seizure frequency in secondarily generalized tonic clonic seizure: 
- 
 Mean, standard deviation, median, minimum, maximum and 95% CI will be provided. 
 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
Not applicable  
 
Pharmacokinetic Analyses 
Not applicable  
 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable  
 
Safety Analyses 
For adverse events, drug-related adverse events, serious adverse events and adverse events 
leading to discontinuation, the frequency, percent and 95% confidence interval will be 
provided. All adverse events will be categorized by the body system and preferred term 
assigned to the event using Medical Dictionary for Regulatory Activities (MedDRA) terms. 
Laboratory data, vital signs and body weight will be presented according to their scale. For 
continuous variable, the mean, standard deviation, median, minimum and maximum will be 
provided. For categorical variable, the shift table will be provided. 
 
Other Analyses 
Not applicable 
Interim Analyses 
No interim analysis is planned for this study. 
Sample Size Rationale  
This study will be evaluated for the efficacy of adjunctive perampanel for partial-onset 
seizures. Primary endpoint is 50% responder rate in total seizures. 
There is no statistical hypothesis to be tested in this study and 105 subjects is set to keep 94 
subjects for the primary analysis with approximately 10% drop-out rate from the view point 
of feasibility. 
When 94 subjects for the primary analysis is kept and 50% responder rates can be assumed 
as 35.3% in test group and 19.3% as reference value according to Bernhard J. Steinhoff et 


Clinical Study Protocol  
E2007-M065-412 
 
 
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DRAFT (V1.0): 30 Dec 2015. 
Confidential 
Page 10 of 73 
 
al.1, lower limit of 95% confidence interval of 50% responder rate will be more than 19.3% 
with more than 90% power.    
 
𝑛=
ቀZα 2
ൗ+ Zβቁ
2
 [pT(1 −pT)]
(pT −pR)2
 
= (1.96 + 1.282)2 [0.353(1 −0.353)]
(0.353 −0.193)2
 
= 93.78 ≈94 
 
 
Zα/2 : Type I error (0.05/2) 
Zβ  : Type II error (0.1) 
pT  : 50% responder rate in test group 
pR  : reference value 
 
Considering a drop-out rate of 10%, total sample size require 105. 
 
[ Reference ] 
Bernhard J. Steinhoffet al., Efﬁcacy and safety of adjunctive perampanel for the treatmentof 
refractory partial seizures: A pooled analysisof three phase III studies, Epilepsia, 
54(8):1481–1489, 2013doi: 10.1111/epi.12212 
 
 


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[Schedule of Procedures/Assessments in Study E2007-M065-412] 
Period 
Screening 
Period 
Titrationa 
Maintenanceb 
Discontinua-
tion 
Follow-
upb,c 
Un-
scheduledi 
Study Week(s) 
Week -8~0 
Week 0 
Week 6 
Week 12 
Week 24 
Week 36 
 
 
 
Study Day(s) 
Day -56~0 
Day 0 
Day 42 
Day 84 
Day 168 
Day 252 
 
 
 
Visit Number 
(Retrospec-
tively) 
1 
2 
3 
4 
5 
 
 
 
Procedure/Assessment 
 
 
 
 
 
 
 
 
 
Informed consent/assentd 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
Seizure type and frequency 
 
X 
 
 
 
 
 
 
 
Medical historye 
 
X 
 
 
 
 
 
 
 
Concomitant medications 
 
Xf 
X 
X 
X 
X 
X 
X 
X 
Concomitant AED 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
evaluations 
 
X 
 
 
 
X 
X 
X 
 
Pregnancy test 
 
X 
 
 
 
X 
X 
X 
 
Adverse eventsh 
 
 
X 
X 
X 
X 
X 
X 
X 
Dispense the study drug 
 
X 
X 
X 
X 
 
X 
 
 
Return the study drug 
 
 
X 
X 
X 
X 
X 
X 
 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
 


Clinical Study Protocol  
E2007-M065-412 
 
 
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Confidential 
Page 12 of 73 
 
[Schedule of Procedures/Assessments in Study E2007-M065-412] 
Period 
Screening 
Period 
Titrationa 
Maintenanceb 
Discontinua-
tion 
Follow-
upb,c 
Un-
scheduledi 
Study Week(s) 
Week -8~0 
Week 0 
Week 6 
Week 12 
Week 24 
Week 36 
 
 
 
Study Day(s) 
Day -56~0 
Day 0 
Day 42 
Day 84 
Day 168 
Day 252 
 
 
 
Visit Number 
(Retrospec-
tively) 
1 
2 
3 
4 
5 
 
 
 
Procedure/Assessment 
 
 
 
 
 
 
 
 
 
Dispense subject diary 
 
X 
X 
X 
X 
 
X 
 
 
Return and review subject 
diary 
 
 
X 
X 
X 
X 
X 
X 
 
 
a: 
All visits to be done within ±5 days of the schedule. 
b: 
Visit to be done within ±7 days of the schedule. 
c: 
To be completed by subjects who are withdrawn from the study for any reason after Visit 1 (Week 0) and before Visit 5 (Week 36). When a 
taper is provided after discontinuation, it should be performed 4 weeks after the last dose. 
d: 
Informed consent/assent may be obtained prior to study start; it must be obtained prior to any study related procedures. 
e: 
All pertinent medical and surgical history within 5 years before Visit 1 (Week 0). 
f: 
Prior and concomitant medication(s) within 24 weeks before Visit 1 (Week 0). 
g: 
Prior and concomitant AED. 
h: 
Adverse events will be collected from the time subject starts to receive the study drug form through the last visit. Serious adverse events will 
be collected for 28 days after the subject’s last dose or last visit, whichever is longer. 
i: 
At the unscheduled visit, only the assessments that the investigator(s) judged the necessity based on the subject’s condition will be performed. 


Clinical Study Protocol  
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................18 
5 
ETHICS............................................................................................................................20 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................20 
5.2 
Ethical Conduct of the Study .................................................................................20 
5.3 
Subject Information and Informed Consent ...........................................................21 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................22 
7 
INTRODUCTION ...........................................................................................................22 
7.1 
Epilepsy..................................................................................................................22 
7.2 
Current Therapeutic Options..................................................................................23 
7.3 
Perampanel (Fycompa®) ........................................................................................24 
7.3.1 
Mechanism of Action ...................................................................................25 
7.3.2 
Preclinical Experience with E2007/perampanel (Fycompa®) .....................26 
7.3.2.1 
in vitro pharmacology ..........................................................................26 
7.3.2.2 
in vivo pharmacology ...........................................................................26 
7.3.3 
Clinical Experience with E2007/perampanel (Fycompa®) ..........................27 
7.3.3.1 
Phase I (Pharmacokinetics, PK) ...........................................................27 
7.3.3.2 
Phase II (Dose-escalation studies) .......................................................28 
7.3.3.3 
Phase III ...............................................................................................28 
7.3.3.4 
Extension study ....................................................................................30 
7.3.4 
Common Adverse Events ............................................................................30 
7.4 
Study Rationale ......................................................................................................31 
8 
STUDY OBJECTIVES ....................................................................................................31 
8.1 
Primary Objective ..................................................................................................31 
8.2 
Secondary Objectives.............................................................................................32 
9 
INVESTIGATIONAL PLAN ..........................................................................................32 
9.1 
Overall Study Design and Plan ..............................................................................32 
9.1.1 
Screening Period/Visit 1 (Week -8 ~ Week 0) ............................................33 
9.1.2 
Titration Period (0 ~ 12 weeks) ...................................................................34 
9.1.3 
Maintenance Period (12 ~ 36 weeks) ...........................................................34 
9.1.4 
Follow-up visit (Only withdrawn subject) ...................................................34 
9.2 
Discussion of Study Design ...................................................................................35 
9.2.1 
Rationale for Efficacy Variables ..................................................................35 
9.2.2 
Rationale for Prohibited/Restricted Concomitant Drug/Therapy ................35 


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9.3 
Selection of Study Population ................................................................................35 
9.3.1 
Inclusion Criteria .........................................................................................35 
9.3.2 
Exclusion Criteria ........................................................................................36 
9.3.3 
Removal of Subjects from Therapy or Assessment .....................................37 
9.4 
Treatment ...............................................................................................................38 
9.4.1 
Treatment Administered ..............................................................................38 
9.4.2 
Identity of Investigational Product...............................................................38 
9.4.2.1 
Chemical Name, Structural Formula of E2007 ....................................39 
9.4.2.2 
Comparator Drug .................................................................................39 
9.4.2.3 
Labeling for Study Drug ......................................................................39 
9.4.2.4 
Storage Conditions ...............................................................................39 
9.4.3 
Method of Assigning Subjects to Treatment Group ....................................40 
9.4.4 
Selection of Doses in the Study ...................................................................40 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................40 
9.4.6 
Blinding........................................................................................................40 
9.4.7 
Prior and Concomitant Drug/Therapy .........................................................40 
9.4.8 
Treatment Compliance .................................................................................41 
9.4.9 
Drug Supplies and Accountability ...............................................................42 
9.5 
Study Assessments .................................................................................................43 
9.5.1 
Assessments .................................................................................................43 
9.5.1.1 
Demographic/Baseline Assessments ...................................................43 
9.5.1.1.1 
Demography ...................................................................................43 
9.5.1.1.2 
Diagnosis........................................................................................43 
9.5.1.1.3 
Seizure type and frequency ............................................................43 
9.5.1.1.4 
Medical History .............................................................................43 
9.5.1.1.5 
Prior and concomitant medications ................................................43 
9.5.1.1.6 
concomitant AED...........................................................................44 
9.5.1.2 
Efficacy Assessments...........................................................................44 
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................45 
9.5.1.4 
Safety Assessments ..............................................................................45 
9.5.1.4.1 
Adverse Events and Events Associated with Special Situations ...45 
9.5.1.4.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................47 
9.5.1.4.3 
Laboratory Measurements .............................................................48 
9.5.1.4.4 
Vital Signs and Weight Measurements ..........................................49 
9.5.1.4.5 
Pregnancy Test ...............................................................................49 
9.5.2 
Schedule of Procedures/Assessments ..........................................................50 


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9.5.2.1 
Schedule of Procedures/Assessments ..................................................50 
9.5.2.2 
Description of Procedures/Assessments Schedule ...............................52 
9.5.2.2.1 
Demographic/Baseline Assessments .............................................52 
9.5.2.2.2 
Treatment Period Assessments ......................................................52 
9.5.2.2.3 
Follow-up assessments (only withdrawn subject) .........................54 
9.5.2.2.4 
Unscheduled assessments ..............................................................54 
9.5.3 
Appropriateness of Measurements ...............................................................54 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................55 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................55 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................55 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................56 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................56 
9.5.4.4 
Expedited Reporting ............................................................................56 
9.5.4.5 
Breaking the Blind ...............................................................................57 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................57 
9.5.5 
Completion/Discontinuation of Subjects .....................................................57 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................57 
9.6 
Data Quality Assurance .........................................................................................58 
9.6.1 
Data Collection ............................................................................................58 
9.6.2 
Clinical Data Management ..........................................................................58 
9.7 
Statistical Methods .................................................................................................58 
9.7.1 
Statistical and Analytical Plans ....................................................................58 
9.7.1.1 
Study Endpoints ...................................................................................59 
9.7.1.1.1 
Primary Endpoint ...........................................................................59 
9.7.1.1.2 
Secondary Endpoints .....................................................................59 
9.7.1.1.3 
Exploratory Endpoint .....................................................................59 
9.7.1.2 
Definitions of Analysis Sets.................................................................59 
9.7.1.3 
Subject Disposition ..............................................................................59 
9.7.1.4 
Demographic/Baseline Characteristics ................................................60 
9.7.1.5 
Efficacy Analyses ................................................................................60 
9.7.1.5.1 
Primary Efficacy Analysis .............................................................60 
9.7.1.5.2 
Secondary Efficacy Analyses ........................................................60 
9.7.1.5.3 
Exploratory Efficacy Analyses ......................................................61 
9.7.1.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................61 


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9.7.1.6.1 
Pharmacokinetic Analyses .............................................................61 
9.7.1.6.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................62 
9.7.1.7 
Safety Analyses ....................................................................................62 
9.7.1.7.1 
Extent of Exposure .........................................................................62 
9.7.1.7.2 
Adverse Events ..............................................................................62 
9.7.1.7.3 
Laboratory Values ..........................................................................63 
9.7.1.7.4 
Vital Signs and Weight Measurements ..........................................63 
9.7.2 
Determination of Sample Size .....................................................................63 
9.7.3 
Interim Analysis ...........................................................................................64 
9.7.4 
Other Statistical/Analytical Issues ...............................................................64 
10 REFERENCE LIST .........................................................................................................64 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......67 
11.1 
Changes to the Protocol .........................................................................................67 
11.2 
Adherence to the Protocol ......................................................................................67 
11.3 
Monitoring Procedures...........................................................................................68 
11.4 
Recording of Data ..................................................................................................68 
11.5 
Identification of Source Data .................................................................................69 
11.6 
Retention of Records..............................................................................................69 
11.7 
Auditing Procedures and Inspection ......................................................................69 
11.8 
Handling of Study Drug .........................................................................................69 
11.9 
Publication of Results ............................................................................................70 
11.10 Disclosure and Confidentiality ..............................................................................70 
11.11 Discontinuation of Study .......................................................................................71 
11.12 Subject Insurance and Indemnity ...........................................................................71 
12 APPENDICES .................................................................................................................71 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Clinical Laboratory Tests ...........................................................................48 
Table 2 
Schedule of Procedures/Assessments in Study E2007-M065-412 ............50 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................33 
 
LIST OF APPENDICES 
Appendix 1 
Expected Adverse Events and Precautions ................................................71 
 
 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AED 
Anti-Epilepsy Drug 
AMPA 
α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CYP 
Cytochrome P450  
ECG 
Electrocardiography 
ED50 
Effective Dose with 50% Reduction 
EEG 
Electroencephalogram 
EMA 
European Medicines Agency 
f-EPSPs 
Excitatory Postsynaptic Field Potentials 
EU 
European Union 
FDA 
Food and Drug Administration 
GABA 
γ-Amino-Butyric Acid 
GCP 
Good Clinical Practice 
HIRA 
Health Insurance Review & Assessment Service 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
ILAE 
International League Against Epilepsy 
IRB 
Institutional Review Board 
ISF 
Investigator’s Study File 
ITT 
Intention-to-Treat 
LNH 
Low/Normal/High 
MedDRA 
Medical Dictionary for Regulatory Activities 
MES 
Maximal Electroshock 
MFDS 
Ministry of Food and Drug Safety 
MRI 
Magnetic Resonance Imaging 


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Abbreviation 
Term 
NICE 
National Institute for Health and Care Excellence 
NMDA 
N-Methyl-D-Aspartic Acid 
OLE 
Open-Label Evaluation 
PK 
Pharmacokinetic 
POS 
Partial-Onset Seizures 
PT 
Preferred Term 
PTZ 
Pentylenetetrazole 
QD 
Once Daily 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TD50 
Toxic Dose with 50% Reduction 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
VNS 
Vagus Nerve Stimulation 
 
 
 


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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (Good Clinical Practice, GCP), Section 3, and any local regulations. Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate(s) (CRA[s]), change of telephone number[s]). 
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4). If the IRB/IEC decides to 
suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations. If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report. 
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice. Upon completion of the study, the investigator will provide 
the IRB/IEC with a brief report of the outcome of the study, if required. 
At the end of the study, the sponsor should notify the IRB/IEC within the period, according 
to requirement of each IRB/IEC. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC within the period, according to requirement of each IRB/IEC, and a detailed written 
explanation of the reasons for the termination/halt should be given. 
 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
• 
Principles of the World Medical Association Declaration of Helsinki (2008) 


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• 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use 
• 
Korea Good Clinical Practice (2014) 
 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject and/or guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records. Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language. The subject and/or the subject’s legally acceptable representative 
should understand the statement before signing and dating it and will be given a copy of the 
signed document. If a subject is unable to read or if a legally acceptable representative is 
unable to read, an impartial witness should be present during the entire informed consent 
discussion. After the ICF and any other written information to be provided to subjects is read 
and explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the ICF, 
the witness should sign and personally date the consent form. The subject will be asked to 
sign an ICF at the Visit 1 before any study-specific procedures are performed. No subject can 
enter the study before his/her informed consent has been obtained. 
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations. Each subject must sign an approved ICF 
before study participation. The form must be signed and dated by the appropriate parties. The 
original, signed ICF for each subject will be verified by the sponsor, kept on file and archived 
by the investigator in the Investigator’s Study File (ISF). 
The subject and/or the subject’s legally authorized representative should be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. The communication of this information 
should be documented. 
 


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6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 15 investigational sites in Korea. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and C&R research which is the contract research organization (CRO) are listed 
in the ISF provided to each site. 
 
7 
INTRODUCTION 
7.1 
Epilepsy 
Epilepsy is a chronic neurological disorder characterized by recurrent seizures,2 which are 
caused by excessive electrical discharges in the brain.3 According to the Epilepsy Foundation, 
epilepsy is the fourth most common neurological disorder following migraine, stroke and 
Alzheimer’s disease and affects approximately 50 million people worldwide.4 The 
International League Against Epilepsy (ILAE) Commission on Classification and 
Terminology suggests two diagnostic process steps for clinical practice: 1) seizure 
type/epilepsy syndrome and 2) the cause of epilepsy.5 ILAE established Classification of 
Epileptic Seizures in 1981 and Classification of Epilepsies and Epileptic Syndromes in 
1989.6 ILAE Task Force was appointed in 1997 in attempts to improve or complete the 
classifications and has published several reports; however, the guidelines have focused on 
proposing a diagnostic scheme rather than a replacement of the current international 
classification with refined classification, since the current classification is widely accepted.6,7 
Diagnosis of epilepsy requires electroencephalogram (EEG), computed tomography (CT) and 
magnetic resonance imaging (MRI) in addition to seizure type and epilepsy syndrome.8 
Syndromic diagnosis is not always feasible due to the complexity of epilepsies; therefore the 
Classification of Epileptic Seizures is simultaneously referred to supplement the diagnosis of 
epilepsy.6 In 1981 Classification of Epileptic Seizures, seizures are classified into two main 
types, which are generalized seizures and focal seizures. Generalized seizures are further 
divided into tonic-clonic, absence, clonic, tonic, atonic and myoclonic, and focal seizures 
(partial-onset seizures, POS) are characterized by features such as aura, motor, autonomic 
and awareness/responsiveness.9-11 Brief seizure episodes include involuntary movement of a 
part of the body (partial) or the whole body (generalized), and other than movement, the 
abnormal electrical changes may also disturb emotion/sensation, behavior and awareness of 
surroundings.11 More specifically, generalized seizures are affected by both sides of the brain, 
originating from bilaterally distributed networks of the brain whereas POS start from one 
hemisphere of the brain.10,11 POS are the most common type of seizures and shown on 60% 
of epilepsy patients.12 Partial-onset seizures may arise from brain tumors, injury to brain, 


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infections in the brain, genetic/nerve disorders and stroke from brain vessels, however, the 
causes sometimes are unclear. 
In South Korea, a nationwide epidemiological study had been conducted collaboratively by 
Korean Epilepsy Society and the department of Social & Preventive Medicine at 
Sungkyunkwan University School of Medicine using source data from Health Insurance 
Review & Assessment Service (HIRA) and medical records from medical institutions. In 
South Korea, 4.0 people in every 1,000 people have epilepsies (CI: 3.85~4.15), and there are 
192,254 patients with epilepsies. Males (4.5) had higher prevalence rate than female (3.5), 
and children under 10 and elders over 70 showed higher rates than other age ranges. Among 
epilepsy diagnosis, 78.1% epilepsies were characterized with partial seizures, 8.0% 
generalized seizures, and 1.1% distinctive constellation.13 
Although many different pathologic processes influence seizures and epilepsy, imbalance in 
neuronal excitability, specifically between neuronal inhibition and excitation, is thought to be 
a governing factor for neurological disorders. Animal experiments on excitatory glutamate 
receptors demonstrated an induced seizure activity with N-methyl-D-aspartic acid (NMDA), 
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate agonists and 
suppressed seizure activity by their antagonists.14,15 By contrast to the excitatory receptors, 
inhibitory receptors of γ-amino-butyric acid (GABA) hindered seizure activity with GABAA 
receptor agonists such as barbiturates and benzodiazepines.15 Number of anti-epileptic drugs 
(AEDs) have been generated, however, one-third of the patients experience nonadherence to 
current treatments and are at an increased risk of mortality, spinal and head injury from 
seizures, psychiatric disorders, prejudice, stigma and poor quality of life.16 Chronic refractory 
patients with AED discontinuation are majorly influenced by adherence to treatment and 
poor tolerability on the available medications.17 
 
7.2 
Current Therapeutic Options 
The use of AEDs is generally recommended after a second epileptic seizure according to the 
current guidelines. Appropriate AED is determined by number of factors such as type of 
seizure/epilepsy 
syndrome, 
individual/carer 
preferences, 
the 
presence 
of 
co-
morbidity/concomitant drugs, potential drug interactions, childbearing potential, adverse 
effects and the licensed indications of the drug. Although monotherapy with a single AED as 
first-line treatment for epilepsy is suggested, adjunctive treatment is often required with one 
or more concomitant AEDs for the treatment. National Institute for Health and Care 
Excellence (NICE) guideline instructs the use of combination therapy (‘add-on’ therapy) 
only when attempts of monotherapy with a single AED (first-line or alternative first-line) 
have failed to produce seizure freedom. Discontinuation or withdrawal of AED therapy may 
be discussed with patients who have been seizure free for at least 2 years. Alternative 
approaches for refractory epilepsy involve psychological intervention, ketogenic diet or 
vagus nerve stimulation (VNS).8 


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AEDs are one of therapeutic class of drugs that are highly concerned with drug interaction 
due to its pharmacokinetic properties and adverse clinical consequences. A desirable 
antiepileptic effect is achieved with a certain plasma level of AEDs which is close to the 
plasma level that may lead to undesirable adverse effects. Loss of seizure control or signs of 
intoxication may result from subtle changes of the AED plasma concentration. Another 
major influence of pharmacokinetics of AEDs is on the activity of hepatic drug metabolizing 
enzymes. A wide variety of metabolization and elimination of other drugs that are affected 
by the same kind of enzymes may occur as a result of the pharmacokinetic interactions. Some 
AEDs stimulating hepatic metabolizing enzymes include phenytoin, carbamazepine, 
primidone and phenobarbital, and inhibitory AEDs are valproic acid, stiripentol and 
sulthiame.18 Compared to the first-generation AEDs (phenytoin, phenobarbital, primidone, 
carbamazepine and valproate), many new AEDs developed since 1989 (second- and third-
generation AEDs) are indicated to have less interaction with other drugs and no effect on 
hepatic enzyme activity. However, avoidance of hepatic metabolism results in eliminated 
unchanged through the kidneys, leaving susceptibility in metabolic interactions of the drugs 
which include gastrointestinal absorption, excretion (usually renal) and displacement of 
protein binding, mostly from plasma albumin binding. 16 new AEDs have been introduced 
after the first-generation AEDs: eslicarbazepine acetate, gabapentin, lamotrigine, 
oxcarbazepine, pregabalin, rufinamide, tiagabine, vigabatrin, zonisamide, felbamate, 
lacosamide, levetiracetam, perampanel, retigabine (ezogabine), stiripentol and topiramate.19 
The current guidelines for pharmacological treatment of AEDs are generated into two 
versions in regard to epilepsy syndrome and seizure type. 
Carbamazepine, lamotrigine, oxcarbazepine and sodium valproate are instructed as the first-
line or alternative AEDs for generalized tonic-clonic seizures (GTC) on the current NICE 
guideline. GTC is a type of seizure involved with generalized stiffening and rhythmic jerking 
of the limbs, caused by bilateral malfunction of the brain. Focal seizures, or partial-onset 
seizures, are recommended to be treated with carbamazepine, lamotrigine, levetiraetam, 
oxcarbazepine and sodium valproate as the first-line or alternative AEDs. For its add-on 
therapy, carbamazepine, clobazam, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, 
sodium valproate and topiramate are suggested. The guideline is listed with number of other 
seizure types for pharmacological treatment options such as tonic or atonic seizures, absence 
seizures and myoclonic seizures.8 
 
7.3 
Perampanel (Fycompa®) 
Perampanel is a novel selective, non-competitive AMPA glutamate receptor antagonist.20 
AMPA receptor antagonists have recently been focused for its novel therapeutic target, 
which can potentially influence an epileptic disorder in pharmacoresistant patients. 
Perampanel showed a wide range of antiseizure activity in preclinical models and was 
demonstrated to have consistent pharmacokinetic (PK) data with once-daily regimen. In 


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randomized clinical trials, perampanel has been shown to be effective and safe as a treatment 
in the management of seizure frequency for the patients with POS.20 Currently, perampanel is 
approved by European Medicines Agency (EMA) and the United States (US) Food and Drug 
Administration (FDA) in July 2012 and October 2012, respectively. Ministry of Food and 
Drug Safety (MFDS) in Korea has approved 2, 4, 6, 8, 10 and 12 mg of perampanel (July 
2015) for an indication of an adjunctive therapy for partial-onset seizures in ≥12 year old 
epilepsy patients with or without secondarily generalized seizures. Perampanel is approved 
for the same indication as in Korea for the European Union (EU) and the United States with 
an additional indication of an adjunctive therapy for primary generalized tonic-clonic 
seizures in ≥12 year old patients with epilepsy. In Korea, administration of perampanel is 
instructed to start with a dose of 2 mg once daily and gradually increase up to the 
maintenance dose of 4~8 mg with increments of 2 mg based on clinical response and 
tolerability of patients, and a minimum of 2-week intervals for the increment should be 
arranged. The dose may be increased to 12 mg when necessary, and patients taking 
concomitant medication that may reduce perampanel plasma level (phenytoin, 
carbamazepine and oxcarbazepine) should have 2 mg increment with a minimum of weekly 
intervals. 
 
7.3.1 
Mechanism of Action 
Perampanel (2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydro-pyridin-3-yl)benzonitrile) is an 
orally active, non-competitive and highly selective antagonist of AMPA-type glutamate 
receptor, a class of ionotropic glutamate receptors on post-synaptic neurons, shown to be 
effective in various preclinical seizure models.21 The chemical structure is as below:20 
 
Glutamate is diffused to AMPA and NMDA receptors of post-synaptic neurons and induces a 
major excitatory response by depolarization. Excitotoxicity with elevated levels of glutamate 
is reported in epilepsy models of human brain tissues and animals.22-24 Perampanel 
noncompetitively and allosterically inhibits AMPA receptor activity, reducing excessive 
excitation and subsequently modulating seizure activity, even in the presence of high 
concentrations of glutamate. Hyperexcitatory states are also reported to be sustained as an 
effect of perampanel.20 
 


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7.3.2 
Preclinical Experience with E2007/perampanel (Fycompa®) 
7.3.2.1 
in vitro pharmacology 
In preclinical studies, perampanel was shown to have a dose-dependent inhibitory effect on 
AMPA-induced intracellular calcium concentration ([Ca2+]i) with an the half maximal 
inhibitory concentration (IC50) of 93 nM in cultured rat cortical neurons. NMDA-induced 
[Ca2+]i and the kainate receptor agonist SYM2081, by contrast, were only slightly inhibited 
by perampanel, reflecting its selective specificity.21 AMPA-induced Ca2+ was inhibited in 
similar magnitudes even in the presence of 2 μM (low) and 100 μM (high) of AMPA 
concentrations.25 Patch clamp recordings with cultured rat hippocampal neurons indicated 
that perampanel had no effect on AMPA receptor desensitization (reduced response after 
prolonged exposure to ligands or neurotransmitters).21 Patch recordings further showed that 
perampanel induced a rapid desensitization of AMPA receptor currents with 10μM of 
perampanel, showing nearly a complete block, whereas NMDA receptor currents had no 
change with 30 μM of perampanel.25 In the hippocampus, specifically in the stratum radiatum 
of the CA1 area, perampanel demonstrated IC50 of 0.23 μM for inhibition of excitatory 
postsynaptic field potentials (f-EPSPs), and a complete block of AMPA receptor-mediated f-
EPSPs was observed with 3 μM of perampanel, without affecting NMDA- or kainate 
receptor-mediated f-EPSPs at doses 100-fold higher than 3 μM.26 Perampanel has similar 
affinities for AMPA receptors in the open and closed states,21 non-competitively interacts at 
the allosteric binding site of the AMPA receptor and is thought to disrupt agonist binding 
process and channel opening by the interaction, which occurs between S1 and S2 glutamate 
binding core and channel transmembrane domains.27-28 No interaction of perampanel with the 
glutamate binding site of AMPA receptors was supported by functional studies with 
radiolabelled peramapanel, [3H]perampanel, which demonstrated no displacement of the drug 
even in the presence of AMPA, glutamate, kainite or NBQX (AMPA receptor antagonist).25 
By contrast, GYKI 52466, an AMPA receptor antagonist, displaced [3H]perampanel, 
suggesting that GYKI 52466 and perampanel may bind to similar site of the receptor. GYKI 
52466, however, is the prototypical non-competitive AMPA antagonist with IC50 of 7.8 μM 
for the inhibition of AMPA receptor-mediated f-EPSPs, requiring 34-fold higher 
concentration to induce the desired effect compared with perampanel.25,26 
 
7.3.2.2 
in vivo pharmacology 
Higher potency of perampanel was observed in mice against audiogenic seizures, maximal 
electroshock (MES) seizure test, pentylenetetrazole (PTZ) test and 6 Hz seizure test 
compared to phenytoin (included only in the 6 Hz seizure test), carbamazepine and sodium 
valproate. Mouse models with tonic-clonic generalized seizures were selected for the 
audiogenic and MES seizure test and absence/myoclonic seizures for the PTZ test. Activity 


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of perampanel was presented both in partial and generalized seizures, except in genetic 
absence epilepsy rats from Strasbourg.21 Especially, perampanel resulted superior outcomes 
compared to AEDs of sodium channel blockers in the 6 Hz seizure test and PTZ test since the 
Na+ channel blocking AEDs have weak or inactive status in those tests. Amygdala-kindling 
rat models, displaying a chronic epilepsy model, had increased afterdischarge (discharge of 
neural impulses) threshold and reduced motor seizure duration with perampanel. Reduced 
seizure severity and afterdicharge duration were also presented after the drug treatment, 
suggesting a broad spectrum of perampanel activity in both acute and chronic epilepsy 
models. Rotarod test was experimented with perampanel for a determination of motor 
coordination. Toxic dose with 50% reduction (TD50) in motor control of 1.8 mg/kg and 9.14 
mg/kg in mice and rats were observed, respectively. Effective dose with 50% reduction 
(ED50) in seizures from individual seizure tests (audiogenic, PTZ and MES) were used for 
the protective index of perampanel with the TD50. The protective index, TD50/ED50, resulted 
in 3.8, 1.9 and 1.1 for audiogenic, PTZ and MES tests, respectively. Despite the low 
therapeutic window of perampanel as an AMPA receptor antagonist, acute motor toxicity of 
the antagonists is expected since excitatory neurotransmission is majorly mediated by AMPA 
receptors throughout the brain. In addition, the low therapeutic window in animal models is 
not necessarily implied with reduced tolerability in clinical application.21,25 
 
7.3.3 
Clinical Experience with E2007/perampanel (Fycompa®) 
7.3.3.1 
Phase I (Pharmacokinetics, PK) 
In Phase I clinical studies (study 001 and study 002) in healthy subjects, perampanel was 
rapidly absorbed and reached maximal plasma concentration in about 1hour. Mean apparent 
half-life had a range of 52-129 hours in the single-dose study and 66-90 hours in the 
multiple-dose study. Steady-state plasma concentrations were achieved by day 14 in the 
multiple-dose study. Sedative effects were dose-dependent and remained similar on day 14 in 
spite of increased perampanel exposure versus day 1. Data from these studies demonstrated 
that perampanel possessed favorable pharmacological properties and PK profile of 
perampanel was consistent with once-daily dosing. 
Also, the results in study 017 to determine the absolute bioavailability of perampanel showed 
that perampanel was readily absorbed and reflected high oral bioavailability.20 
Perampanel is mainly metabolized by cytochrome P450 3A4 (CYP3A4) and CYP3A5. Thus, 
concomitant use of strong CYP3A inducers is not recommended. Also, CYP450 inducing 
AEDs such as carbamazepine, oxcarbazepine and phenytoin may also lead to decreased 
perampanel exposure and increased perampanel clearance. When related enzyme-inducing 
AEDs are introduced or withdrawn, patients should be closely monitored.20,30   
 


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7.3.3.2 
Phase II (Dose-escalation studies) 
The safety and tolerability of perampanel were examined, and a favorable tolerability and a 
preliminary evidence of efficacy were shown in randomized, double-blind, placebo-
controlled, dose-escalation, parallel-group Phase II studies (study 206 and study 208). Both 
studies included patients aged 18~70 years with POS with or without secondary 
generalization, presenting an uncontrolled POS despite treatment of at least three different 
AEDs within the last 2 years. In study 206 (n=153), patients received placebo or perampanel 
up to 4 mg/day (once- or twice-daily) during 12 weeks (8 weeks of titration and 4 weeks of 
maintenance). In study 208 (n=48), patients were given with placebo or perampanel up to a 
maximum dose of 12 mg/day (once-daily) for  16 weeks (12 weeks of titration and 4 weeks 
of maintenance).  
As a result, in study 206 the highest dose (4 mg/day) was well-tolerated, and the proportion 
of patients tolerating 4 mg/day was the same in the once-daily (82.4%) and twice-daily 
(82.4%) perampanel and placebo (82.4%) treatments. Responder rate and seizure frequency 
were the preliminary efficacy endpoints of the study and showed a favorability of 
perampanel (4 mg/day) over placebo, however, were statistically insignificant. In study 208, 
doses of ≥6 mg perampanel once-daily was tolerated by most patients with a Kaplan-Meier 
analysis. The small numbers of patients for each group inevitably obstructed an assessment 
of statistical analysis of efficacy endpoints for this dose-escalation study, however, 
differences between treatment groups were observed for the efficacy endpoints. 
Adverse events were not dose-limiting, and most commonly occurred AEs were central 
nervous system (CNS)-related while most of them were mild or moderate in severity. In 
study 206, the proportion of patients with at least one AE had similarity in placebo (62.7%) 
and perampanel (66.7%, once- and twice-daily. combined). The four common treatment-
emergent adverse events (TEAEs) in perampanel-treated patients (once-daily, n = 51; twice-
daily, n = 51) were dizziness, headache, somnolence and fatigue, and most of AEs had 
severity of mild or moderate. Patients with once-daily and twice-daily regimens showed no 
difference in tolerability, and 4 of the five reported serious AEs (SAEs) were treatment 
related and AEs associated with seizure activity (status epilepticus, convulsive seizure, 
mental status changes and post-ictal state). In study 208 patients with ≤6 mg (once-daily) and 
>6 mg (once-daily) were reported with similar distributions of AEs. Dizziness was the most 
common AE with 42.1% and 42.9% in ≤6 mg and >6 mg patients, respectively. Other 
common AEs were headache, somnolence, fatigue, diarrhea and rhinitis.31 
 
7.3.3.3 
Phase III 
In multicenter, double-blind, randomized, placebo-controlled three Phase III trials (study 304, 
305 and 306), the efficacy and tolerability of adjunctive perampanel have been assessed in 


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patients aged ≥12 years with an uncontrolled POS despite a treatment of at least two different 
AEDs within the last 2 years.1,32,33  
In study 306, a total of 706 patients were randomized and received placebo or perampanel 
(once-daily) with doses titrated from 2 mg to the target doses of 2, 4 or 8 mg of perampanel 
in 2 mg increments every week for 6-week titration period, followed by a subsequent 
maintenance period of 13 weeks. 2 mg of perampanel showed no significant difference from 
placebo; however, 4 mg and 8 mg of perampanel significantly reduced seizure frequency 
(p=0.003 and p<0.001, respectively). The responder rate was also significantly increased 
compared to placebo at these doses (p=0.013 and p<0.001, respectively).33 
In study 304 and 305, higher perampanel doses than those of study 306 were explored: 8 and 
12 mg once-daily. Study 304 involved 388 patients in North and South America, and study 
305 involved 386 patients worldwide. The identically designed trials (study 304 and 305) 
both showed significant improvements in seizure frequency in AED-resistant patients with 8 
and 12 mg perampanel (304: p=0.026 and p=0.016, respectively; 305: p<0.001 and p=0.01, 
respectively). When complex partial plus secondary generalized seizures were specifically 
evaluated, similar improvements in seizure frequency were observed: -33.0% (8 mg) and -
33.1% (12 mg) compared with -17.9% (placebo) in study 304. Although statistical 
significance was absent in responder rates of study 304, when a subsequent sub-analysis was 
examined, significant differences were observed between placebo and both doses (p<0.05 for 
both) and -30.5% (8 mg) and -17.6% (12 mg) compared with -9.7% (placebo) in study 304 
and 305, respectively.1,32  
In the Intention-to-treat (ITT) analysis which includes 1,478 patients from 304 (n=387), 305 
(n=386) and 306 (n=705) studies, 50% responder rates were higher with 4, 8 and 12 mg than 
placebo (28.5%, 35.3%, 35.0% and 19.3%, respectively, p<0.05) for all partial seizures. 
Median percentage changes in seizure frequency for all partial seizures were higher in 4, 8 
and 12 mg (-23.3%, -28.8% and -27.2%, respectively) than placebo (-12.8%) with p<0.01. 
For complex partial seizures with secondarily generalized seizures, significantly (p<0.001) 
higher median percentage changes in seizure frequency were reported with 4, 8 and 12 mg (-
31.2%, -35.6% and -28.6%, respectively) compared to placebo (-13.9%). 
In the three clinical trials, perampanel-treated patients achieved a higher seizure-free rate 
than patients with placebo:1,32-34 
 
Seizure-free status 
Study 
Placebo 
2 mg 
4 mg 
8 mg 
12 mg 
304 
0.0% 
NA 
NA 
2.2% 
1.5% 
305 
1.5% 
NA 
NA 
2.3% 
1.5% 
306 
1.2% 
1.9% 
4.4% 
4.8% 
NA 
 


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In study 304, the proportion of patients who experienced at least one AE in 8, 12 mg/day and 
placebo was over 80% (88.0%, 91.8% and 82.6%, respectively), and most TEAEs were mild 
or moderate in its severity. The most common TEAEs which had occurred ≥10% in any 
treatment group include dizziness, somnolence, headache, fall, irritability and ataxia. In study 
305, 86.8%, 86.0% and 68.4% of 8 and 12 mg groups and placebo group, respectively, 
showed at least one TEAE. 7 patients in placebo, 10 in 8 mg and 12 in 12 mg experienced 
SAEs (5.1%, 7.8% and 9.9%, respectively), and those who had more than one SAE were all 
related to epilepsy. The common TEAEs with ≥10% occurrence were similar to those of 
study 304: dizziness, somnolence, fatigue and headache, and most of TEAE severity were 
mild and moderate.1,32 In study 306, four most common TEAEs with ≥10% occurrence in any 
treatment group include dizziness, headache, somnolence and fatigue.33 
 
7.3.3.4 
Extension study 
In study 207, long-term open-label evaluation (OLE) in patients with epilepsy was conducted. 
Completion of study 206 or 208 was eligibility for the enrollment of patients, and 138 from 
180 patients who completed were enrolled for the study 207. The study was designed with 
12-week titration period with 2 mg increments of perampanel with 2-week intervals up to a 
maximum of 12 mg/day and a planned maxium maintenance period of 424 weeks, 
approximately 8 years. 86.2% of patients (n=119) was exposed to perampanel for more than 
6 months and 69.6% with more than a year of treatment. In regard of tolerability and safety, 
129 patients had experience at least one TEAE during the lengthy exposures, however, 
frequencies of the most common TEAEs (dizziness, headache and somnolence) were reduced 
more than half in the second year, and halved again in the following year. -31.5% of the 
median percent change in seizure frequency per 28 days during the entire treatment period 
was observed, and -39.4% was shown for the maintenance period only.35 
Phase III extension study (study 307) consisting of a 16-week blinded conversion period and 
a subsequent long-term open-label treatment period was conducted in 1,216 patients from 
study 304, 305 and 306, increasing the dose from 8 mg/day to 12 mg/day. During more than 
3 years of treatment period, stable reductions in seizure frequency was observed. For patients 
with secondarily generalized seizures, seizure frequency of secondarily generalized seizures 
was reduced up to 90%. AEs occurred most frequently during titration period, and individual 
SAEs were rare during long exposure period. Common AEs were dizziness, somnolence and 
headache, and SAEs included psychiatric symptoms and seizure events. No new major safety 
concerns were raised during the long exposures of perampanel.36 
 
7.3.4 
Common Adverse Events 
In Phase II (study 206 and 208) and Phase III clinical trials (study 304, 305 and 306) of 
perampanel in treatment-resistant patients, the most TEAEs were CNS-related and not dose-


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dependent. Many AEDs suppress the neuronal hyperexcitability pathologically, and 
subsequent adverse reactions in the CNS are not unexpected. Most AEDs are known to cause 
sedation, incoordination, drowsiness, fatigue and nausea, and these AEs are mainly dose-
related.37 The most common adverse drug reactions (ADRs) of perampanel were dizziness, 
fatigue, somnolence, nausea, irritability and falls. Perampanel treated patients had higher 
frequency of depression and aggression than patients taking placebo, with particularly at 
higher doses. The majority of TEAE severities were mild and moderate, with a relatively low 
incidence of SAEs. Patients taking perampanel had greater rate of side effects in psychiatrics 
than with placebo, primarily irritability. 
 
7.4 
Study Rationale 
Perampanel is the first in a new class of highly selective, non-competitive AMPA receptor 
antagonists for treatment-resistant partial-onset seizures.20 It was recently approved as an 
adjunctive treatment for partial seizures with or without secondary generalization, in patients 
aged ≥ 12 years, in the EU (EMA, 2012), the United States (FDA, 2012) and the Korea 
(MFDS, 2015).34 The efficacy and tolerability of adjunctive perampanel has been 
demonstrated in 3 pivotal studies about patients inadequately controlled despite treatment 
with 1-3 approved AEDs.36,39 Overall, 1,480 patients were randomized and treated (safety 
analysis set) in 3 pivotal studies. Most patients were receiving two or more concomitant 
AEDs at baseline (one, n=206, 13.9%; two, n=751, 50.7%; three, n=522, 35.3%).34 In other 
words, more than 80% of patients were treated with more than 2 concomitant AEDs in these 
trials, therefore there is limited data to show the efficacy and safety of perampanel as a first 
add-on therapy to date. 
Meanwhile probability of seizure freedom decreases significantly with subsequent AED 
regimens,40 so it is of interest to assess the first add-on therapy. Further, considering the 
novel mode of action of perampanel, there is a possibility of synergistic effects on the 
combination therapy which can only be demonstrated by a study of perampanel as the first 
adjunctive AED. 
Therefore, we try to assess the efficacy and safety of perampanel in patients with partial 
onset seizure with or without secondary generalized seizure as a first add-on therapy in Korea. 
 
 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
To evaluate the efficacy of perampanel added to monotherapy for partial onset seizures with 
or without secondarily generalized seizures (total seizures) as measured by 50% responder 
rate. 


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8.2 
Secondary Objectives 
1) To evaluate the safety of perampanel added to monotherapy for partial onset seizures 
with or without secondarily generalized seizures 
2) To evaluate efficacy of perampanel added to monotherapy for secondarily generalized 
tonic clonic seizure in partial onset seizures 
 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a multi-center, open-label, single-arm, phase 4 study. Subjects who meet all of the 
inclusion and none of the exclusion criteria will be received perampanel. 
Baseline seizure counts (frequency) data is collected by subjects or guardian/legally 
authorized representative, retrospectively. The study consists of 2 periods; titration period 
(12 weeks) and maintenance period (24 weeks). 
 
Titration Period 
Subjects will begin receiving perampanel 2 mg/day and be up-titrated no less than 2-week 
intervals in increments of 2 mg up to 12 mg according to the investigator’s judgment. 
Subjects experiencing intolerable AEs may remain on the same dose or have their dose 
reduced to the previously tolerated dose. Subjects who cannot tolerate the 4 mg dose will be 
discontinued from the study. Subjects who are taking any concomitant drug that shortens the 
half-life of perampanel (phenytoin, carbamazepine, oxcarbazepine, etc.) can be up-titrated by 
2 mg no less than 1-week intervals, if needed. Adjustment of the concomitant AED dose 
level during this period is not permitted. 
 
Maintenance Period 
Subjects will enter this period on the last dose they achieved at the end of the titration period 
and will continue taking this dose level once daily for the remainder of the study. According 
to the investigator’s clinical judgment, subjects experiencing intolerable AEs can have their 
dose reduced and having failure to control seizure can have their dose increased up to 12 mg. 
During the Maintenance Period, subjects whose dose has been reduced can have the dose 
increased again, as soon as the tolerability improves. Subjects who cannot tolerate 4 mg dose 
will be discontinued from the study. Adjustment of the concomitant AED dose level during 
this period is not permitted. 
 
In the case of tapering, withdrawal will be performed four weeks after last dose of 
perampanel. 


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Subjects will visit the study institution at Visit 1 (Week 0), Visit 2 (Week 6), Visit 3 (Week 
12), Visit 4 (Week 24) and Visit 5 (Week 36). 
 
 
 
Figure 1 
Study Design 
 
9.1.1 
Screening Period/Visit 1 (Week -8 ~ Week 0) 
Before/At the Visit 1 (Week 0), informed consent will be obtained after the study has been 
fully explained to each subject and before the conduct of any baseline procedures or 
assessments. Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3. 
Investigators will confirm the inclusion/exclusion criteria and perform the evaluations to the 
subjects. Subjects should be greater than or equal to 12 years of age, be/have diagnosed with 
epilepsy with partial onset seizures with or without secondarily generalized seizures 
according to ILAE’s Classification of Epileptic seizures and need the initially add-on therapy 
after failure to control seizures with the first or further monotherapy at the optimal dose and 
duration.  
Results of the Screening information must be recorded on the appropriate case report form 
(CRF) to indicate whether the subject is eligible to participate in the study and to provide 
reasons for screen failure, if applicable. 
In addition, medical history, prior concomitant medications and prior concomitant AED of 
subjects will be obtained. 
Subjects who complete the Visit 1 (Week 0) and meet all of the inclusion/exclusion criteria 
(Sections 9.3.1 and 9.3.2) will be enrolled and begin the treatment period. 
 


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9.1.2 
Titration Period (0 ~ 12 weeks) 
In the 12-week Titration Period, subjects will begin receiving perampanel 2 mg once daily 
(QD) before bedtime and can be up-titration no less than 2-week intervals in increments of 2 
mg QD up to 12 mg QD according to the investigator’s judgment. Subjects experiencing 
intolerable AEs may remain on the same dose or have their dose reduced to the previously 
tolerated dose. Subjects who cannot tolerate 4 mg QD dose will be discontinued from the 
study. Subjects who are taking concomitant drug that shorten the half-life of perampanel 
(phenytoin, carbamazepine, oxcarbazepine, etc.) can be up-titrated by 2 mg QD no less than 
1-week intervals, if needed. Adjustment of the concomitant AED dose level during this 
period is not permitted. 
 
9.1.3 
Maintenance Period (12 ~ 36 weeks) 
In the 24-week Maintenance Period, subjects will enter this period on the last dose they 
achieved at the end of the titration period and will continue taking this dose level once daily 
for the remainder of the study. According to the investigator’s clinical judgment, subjects 
experiencing intolerable AEs can have their dose reduced and having failure to control 
seizure can have their dose increased up to 12 mg QD. During the Maintenance Period, 
subjects whose dose has been reduced can have the dose increased again, as soon as the 
tolerability improves. Subjects who cannot tolerate 4 mg QD dose will be discontinued from 
the study. Adjustment of concomitant AED dose level during this period is not permitted. 
 
9.1.4 
Follow-up visit (Only withdrawn subject) 
A Follow-up Visit will be applies to the subjects who are withdrawn from the study for any 
reason. There is the potential of increased seizure frequency in subjects with seizure 
disorders when antiepileptic drugs are withdrawn abruptly. Therefore, a gradual withdrawal, 
a taper, is provided after discontinuation, and it should be performed 4 weeks after the last 
dose of perampanel. But, prompt withdrawal can be considered when adverse drug reaction 
occurs.  
 
The end of the study will be the date of the last study visit for the last subject. However, if 
there are AEs that be not resolved and present on the last visit scheduled, the subject(s) 
having the AE(s) should be monitored until resolution of AE(s) or deciding to stop the 
observation by the investigator(s). 
 


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9.2 
Discussion of Study Design 
9.2.1 
Rationale for Efficacy Variables 
According to ‘Guideline on clinical investigation of medicinal products in the treatment of 
epileptic disorders’ of EMA, in add-on study, the primary endpoint should dichotomize the 
data into responders/non-responders, where responders are patients who obtained at least a 
certain pre-defined percentage reduction of seizure frequency.41 The at least 50% reduction 
of seizure frequency is commonly used in the studies and these endpoints are used as primary 
or key secondary endpoint in previous global pivotal studies. Therefore, 50% responder rate 
in total seizures as the primary efficacy variable is adopted in this study for evaluating the 
efficacy in Korean subjects. 
 
9.2.2 
Rationale for Prohibited/Restricted Concomitant Drug/Therapy 
During the study, the use of medications including AEDs and therapy that could affect the 
efficacy or safety of the study can be prohibited or restricted to minimize the confound 
factors.  
However, for the evaluation of perampanel as first add on therapy, the use of only one 
concomitant AED is permitted, if it have be administrated at the stable dose for 8 weeks prior 
to the Visit 1 (Week 0) and will be provided at same dosage and by same route of 
administration during the study. The detailed prohibited/restricted concomitant drug or 
therapy is presented in the Section 9.4.7. 
  
9.3 
Selection of Study Population 
Approximately 105 subjects will be enrolled at approximately 15 sites in Korea. Subjects 
who do not meet all of the inclusion criteria or who meet any of the exclusion criteria will not 
be eligible to receive study drug. 
 
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
 
1. Male or female and greater than or equal to 12 years of age  
2. Have a diagnosis of epilepsy with partial onset seizures with or without secondarily 
generalized seizures according to the ILAE’s Classification of Epileptic Seizures (1981)  
3. Need an initial add-on therapy after failure to control seizures with the first or further 
monotherapy at the optimal dose and duration  


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4. Despite AED treatment within the last 8 weeks, subjects must have had ≥2 partial onset 
seizures and the interval between those seizures should be more than 24 hours prior to 
Visit 1 (Week 0).  
5. Are currently being treated with stable doses of monotherapy for 8 weeks prior to Visit 1 
(Week 0) [Standard AEDs]; Carbamazepine, phenytoin, zonisamide, phenobarbital, 
valproate, clobazam, clonazepam, primidone, gabapentin, topiramate, lamotrigine, 
levetiracetam, oxcarbazepine, pregabalin, tiagabine, felbamate, vigabatrin 
6. If antidepressants or antianxiety drugs are used, subjects on stable doses and 
administrations of antidepressants or antianxiety drugs for 8 weeks prior to Visit 1 
(Week 0) 
 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
 
1. Females who are pregnant (positive β-hCG test) or breastfeeding 
2. Presence of previous history of Lennox-Gastaut syndrome 
3. Presence of nonmotor simple partial seizures only  
4. Presence of primary generalized epilepsies or seizures such as absences and/or 
myoclonic epilepsies 
5. A history of status epilepticus within 12 weeks before Visit 1 (Week 0) 
6. Subjects on antipsychotics or who have psychotic disorder(s) or unstable recurrent 
affective disorder(s) with a history of attempted suicide within 1 year before Visit 1 
(Week 0) 
7. Presence of a progressive CNS disease, including degenerative CNS diseases and 
progressive tumors 
8. Concomitant use of barbiturates (except for seizure control indication and premedication 
for EEG) and benzodiazepines (except for seizure control indication) within 8 weeks 
prior to Visit 1 (Week 0) 
9. Use of intermittent rescue benzodiazepines (i.e., 1-2 doses over a 24-hr period 
considered one-time rescue) 2 or more times in 8 weeks period prior to Visit 1 (Week 0) 
10. Moderate to severe kidney problems or patients who receive hemodialysis. (Amendment 
01) 
11. Severe liver problems. (Amendment 01) 
12. Hypersensitivity to perampanel or any substances of this drug. (Amendment 01) 
13. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption (Amendment 01) 
14. Patient who is participating in other intervention clinical trial. (Amendment 01) 
15. Patient who judged to be inadequate to participate in the study by investigator 


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9.3.3 
Removal of Subjects from Therapy or Assessment 
1) Scheduled Termination 
Subjects will be considered to have completed the titration period after 12 weeks of titration 
treatment and completion of the Visit 3 (Week 12) visit procedures. Subjects who have 
completed the titration period will enter the maintenance period. The subject will be 
considered to have completed the maintenance period after 24 weeks of maintenance 
treatment and completion of the Visit 5 (Week 36) visit procedures. Upon completion of the 
titration period and the maintenance period, and after resolution of any AEs that may be 
present on the last visit, the subject will be considered to have completed the study. 
 
2) Unscheduled Termination or Removal of Subjects from the Study 
Subjects who had administered the study drug and could not participate the entire period of 
clinical trial are classified as ‘withdrawals’. If the subject declines further participation or the 
investigator determines that a subject should be removed from the study, the subject can be 
withdrawn at any time. 
Reasons for withdrawal are as the followings:  
 
1) Withdrawal of informed consent 
2) AE(s) requiring discontinuation of study therapy  
3) Eligibility violation 
4) Administration of prohibited medications 
5) Lost to follow-up 
6) Unable to continue the study in the investigator’s judgment 
 
The investigator will make every reasonable effort to keep each subject followed-up for any 
adverse events. He/she will use all possible ways to communicate (phone call, letters, and 
visit to home) with the subject. Reason for withdrawal should be documented on CRF. Final 
assessment to withdrawn subjects should be conducted and documented. Withdrawn subjects 
cannot re-participate to study.   
 
The Sponsor can discontinue the entire study or study at a specific study site at any time with 
appropriate notification. The reasons for discontinuation of study can be as the followings:  
 
1) The enrollment of stated objective number of subjects in all study sites or in a specific 
study site had failed 
2) Emergence of any information regarding the efficacy or safety which could affect the 
continuation of the study 


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3) Any violation of GCP, study protocol or the contract by the study site or the 
investigator which could raise a problem to continue the study  
4) Other administrative reason affecting the continuation of the study  
 
9.4 
Treatment 
9.4.1 
Treatment Administered 
Perampanel will be administered to subjects in each period. Tablet(s) will be taken orally 
once daily before bedtime. The strength of one tablet is 2 mg and subjects can receive N x 2-
mg tablet(s) of perampanel based on daily dose. At the beginning of the 12-week titration 
period, oral perampanel will start at a dose of 2 mg once daily. Then, doses of perampanel 
will be up-titrated in 2 mg/day increments no less than 2-week intervals to a maximum of 12 
mg/day according to the investigator’s judgment. Also, subjects who are taking concomitant 
AED known as CYP enzyme inducer (phenytoin, carbamazepine, oxcarbazepine, etc.) that 
shorten the half-life of perampanel can be up-titrated by 2 mg once daily no less than 1-week 
intervals. 
 
The study drug will be dispensed to each subject or guardian/legally authorized 
representative at the Visit 1 (Week 0), Visit 2 (Week 6), Visit 3 (Week 12), Visit 4 (Week 
24), Discontinuation Visit.  
Tablet(s) cannot be split, broken or crushed prior to administration, and must be 
administrated whole with approximately 225 mL of water.  
 
9.4.2 
Identity of Investigational Product 
Study drug, perampanel, will be supplied by the sponsor.   
 
• 
Product name/ Manufacturer: Fycompa®/ Eisai Inc. 
• 
Formulation/ Drug identification (appearance)/ Active ingredient and dosage/ Expiration 
date 
Tablet 
strength 
Tablet color/shape 
Active ingredient and dosage 
Expiration date 
2 mg 
Orange, round, biconvex, 
film-coated tablets 
Perampanel 2.1 mg 
(2 mg as perampanel anhydrous) 
60 months after 
manufacture 
• 
Storage condition: at 1~30℃ 
 
 


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9.4.2.1 
Chemical Name, Structural Formula of E2007 
• 
Test drug code:  E2007 
• 
Generic name:  Perampanel 
• 
Chemical name: 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile 
• 
Molecular formula: C23H15N3O 
• 
Molecular weight: 349.38 (anhydrous) 
• 
Structural formula:   
 
 
 
9.4.2.2 
Comparator Drug 
Not applicable. 
 
9.4.2.3 
Labeling for Study Drug 
The sponsor will provide study drug labeled with the followings; 
1) Cautionary statement for “For clinical trial”  
2) Product code or generic name of active ingredient 
3) Lot number and expiration date 
4) Storage condition 
5) Name and address of the approved party for the clinical trial 
6) Cautionary statement for "Investigational use only" 
7) Statement for “Keep this product out of the reach of children” (Amendment 02) 
8) Packing unit  (Amendment 02) 
9) Name, address, and contact number of the sponsor  (Amendment 02) 
 
9.4.2.4 
Storage Conditions 
Perampanel will be stored in accordance with the labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the perampanel is maintained 
within an established temperature range, 1°C to 30°C.  
 


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9.4.3 
Method of Assigning Subjects to Treatment Group 
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to receive perampanel for the titration period and maintenance period as initially 
added to monotherapy in patient with partial onset seizures. There is no randomization in this 
study. 
 
9.4.4 
Selection of Doses in the Study 
Perampanel is approved from MFDS on May, 2015, as adjunctive therapy for the treatment 
of partial-onset seizures with or without secondarily generalized seizures in patients with 
epilepsy 12 years of age and older. In label paper, initial dose of perampanel is 2 mg/day and 
can be escalated by increments of 2 mg/day no less than at 2-week intervals, up to 12 mg, a 
maximum dose, depending on the clinical response and tolerability in patient. Also, subjects 
who are taking concomitant AED known as CYP enzyme inducer (phenytoin, carbamazepine, 
oxcarbazepine, etc.) that shorten the half-life of perampanel can be up-titrated by 2 mg once 
daily no less than 1-week intervals. 
 
9.4.5 
Selection and Timing of Dose for Each Subject 
Subjects will begin receiving perampanel 2 mg/day and be up-titrated in increments of 2 mg 
up to 12 mg depending on the clinical response and tolerability in each subject. Subjects will 
start taking study drug in the bedtime at Visit 1 (Week 0). Study drugs will be taken orally 
once daily in the bedtime throughout the study. 
 
9.4.6 
Blinding 
The study will not be blinded. 
 
9.4.7 
Prior and Concomitant Drug/Therapy 
1) Concomitant antiepilepsy drug 
a: Only one AED can be used 
A concomitant AED must be used at the stable dose and administration between 8 
weeks prior to Visit 1 (Week 0) and the end of follow-up examination. 
2) Concomitant medication 
a: Prohibited concomitant drug 
The following concomitant drugs are prohibited throughout the study period (up to 
early discontinuation visit).  


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• 
The CYP3A4-inducing drugs and food below. If having been treated at 
enrollment, washout of these drugs is to start at the enrollment. 
[Rifampicin, troglitazone, barbiturates except for use as AED, modafinil, 
efavirenz, nevirapine, glucocorticoid except for topical use, pioglitazone, 
rifabutin, and food containing St. John’s Wort (Hypericum perforatum)] 
• 
Antipsychotics 
• 
Other trial drugs 
b: Restricted concomitant drug  
The dosing regimen of the following drugs must not be altered, newly introduced, or 
discontinued throughout the study (up to early discontinuation visit). 
[Antidepressants and antianxiety drugs] 
3) Concomitant therapy 
a: Prohibited concomitant therapy  
The following therapies must not concurrently implemented during the study. 
• 
Brain surgery 
• 
Medical device under clinical trial 
b: Restricted concomitant therapy 
A VNS is allowed, but stimulator parameters cannot be changed for 8 weeks prior to 
Visit 1 (Week 0) or thereafter during the study. A ketogenic diet will be allowed as 
long as the subject has been on this diet for 8 weeks prior to Visit 1 (Week 0). 
Additionally, a ketogenic diet cannot be newly added or discontinued during the 
study. 
 
9.4.8 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study. Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study. 
The importance of compliance with the treatment regimen will be emphasized at each visit. 
The subject must be reminded to return all unused medication from the previous treatment 
period and report the number of tablet(s) lost to the investigator if tablet(s) would be lost. 
The investigator or designated study site personnel should count the number of tablets 
returned by the subject and investigate the number of tablet(s) lost from the subject to 
establish the number of tablets used, and compare this to the number of tablets expected to be 
used for the period. A record of this reconciliation must be maintained using the 
accountability forms, and any issues of non-compliance discussed with the subject. 
 


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9.4.9 
Drug Supplies and Accountability 
The investigator and the designated pharmacist will be responsible for the accountability of 
all study drugs (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements. 
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol. Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following: receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site. This includes, but may not be limited to: (a) documentation 
of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, (c) study drugs 
accountability log, and (d) documentation of returns to the sponsor. All forms will be 
provided by the sponsor. Any comparable forms that the site wishes to use must be approved 
by the sponsor. 
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
MFDS). As applicable, all unused study drugs and empty and partially empty containers 
from used study drugs are to be returned to the investigator or the designated pharmacist by 
the subject and, together with unused study drugs that were shipped to the site but not 
dispensed to subjects, are to be returned to the sponsor’s designated central or local depot(s) 
during the study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs and containers at the site. Destruction at the site will only occur 
under circumstances where regulation or supply type prohibits the return of study drugs to 
the central or local depot(s). Approval for destruction to occur at the site must be provided by 
the sponsor in advance. Upon completion of drug accountability and reconciliation 
procedures by the site’s personnel and documentation procedures by the sponsor’s personnel, 
study drugs that are to be returned to the sponsor’s designated central or local depot(s) must 
be boxed, sealed, and shipped back to the central or local depot(s) following all local 
regulatory requirements. In some regions, study drugs may be removed from the site and 
hand delivered to the central or local depot by sponsor representatives. Where study drugs 
are approved for destruction at the site, destruction will occur following the site’s standard 
procedures and certificates of destruction will be provided to the sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 
 


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9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Demographic/Baseline Assessments 
9.5.1.1.1 DEMOGRAPHY 
Subject demography information will be collected at the Visit 1 (Week 0). Demography 
information includes date of birth (or age), sex. 
 
 
9.5.1.1.2 DIAGNOSIS 
Subject must be/have diagnosed with epilepsy with partial onset seizures with or without 
secondarily generalized seizures according to the ILAE’s Classification of Epileptic Seizures 
(1981). In addition, Subject should need the first add-on therapy after failure to control 
seizure with the first or further monotherapy at the optimal dose and duration. 
 
9.5.1.1.3 SEIZURE TYPE AND FREQUENCY 
Seizure type and frequency/interval within 8 weeks prior to the Visit 1 (Week 0) will be 
collected, retrospectively. 
 
9.5.1.1.4 MEDICAL HISTORY  
Medical and surgical history and current medical conditions will be recorded at the Visit 1 
(Week 0). All pertinent medical and surgical history within 5 years prior to the Visit 1 (Week 
0) must be noted on the appropriate CRF. 
Vital signs including blood pressure, body temperature, respiratory rate and pulse rate will be 
performed as designated in the Schedule of Procedures/Assessments (Table 2). 
Documentation of vital signs will be included in the source documentation at the site. 
Significant findings at the Visit 1 (Week 0) will be recorded on the Medical History and 
Current Medical Conditions CRF.  
 
9.5.1.1.5 PRIOR AND CONCOMITANT MEDICATIONS 
The medications including drug name, dosage, administration route, within 24 weeks prior to 
the Visit 1 (Week 0) will be obtained. 
 


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9.5.1.1.6 
CONCOMITANT AED 
AED treatment including drug name, dosage, administration route, within 8 weeks prior to 
the Visit 1 (Week 0) will be obtained. 
 
9.5.1.2 
Efficacy Assessments 
Primary efficacy variable and secondary efficacy variables are based on seizure counts 
(frequency). Seizure frequency data will be collected in subject diaries by subjects or 
guardian/legally authorized representative during the study including the Titration Period and 
the Maintenance Period.  Baseline seizure frequency data during 8 weeks prior to the Visit 1 
(Week 0) is collected by subjects or guardian/legally authorized representative, 
retrospectively. The investigators or designees will be given standardized training on seizure 
identification to ensure that subjects will be educated in the same standardized fashion at 
each visit. Seizure frequency data in subject diaries will be reviewed with the investigator(s) 
at Visit 2, 3, 4 and 5.  
 
50% Responder rate 
The 50% responder rate is defined the proportion of subjects achieving at least 50% 
reduction in seizure frequency during the Maintenance Period relative to the Baseline. 
 
75% Responder rate 
The 75% responder rate is defined the proportion of subjects achieving at least 75% 
reduction in seizure frequency during the Maintenance Period relative to the Baseline. 
 
100% Responder rate (seizure free rate) 
The 100% responder rate, seizure free rate, is defined the proportion of subjects achieving 
100% reduction in seizure frequency during the Maintenance Period relative to the Baseline. 
 
The percent change in total seizure frequency in the Titration and Maintenance Period 
relative to the Baseline 
The Percentage change is defined the reduction rate in seizure frequency during the Titration 
Period and the Maintenance Period relative to the Baseline. 
 
50% responder rate in secondarily generalized tonic clonic seizures 
The 50% responder rate in secondarily generalized tonic clonic seizures is defined the 
proportion of subjects with secondarily generalized tonic clonic seizures achieving at least 
50% reduction in seizure frequency during the Maintenance Period relative to the Baseline. 
 
75% responder rate in secondarily generalized tonic clonic seizures 


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The 75% responder rate in secondarily generalized tonic clonic seizures is defined the 
proportion of subjects with secondarily generalized tonic clonic seizures achieving at least 
75% reduction in seizure frequency during the Maintenance Period relative to the Baseline. 
 
100% responder rate (seizure free rate) in secondarily generalized tonic clonic seizures 
The 100% responder rate, seizure free rate, in secondarily generalized tonic clonic seizures is 
defined the proportion of subjects with secondarily generalized tonic clonic seizures 
achieving 100% reduction in seizure frequency during the Maintenance Period relative to the 
Baseline. 
 
The percent change in secondarily generalized tonic clonic seizure frequency in the Titration 
and Maintenance Period relative to the Baseline 
The Percentage change in secondarily generalized tonic clonic seizures is defined the 
reduction rate in seizure frequency in subjects with secondarily generalized tonic clonic 
seizures during the Titration Period and the Maintenance Period relative to the Baseline. 
 
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
Not applicable.  
 
9.5.1.4 
Safety Assessments 
9.5.1.4.1 ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product. An AE does not necessarily have a causal 
relationship with the medicinal product. For this study, the study drug is perampanel.  
 
The criteria for identifying AEs in this study are: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE) 
• 
Any new disease or exacerbation of an existing disease 
• 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, electrocardiography (ECG) or X-ray) that results in symptoms, a change 
in treatment, or discontinuation of study drug 


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• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
 
All AEs observed during the study will be reported on the CRF. All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit. Subjects who fail screening primarily due to 
AE(s) must have the AE(s) leading to screen failure reported on the Screening Disposition 
CRF. SAEs will be collected for 28 days after the last dose. 
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE. It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE. Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE. Any laboratory abnormality considered 
to constitute an AE should be reported on the Adverse Event CRF.  
Every effort must be made by the investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
 
Assessing Severity of Adverse Events 
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF. The definitions are as follows: 
 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
 Incapacitating, with inability to work or to perform normal daily activity 
 
The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.4.2 for the definition of an SAE). 
 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment 
• 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 


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• 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question: 
 
Is there a reasonable possibility that the study drug caused the AE? 
 
(Amendment 01) 
1) Probable/Likely 
 
2) Possible 
 
3) None 
 
9.5.1.4.2 SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
A SAE is any untoward medical occurrence that at any dose: 
 
• 
Results in death 
• 
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs. Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 


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the above criteria. All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
 
• 
Hospitalizations for respite care  
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
• 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
• 
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry 
 
9.5.1.4.3 LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1. Subjects should be in a seated or supine position during blood 
collection. The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected. 
 
Table 1 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and WBC count  
Chemistry 
 
 Electrolytes 
Chloride, potassium, sodium  
 Liver function tests 
Alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, total bilirubin 
 Renal function tests 
Blood urea urea nitrogen, creatinine 
 Other 
Albumin, calcium, total cholesterol, glucose, phosphorus, total 
protein, triglycerides, uric acid 
Urinalysis 
glucose, ketones, occult blood, pH, protein,  specific gravity, WBCs 
RBC = red blood cell, WBC = white blood cell. 
 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.4.1) and the CRF Completion Guidelines. In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF. 
 


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9.5.1.4.4 VITAL SIGNS AND WEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure (BP) [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), weight (kg) and 
height (cm) will be obtained at the visits designated in the Schedule of Procedures/ 
Assessments (Table 2) by a validated method. Blood pressure and pulse will be measured 
after the subject has been sitting for at least 5 minutes. All BP measurements should be 
performed on the same arm, preferably by the same person.  
 
9.5.1.4.5 PREGNANCY TEST 
A urine or serum-hCG pregnancy test will be performed for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months during the 
Screening Period and/or at the Visit 1 (Week 0), Visit 5 (Week 36) and Follow-up Visit.  
 


 
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9.5.2 
Schedule of Procedures/Assessments  
9.5.2.1 
Schedule of Procedures/Assessments 
 
Table 2 
Schedule of Procedures/Assessments in Study E2007-M065-412 
Period 
Screening 
Period 
Titrationa 
Maintenanceb 
Discontinua-
tion 
Follow-
upb,c 
Un-
scheduledi 
Study Week(s) 
Week -8~0 
Week 0 
Week 6 
Week 12 
Week 24 
Week 36 
 
 
 
Study Day(s) 
Day -56~0 
Day 0 
Day 42 
Day 84 
Day 168 
Day 252 
 
 
 
Visit Number 
(Retrospec-
tively) 
1 
2 
3 
4 
5 
 
 
 
Procedure/Assessment 
 
 
 
 
 
 
 
 
 
Informed consent/assentd 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
Seizure type and frequency 
 
X 
 
 
 
 
 
 
 
Medical historye 
 
X 
 
 
 
 
 
 
 
Concomitant medications 
 
Xf 
X 
X 
X 
X 
X 
X 
X 
Concomitant AED 
 
Xg 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical laboratory 
evaluations 
 
X 
 
 
 
X 
X 
X 
 
Pregnancy test 
 
X 
 
 
 
X 
X 
X 
 
Adverse eventsh 
 
 
X 
X 
X 
X 
X 
X 
X 


 
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Table 2 
Schedule of Procedures/Assessments in Study E2007-M065-412 
Period 
Screening 
Period 
Titrationa 
Maintenanceb 
Discontinua-
tion 
Follow-
upb,c 
Un-
scheduledi 
Study Week(s) 
Week -8~0 
Week 0 
Week 6 
Week 12 
Week 24 
Week 36 
 
 
 
Study Day(s) 
Day -56~0 
Day 0 
Day 42 
Day 84 
Day 168 
Day 252 
 
 
 
Visit Number 
(Retrospec-
tively) 
1 
2 
3 
4 
5 
 
 
 
Procedure/Assessment 
 
 
 
 
 
 
 
 
 
Dispense the study drug 
 
X 
X 
X 
X 
 
X 
 
 
Return the study drug 
 
 
X 
X 
X 
X 
X 
X 
 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
 
Dispense subject diary 
 
X 
X 
X 
X 
 
X 
 
 
Return and review subject 
diary 
 
 
X 
X 
X 
X 
X 
X 
 
 
a: 
All visits to be done within ±5 days of the schedule. 
b: 
Visit to be done within ±7 days of the schedule. 
c: 
To be completed by subjects who are withdrawn from the study for any reason after Visit 1 (Week 0) and before Visit 5 (Week 36). When a 
taper is provided after discontinuation, it should be performed 4 weeks after the last dose. 
d: 
Informed consent/assent may be obtained prior to study start; it must be obtained prior to any study related procedures. 
e: 
All pertinent medical and surgical history within 5 years before Visit 1 (Week 0). 
f: 
Prior and concomitant medication(s) within 24 weeks before Visit 1 (Week 0). 
g: 
Prior and concomitant AED. 
h: 
Adverse events will be collected from the time subject starts to receive the study drug form through the last visit. Serious adverse events will 
be collected for 28 days after the subject’s last dose or last visit, whichever is longer. 
i: 
At the unscheduled visit, only the assessments that the investigator(s) judged the necessity based on the subject’s condition will be performed.


 
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9.5.2.2 
Description of Procedures/Assessments Schedule 
9.5.2.2.1 DEMOGRAPHIC/BASELINE ASSESSMENTS 
Visit 1 (Week 0, Day 0) 
Written informed consent is obtained from the subjects and/or legal guardian prior to study 
start. Once informed consent has been obtained, the following procedures and evaluations 
will be performed. 
 
 Review of inclusion/exclusion criteria for subject. 
 Diagnosis: epilepsy with partial onset seizures with or without secondarily 
generalized seizures according to ILAE’s Classification of Epileptic Seizures (1981) 
 Subject medical history: subject demographic information 
 Record prior and concomitant medication use over the past 24-week. 
 Record prior and concomitant AED use over the past 8-week. 
 
Only subjects who continue to meet all of the inclusion and none of the exclusion criteria are 
eligible to continue in the study and perform the following procedures and evaluations. 
 
 Vital signs (systolic and diastolic BP in sitting position, pulse), body temperature, , 
weight and height 
 Blood and urine samples for clinical laboratory evaluations and pregnancy testing 
(serum or urine, only females of childbearing potential) 
 Dispense study drug. 
 Dispense subject diary. 
 Schedule Visit 2. 
 
 
9.5.2.2.2 TREATMENT PERIOD ASSESSMENTS 
TITRATION PERIOD ASSESSMENTS 
Visit 2 (Week 6, Day 42±5) 
The following procedures and evaluations will be performed: 
 
 Vital signs (systolic and diastolic BP in sitting position, pulse), body temperature 
 Record all concomitant medication use. 
 Record concomitant AED use. 
 Record any AEs. 
 Collect unused study drug and record compliance. 
 Return and review subject diary. 


 
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 Dispense study drug. 
 Dispense subject diary. 
 Schedule Visit 3. 
 
Visit 3 (Week 12, Day 84±5) 
The following procedures and evaluations will be performed: 
 
 Vital signs (systolic and diastolic BP in sitting position, pulse), body temperature 
 Record all concomitant medication use. 
 Record concomitant AED use. 
 Record any AEs. 
 Collect unused study drug and record compliance. 
 Return and review subject diary. 
 Dispense study drug. 
 Dispense subject diary. 
 Schedule Visit 4. 
 
MAINTENANCE PERIOD ASSESSMENTS 
Visit 4 (Week 24, Day 168±7) 
The following procedures and evaluations will be performed: 
 
 Vital signs (systolic and diastolic BP in sitting position, pulse), body temperature 
 Record all concomitant medication use. 
 Record concomitant AED use. 
 Record any AEs. 
 Collect unused study drug and record compliance. 
 Return and review subject diary. 
 Dispense study drug. 
 Dispense subject diary. 
 Schedule Visit 5. 
 
Visit 5 (Week 36, Day 252±7) or Discontinuation 
The following procedures and evaluations will be performed: 
 
 Vital signs (systolic and diastolic BP in sitting position, pulse), body temperature, 
weight. 
 Blood and urine samples for clinical laboratory evaluations and pregnancy testing 
(serum, only females of childbearing potential) 
 Record all concomitant medication use. 
 Record concomitant AED use. 


 
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 Record any AEs. 
 Collect unused study drug and record compliance. 
 Return and review subject diary. 
 Dispense study drug. (Discontinuation Only) (Amendment 02) 
 Dispense subject diary. (Discontinuation Only) (Amendment 02) 
 
9.5.2.2.3 FOLLOW-UP ASSESSMENTS (ONLY WITHDRAWN SUBJECT) 
Follow-up Visit (4 weeks after the last dose±7) 
The following procedures and evaluations will be performed: 
 
 Vital signs (systolic and diastolic BP in sitting position, pulse), body temperature, 
weight. 
 Blood and urine samples for clinical laboratory evaluations and pregnancy testing 
(serum, only females of childbearing potential) 
 Record all concomitant medication use. 
 Record concomitant AED use. 
 Record any AEs. 
 Collect unused study drug and record compliance. (Amendment 02) 
 Return and review subject diary. (Amendment 02) 
 
9.5.2.2.4 UNSCHEDULED ASSESSMENTS 
Unscheduled Visit 
The following procedures and evaluations will be performed: 
 
 Vital signs (systolic and diastolic BP in sitting position, pulse), body temperature 
 Record all concomitant medication use. 
 Record concomitant AED use. 
 Record any AEs. 
 
9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of initial add-
on treatment for partial onset seizures with or without secondary generalized seizure. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety. 
 


 
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9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations 
9.5.4.1 
Reporting of Serious Adverse Events 
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 1 business day from the date the investigator becomes aware of the event. 
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit. All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  
Any SAE judged by the investigator to be related to the study treatment or any protocol-
required procedure should be reported to the sponsor regardless of the length of time that has 
passed since study completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File. 
For urgent safety issues call:  Designated CRO (C&R Research) contact number. 
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the ISF. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report. This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt. If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 
 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]). 


 
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Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy. The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the ISF. The Pregnancy 
Report Form must be used for reporting. All pregnancies must be followed to outcome. The 
outcome of the pregnancy must be reported as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study. 
 
9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol. 
Overdose, misuse, abuse, and medication error are defined as follows:  
 
Overdose 
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose  
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol 
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject.  
 
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF. 
 
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 


 
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specific time frames). For this reason, it is imperative that sites provide complete SAE 
information in the manner described above. 
 
9.5.4.5 
Breaking the Blind 
Not applicable 
 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance. The format of these reports will be dictated by the local and regional requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC. All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states. 
 
9.5.5 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason. All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 2). 
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject. A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.   
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, progression 
of disease, withdrawal of consent, pregnancy, study terminated by sponsor, or other. In 
addition to the primary reason, the subject may indicate 1 or more secondary reason(s) for 
discontinuation. Study disposition information will be collected on the Subject Disposition 
CRF. 
A subject removed from the study for any reason may not be replaced. 
 
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 
 


 
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9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines. Site audits will be 
made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, which 
is an independent function from the study team responsible for conduct of the study.  
   
9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements. As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF. The investigator or designee must sign the completed CRF 
to attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements. All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
 
9.7 
Statistical Methods 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released. Statistical analyses will be performed 
using SAS software or other validated statistical software as required. Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP). 
 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of study data are described in this section. Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock. 
 


 
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9.7.1.1 
Study Endpoints 
9.7.1.1.1 PRIMARY ENDPOINT 
50% responder rate in total seizures: 50% responders are defined as subjects who have at 
least 50% reduction in total seizure frequency during the Maintenance Period relative to the 
Baseline. 
 
9.7.1.1.2 SECONDARY ENDPOINTS 
- 
75% responder rate in total seizures 
- 
100% responder rate (seizure free rate) in total seizures 
- 
The percent change in total seizure frequency in the Titration and Maintenance Period 
relative to the Baseline 
- 
50% responder rate in secondarily generalized tonic clonic seizures 
- 
75% responder rate in secondarily generalized tonic clonic seizures 
- 
100% responder rate (seizure free rate) in secondarily generalized tonic clonic seizures 
- 
The percent change in  secondarily generalized tonic clonic seizure frequency in the 
Titration and Maintenance Period relative to the Baseline 
 
9.7.1.1.3 EXPLORATORY ENDPOINT  
Not applicable. 
 
9.7.1.2 
Definitions of Analysis Sets 
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment. 
 
The Full Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 postdose primary efficacy measurement.   
 
The Per Protocol Analysis Set is the group of subjects who sufficiently complied with the 
protocol.  Details of the evaluability criteria will be determined before database lock and will 
be specified in the SAP. 
 
9.7.1.3 
Subject Disposition 
The disposition of all subjects will be summarized. Subject disposition tables will include the 
number (percent) of subjects who will be: 
 included in each analysis populations; 


 
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 discontinued from the study early, summarized by reason for discontinuation. 
The number of subjects screened and the number (percent) who fail screening will 
also be summarized. 
 
9.7.1.4 
Demographic/Baseline Characteristics 
Demographic and other baseline characteristics (eg. age, sex, etc.) for Full Analysis Set will 
be summarized using descriptive statistics. Continuous variables will be summarized in mean, 
SD, median, minimum, maximum and categorical variables will be summarized in number 
and percentages of subjects.  
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the Full Analysis Set, Anatomical Therapeutic Chemical (ATC) class. Prior 
medication is defined as any medication that stopped before the first dose of study drug. 
Concomitant medication is defined as any medication that (1) started before the first dose of 
study drug and was continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the study drug until the last dose of study drug.  
 
9.7.1.5 
Efficacy Analyses 
The efficacy analysis will be performed on the Full Analysis Set. The analysis performed on 
Per Protocol Analysis Set will be supportive. This is a single-arm study having no reference 
arm. Therefore, formal hypothetical inferences are not necessary and only descriptive 
statistics will be given. Continuous variables will be summarized with mean, standard 
deviation, median, minimum and maximum. Categorical variables will be summarized by 
number and percentages of subjects. Seizure frequency will be based on number of seizures 
per 28 days, calculated as the number of seizures over the entire time interval divided by the 
number of days in the interval and multiplied by 28. (Amendment 02) 
 
9.7.1.5.1 PRIMARY EFFICACY ANALYSIS 
For 50% Responder rate in total seizures, the following will be provided: 
- 
Number of 50% responders 
- 
50% responder rate and its 95% confidence interval (CI) 
 
9.7.1.5.2 SECONDARY EFFICACY ANALYSES 
For 75% Responder rate in total seizures, the following will be provided: 
- 
Number of 75% responders 
- 
75% responder rate and its 95% CI 
 


 
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For 100% Responder rate (seizure free) in total seizures, the following will be provided: 
- 
Number of 100% responders 
- 
100% responder rate and its 95% CI 
 
For total seizure frequency and the percent change in total seizure frequency in the Titration 
and the Maintenance Period relative to the Baseline, the following will be provided: 
- 
Mean, standard deviation, median, minimum, maximum and 95% CI 
 
For 50% Responder rate in secondarily generalized tonic clonic seizures, the following will 
be provided: 
- 
Number of 50% responders 
- 
50% responder rate and its 95% CI 
 
For 75% Responder rate in secondarily generalized tonic clonic seizures, the following will 
be provided: 
- 
Number of 75% responders 
- 
75% responder rate and its 95% CI 
 
For 100% Responder rate (seizure free) in secondarily generalized tonic clonic seizures, the 
following will be provided: 
- 
Number of 100% responders 
- 
100% responder rate and its 95% CI 
 
The percent change in secondarily generalized tonic clonic seizure frequency in the Titration 
and Maintenance Period relative to the Baseline: 
- 
Mean, standard deviation, median, minimum, maximum and 95% CI 
 
9.7.1.5.3 EXPLORATORY EFFICACY ANALYSES 
Not applicable. 
 
9.7.1.6 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
Not applicable. 
 
9.7.1.6.1 PHARMACOKINETIC ANALYSES 
Not applicable. 
 


 
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9.7.1.6.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable. 
 
9.7.1.7 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  
Safety variables include TEAEs, clinical laboratory parameters, vital signs results. 
 
9.7.1.7.1 EXTENT OF EXPOSURE 
The extent of exposure to the study drug during the Titration and Maintenance Period will be 
summarized descriptively.  
 
9.7.1.7.2 ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (most recent version) lower level 
term (LLT) closest to the verbatim term. The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or  
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT. A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT. The number 
(percentage) of subjects with TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe). 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]). 
 


 
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9.7.1.7.3 LABORATORY VALUES 
For all quantitative parameters listed in Section 9.5.1.4.3 Laboratory Measurements, the 
actual value and the change from baseline to each postbaseline visit and to the end of 
treatment (defined as the last on-treatment value) will be summarized by visit using 
descriptive statistics. Qualitative parameters listed in Section 9.5.1.4.3 will be summarized 
using frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables. Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period. 
 
9.7.1.7.4 VITAL SIGNS AND WEIGHT MEASUREMENTS 
Descriptive statistics for vital signs parameters, weight and changes from baseline will be 
presented by visit. 
 
9.7.2 
Determination of Sample Size 
This study will be evaluated for the efficacy of adjunctive perampanel for partial-onset 
seizures. Primary endpoint is 50% responder rate in total seizures. 
There is no statistical hypothesis to be tested in this study and 105 subjects is set to keep 94 
subjects for the primary analysis with approximately 10% drop-out rate from the view point 
of feasibility. 
When 94 subjects for the primary analysis is kept and 50% responder rates can be assumed as 
35.3% in test group and 19.3% as reference value according to Bernhard J. Steinhoff et al.1, 
lower limit of 95% confidence interval of 50% responder rate will be more than 19.3% with 
more than 90% power.    
 
𝑛=
ቀZα 2
ൗ+ Zβቁ
2
 [pT(1 −pT)]
(pT −pR)2
 
= (1.96 + 1.282)2 [0.353(1 −0.353)]
(0.353 −0.193)2
 


 
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= 93.78 ≈94 
 
 
Zα/2 : Type I error (0.05/2) 
Zβ  : Type II error (0.1) 
pT  : 50% responder rate in test group 
pR  : reference value 
 
Considering a drop-out rate of 10%, total sample size require 105. 
 
[ Reference ] 
Bernhard J. Steinhoffet al., Efﬁcacy and safety of adjunctive perampanel for the treatmentof 
refractory partial seizures: A pooled analysisof three phase III studies, Epilepsia, 54(8):1481–
1489, 2013doi: 10.1111/epi.12212 
9.7.3 
Interim Analysis 
No interim analysis is planned for this study. 
 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable  
 
10 REFERENCE LIST 
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in brain. J Neurosci Res. 2007;85(15):3347-58. 
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epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic 
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AMPA receptor noncompetitive antagonism. Neuron. 2005;48(2):279-88. 
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an AMPA-subtype glutamate receptor. Nature. 2009;462(7274):745-56.  
29. Abstracts from the 2009 Annual Meeting of the American Epilepsy Society. December 
4-8, 2009. Boston, Massachusetts, USA. Epilepsia. 2009;50 Suppl 11:1-502. 
30. FDA Approved labeling text. Prescribing information: Fycompa® (perampanel) tablets, 
for oral use, CIII. NDA 202834/S-005. Jun 2015. 
31. Krauss GL, Bar M, Biton V, Klapper JA, Rektor I, et al. Tolerability and safety of 
perampanel: two randomized dose-escalation studies. Acta Neurol Scand. 2012;125(1):8-
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32. French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, et al. Evaluation of 
adjunctive perampanel in patients with refractory partial-onset seizures: results of 
randomized global phase III study 305. Epilepsia. 2013;54(1):117-25. 
33. Krauss GL, Serratosa JM, Villanueva V, Endziniene M, Hong Z, et al. Randomized 
phase III study 306: adjunctive perampanel for refractory partial-onset seizures. 
Neurology. 2012;78(18):1408-15. [Abstract] 
34. Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, et al. Efficacy and 
safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled 
analysis of three phase III studies. Epilepsia. 2013;54(8):1481-9.  
35. Rektor I, Krauss GL, Bar M, Biton V, Klapper JA, et al. Perampanel Study 207: long-
term open-label evaluation in patients with epilepsy. Acta Neurol Scand. 
2012;126(4):263-9.  
36. Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, et al. Long-term safety of 
perampanel and seizure outcomes in refractory partial-onset seizures and secondarily 
generalized seizures: results from phase III extension study 307. Epilepsia. 
2014;55(7):1058-68. 
37. Kennedy GM, Lhatoo SD. CNS adverse events associated with antiepileptic drugs. CNS 
Drugs. 2008;22(9):739-60. 
38. Rugg-Gunn F. Adverse effects and safety profile of perampanel: a review of pooled data. 
Epilepsia. 2014;55 Suppl 1:13-5.  
39. Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, et al. Perampanel, a 


 
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selective, 
noncompetitive 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic 
acid 
receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim 
results from phase III, extension study 307. Epilepsia. 2013;54(1):126-34. 
40. Zadeh WW, Escartin A, Byrnes W, Tennigkeit F, Borghs S, et al. Efficacy and safety of 
lacosamide as first add-on or later adjunctive treatment for uncontrolled partial-onset 
seizures: A multicentre open-label trial. Seizure. 2015;31:72-9.  
41. Guideline on clinical investigation of medicinal products in the treatment of epileptic 
disorders. European medicines Agency. CHMP/EWP/566/98 Rev.2/Corr. London. Jul 
2010. 
 
 
11 PROCEDURES 
AND 
INSTRUCTIONS 
(ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation. Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs. These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study. If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately. The sponsor must notify the health or 
regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes. 
 
11.2 Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5). 
 


 
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11.3 Monitoring Procedures 
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits. Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan. The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements. The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB/IEC review. 
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, 
the following: 
• 
Clinic, office, or hospital charts 
• 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
• 
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, 
rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of how 
these images are stored, including microfiche and photographic negatives 
• 
Pain, quality of life, or medical history questionnaires completed by subjects 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks) 
• 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
• 
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source 
 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel. All data on the CRF must reflect the corresponding source document, except when 
a section of the CRF itself is used as the source document. Any correction to entries made on 
the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 


 
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original data are not obscured. Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF. The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.  
 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, ICFs, and IRB/IEC correspondence). The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. 
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of the period of retaining the study records. (Amendment 01) 
 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations. If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
 
11.8 Handling of Study Drug 
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 


 
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review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or, when approval is given by the sponsor, will destroy supplies and 
containers at the site. 
 
11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate. 
 
11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO. 
 


 
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11.11 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so dictate.  
If the investigator terminates or suspends a study without prior agreement of the sponsor, the 
investigator should inform the institution where applicable, and the investigator/institution 
should promptly inform the sponsor and the IRB/IEC and provide the sponsor and the 
IRB/IEC with a detailed written explanation of the termination or suspension.  Study records 
must be retained as noted above. 
 
11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 
 
12 APPENDICES 
Appendix 1 
Expected Adverse Events and Precautions 
The up-to-date label of Fycompa®  (Perampanel) in Korea is included in this section. 
 


 
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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: E2007-M065-412 
Study Protocol Title: 
Multicenter, open-label trial, evaluating the efficacy and safety 
of perampanel added to monotherapy in patients with partial 
onset seizures with or without secondary generalized seizures 
Investigational Product 
Name: 
E2007/Fycompa® (Perampanel) 
 
SIGNATURES 
 
 
Authors: 
 
 
 
Study Director (always include) 
 
 
 
<Name, degree(s)> 
<function> 
<title, department> 
<legal name of sponsoring company> 
 
Date 
 
Designated Medical Monitor (include only if the Study 
Director is not medically qualified) 
 
 
 
<Name, degree(s)> 
<function> 
<title, department> 
<legal name of sponsoring company> 
 
Date 
 
Clinical pharmacologist (include only if PK samples are 
analyzed) 
 
 
 
<Name, degree(s)> 
<function> 
<title, department> 
<legal name of sponsoring company> 
 
Date 
 
Primary statistician (always include) 
 
 
 
<Name, degree(s)> 
<function> 
<title, department> 
<legal name of sponsoring company> 
 
Date 
 


 
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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E2007-M065-412 
Study Protocol Title: 
Multicenter, open-label trial, evaluating the efficacy and safety 
of perampanel added to monotherapy in patients with partial 
onset seizures with or without secondary generalized seizures 
Investigational Product 
Name: 
E2007/Fycompa® (Perampanel) 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
Medical Institution 
 
 
  
  
Investigator 
 Signature 
 Date 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Title
Multicenter, open-label trial evaluating the efficacy and safety of 
perampanel added to monotherapy in patients with partial onset seizures 
with or without secondary generalized seizures 
 
Protocol No./ Version
E2007-M065-412 / v2.1 
Sponsor 
Eisai Korea Inc. 
Version No. (Version Date)  
V1.0 (15-Jun-2018) 
Written By 
 / Biostatistician 
 
C&R Research 
 
PPD


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Signature page (C&R) 
 
Prepared by: 
 
 
 
 
          
Name/ Role 
Signature 
Date (DD-MMM-YYYY) 
 
 
 
Reviewed by: 
 
 
 
 
     
Name/ Role 
Signature 
Date (DD-MMM-YYYY) 
 
 
 
Approved by: 
 
 
 
 
    
Name/ Role 
Signature 
Date (DD-MMM-YYYY) 
 
 


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Signature page (Sponsor) 
 
Reviewed by: 
 
 
 
 
     
Name/ Role 
Signature 
Date (DD-MMM-YYYY) 
 
 
 
Approved by: 
 
 
 
 
    
Name/ Role 
Signature 
Date (DD-MMM-YYYY) 
 
 


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Version Information (Document revision history) 
Version 
Effective Date 
Prepared by Name
Details 
1.0 
Sponsor’s approval date
 
First version 
 
 
 
PPD


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Abbreviation 
Term 
Definition 
ADR 
Adverse Drug Reaction 
AE 
Adverse Events 
ATC code 
Anatomical Therapeutic Chemical code 
FAS 
Full Analysis Set 
MedDRA 
Medical Dictionary for Regulatory Activities 
PPS 
Per-Protocol Set 
PT  
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
WHODD 
WHO Drug Dictionary 


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Contents 
 
Signature page (Sponsor).............................................................................................................. 3 
Version Information (Document revision history) ........................................................................ 4 
Abbreviation ................................................................................................................................... 5 
1. Study Design ............................................................................................................................. 8 
2. Study Objectives ....................................................................................................................... 9 
3. Justification of Sample Size ...................................................................................................... 9 
4. Efficacy and Safety Endpoints ................................................................................................ 10 
4.1 
Efficacy Endpoints ........................................................................................................ 10 
4.1.1 
Primary Efficacy Endpoint................................................................................. 10 
4.1.2 
Secondary Efficacy Endpoints .......................................................................... 10 
4.2 
Safety Endpoints .......................................................................................................... 11 
5. Analysis Sets............................................................................................................................ 11 
5.1 
Efficacy Analysis Set ..................................................................................................... 11 
5.2 
Safety Analysis Set ....................................................................................................... 11 
6. Statistical Analysis Method ..................................................................................................... 12 
6.1 
Analysis Program.......................................................................................................... 12 
6.2 
General Principles of Result Analysis........................................................................... 12 
6.3 
Handling of Withdrawal and Missing Data ................................................................. 12 
6.4 
Adjustment for covariate ............................................................................................. 12 
6.5 
Multiple Comparison or Multiplicity of Testing .......................................................... 12 
6.6 
Interim Analysis ............................................................................................................ 12 
6.7 
Sensitivity Analysis ....................................................................................................... 12 
6.8 
Study Participation ....................................................................................................... 13 
6.8.1 
Subject Disposition ........................................................................................... 13 
6.8.2 
Subject Disposition by Study Site .................................................................... 13 
6.8.3 
Protocol Deviation ............................................................................................ 13 
6.8.4 
Analysis Sets ..................................................................................................... 13 
6.9 
Demographic Information ........................................................................................... 13 
6.10 
Treatment Compliance ............................................................................................... 15 
6.11 
Efficacy Analysis ......................................................................................................... 15 
6.11.1 
Analysis of primary efficacy endpoint ............................................................. 16 
6.11.2 
Analysis of secondary efficacy endpoints ........................................................ 16 


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6.12 
Safety Analysis ............................................................................................................ 18 
6.12.1 
Extent or Exposure ............................................................................................ 18 
6.12.2 
Adverse Events.................................................................................................. 18 
6.12.3 
Laboratory Tests ............................................................................................... 19 
6.12.4 
Vital Signs ......................................................................................................... 19 
6.12.5 
Physical Measurement (Body Weight) ............................................................. 19 
7. Plan for Revision of Analysis Method .................................................................................... 19 
8. TLF shell .................................................................................................................................. 19 
9. Roles and Responsibilities ...................................................................................................... 22 
10. Applied SOPs .......................................................................................................................... 22 
11. Applied SOP SDs .................................................................................................................... 22 
 


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1. 
Study Design  
This is a multicenter, open label, single arm, for therapeutic use, study.  
 
Prior to the study initiation, approval from IRB of each study site as well as written contract is 
required. Prior to the study participation, patients should receive sufficient explanation about the 
study and provide written consent regarding the access to and use of personal and medical 
information. After the consent process, subjects who meet all of the inclusion criteria and none 
of the exclusion criteria will receive the investigational product (Fycompa film-coated tablet). 
Information on baseline seizure count (frequency) will be collected retrospectively by the subject 
or guardian. This study consists of titration period (12 weeks) and maintenance period (24 weeks).  
 
[Titration period (12 weeks)] 
Subjects will initiate perampanel at 2 mg/day, which can be increased up to 12 mg by increments 
of 2 mg no more frequently than at 2-week interval according to the investigator’s judgment. 
The dose can be maintained or reduced based on the subject’s clinical response and tolerability 
according to the investigator’s judgment. Subjects who cannot tolerate 4 mg/day will be 
withdrawn from the study. Subjects who are taking concomitant drugs that shorten the half-life 
of perampanel (phenytoin, carbamazepine, oxcarbazepine, etc.) will titrate the dose by increments 
of 2 mg/day no more frequently than at 1-week interval. Adjusting the type or dose of 
concomitant anti-epileptic drug is not allowed during this period. 
 
[Maintenance period (24 weeks)] 
Throughout the maintenance period, subjects will maintain the dose administered at the end of 
the titration period. However, the dose can be increased to maximum 12 mg/day or reduced to 
minimum 4 mg/day based on the subject’s clinical response and tolerability according to the 


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investigator’s judgment. Subjects who reduce the dose during the maintenance period can 
increase the dose once tolerability is improved. Subjects who cannot tolerate 4 mg/day will be 
withdrawn from the study. Adjusting the type or dose of concomitant anti-epileptic drug is not 
allowed during this period. 
 
In case of withdrawal, the dose will be tapered down and follow-up visit will take place 4 weeks 
after the last dose.  
 
Subjects will visit the site for Visit 1 (Week 0), Visit 2 (Week 6), Visit 3 (Week 12), Visit 4 (Week 
24) and Visit 5 (Week 36).  
 
2. 
Study Objectives  
2.1. Primary Objective 
To evaluate the efficacy of perampanel added to monotherapy in patients with partial onset 
seizures with or without secondary generalization as measured by 50% responder rate 
 
2.2. Secondary objectives 
1) 
To evaluate the safety of perampanel added to monotherapy in patients with partial onset 
seizures with or without secondary generalization 
2) 
To evaluate efficacy of perampanel added to monotherapy in patients with secondary 
generalized tonic clonic seizure 
 
3. 
Justification of Sample Size  
This study determines the efficacy and safety of perampanel as add-on therapy in patients with 
partial onset seizure. Primary efficacy endpoint is the 50% responder rate for partial onset seizure 
with or without secondary generalization. According to Bernhard J. Steinhoff et al.34, the 50% 
responder rate was 35.3% in the test group and 19.3% in the control group. To ensure 90% 
power at two-sided significance level of 5%, 94 subjects are required. Considering 10% drop-out 
rate, a total of 105 subjects are required. 
 
𝑛=
ቀZ஑ଶ
ൗ+ Zஒቁ
ଶ
 [p୘(1 −p୘)]
(p୘−pୖ)ଶ
 


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= (1.96 + 1.282)ଶ [0.353(1 −0.353)]
(0.353 −0.193)ଶ
 
 
= 93.77 ≈94 
 
Zα/2 : Type I error (0.05/2) 
Zβ  : Type II error (0.1) 
pT  : 50% responder rate in the test group 
pR  : Reference value 
 
4. 
Efficacy and Safety Endpoints 
4.1 
Efficacy Endpoints 
4.1.1 
Primary Efficacy Endpoint 
50% responder rate for partial onset seizures with or without secondary generalization: the 
proportion of subjects achieving at least 50% reduction in the frequency of partial onset seizures 
with or without secondary generalization during the maintenance period compared to baseline 
 
4.1.2 
Secondary Efficacy Endpoints 
1) 
75% responder rate for partial onset seizures with or without secondary generalization 
2) 
100% responder (seizure free) rate for partial onset seizures with or without secondary 
generalization  
3) 
Percent change from baseline in the frequency of partial onset seizures with or without 
secondary generalization during the titration period and maintenance period 
4) 
50% responder rate for secondary generalized tonic-clonic seizure 
5) 
75% responder rate for secondary generalized tonic-clonic seizure 
6) 
100% responder (seizure free) rate for secondary generalized tonic-clonic seizure 
7) 
Percent change from baseline in the frequency of secondary generalized tonic-clonic seizure 
during the titration period and maintenance period 
* 
Secondary generalized tonic-clonic seizure is collected as ‘complex partial onset seizure with 
secondary generalization’ 
 


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4.2 
Safety Endpoints 
1) 
Adverse events 
2) 
Laboratory tests  
3) 
Vital signs 
4) 
Physical measurements  
 
5. 
Analysis Sets 
5.1 
Efficacy Analysis Set 
Efficacy is analyzed primarily in the Full Analysis Set (FAS), and secondarily in the Per-Protocol 
Set (PPS). Safety is analyzed in the Safety Analysis Set. 
 
 
FAS: subjects who received at least one dose of investigational product and were assessed 
for primary efficacy at least once during the maintenance period (Week 12 - 5 days ~ Week 
36 + 7 days). 
 
 
PPS: subjects in FAS who completed the study per protocol without major violation. 
Subjects who meet any of the following conditions are excluded from PPS.  
1) 
Deviation from selection criteria  
2) 
Use of prohibited concomitant medication or therapy 
3) 
Withdrawal 
4) 
Deviation from treatment compliance 
5) 
Other deviation considered as major protocol violation 
 
5.2 
Safety Analysis Set 
Safety is analyzed in the Safety Analysis Set. 
 
 
Safety Analysis Set: subjects who received at least one dose of investigational product and 
were assessed for safety at least once. 
 


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6. 
Statistical Analysis Method  
6.1 
Analysis Program 
Statistical analysis will use SAS® Version 9.4 (SAS Institute, Cary, NC, USA) or subsequent version. 
 
6.2 
General Principles of Result Analysis 
All analyses will be descriptive. Continuous variables will be presented using descriptive statistics 
(number of subjects, mean, standard deviation, median, minimum and maximum), while 
categorical variables will be presented using frequency and percentage. In addition, with regard 
to efficacy, 95% confidence interval (t-distribution) for the mean will be presented for continuous 
variables, while 95% exact confidence interval will be presented for categorical variables. Values 
with a decimal point, such as mean, standard deviation, and percentage, will be rounded to two 
decimal places.  
 
6.3 
Handling of Withdrawal and Missing Data 
All evaluation data will be analyzed as is without imputation for missing data.   
 
In the analysis of duration of disease, missing month of the date of epilepsy diagnosis will be 
substituted with June and missing day will be substituted with 15. If the year is missing, the date 
of epilepsy diagnosis will be handled as missing data. If imputation results in negative duration 
of disease, the duration of disease will be 0.  
 
6.4 
Adjustment for covariate 
Adjustment for covariate is not planned. 
 
6.5 
Multiple Comparison or Multiplicity of Testing 
Multiple comparison or analysis of multiplicity of testing is not planned. 
 
6.6 
Interim Analysis 
Interim analysis is not planned. 
 
6.7 
Sensitivity Analysis 
Sensitivity analysis is not planned. 
 


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6.8 
Study Participation 
6.8.1 
Subject Disposition  
Subjects who completed the study and subjects who discontinued the study are presented using 
frequency and percentage. For those who discontinued the study, reason for discontinuation is 
presented using frequency and percentage. 
 
6.8.2 
Subject Disposition by Study Site 
Subjects who completed the study and subjects who discontinued the study are presented by 
study site using frequency and percentage. 
 
6.8.3 
Protocol Deviation 
For subjects with protocol deviation, excluding those who discontinued the study, reason for 
deviation is presented using frequency and percentage. 
 
6.8.4 
Analysis Sets  
Number of subjects included in the Safety Analysis Set, FAS, and PPS is presented. Reason for 
exclusion from the data set is presented using frequency and percentage. 
 
6.9 
Demographic Information 
Demographic and baseline disease characteristics, past/current disease, previous/concomitant 
medication, previous/concomitant medication (anti-epileptic drug), and concomitant non-
pharmacological therapy at the time of enrollment are analyzed in the FAS. 
 
 
Demographic characteristics   
Continuous data (age, height, body weight, BMI) is presented using descriptive statistics 
(number of subjects, mean, standard deviation, median (minimum, maximum)), and categorical 
data (age group (<65 years or ≥65 years), sex) is presented using frequency and percentage.  
 
BMI (kg/m2) = body weight (kg) / height (m)2 
 
 
Baseline disease characteristics (epilepsy diagnosis: duration of disease, ILAE 
classification, cause, seizure type and frequency: partial-onset seizure with or without 
secondary generalization, simple partial seizure with motor involvement, complex 
partial seizure, complex partial seizure with secondary generalization, other seizures)  


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Continuous data (duration of disease, partial-onset seizure with or without secondary 
generalization, simple partial seizure with motor involvement, complex partial seizure, complex 
partial seizure with secondary generalization, other seizures) is presented using descriptive 
statistics (number of subjects, mean, standard deviation, median (minimum, maximum)); for 
seizure type and frequency, 1st and 3rd quartiles are presented as well. Categorical data (ILAE 
classification, cause) is presented using frequency and percentage. 
 
Duration of disease (years) = (date of signing the consent form – date of initial 
diagnosis) / 365.25 
 
Seizure frequency = (number of seizures / (date of Visit 1 – date of 8 weeks prior to 
Visit 1)) x 28 
  
 
Past and Current Medical History  
Diseases/procedures in past/current medical history are coded using SOC (System Organ Class) 
and PT (Preferred Term) of MedDRA (21.0 version). Represented codes are presented using 
frequency, percentage, and count.  
 
Past medical history is defined as medical history ‘not ongoing’ at the time of visit, while current 
medical history is defined as medical history ‘ongoing’ at the time of visit. 
 
 
Previous and Concomitant Medication   
Previous and concomitant medications are coded using 1st level (Anatomical main group) and 
4th level (Chemical subgroup) of ATC classification system (2018 version). Represented codes are 
presented using frequency, percentage, and count. 
 
Previous medications are defined as those taken before the study treatment, while concomitant 
medications are defined as those taken after the study treatment. Any medication for which the 
date of last dose is ‘UK’ (thus, it is not known whether the drug was administered before or after 
the study treatment) is included in both previous and concomitant medications.  
 
 
Previous and Concomitant Medications (anti-epileptic drugs) 
Previous and concomitant medications (anti-epileptic drugs) are coded using 4st level (Chemical 
subgroup) and 5nd level (Chemical substance) of ATC classification system (2018 version). 


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Represented codes are presented using frequency, percentage, and count. 
 
Previous medications are defined as those taken before the study treatment, while concomitant 
medications are defined as those taken after the study treatment. Any medication for which the 
date of last dose is ‘UK’ (thus, it is not known whether the drug was administered before or after 
the study treatment) is included in both previous and concomitant medications. 
 
 Concomitant Non-Pharmacological Therapy 
Concomitant non-pharmacological therapies are coded using SOC (System Organ Class) and 
PT (Preferred Term) of MedDRA (21.0 version). Represented codes are presented using 
frequency, percentage, and count. 
 
6.10 Treatment Compliance 
Treatment compliance during the study period is calculated as follows, and presented using 
descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and 
maximum).   
 
Treatment compliance (%) = 
Actual number of administration days during the 
study period 
 100 
Expected number of administration days during the 
study period 
 
6.11 Efficacy Analysis 
In the efficacy analyses, seizure frequency is calculated as follows.  
 
Seizure frequency during the screening period = (number of seizure / (date of Visit 1 – 
date of 8 weeks prior to Visit 1)) x 28 
 
Seizure frequency during the titration period = (number of seizure / (date of end of Visit 
3 or date of withdrawal during the titration period – date of start of Visit 2)) x 28 
 
Seizure frequency during the maintenance period = (number of seizure / (date of end of 
Visit 5 or date of withdrawal during the maintenance period – date of start of Visit 4)) x 
28 
 


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6.11.1 Analysis of primary efficacy endpoint 
50% responder rate for partial onset seizure with or without secondary generalization 
Seizure frequency during the screening period and seizure frequency during the maintenance 
period in 50% responders, defined as subjects achieving at least 50% reduction in the frequency 
of partial onset seizures with or without secondary generalization during the maintenance period 
compared to baseline, are presented using descriptive statistics (number of subjects, mean, 
standard deviation, median (minimum, maximum), 1st quartile, and 3rd quartile), rate, and 95% 
CI. Seizure frequency is calculated as follows.  
 
6.11.2 Analysis of secondary efficacy endpoints 
1) 
75% responder rate for partial onset seizure with or without secondary generalization 
Seizure frequency during the screening period and seizure frequency during the maintenance 
period in 75% responders, defined as subjects achieving at least 75% reduction in the frequency 
of partial onset seizures with or without secondary generalization during the maintenance period 
compared to baseline, are presented using descriptive statistics (number of subjects, mean, 
standard deviation, median (minimum, maximum), 1st quartile, and 3rd quartile), rate, and 95% 
CI. Seizure frequency is calculated as follows. 
 
2) 
100% responder (seizure-free) rate for partial onset seizure with or without secondary 
generalization 
Seizure frequency during the screening period and seizure frequency during the maintenance 
period in 100% responders (seizure-free subjects), defined as subjects achieving 100% reduction 
in the frequency of partial onset seizures with or without secondary generalization during the 
maintenance period compared to baseline, are presented using descriptive statistics (number of 
subjects, mean, standard deviation, median (minimum, maximum), 1st quartile, and 3rd quartile), 
rate, and 95% CI. Seizure frequency is calculated as follows. 
 
3) 
Percent change from baseline in the frequency of partial onset seizure with or without 
secondary generalization during the titration period and maintenance period  
Frequency of partial onset seizure with or without secondary generalization during the screening 
period, titration period, and maintenance period is presented using descriptive statistics (number 
of subjects, mean, standard deviation, median (minimum, maximum), 1st quartile, and 3rd quartile). 
Also, percent change in the frequency of partial onset seizure with or without secondary 
generalization during the titration period and maintenance period compared to the screening 


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period is calculated and presented using descriptive statistics (number of subjects, mean, 
standard deviation, median (minimum, maximum), 1st quartile, and 3rd quartile) along with 
corresponding 95% CI. Seizure frequency is calculated as follows. 
 
4) 
50% responder rate for secondary generalized tonic-clonic seizure 
Seizure frequency during the screening period and seizure frequency during the maintenance 
period in 50% responders, defined as subjects achieving at least 50% reduction in the frequency 
of secondary generalized tonic-clonic seizure during the maintenance period compared to 
baseline, are presented using descriptive statistics (number of subjects, mean, standard deviation, 
median (minimum, maximum), 1st quartile, and 3rd quartile), rate, and 95% CI. Seizure frequency 
is calculated as follows. 
 
5) 
75% responder rate for secondary generalized tonic-clonic seizure 
Seizure frequency during the screening period and seizure frequency during the maintenance 
period in 75% responders, defined as subjects achieving at least 75% reduction in the frequency 
of secondary generalized tonic-clonic seizure during the maintenance period compared to 
baseline, are presented using descriptive statistics (number of subjects, mean, standard deviation, 
median (minimum, maximum), 1st quartile, and 3rd quartile), rate, and 95% CI. Seizure frequency 
is calculated as follows. 
 
6) 
100% responder (seizure free) rate for secondary generalized tonic-clonic seizure 
Seizure frequency during the screening period and seizure frequency during the maintenance 
period in 100% responders (seizure-free subjects), defined as subjects achieving 100% reduction 
in the frequency of secondary generalized tonic-clonic seizure during the maintenance period 
compared to baseline, are presented using descriptive statistics (number of subjects, mean, 
standard deviation, median (minimum, maximum), 1st quartile, and 3rd quartile), rate, and 95% 
CI. Seizure frequency is calculated as follows. 
 
7) 
Percent change from baseline in the frequency of secondary generalized tonic-clonic seizure 
during the titration period and maintenance period 
Frequency of secondary generalized tonic-clonic seizure during the screening period, titration 
period, and maintenance period is presented using descriptive statistics (number of subjects, 
mean, standard deviation, median (minimum, maximum), 1st quartile, and 3rd quartile). Also, 
percent change in the frequency of secondary generalized tonic-clonic seizure during the 


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titration period and maintenance period compared to the screening period is calculated and 
presented using descriptive statistics (number of subjects, mean, standard deviation, median 
(minimum, maximum), 1st quartile, and 3rd quartile) along with corresponding 95% CI. Seizure 
frequency is calculated as follows. 
 
6.12 Safety Analysis 
6.12.1 Extent of Exposure  
With regard to extent of exposure during the study period, duration of treatment and total dose 
in the titration period and maintenance period are calculated as follows and presented using 
descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and 
maximum).   
Duration of treatment in the titration period (days)
= date of last dose  −date of first dose + 1 
Duration of treatment in the maintenance period (days)
= date of last dose – date of first dose + 1 
 Total dose (mg) = sum of doses administered (daily dose x number of dosing days) 
 
6.12.2 Adverse Events 
Treatment-emergent adverse events (TEAEs) were analyzed (TEAEs refer to adverse events that 
were absent before study treatment and emerged after study treatment, or adverse events that 
were present before study treatment and worsened after study treatment). Subjects who 
experienced more than one TEAE are counted once. 
 
ADRs are related adverse events considered as probably related or possibly related by the 
investigator, for which causal relationship to the investigational product cannot be ruled out. 
Those considered as not related by the investigator are defined as unrelated adverse events.   
 
Incidence of TEAEs, ADRs, SAEs, and AEs leading to treatment discontinuation is presented using 
frequency and percentage along with 95% CI.  
 
AEs, ADRs, SAEs, and AEs leading to treatment discontinuation are coded using SOC (System 
Organ Class) and PT (Preferred Term) of MedDRA and analyzed by causality and severity. 
Represented codes are presented using the number of subjects and incidence. Listing will be 


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provided for SAEs. 
 
6.12.3 Laboratory Tests 
For laboratory tests that are continuous variables, results at baseline, Week 36 (Visit 5), end-of-
study visit, and follow-up as well as the change from baseline to the last dose of study treatment 
are presented using descriptive statistics (number of subjects, mean, standard deviation, median, 
minimum, and maximum). Categorical variables are classified as ‘Normal’ or ‘Abnormal’ and the 
change from baseline to the last dose of study treatment is summarized using a shift table to 
present the frequency and percentage. Percentage is based on subjects who have results both 
at baseline and at subsequent timepoints. 
In addition, laboratory test results will be classified into low (L), normal (N), or high (H) (LNH). 
To compare the laboratory parameters during the treatment period, 3 x 3 shift table presenting 
the LNH classification at baseline and LNH classification at each visit will be presented. 
 
6.12.4 Vital Signs 
Results at baseline (Visit 1), Week 6 (Visit 2), Week 12 (Visit 3), Week 24 (Visit 4), Week 36 (Visit 
5), end-of-study visit, and follow-up as well as the change from baseline to each timepoint post-
treatment are presented using descriptive statistics (number of subjects, mean, standard 
deviation, median, minimum, and maximum). 
 
6.12.5 Physical Measurement (Body Weight) 
Results at baseline (Visit 1), Week 36 (Visit 5), end-of-study visit, and follow-up as well as the 
change from baseline to each timepoint post-treatment are presented using descriptive statistics 
(number of subjects, mean, standard deviation, median, minimum, and maximum). 
 
7. 
Plan for Revision of Analysis Method  
Revision of analysis method is not planned. 
 
8. 
TLF shell 
List of Tables 
Table 
Table Description 


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Number 
s1 
14.1.1 Subject Disposition - All Enrolled Subject  
s2 
14.1.2 Subject Disposition by Study Site - All Enrolled Subject  
s3 
14.1.3 Major Protocol Deviations - All Enrolled Subject  
s4 
14.1.4 Analysis Sets - All Enrolled Subject  
b1 
14.1.5 Demographic Characteristics - Full Analysis Set 
b2 
14.1.6 Baseline Disease Characteristics - Full Analysis Set 
b3 
14.1.7 Past Medical History - Full Analysis Set 
b4 
14.1.8 Current Medical History - Full Analysis Set 
b5 
14.1.9 Previous Medications - Full Analysis Set 
b6 
14.1.10 Concomitant Medications - Full Analysis Set 
b7 
14.1.11 Previous Medications (anti-epileptic drugs) - Full Analysis Set 
b8 
14.1.12 Concomitant Medications (anti-epileptic drugs) - Full Analysis Set 
b9 
14.1.13 Concomitant Non-Pharmacological Therapy - Full Analysis Set 
e1_1 
14.2.2.1 50% Responder Rate for Partial Onset Seizures with or without Secondary 
Generalization - Full Analysis Set 
e1_2 
14.2.2.2 50% Responder Rate for Partial Onset Seizures with or without Secondary 
Generalization - Per Protocol Set 
e2_1 
14.2.3.1 75% Responder and 100% Responder (Seizure-Free) Rate for Partial 
Onset Seizures with or without Secondary Generalization - Full Analysis Set 
e2_2 
14.2.3.2 75% Responder and 100% Responder (Seizure-Free) Rate for Partial 
Onset Seizures with or without Secondary Generalization - Per Protocol Set 
e3_1 
14.2.4.1 Percent Change in the Frequency of Partial Onset Seizures with or 
without Secondary Generalization during the Titration Period and Maintenance 
Period compared to Screening Period - Full Analysis Set 
e3_2 
14.2.4.2 Percent Change in the Frequency of Partial Onset Seizures with or 
without Secondary Generalization during the Titration Period and Maintenance 
Period compared to Screening Period - Per Protocol Set 
e4_1 
14.2.5.1 - 50% Responder, 75% Responder, and 100% Responder (Seizure-Free) 
Rate for Secondary Generalized Tonic-Clonic Seizure - Full Analysis Set 
e4_2 
14.2.5.2 - 50% Responder, 75% Responder, and 100% Responder (Seizure-Free) 
Rate for Secondary Generalized Tonic-Clonic Seizure - Per Protocol Set 


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e5_1 
14.2.6.1 Percent Change in the Frequency of Secondary Generalized Tonic-Clonic 
Seizure during the Titration Period and Maintenance Period compared to 
Screening Period - Full Analysis Set 
e5_2 
14.2.6.2 Percent Change in the Frequency of Secondary Generalized Tonic-Clonic 
Seizure during the Titration Period and Maintenance Period compared to 
Screening Period - Per Protocol Set 
ex1 
14.3.1 Extent of Exposure - Safety Analysis Set 
a1 
14.3.2 Summary of Adverse Events - Safety Analysis Set 
a2 
14.3.3 Incidence of Treatment-Emergent Adverse Events by System Organ Class - 
Safety Analysis Set 
a3 
14.3.4 Incidence of Treatment-Emergent Adverse Drug Reactions by System 
Organ Class - Safety Analysis Set 
a4 
14.3.5 Incidence of Treatment-Emergent Serious Adverse Events by System Organ 
Class - Safety Analysis Set 
a5 
14.3.6 Incidence of Adverse Events Leading to Treatment Discontinuation by 
System Organ Class - Safety Analysis Set 
a6 
14.3.7 List of Treatment-Emergent Serious Adverse Events - Safety Analysis Set 
a7 
14.3.8 Incidence of Treatment-Emergent Adverse Events by System Organ Class 
and Severity - Safety Analysis Set 
a8 
14.3.9 Incidence of Treatment-Emergent Adverse Events by System Organ Class 
and Causality - Safety Analysis Set 
l1 
14.4.1.1 Hematology - Safety Analysis Set 
l2 
14.4.1.2 Blood Chemistry - Safety Analysis Set 
l3 
14.4.1.3 Urinalysis - Safety Analysis Set 
l4 
14.4.2 Urinalysis: Normal/Abnormal - Safety Analysis Set 
l5 
14.4.3.1 Hematology: LNH - Safety Analysis Set 
l6 
14.4.3.2 Blood Chemistry: LNH - Safety Analysis Set 
l7 
14.4.3.3 Urinalysis: LNH - Safety Analysis Set 
v1 
14.4.4 Vital Signs - Safety Analysis Set 
pe1 
14.4.5 Physical Measurement (Body Weight) - Safety Analysis Set 
 


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9. 
Roles and Responsibilities 
Role 
Name 
Responsibility 
Biostatistician 
 
Statistical analysis 
QC Biostatistician 
 
Quality control for the 
statistical analysis process 
 
10. Applied SOPs 
SOP No. 
SOP Version 
SOP Name 
0400 
2.0_23-Oct-2017 
Statistical Analysis Plan 
0401 
3.0_01-Jun-2017 
Statistical Analysis Process 
 
11. Applied SOP SDs 
SD No. 
SD Version 
SD Title 
SD 0400 A
2.0_03-May-2018 
Statistical Analysis Plan 
SD 0408 A
3.0_23-Oct-2017 
STAT Master File Index 
 
PPD
PPD