Conditions: Partial-Onset or Primary Generalized Tonic-Clonic Seizures
Keywords: Partial-Onset Seizures Primary Generalized Tonic-Clonic Seizures Adjunctive Therapy Epilepsy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 180
Healthy volunteers: no

Brief summary:
This is an open-label, multicenter study with an Extension Phase to evaluate the safety and tolerability of perampanel oral suspension when administered as an adjunctive therapy in children (ages 4 to less than \[\<\] 12 years) with inadequately controlled partial onset seizures (POS) or primary generalized tonic clonic (PGTC) seizures.

Detailed description:
This is a multicenter, open-label, single-arm study in children (age 4 to \<12 years) with inadequately controlled POS or PGTC seizures. The study will consist of a Core Phase and two Extension Phases (Extension Phase A \[for all countries in the study\], and Extension Phase B \[available for participants enrolled in Japan and in countries where an extended access program {EAP} cannot be implemented, after completion of Extension Phase A\]). The Core Phase will consist of the following 2 phases: Pretreatment and Treatment Phase. The Pretreatment Phase, during which participants will be assessed for eligibility, will consist of up to a 4-weeks +/- 3 days Screening/Baseline Period. The Treatment Phase will consist of 3 periods: Titration Period (up to an 11-weeks: dose titration on the basis of individual clinical response and tolerability), Maintenance Period (up to a 12-weeks: continuation of perampanel oral suspension once daily at the dose level achieved at the end of the Titration Period), and Follow-up Period (up to 4-weeks +/- 7 days: only for those participants not entering into Extension Phase A or those who prematurely discontinue from the study). Extension Phase A will consist of up to 29-weeks Maintenance Period and up to 4-weeks +/- 7 days Follow-up Period after the last dose of perampanel only for participants who did not enter into Extension Phase B. All participants who complete all scheduled visits up to and including Visit 9 in the Treatment Phase will be eligible to participate in Extension Phase A of the study. During the Maintenance Period of Extension Phase A, all participants will continue with their optimal perampanel dose (that is, dose level that they complete on during the Core Phase). After completing Extension Phase A, participants in Japan and in countries where EAP cannot be implemented, participants will be eligible to participate in Extension Phase B. In Japan, treatment will continue as long as clinically appropriate according to the judgment of the investigator. However, treatment of participants in Extension B will be completed when the participant reaches 12 years of age or when perampanel is commercially available in Japan for treatment of POS in pediatric participants (4 to less than 12 years of age). In countries where an EAP cannot be implemented, participation in Extension B will continue as long as clinically appropriate according to the judgment of the investigator, until the participants reaches 12 years of age or perampanel oral suspension is commercially available.

Arms:
arm 1: Perampanel 0.5 milligrams per milliliter (mg/mL) oral suspension

Interventions: intervention 1: Perampanel
Intervention descriptions: intervention 1: E2007

Protocol document:
Prot_000.pdf: 
Clinical Study Report 
E2007-G000-311 
 
16.1.1 
Protocol and Protocol Amendments 
The latest version of the study protocol all previous versions are provided on the following 
pages: 
• V9.0 Final, 13 Jul 2018 (per Amendment 04) 
• V8.0 Final, 19 Jan 2018 (per Amendment 03) 
• V7.0 Final, 03 Dec 2017 (per Amendment 03) 
• V6.0 Final, 19 Oct 2017 (per Amendment 02) 
• V5.0 Final, 20 Apr 2017 (per Amendment 01) 
• V4.0 Final, 02 Nov 2016 (per Administrative Change) 
• V3.0 Final, 30 Aug 2016 (per Administrative Change) 
• V2.0 Final, 17 May 2016 (per Administrative Change) 
• V1.0 Final, 17 May 2016 (original protocol) 
 
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Revision History
Revisions to Version v8.0
New version/date:  Version 9.0/13 Jul 2018 (per Amendment 04, Version 9.0)
Change
Rationale
Affected Protocol Section(s)
Clarified, in the text, that the 
Pretreatment Phase consists of a 
Screening/Baseline period
Document quality
Synopsis (Section 2) –

Study Period and Phase 
of Development
Section 7.2
Clarified, in the text, the approximate 
total study duration.
Document quality
Synopsis (Section 2)

Study Period and Phase 
of Development
Clarified, in the text, that subjects in 
Japan and and in countries where an 
extended access program (EAP) cannot
be implemented can enroll in 
Extension B 
To provide managed 
access of study drug to 
subjects until 
commercial availability 
of perampanel
Synopsis (Section 2) –

Study Period and Phase 
of Development

Study Design

Statistical Methods

Duration of Treatment
Section 7.2
Figure 1
Section 9.1
Section 9.1.3
Section 9.1.3.2
Section 9.1.4.1
Section 9.4.1
Appendix 1
Appendix 2
Table 5
Table 6
Specified criteria for participation in 
Extension B for subjects in countries 
where an EAP cannot be implemented.
To provide managed 
access of study drug to 
subjects until 
commercial availability 
of perampanel
Synopsis (Section 2) –

Study Period and Phase 
of Development

Study Design

Duration of Treatment
Section 9.1
Section 9.1.4.1
Appendix 2
Table 6
Clarified the CGI objective (CGIS is 
the baseline assessment and CGIC is 
the postbaseline assessment of the 
CGI)
Document quality 
Synopsis (Section 2) –

Objectives

Assessments
Section 8.2
Updated Medical Monitor information
Personnel change
Protocol Signature Page
Grammatical, typographical, and 
formatting changes were also made.
Document quality 
Throughout the document
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Revisions to Version v7.0
New version/date:  Version 8.0/19 Jan 2018 (per Amendment 03, Version 8.0)
Change
Rationale
Affected Protocol Section(s)
Clarified, in the text, that the Follow-
up Visit would be conducted at 
4 weeks ± 7 days after the last dose of 
study drug for all subjects, except for 
subjects entering into Extension A. 
Document quality
Synopsis (Section 2) –

Study Design

Duration of Treatment
Section 9.1.2
Section 9.1.2.2
Section 9.3.3
Clarified, in the text, that the follow-up 
period of Extension A was only for 
subjects not entering into Extension B
and that Extension B will occur in 
Japan only.
Document quality
Synopsis (Section 2) –

Study Period and Phase 
of Development

Study Design

Duration of Treatment
Section 7.2
Section 9.1
Section 9.1.3
Section 9.1.3.2
Appendix 1
Table 5
Clarified, in the text, that a follow-up 
period of Extension B, would include a 
Follow-up visit at 4 weeks ± 7 days
after the Discontinuation Visit, and 
would occur for subjects who
discontinue or who choose not to
switch to the commercial product.
Document quality
Synopsis (Section 2) –

Study Period and Phase 
of Development

Study Design

Duration of Treatment
Section 9.1
Appendix 2
Table 6
Clarified, in the text, that subjects in all 
countries can enroll in Extension A
Document quality
Section 9.1
Clarified that the study visit window 
during Extension B is ±6 days of the 
scheduled visit.
Document quality.
Table 6
Clarified that the initial assessment of 
Extension B was performed at the final 
visit of Extension A Maintenance 
period (ie, Visit 12)
Document quality
Table 6
Grammatical, typographical, and 
formatting changes were also made.
Document quality
Throughout the document
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Revisions to Version v6.0
New version/date:  Version 7.0/03 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Added an Additional Extension 
Phase (Extension B) for subjects in 
Japan only.
To provide managed access 
to perampanel for subjects 
in Japan.
Synopsis – Study Period and 
Phase of Development
Synopsis – Study Design
Synopsis – Duration of 
Treatment
Synopsis – Statistical Methods
Section 5.3
Section 7.2
Section 9.1 and Figure 1
Section 9.1.3
Section 9.1.3.2
Section 9.1.4
Section 9.4.1
Section 9.5.1.6
Section 9.5.2.1
Section 9.5.2.2
Appendix 1
Appendix 2
Updated references to the Extension 
Phase to Extension A. 
Clarification to distinguish 
the original Extension 
Phase from the Additional 
Extension Phase in Japan.
Throughout the document
Clarified, in text, the study visit 
window during Extension A is
±6 days of the scheduled visit.
Document quality.
Synopsis – Study Design
Section 9.1.3
Revised the Sponsor signature page.
To reflect updated team 
members.
PROTOCOL SIGNATURE 
PAGE
Grammatical, typographical, and 
formatting changes were also made.
Document quality. 
Throughout the document
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Revisions to Version v5.0
New version/date:  Version 6.0/19 Oct 2017 (per Amendment 02)
Change
Rationale
Affected Protocol Section(s)
Revised the Pretreatment 
Screening/Baseline Period (outside 
of Japan) to allow subjects to enrol 
sooner after a qualifying seizure, 
while maintaining the 4 weeks 
±3 days required in Japan.
Added that the study period 
durations were “up to” the specified 
nominal times.
To shorten the time to 
enroll (outside of Japan) 
and add flexibility to study 
period durations in line 
with visit windows.  
Synopsis – Study Period and 
Phase of Development
Synopsis – Pretreatment Phase
Synopsis – Inclusion Criteria
Synopsis – Duration of
Treatment
Section 7.2
Section 9.1 and Figure 1
Section 9.1.1
Section 9.1.2
Section 9.4.1
Section 9.5.2.1 (Table 4)
Appendix 1
Revised inclusion #5, for subjects in 
Japan, such that the 4-week 
time-frame for partial-onset seizures 
(POS)/primary generalized 
tonic-clonic seizures (PGTC) 
seizure occurrence prior to Visit 2.
To assess efficacy only in 
the Japanese subjects, per 
agreement between the 
sponsor and The 
Pharmaceuticals and 
Medical Devices Agency 
(PMDA) in Japan.
Synopsis – Inclusion Criteria
Section 9.3.1
Added that analyses for regional 
submissions may be performed 
during the course of the study.
To allow for regional data 
submission during the 
course of the study.
Synopsis – Interim Analyses
Section 9.7.3
Appendix 1
Revised the sample size to state “at 
least” 160 subjects “(with up to 
40 subjects with PGTC and the 
balance with POS).”
To allow flexibility in 
enrollment
Synopsis – Sample Size 
Rationale
Section 9.7.2
Section 9.3
Added that each study visit is based 
on the actual prior visit (eg, Visit 3 
is completed 2 weeks ±3 days of 
Visit 2, Visit 4 is completed 
3 weeks ±3 days of Visit 3, etc).
Clarification.  
Section 9.1.2.1
Section 9.1.2.2
Section 9.1.3
Section 9.5.2.1 (Table 4)
Revised study visit window during 
the Extension Phase back to ±6 days 
of the scheduled visit for Visits 10 
through 12 (as per the original 
protocol).
The ±6 days window is 
necessary to ensure that 
investigational product (IP) 
is administered within the 
90-day shelf life once 
opened. 
Appendix 1 (Table 5)
Revised the Sponsor signature.
To reflect updated team 
members.
PROTOCOL SIGNATURE 
PAGE
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Revisions to Version v5.0
New version/date:  Version 6.0/19 Oct 2017 (per Amendment 02)
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, and 
formatting changes were also made.
Document quality
Throughout the document
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Revisions toVersion v4.0
New version/date:  Version 5.0/20 Apr 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Added that the Titration Period is a 
fixed duration of 11 weeks and
subjects will remain on their 
optimum dose once it is achieved 
during this period.
For clarification
Synopsis – Study Design:  
Titration Period;
Duration of Treatment
Section 7.2
Section 9.1
Section 9.1.2.1
Section 9.4.1
Separated the Titration Period
dosing schedule into separate 
presentations for Global sites and 
Japan sites.
For clarification
Synopsis – Study Design:  
Titration Period
Section 9.4.1 (Table 4 and
Table 5)
Increased the time prior to Visit 2 
that subjects must meet the prior 
seizure criterion from 4 to 
12 weeks.
To improve enrolment
Synopsis – Inclusion criteria
Section 9.1.1
Section 9.3.1
Increased the number of approved 
antiepileptic drug (AEDs) subjects 
may currently be receiving from 2 
to 3.
To improve enrolment
Synopsis – Inclusion criteria
Section 9.1.1
Section 9.3.1
Expanded the exclusion criteria for 
renal impairment and defined 
moderate and severe renal 
impairment.
Regulatory request
Synopsis – Exclusion criteria
Section 9.3.2
Removed exclusion of barbiturate 
use within 4 weeks before to 
Visit 1.  
To improve enrolment
Synopsis – Exclusion criteria
Section 9.3.2
Revised exclusion criteria for 
previous use of benzodiazepines for 
epilepsy (with exception for use as 
rescue medication for seizure 
control) or intermittent use for other 
indications.
For clarification
Synopsis – Exclusion criteria
Section 9.3.2
Added exclusion criterion for 
cannabinoids.
For clarification
Synopsis – Exclusion criteria
Section 9.3.2
Added exclusion of subjects with 
hereditary problems of galactose 
intolerance, the Lapp lactase 
deficiency or glucose-galactose 
malabsorption.
Regulatory request
Synopsis – Exclusion criteria
Section 9.3.2
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Revisions toVersion v4.0
New version/date:  Version 5.0/20 Apr 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Added emphasis that efforts should 
be made to perform all clinical 
laboratory and screening tests on the 
scheduled day, or as close as 
possible to that day, within 4 week 
period prior Visit 2.  
For clarification
Section 9.1
Added urine drug screen.
Assessment needed for 
exclusion criteria 18
Section 9.5.1.5.3 and Table 3
Added mandatory blood collection 
for pharmacokinetic (PK) 
assessment.
For clarification
Section 9.5.1.4.1
Removed “bands” from clinical 
hematology laboratory tests.
Correction
Section 9.5.1.5.3 (Table 3)
Revised text to stipulate that a 
serum pregnancy test is performed 
at screening and urine pregnancy 
tests are performed after screening, 
unless urine can not be obtained. 
Correction
Section 9.5.1.5.7
Section 9.5.2.1 (Table 4)
Revised footnote “r” to indicate that 
blood for PK was collected for 
serious adverse events, rather than 
adverse events.
Correction
Section 9.5.2.1 (Table 4)
Added “Safety” to the section title.
For clarification
Section 9.7.3
Added additional information 
describing the Principal 
Investigator’s responsibility and use 
of data generated by the site or 
Principal Investigator regarding 
queries and future publications.
For clarification
Section 11.4 and Section 11.5
Revised study visit window to 
±7 days of the scheduled visit.
For consistency with the 
Core study
Appendix 1 (Table 5)
Grammatical, typographical, and 
formatting changes were also made.
Document quality
Throughout
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Previous Version (Revised protocol): v3.0
Current Version (Revised per administrative change): v4.0
Date of Revisions:  02 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Change the sign of the prespecified 
threshold for median percent 
reduction in seizure frequency, from 
negative to positive.
To correct an error
Synopsis - Efficacy Analyses
Synopsis - Sample Size 
Rationale
Section 9.7.1.6
Section 9.7.2
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Previous Version (Revised original): v2.0
Current Version (Revised protocol): v3.0
Date of Revisions:  30 Aug 2016
Change
Rationale
Affected Protocol Section(s)
Provide criteria for efficacy in 
Japanese subjects (ie, comparison of 
perampanel in the present study
with placebo subjects in study 
E2007-J000-335).
Per request from PMDA
Synopsis - Objectives
Section 8.2
Provide that subjects enrolled in 
Japan may not receive perampanel 
doses higher than 12 mg/day.
Per request from PMDA
Synopsis - Study Design
Section 7.3
Figure 1
Section 9.1.2.1
Section 9.1.3.1
Section 9.4.1
Table 1
State threshold criterion for 
efficacy, for purposes of registration 
in Japan.
Per request from PMDA
Synopsis - Efficacy Analyses
Section 9.7.1.6
Describe sample size for purposes 
of submission in Japan.
Per discussion with PMDA 
Synopsis - Sample Size 
Rationale
Section 9.7.2
Correct the window for Follow-up 
to 7 days.
For consistency and to 
correct an error
Section 9.1.3.2
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Previous Version (Original): v1.0
Current Version (Revised original): v2.0
Date of Revisions: 17 May 2016
Change
Rationale
Affected Protocol Section(s)
Clarified Asia Pacific throughout
Clarification
Synopsis – Investigators
Section 6
Section 9.3
Added a window of ±3 days to the 
Screening/Baseline Period.
The current version has 
screening period of 
4 weeks. This windows 
will give 
operational/logistical 
flexibility.  
Synopsis – Study Design
Synopsis – Duration of 
Treatment
Section 7.2
Section 9.1.1
Section 9.4.1
Revised cognitive testing from 
Vineland Adaptive Behavior Scale 
(VABS) to A-B neuropsychological 
assessment schedule (ABNAS).
The proposed A-B 
Neuropsychological 
Assessment Schedule 
(ABNAS), is simpler can be 
administered by any 
healthcare provider, 
caregiver. The logistics and 
burden of administering the 
scale is important 
consideration in this study 
population given the nature 
of the disease. We aim to 
achieve greater compliance 
and completeness of the 
data to compare at various 
time points during the study
using the proposed scale. 
There is no negative impact 
or in any way to jeopardize 
the secondary endpoints 
proposed particularly 
cognitive assessments. 
Synopsis – Safety Assessments
Synopsis – Secondary 
Endpoints
Synopsis – Safety Analyses
Section 7.2
Section 9.5.1.5
Section 9.5.1.5.7
Table 4
Section 9.7.1.1.2
Section 9.7.1.8.6
Appendix 1
Removed requirement for placebo 
PK sample testing.
Not required as this is an 
open-label study
Section 9.5.1.4.1
Updated Statistician responsible for 
the study.
Change in Eisai personnel
Signature Page
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2007-G000-311
Study Protocol Title:
An Open-Label, Multicenter Study with an Extension Phase to Evaluate the 
Safety, Tolerability, and Exposure-Efficacy Relationship of Perampanel Oral 
Suspension when Administered as an Adjunctive Therapy in Pediatric Subjects 
(Age 4 to less than 12 years) with Inadequately Controlled Partial-Onset 
Seizures or Primary Generalized Tonic-Clonic Seizures
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake,
New Jersey 07677
USA
Eisai Ltd.
European 
Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire
AL10 9SN UK
Eisai Co., Ltd.
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
E2007/perampanel
Indication:
Partial-Onset Seizures or Primary Generalized Tonic-Clonic Seizures
Phase:
3
Approval Date:
V1.0
17 May 2016 (original protocol)
V2.0
17 May 2016 (revised original protocol)
V3.0
30 Aug 2016 (revised protocol)
V4.0
02 Nov 2016 (revised per administrative change)
V5.0
20 Apr 2017 (Amendment 01)
V6.0
19 Oct 2017 (Amendment 02)
V7.0
03 Dec 2017 (Amendment 03)
V8.0
19 Jan 2018 (revised per administrative change)
V9.0
13 Jul 2018 (Amendment 04)
IND Number:
112515
EudraCT Number:
2014-002167-16
GCP Statement:
This study is to be performed in full compliance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) and all applicable local 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.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2007
Name of Active Ingredient:  perampanel
Study Protocol Title
An Open-Label, Multicenter Study with an Extension Phase to Evaluate the Safety, Tolerability, and 
Exposure-Efficacy Relationship of Perampanel Oral Suspension when Administered as an Adjunctive 
Therapy in Pediatric Subjects (Age 4 to less than 12 years) with Inadequately Controlled
Partial-Onset Seizures or Primary Generalized Tonic-Clonic Seizures
Investigators
Investigators in the US, EU, and Asia Pacific
Sites
Approximately 60 to 80 sites
Study Period and Phase of Development
The total study duration from 1st subject enrolled to last subject’s last visit/last assessment will be
approximately 112 weeks (52 weeks of recruitment, up to 4 weeks ±3 days of Screening/Baseline, up 
to 52 weeks of treatment [including up to an 11-week Titration Period, up to 12-week Maintenance 
Period, and up to 29-week Extension Phase (Extension A)], and up to 4 weeks of follow-up [only for 
those subjects not entering into Extension B]). (revised per Amendments 03 and 04)  In Japan, 
4 weeks ±3 days of baseline is required; however, subjects outside of Japan may begin treatment as 
soon as baseline procedures have been completed and documentation of eligibility has been 
established.
Extension Phase (Extension B) with open-label treatment will be available to subjects enrolled in 
Japan and in countries where an extended access program (EAP) cannot be implemented, after having
completed Extension A.  In Japan, participation in Extension B will continue as long as clinically 
appropriate according to the judgment of the investigator, until the subject reaches 12 years of age or 
perampanel is commercially available in Japan for treatment of partial-onset seizures (POS) in 
pediatric subjects (4 to less than 12 years of age).  In countries where an EAP cannot be implemented, 
participation in Extension B will continue as long as clinically appropriate according to the judgment 
of the investigator, until the subject reaches 12 years of age or perampanel oral suspension is 
commercially available. (revised per Amendments 02, 03, and 04)
Phase 3
Objectives
Primary Objective
1.
To evaluate the safety and tolerability of E2007/perampanel oral suspension when administered 
as an adjunctive therapy in children (ages 4 to <12 years) with inadequately controlled POS or 
primary generalized tonic-clonic seizures (PGTC)
Secondary Objectives
1.
To characterize the pharmacokinetics (PK) of perampanel and the relationship between 
perampanel plasma concentrations, efficacy, and safety using population PK/pharmacodynamics
(PD) modeling
2.
To evaluate the effects of perampanel on cognition, behavior, visuomotor skills, and growth and 
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development in children during short-term (23 weeks) and long-term (up to 52 weeks) treatment
3.
To evaluate the frequency of EEG abnormalities during awake and sleep state during 52 weeks of
treatment
4.
To evaluate suicidal ideation and suicidal behavior in children 6 years to less than 12 years as 
measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) during 52 weeks of 
treatment
5.
To evaluate the efficacy of perampanel as measured by the median percent change per 28 days in 
seizure frequency, by the proportion of responders (≥25%, ≥50%, and ≥75%), and by the 
proportion of subjects who are seizure-free for POS, PGTC, and Generalized Tonic-Clonic 
(GTC) seizures
6.
To evaluate, in Japanese subjects, the efficacy of perampanel on POS in the present study as 
compared with placebo in Study E2007-J000-335
7.
To assess the effects of perampanel on the Clinical Global Impression (CGI), as measured by the 
CGI of Change (CGIC) (revised per Amendment 04)
Exploratory Objective
To assess the impact of perampanel on the health utility of children using the 
EuroQol 5 Dimensions-Youth (EQ-5D-Y) scale
Study Design
This is a multicenter, open-label single-arm study in children (ages 4 to less than 12 years) with 
inadequately controlled POS or PGTC. The study will consist of a Core Study, Extension Phase A, 
and Extension Phase B (for subjects in Japan and in countries where an EAP cannot be implemented,
after having completed Extension A).  (revised per Amendments 03 and 04)
Core Study
The Core Study will consist of the following 2 phases: Pretreatment and Treatment Phase.
Pretreatment Phase
The Pretreatment Phase will consist of a Screening/Baseline Period that lasts up to 4 weeks ±3 days. 
During this phase, subjects will be assessed for eligibility to participate in the study.  Subjects in Japan 
are required to complete 4 full weeks ±3 days of the Screening/Baseline Period before they may enter 
the Treatment Phase (ie, Visit 2).  However, subjects outside of Japan may begin treatment as soon as 
baseline procedures have been completed and documentation of eligibility (such as a documented 
seizure diary entry for a qualifying seizure during the preceding 12 weeks prior to Visit 2 or a qualifying 
seizure during the prospective Screening/Baseline Period) has been established.  (revised per 
Amendment 02)
Treatment Phase
The Treatment Phase will consist of 3 periods:  Titration (up to 11 weeks), Maintenance (up to 
12 weeks), and Follow-up (up to 4 weeks; only for those subjects not rolling over into Extension A).  
(revised per Amendments 01, 02, and 03)
Titration Period
During the Titration Period, subjects will be stratified by the presence or absence of concomitant 
enzyme inducing antiepileptic drugs (EIAEDs) and will undergo dose titration using the dosing 
schedule below on the basis of individual clinical response and tolerability, but no more frequently 
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than at weekly intervals, up to 8 mg/day for subjects not receiving concomitant EIAEDs or 
12 mg/day for subjects receiving EIAEDs. With the exception of subjects enrolled in Japan, subjects 
receiving concomitant EIAEDs may undergo dose titration beyond 12 mg/day and up to 16 mg/day if 
they tolerate 12 mg/day and are deemed likely to benefit from a higher dose. Subjects enrolled in 
Japan who are receiving concomitant EIAEDs will undergo a Japan-specific dosing schedule (see 
below).  The dose of perampanel during this dose titration will not exceed 12 mg/day.  Subjects not 
receiving EIAEDs may receive dose higher than 8 mg/day and up to 12 mg/day if they tolerate 
8 mg/day and are deemed likely to benefit from a higher dose.  Subjects will be flexibly dosed on the 
basis of individual tolerability.  The Titration Period is a duration of up to 11 weeks, during which 
multiple dose adjustments are allowed in order to identify each subject’s optimum dose.  Each study 
visit is based on the actual prior visit (eg, Visit 3 is completed 2 weeks ±3 days of Visit 2, Visit 4 is 
completed 3 weeks ±3 days of Visit 3, Visit 5 is completed 3 weeks ±3 days of Visit 4.  (revised per 
Amendment 02)  Subjects will remain on their optimum dose once it is achieved during the Titration 
Period.  (revised per Amendment 01)
Dosing Schedule (Global) (revised per Amendment 01)
Week
Subjects on Concomitant EIAEDs
(mg/day)
Subjects not on Concomitant EIAEDs
(mg/day)
0
4
2
1
6
4
2
8
6
3
10
6
4
10
8
5
12
8
6
12
10
7
14
10
8
14
12
9
16
12
10
16
—
Dosing Schedule (Japan Only) (revised per Amendment 01)
Week
Subjects on Concomitant EIAEDs
(mg/day)
Subjects not on Concomitant EIAEDs
(mg/day)
0
2
2
1
4
4
2
6
6
3
6
6
4
8
8
5
8
8
6
10
10
7
10
10
8
12
12
9
12
12
10
—
—
According to the investigator’s clinical judgment, subjects experiencing intolerability at any dose 
may remain at the same dose or have their dose decreased 1 dose level down to the previously 
tolerated dose.  If the subject continues to present significant intolerable adverse events (AEs) at the 
decreased dose and the investigator deems it is necessary, the dose can be decreased further to the 
next dose level down.  Dose decreases can be done via telephone.  Subjects whose dose has been 
decreased can have their dose increased again if tolerability improves; this can be done at the next 
clinic visit after the investigator has deemed it is appropriate in view of resolution of the AE(s).
Multiple dose adjustments will be allowed during the Titration Period.
Upon completion of the 
Titration Period, subjects will enter the Maintenance Period.
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Maintenance Period 
During the Maintenance Period of the Core Study (up to 12-week), subjects will continue taking 
perampanel oral suspension once daily at the dose level they achieved at the end of the Titration 
Period.  (revised per Amendment 02)  Multiple dose adjustment is allowed if a subject is 
experiencing intolerable AE(s) or a higher dose is deemed to be beneficial.  All visits are to be done 
within ±7 days of the schedule.  Each study visit is based on the actual prior visit (eg, Visit 6 is 
completed 3 weeks ±7 days of Visit 5, Visit 7 is completed 4 weeks ±7 days of Visit 6, Visit 8 is 
completed 4 weeks ±7 days of Visit 7, Visit 9 is completed 4 weeks ±7 days of Visit 8.  (revised per 
Amendment 02)
During the Titration and Maintenance Periods, all dose adjustments will be done via 1 dose level up 
or down. Those who cannot tolerate a minimum of 2 mg dose must discontinue from the study.
Follow-Up Period
Follow-up Visit should be conducted 4 weeks (±7 days) after the last dose of study drug for all 
subjects, except for subjects entering into Extension A.  (revised per Amendments 03 and 04)
Extension A
Extension A will consist of a Maintenance Period (up to 29 weeks) and a Follow-up Period (up to 
4 weeks; only for those subjects not entering into Extension B).  Visit 10 is completed 5 weeks ±6
days of Visit 9.  (revised per Amendments 02, 03, and 04)
All subjects who complete all scheduled visits up to and including Visit 9 in the Treatment Phase will 
be eligible to participate in Extension A of the study.  (revised per Amendment 03)
Maintenance Period
During the Maintenance Period of the Extension A, all subjects will continue with their optimal 
perampanel dose (ie, that dose level that they completed on during the Core Study).  Multiple dose 
adjustment is allowed if a subject is experiencing intolerable AE(s) or a higher dose is deemed to be 
beneficial.  The maximum dose of perampanel is 12 mg/day for subjects who are not receiving 
EIAEDs.  For subjects who are receiving EIAEDs, the maximum dose is 16 mg except that for 
subjects enrolled in Japan, the maximum dose is 12 mg/day.
Addition, deletion, and dose changes to the concomitant antiepileptic drugs (AEDs) are allowed 
during Extension Maintenance Period. Conversion to monotherapy on perampanel is also permitted 
at the discretion of the investigator, if it is considered appropriate to control the seizures.
Follow-Up Period
Subjects who do not continue in Extension A or B or those who prematurely discontinue from the 
study will enter a Follow-up Period (up to 4 weeks).  (revised per Amendment 03)
Extension B
Subjects in Japan and in countries where an EAP cannot be implemented, and who complete 
Extension A, will be eligible to participate in Extension B.  
Treatment Phase 
Extension B will consist of a Treatment Phase which will continue as long as clinically appropriate 
according to the judgment of the investigator.  In Japan, treatment of subjects in Extension B will be 
completed when the subject reaches 12 years of age or when perampanel is commercially available in 
Japan for treatment of POS in pediatric subjects (4 to less than 12 years of age).  In countries where 
an EAP cannot be implemented, participation in Extension B will continue as long as clinically 
appropriate according to the judgment of the investigator, until the subject reaches 12 years of age or 
perampanel oral suspension is commercially available. (revised per Amendment 04)
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Follow-Up Period
Subjects who discontinue or choose not to switch to the commercial product will require a Follow-up 
Visit which will be conducted 4 weeks (±7 days) after the Discontinuation Visit. (revised per 
Amendments 03 and 04)
Number of Subjects
At least 160 subjects will be enrolled and treated: at least 120 with POS and at least 40 with PGTC.  
A minimum of 30% of the subjects for each seizure type will be enrolled in the younger age group 
(4 to <7 years) (ie, at least 36 subjects with POS and at least 12 subjects with PGTC).
Inclusion Criteria (Core Study)
1.
Have a diagnosis of epilepsy with POS with or without secondarily generalized seizures or PGTC 
according to the International League Against Epilepsy’s (ILAE) Classification of Epileptic 
Seizures (1981).  Diagnosis should have been established at least 6 months prior to Visit 1 by 
clinical history and an EEG that is consistent with the diagnosis; normal interictal EEGs will be 
allowed provided that the subject meets the other diagnosis criterion (ie, clinical history)
2.
Male or female subject, from age 4 to less than 12 years at the time of informed consent/assent
3.
Have a minimum weight of 16 kg (35 lb)
4.
Have had a brain imaging (eg, magnetic resonance imaging [MRI] scan or computed 
tomography[CT]) before Visit 1 that ruled out a progressive cause of epilepsy
5.
During the 12 weeks ±3 days (4 weeks ±3 days in Japan only) before Visit 2, subjects must have 
had equal or greater than 1 POS or 1 PGTC seizure.  (revised per Amendments 01 and 02)  Only 
simple POS with motor signs, complex POS, and complex POS with secondary generalization are 
counted toward this inclusion for POS.
6.
Are currently being treated with stable doses of 1 to a maximum of 3 approved AEDs. (revised 
per Amendment 01)  Doses must be stable for at least 4 weeks before to Visit 1; in the case where 
a new AED regimen has been initiated for a subject, the dose must be stable for at least 8 weeks 
prior to Visit 1.  Only 1 EIAED (defined as carbamazepine, phenytoin, oxcarbazepine, or 
eslicarbazepine) out of the maximum of 3 AEDs is allowed (A vagal nerve stimulator [VNS] will 
be counted as one of the 3 allowed AEDs). (revised per Amendment 01)
Exclusion Criteria (Core Study)
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
beta-human chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]).  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours
before the 1st dose of study drug.
2.
Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry and who do not agree 
to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, 
a contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) throughout the entire study period or for 28 days after study drug 
discontinuation.  If a highly effective method is not appropriate or acceptable for the subject, 
then the subject may use a medically effective method (eg, a double barrier method such as 
condom plus diaphragm with spermicide).

Are currently abstinent, and do not agree to use a double-barrier method (as described above) 
or refrain from sexually active during the study period or for 28 days after study drug 
discontinuation.
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
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study or for 28 days after study drug discontinuation.
3.
Current or history of pseudo-seizures (psychogenic nonepileptic seizures) within approximately 
5 years before Visit 1.
4.
Have a history of status epilepticus that required hospitalization during the 6 months before to 
Visit 1.
5.
Have an unstable psychiatric diagnosis that may confound subjects’ ability to participate the 
study or that may prevent completion of the protocol specified tests (eg, significant suicide risk, 
including suicidal behavior and ideation within 6 months before Visit 1, current psychotic 
disorder, acute mania).
6.
Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 (ie, 
answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS) in subjects 
aged 6 and above.
7.
Are scheduled and/or confirmed to have epilepsy surgery within 6 months after Visit 1; however, 
those who have previously documented “failed” epilepsy surgery will be allowed.
8.
Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the 
study assessments.
9.
Evidence of moderate or severe renal insufficiency as defined by estimated glomerular filtration 
rates (eGFRs) of 31 to <60 mL/min and <30 mL/min, respectively.  (revised per Amendment 01)
10. Evidence of significant active hepatic disease.  Stable elevation of liver enzymes, alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) due to concomitant medication(s), 
will be allowed if they are less than 3 times the upper limit of normal (ULN).
11. Evidence of significant active hematological disease; white blood cell (WBC) count equal or less 
than 2500/µL (2.50 1E+09/L) or an absolute neutrophil count equal or less than 1000/µL 
(1.00 1E+09/L).
12. Clinically significant ECG abnormality, including prolonged corrected QT interval (QTc) defined 
as greater than 450 msec.
13. Have a progressive central nervous system (CNS) disease, including degenerative CNS diseases 
and progressive tumors.
14. Multiple drug allergies or a severe drug reaction to an AED(s), including dermatological (eg, 
Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
15. Concomitant use of felbamate as an AED for less than 2 years or where the dose has not been 
stable for at least 8 weeks before Visit 1.  They must not have a history of WBC count below 
equal or less than 2500/μL (2.50 1E+09/L), platelets below 100,000, liver function tests (LFTs) 
above 3 times the ULN, or other indication of hepatic or bone marrow dysfunction while 
receiving felbamate.  If subjects received felbamate in the past, it must have been discontinued 
8 weeks before Visit 1 to be eligible for study participation.
16. Concomitant use of vigabatrin:  Subjects who took vigabatrin in the past must be off vigabatrin 
for at least 5 months before Visit 1 and with documentation showing no evidence of a vigabatrin 
associated clinically significant abnormality in a visual perimetry test.
17. Concomitant use of cannabinoids.  (revised per Amendment 01)
18. Used benzodiazepines for epilepsy during which the dose has not been stable for greater than 
4 weeks prior to Visit 1.  Benzodiazepines use as rescue medication for seizure control is 
allowed; however, intermittent use of benzodiazepines for any other indications (eg, anxiety/sleep 
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disorders) is prohibited.  (revised per Amendment 01)
19. A VNS implanted less than 5 months before Visit 1 or changes in parameter less than 4 weeks 
before Visit 1 (or thereafter during the study)
20. On a ketogenic diet for which the diet is not stable regimen for at least 4 weeks before to Visit 1.
21. History of or a concomitant medical condition that in the opinion of the investigator(s) would 
preclude the subject’s participation in a clinical study or compromise the subject’s ability to 
safely complete the study.
22. Have previously been exposed to perampanel in a clinical trial or by prescription for more than 
2 months or discontinued for AEs.
23. Have participated in a study involving administration of an investigational drug or device within 
4 weeks before Visit 1, or within approximately 5 half-lives of the previous investigational 
compound, whichever is longer.
24. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption.  (revised per Amendment 01)
Study Treatment
Test drug:
Perampanel will be provided as 0.5 mg/mL oral suspension stock.  Perampanel will be administered 
orally and daily. Dosing should occur at bedtime.
Comparator Drug (if applicable):  Not applicable
Duration of Treatment
Core Study: 

Pretreatment Phase:  (Screening/Baseline): up to 4 weeks ±3 days.  Subjects in Japan are 
required to complete 4 full weeks ±3 days of the Screening/Baseline Period before they may 
enter the Treatment Phase (ie, Visit 2).  However, subjects outside of Japan may begin treatment 
as soon as baseline procedures have been completed and documentation of eligibility (such as 
a documented seizure diary entry for a qualifying seizure during the preceding 12 weeks prior to 
Visit 2 or a qualifying seizure during the prospective Screening/Baseline Period) has been 
established. (revised per Amendment 02)

Treatment Phase:  Titration (up to 11 weeks), Maintenance (up to 12 weeks), Follow-up (up 
to 4 weeks; only for those subjects not entering into Extension A):  27 weeks total (23 weeks 
for subjects continuing into Extension A). (revised per Amendments 01, 02, and 03)
Extension A: 

Maintenance (up to 29 weeks) and Follow-up (up to 4 weeks; only for those subjects not 
entering into Extension B):  up to 33 weeks total  (revised per Amendments 02, 03, and 04)
Extension B:

Treatment Phase: 
In Japan, treatment will continue as long as clinically appropriate 
according to the judgment of the investigator.  However, treatment of subjects in Extension B
will end when the subject reaches 12 years of age or when perampanel is commercially 
available in Japan for treatment of POS in pediatric subjects (4 to less than 12 years of age). 
In countries where an EAP cannot be implemented, participation in Extension B will 
continue as long as clinically appropriate according to the judgment of the investigator, until 
the subject reaches 12 years of age or perampanel oral suspension is commercially available. 
(revised per Amendment 04)

Follow-up (for subjects who discontinue or choose not to switch to the commercial product): 
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4 weeks ±7 days after the Discontinuation Visit.  (revised per Amendment 03)
Concomitant Drug/Therapy
Other than carbamazepine, oxcarbazepine, phenytoin, and eslicarbazepine, concomitant use of 
medications known to be inducers of cytochrome (CYP) 3A including, but not limited to:  rifampin, 
troglitazone, St John’s Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), 
modafinil, pioglitazone, and rifabutin will not be permitted and are to be discontinued within 28 days
before Visit 1.  VNS implanted less than 5 months before Visit 1 or changes in parameter less than 
4 weeks before Visit 1 (or thereafter during the study) will be prohibited.
Assessments
Efficacy Assessments
Seizure diaries will be used to collect seizure counts. All seizure types will be counted.
Pharmacokinetic Assessments
Plasma concentrations of perampanel will be determined via collection of blood samples during the 
Maintenance Phase using a sparse sampling technique at specified visits for subsequent population 
PK analysis.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Not applicable.
Safety Assessments
Safety will be assessed by monitoring and recording all AEs and serious adverse events (SAEs). 
Additional assessments will include regular monitoring of hematology, blood chemistry, and urine 
values, regular measurement of vital signs, ECGs, physical, and neurological examinations.
Growth and development will be assessed by weight, height, thyroid, and insulin-like growth factor-1 
(IGF-1).
Cognitive testing A-B neuropsychological assessment schedule (ABNAS), behavioral questionnaires
Child Behavior Checklist (CBCL), and visuomotor skills testing using the Lafayette Grooved 
Pegboard Test (LGPT) will be administered.
An assessment of suicidal ideation and behavior using the C-SSRS will be performed throughout the 
study for subjects aged 6 years and older at the time of consent/assent.  Suicidal ideation and behavior
will be monitored in subjects less than 6 years at the time of consent/assent based upon clinical 
impression.
An EEG will be performed over a minimum of 1-hour up to a 2-hour period in an awake and sleep 
state at specified visits.
Other Assessments
A health related quality of life questionnaire (EQ-5D-Y) will be administered.
For patients with 
mental disabilities and patients ages 4 to 7, caregivers or parents will complete the proxy EQ-5D-Y.  
For ages 8 to 11 with no mental disabilities, patients will self-complete the EQ-5D-Y.  Patients ages 
8 to 11 with physical disabilities but no mental disabilities may have the EQ-5D-Y read to them and 
their responses recorded by a caregiver, parent, or study coordinator.  The CGI (Clinical Global 
Impression of Severity [CGIS], and CGIC) will be administered. (revised per Amendment 04)
Bioanalytical Methods
Plasma concentrations of perampanel will be analyzed using validated liquid chromatography 
coupled with tandem mass spectrometry (LC-MS/MS) methodology.
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Statistical Methods
Study Endpoints
Primary Endpoint
1.
Safety and tolerability, which include incidence of treatment-emergent adverse events (TEAEs) 
and SAEs, laboratory parameters, vital signs, and ECG parameters, of perampanel oral 
suspension in children (ages 4 to <7 years and ≥7 years to <12 years) with POS or PGTC.
Secondary Endpoints
1.
The relationship between plasma levels of perampanel and efficacy endpoints (ie, change in 
average seizure frequency over 28 days, responder probability, and the proportion of subjects 
who are seizure-free in the Maintenance Period of the Core Study) separately for each seizure 
type.
2.
The relationship between plasma levels of perampanel and cognition endpoints including change 
from baseline in ABNAS, CBCL, and LGPT.  In addition, depending on the AE data, the 
relationship between plasma levels of perampanel and select AEs will be assessed.
3.
Change from baseline at Week 23 and Week 52 in ABNAS, CBCL, and LGPT.
4.
Changes from baseline at Week 23 and Week 52 in growth and development parameters (height, 
weight, thyroid, and IGF-1).
5.
Change from baseline in EEG and the frequency of EEG abnormalities during awake and sleep 
state.
6.
Proportion of subjects (aged 6 or older at time of consent/assent) with any treatment-emergent 
reports of suicidal ideation and behavior on the C-SSRS and intensity of these behaviors assessed 
using C-SSRS scores.
7.
The median percent change in seizure frequency per 28 days during Treatment Phase (Titration 
Period and Maintenance Period) of the Core Study, and during the long-term treatment (up to 
52 weeks) relative to the Pretreatment Phase.  Seizure frequency will be based on the 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.
8.
Proportion of responders (25% responders defined as a decrease in 28-day seizure frequency of 
equal or greater than 25% compared to baseline seizure frequency; 50% responders defined as a 
decrease in 28-day seizure frequency of equal or greater than 50% compared to baseline seizure 
frequency; 75% responders defined as a decrease in 28-day seizure frequency of equal or greater 
than 75% compared to baseline seizure frequency) during Maintenance Period of Core Study, and 
during the long term treatment (up to 52 weeks).
9.
Proportion of subjects who are seizure-free during Maintenance Period of Core Study, and during 
the long term treatment (up to 52 weeks).
10. CGI of Change.
Exploratory Endpoint
1.
Change from baseline at Week 23 and Week 52 in EQ-5D-Y.
Analysis Sets
Core Study
Safety Analysis Set:  The group of subjects who received at least 1 dose of study drug and had at 
least 1 postdose safety assessment in the Core Study.
Full Analysis Set:  The group of subjects who received at least 1 dose of study drug and had at least
1 postdose seizure measurement in the Core Study.
Pharmacokinetic Analysis Set:
The group of subjects receiving perampanel and with at least 
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1 quantifiable perampanel concentration at one of the visits during the Maintenance Period of the 
Core Study and with adequately documented dosing history.
Pharmacokinetic/Pharmacodynamic Analysis Set: The group of subjects receiving perampanel 
who have seizure frequency, cognition, or AE data with documented dosing history.  Subjects 
receiving perampanel should have at least 1 quantifiable perampanel concentration at one of the visits 
during the Maintenance Period of the Core Study as per the PK Analysis Set.
Extension A
Safety Analysis Set:  The group of subjects who received at least 1 dose of study drug and had at 
least 1 postdose safety assessment in the Extension A.  (revised per Amendment 03)
Full Analysis Set:  The group of subjects who received at least 1 dose of study drug and had at least 
1 postdose seizure measurement in the Extension A.  (revised per Amendment 03)
Extension B
Safety Analysis Set:  The group of subjects who received at least 1 dose of study drug and had at 
least 1 postdose safety assessment in Extension B. (revised per Amendments 03 and 04)
Efficacy Analyses
Core Study
The percent change in seizure frequency per 28 days will be summarized using descriptive statistics 
(n, mean, median, minimum and maximum) by age cohorts (4 to <7 years, ≥7 to <12 years), by 
disease cohorts (POS, PGTC, and GTC), and by the presence or absence of concomitant EIAED in 
the Full Analysis Set (FAS). 
The proportion of responders and the proportion of subjects who are seizure-free will be summarized 
using frequency count (number and percentage) by age cohorts (4 to <7 years, ≥7 to <12 years), by 
disease cohorts (POS, PGTC, and GTC), and by the presence or absence of concomitant EIAED in 
the FAS.
The CGIC will be summarized using frequency count (number and percentage) by age cohorts (4 to 
<7 years, ≥7 to <12 years), by disease cohorts (POS, PGTC, and GTC), and by the presence or 
absence of concomitant EIAED in the FAS.
For purposes of registration in Japan, perampanel will be determined to be efficacious if, in subjects 
enrolled in Japan, the upper limit of the 95% CI for the median percent change in POS frequency per 
28 days is below the pre-specified threshold.  This pre-specified threshold consists of the median 
percent reduction in seizure frequency (ie, 10.5%) in subjects who received placebo during the 
Randomization Phase of Study E2007-J000-335.
Extension A
The efficacy endpoints will be summarized using descriptive statistics or frequency by age cohorts 
(4 to <7 years, ≥7 to <12 years), by disease cohorts (POS, PGTC, and GTC), and by the presence or 
absence of concomitant EIAED in the FAS.  (revised per Amendment 03)
Pharmacokinetic Analyses
Determination of PK will be performed on the PK Analysis Set.  Perampanel plasma concentrations 
will be listed.
Population PK analysis will be performed to characterize the PK of perampanel by pooling the 
concentration data with other studies, including 19 Phase 1 studies, 2 Phase 2 studies (232 and 235), 
and 5 Phase 3 studies (304, 305, 306, 332, and 335).  A 2-compartment PK model will be fit to the 
data and the effect of intrinsic and extrinsic factors, including body weight and age, on the PK of 
perampanel will be evaluated.  The post-hoc estimates of both maximum observed concentration
(Cmax) and area under the curve (AUC) from the final PK model will be derived for all subjects.  In 
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addition, average steady-state drug concentration (Css,av) will be calculated.  Subsequently, the 
dose-normalized derived exposure parameters will be summarized descriptively by age group 
(≤4 years, >4 to ≤8 years, >8 to <12 years, ≥12 to <18 years, and ≥18 years) for subjects with and 
without inducing AEDs, and also presented in box-plots.
Pharmacodynamic Analyses
PD endpoints to be evaluated as part of PK/PD analyses include endpoints for efficacy, cognition, 
and selected safety parameters.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD analysis will be conducted for the relationship between model-predicted average 
exposure to perampanel at steady-state (Css,av) vs responder rate and percent reduction in seizure 
frequency during the Maintenance Phase.  In addition, the relationship between Css,av and the 
cognition endpoints and most frequent AEs will be explored graphically.  Any emergent relationship 
will be subjected to population PK/PD modeling.  The effect of intrinsic and extrinsic factors (ie, 
most common concomitant AEDs, demographics) on the PK/PD relationship will be evaluated.  Two 
separate analyses will be performed, one for POS, where data from subjects with POS from 
Study 311 will be pooled with data from POS subjects from Studies 304, 305, 306, and 335, and 
another for PGTC, where data from subjects with PGTC from Study 311 will be pooled with data 
from PGTC subjects from Study 332.
Safety Analyses 
Core Study
Safety analyses will be conducted on the Safety Analysis Set. The data will be summarized by age 
cohorts (4 to <7 years, ≥7 to <12 years), by disease cohorts (POS, PGTC, and GTC), and by the 
presence or absence of concomitant EIAEDs.
The incidence of TEAEs, SAEs, AEs associated with fatal outcomes or leading to discontinuations, 
and AEs leading to dose adjustment will be summarized.  The incidence of TEAEs will be 
summarized by severity (mild, moderate, or severe), as well as by relationship to treatment (related or 
not related).  The incidence of TEAEs of special interest defined by standardized Medical Dictionary 
for Regulatory Activities (MedDRA) query will also be summarized.
Changes from baseline in laboratory values will be summarized for continuous variables.  Laboratory 
shift tables showing incidence of new or worsening clinically significant findings from baseline to the 
postbaseline visits will be displayed.  Shift from baseline to the highest postbaseline laboratory value 
and from baseline to the lowest postbaseline laboratory value will also be displayed.
Incidence of treatment-emergent markedly abnormal laboratory values (TEMAV) in laboratory safety 
test variables will be tabulated.  TEMAVs will be obtained from the modified National Cancer
Institute (NCI) criteria.
For ALT and AST analysis, the number of subjects with greater than 3 times, but less than 5 times the 
ULN and the number of subjects with greater than 5 times the ULN will be summarized.  For 
bilirubin, a summary of the number of subjects with serum concentrations greater than 2 times the 
ULN will be created.
The change from baseline in vital signs and ECG parameters will be summarized.
The duration of treatment, (Titration Period and Maintenance Period of the Core Study) will be 
calculated as the number of days between the date the subject receives their 1st treatment dose and 
the date the subject receives the last dose of treatment.  These values will be used to summarize the 
extent of exposure to study medication.
The change from baseline in ABNAS, CBCL, and LGPT will be summarized. 
The change from baseline in growth (height, weight, thyroid, and IGF-1) will be summarized.
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The change from baseline in EEG parameters and the frequency of EEG abnormalities will be 
summarized.
Proportion of subjects with any treatment-emergent report of suicidal ideation and behavior and 
intensity of these behaviors will be summarized. 
Extension A
Safety analyses will be performed similarly to the Core Study analyses and all analyses will be on the 
perampanel treatment duration (Core Study and Extension A).  (revised per Amendment 03)  The 
incidence of TEAEs, SAEs, AEs associated with fatal outcomes or leading to discontinuations, and 
AEs leading to dose adjustment will be summarized.  Laboratory parameters, vital signs, and ECG 
parameters will be summarized.  Change from baseline in CBCL, ABNAS, and LGPT, change from 
baseline in growth parameters, change from baseline in EEG parameters, the frequency of EEG 
abnormalities, and the proportion of subjects with any treatment-emergent report of suicidal ideation 
and behavior and intensity of these behaviors, will also be summarized descriptively.  Baseline for 
these parameters is the last non-missing value before the 1st perampanel dose.
Extension B
Safety analyses for Extension B are described in Appendix 2.  (revised per Amendments 03 and 04)
Exploratory Analyses
The change from baseline in EQ-5D-Y at Week 23 and Week 52 will be summarized.
Interim Analyses
An independent data monitoring committee (DMC) will be constructed to monitor the safety data.  
The responsibilities, membership, and purpose of the DMC, the timing of the meeting(s), and an 
outline of the plan for review of the safety data will be documented in the DMC Charter.  
Analyses for regional submissions may be performed during the course of the study.  (revised per 
Amendment 02)
Sample Size Rationale
A sample size of at least 160 subjects (with up to 40 subjects with PGTC and the balance with POS), 
is deemed sufficient for safety evaluation in this age group (age 4 to <12 years).  (revised per 
Amendment 02)  This sample size matches the total number of adolescents who were enrolled in the 
4 global Phase 3 efficacy and safety studies that support the POS and PGTC indications.
For purposes of registration in Japan, it has been determined that a sample size of 65 subjects enrolled 
in Japan will provide 80% power to exclude the possibility that there would be a reduction smaller 
than that observed in the placebo arm of Study E2007-J000-335 (ie, 10.5%). 
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................14
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................20
5
ETHICS............................................................................................................................22
5.1
Institutional Review Boards/Independent Ethics Committees ..............................22
5.2
Ethical Conduct of the Study.................................................................................22
5.3
Subject Information and Informed Consent...........................................................23
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................24
7
INTRODUCTION ...........................................................................................................24
7.1
Planned Indication .................................................................................................24
7.2
Study Rationale......................................................................................................24
7.3
Dosing Rationale....................................................................................................27
8
STUDY OBJECTIVES....................................................................................................29
8.1
Primary Objective..................................................................................................29
8.2
Secondary Objective(s)..........................................................................................29
8.3
Exploratory Objective............................................................................................29
9
INVESTIGATIONAL PLAN..........................................................................................30
9.1
Overall Study Design and Plan..............................................................................30
9.1.1
Pretreatment Phase.......................................................................................32
9.1.2
Treatment Phase...........................................................................................32
9.1.2.1
Titration Period....................................................................................33
9.1.2.2
Maintenance Period .............................................................................33
9.1.2.3
Follow-Up Period.................................................................................34
9.1.3
Extension Phase (Extension A)....................................................................34
9.1.3.1
Maintenance Period .............................................................................34
9.1.3.2
Follow-Up Period.................................................................................34
9.1.4
Extension Phase B........................................................................................34
9.1.4.1
Treatment Phase...................................................................................34
9.1.4.2
Follow-up Period .................................................................................35
9.2
Discussion of Study Design, Including Choice of Control Groups.......................35
9.3
Selection of Study Population................................................................................35
9.3.1
Inclusion Criteria .........................................................................................36
9.3.2
Exclusion Criteria ........................................................................................36
9.3.3
Removal of Subjects From Therapy or Assessment....................................38
9.4
Treatment ...............................................................................................................39
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9.4.1
Treatment(s) Administered..........................................................................39
9.4.2
Identity of Investigational Product(s) ..........................................................41
9.4.2.1
Chemical Name, Structural Formula of E2007....................................42
9.4.2.2
Comparator Drug .................................................................................42
9.4.2.3
Labeling for Study Drug......................................................................42
9.4.2.4
Storage Conditions...............................................................................42
9.4.3
Method of Assigning Subjects to Treatment Groups...................................43
9.4.4
Selection of Doses in the Study...................................................................43
9.4.5
Selection and Timing of Dose for Each Subject..........................................43
9.4.6
Blinding........................................................................................................43
9.4.7
Prior and Concomitant Therapy...................................................................43
9.4.8
Treatment Compliance.................................................................................44
9.4.9
Drug Supplies and Accountability...............................................................44
9.5
Study Assessments.................................................................................................45
9.5.1
Assessments.................................................................................................45
9.5.1.1
Demography.........................................................................................45
9.5.1.2
Baseline Assessments ..........................................................................46
9.5.1.2.1
Medical History and Physical Examinations.................................46
9.5.1.2.2
Epilepsy Medical history ...............................................................46
9.5.1.3
Efficacy Assessments...........................................................................46
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................46
9.5.1.4.1
Pharmacokinetic Assessments .......................................................46
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................47
9.5.1.5
Safety Assessments..............................................................................47
9.5.1.5.1
Adverse Events and Events Associated With Special Situations ..47
9.5.1.5.2
Serious Adverse Events and Events Associated With Special 
Situations........................................................................................49
9.5.1.5.3
Laboratory Measurements .............................................................50
9.5.1.5.4
Vital Signs and Weight Measurements..........................................51
9.5.1.5.5
Physical Examinations...................................................................51
9.5.1.5.6
Electrocardiograms ........................................................................52
9.5.1.5.7
Other Safety Assessments..............................................................52
9.5.1.6
Other Assessments...............................................................................53
9.5.2
Schedule of Procedures/Assessments – Core Study....................................53
9.5.2.1
Schedule of Procedures/Assessments ..................................................53
9.5.2.2
Description of Procedures/Assessments Schedule...............................58
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9.5.3
Appropriateness of Measurements...............................................................58
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated With Special Situations .............................................................58
9.5.4.1
Reporting of Serious Adverse Events..................................................58
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................59
9.5.4.3
Reporting of Events Associated With Special Situations....................59
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................59
9.5.4.3.2
Reporting of Study-Specific Events...............................................60
9.5.4.4
Expedited Reporting ............................................................................60
9.5.4.5
Breaking the Blind...............................................................................60
9.5.4.6
Regulatory Reporting of Adverse Events ............................................60
9.5.5
Completion/Discontinuation of Subjects.....................................................60
9.5.6
Abuse or Diversion of Study Drug ..............................................................61
9.5.7
Confirmation of Medical Care by Another Physician .................................61
9.6
Data Quality Assurance .........................................................................................61
9.6.1
Data Collection ............................................................................................61
9.6.2
Clinical Data Management ..........................................................................62
9.7
Statistical Methods.................................................................................................62
9.7.1
Statistical and Analytical Plans....................................................................62
9.7.1.1
Study Endpoints...................................................................................62
9.7.1.1.1
Primary Endpoint...........................................................................62
9.7.1.1.2
Secondary Endpoints .....................................................................62
9.7.1.1.3
Exploratory Endpoint.....................................................................63
9.7.1.2
Definitions of Analysis Sets.................................................................63
9.7.1.3
Subject Disposition..............................................................................64
9.7.1.4
Demographic and Other Baseline Characteristics ...............................64
9.7.1.5
Prior and Concomitant Therapy...........................................................64
9.7.1.6
Efficacy Analyses ................................................................................64
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................65
9.7.1.7.1
Pharmacokinetic Analyses.............................................................65
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................66
9.7.1.8
Safety Analyses....................................................................................66
9.7.1.8.1
Extent of Exposure.........................................................................66
9.7.1.8.2
Adverse Events ..............................................................................66
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9.7.1.8.3
Laboratory Values..........................................................................67
9.7.1.8.4
Vital Signs......................................................................................68
9.7.1.8.5
Electrocardiograms ........................................................................68
9.7.1.8.6
Other Safety Analyses....................................................................68
9.7.1.9
Other Analyses.....................................................................................69
9.7.2
Determination of Sample Size .....................................................................69
9.7.3
Interim Analysis...........................................................................................69
9.7.4
Other Statistical/Analytical Issues ...............................................................69
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................69
10
REFERENCE LIST .........................................................................................................70
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......71
11.1
Changes to the Protocol .........................................................................................71
11.2
Adherence to the Protocol......................................................................................71
11.3
Monitoring Procedures...........................................................................................71
11.4
Recording of Data..................................................................................................72
11.5
Identification of Source Data.................................................................................72
11.6
Retention of Records..............................................................................................73
11.7
Auditing Procedures and Inspection......................................................................73
11.8
Handling of Study Drug.........................................................................................73
11.9
Publication of Results ............................................................................................74
11.10 Disclosure and Confidentiality ..............................................................................74
11.11 Discontinuation of Study .......................................................................................74
11.12 Subject Insurance and Indemnity...........................................................................75
11.13 Data Monitoring Committee..................................................................................75
12
APPENDICES .................................................................................................................76
LIST OF IN-TEXT TABLES
Table 1
Dosing Schedule (Global)..........................................................................40
Table 2
Dosing Schedule (Japan Only)...................................................................40
Table 3
Clinical Laboratory Tests...........................................................................51
Table 4
Schedule of Procedures/Assessments in Study E2007-G000-311:  Core 
Study ..........................................................................................................54
Table 5
Schedule of Procedures/Assessments in Study E2007-G000-311:  
Extension A (revised per Amendments 03 and 04) ...................................78
Table 6
Schedule of Procedures/Assessments in Study E2007-G000-311:  
Extension B (revised per Amendments 03 and 04.....................................87
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LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E2007-G000-311.................................................31
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LIST OF APPENDICES
Appendix 1
Extension Phase (Extension A)..................................................................77
Appendix 2
Extension Phase B (revised per Amendment 04) ......................................83
Appendix 3
Sponsor’s Grading for Laboratory Values.................................................89
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ABNAS
A-B neuropsychological assessment schedule
AE(s)
adverse event(s)
AED
antiepileptic drug
ALT
alanine aminotransferase
AST
aspartate aminotransferase
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
CBCL
Child Behavior Checklist
CGI
Clinical Global Impression
CGIC
Clinical Global Impression of Change
CGIS
Clinical Global Impression of Severity
CNS
central nervous system
CRAs
Clinical research associates
CRF
case report form
CRO(s)
contract research organization (s)
Css,av
average steady-state drug concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
CL/F
Clearance
DEA
Drug Enforcement Administration
DMC
Data Monitoring Committee
EAP
extended access program
eGFR
estimated glomerular filtration rate
EIAED
enzyme inducing antiepileptic drug
EMA
European Medicines Agency
EQ-5D-Y
EuroQol 5 Dimensions-Youth
FAS
Full Analysis Set
GTC
Generalized Tonic-Clonic
hCG
human chorionic gonadotropin
HRQL
health-related quality of life
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
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Abbreviation
Term
IGF-1
insulin-like growth factor-1
IP
investigational product 
IRB
Institutional Review Board
IxRS
interactive and response system
LGPT
Lafayette Grooved Pegboard Test
LNH
low/normal/high
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamics
PGTC
primary generalized tonic-clonic seizures
PI
principal investigator
PK
Pharmacokinetics
POS
partial-onset seizures
PT
preferred term
QTc
corrected QT interval (time from the beginning of the QRS complex to the end 
of the T wave, corrected for heart rate)
SAE
serious adverse event
SAP
statistical analysis plan
SMQ
standardized MedDRA queries
SOC
system organ class
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
ULN
upper limit of normal
VNS
vagal nerve stimulator
WBC
white blood cell
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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 Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 
(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 
associates [CRAs], 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 (PI) 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 investigator(s) 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 and Competent Authority 
within 90 days.  The end of the study will be the date of the last study visit for the last subject 
in the study.  The sponsor should also provide the IRB/IEC with a summary of the study’s 
outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and Competent Authority within 15 calendar days, 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 (SOP) 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 (2013).
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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, ICH.

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312.

European GCP Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies 
conducted within any EU country.  All suspected unexpected serious adverse reactions 
(SUSARs) will be reported, as required, to the Competent Authorities of all involved EU 
member states.

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law 
(Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP.
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject 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 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 Screening Visit before any study-specific procedures are performed.  No 
subject can enter the study before his/her informed consent has been obtained.  The local 
legal requirements will be followed with regards to consent and assent of minors.
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 and kept on 
file according to local procedures at the site.  If regionally required, separate written 
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informed consent will be obtained before entering the Extension Phase(s).  (revised per 
Amendment 03)
The subject 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.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 60 to 80 investigational sites in the US, EU, and Asia Pacific.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization(s) (CRO[s]) are listed in the 
Investigator Study File or Regulatory Binder provided to each site.
7
INTRODUCTION
7.1
Planned Indication
Perampanel is approved in the US and EU and other countries as an adjunctive treatment of 
partial-onset seizures (POS) with or without secondarily generalized seizures and primary 
generalized tonic-clonic seizures (PGTC) in patients with epilepsy aged 12 years and older.  
Eisai is seeking to expand both the POS indication and the PGTC indication to pediatric 
patients aged 4 years to less than 12 years.
7.2
Study Rationale
In the EU, Study E2007-G000-311 is part of the approved Pediatric Investigation Plan (PIP) 
to which Eisai is committed to perform.  In the US, Post Marketing Requirement (PMR) 
studies were issued by the FDA as deferred Pediatric Research Equity Act (PREA) 
requirements to evaluate perampanel in subjects less than 12 years of age for patients with 
epilepsy with both POS and PGTC.
An alternative regulatory pathway is being pursued by Eisai to attain the POS and PGTC 
indications in children ages 4 to equal or less than 12 years via extrapolation of adult and 
adolescent adjunctive therapy efficacy to this age group, in lieu of conducting pivotal 
efficacy studies.
This approach is based on the results of discussions amongst global epileptologist key 
opinion leaders as part of the Pediatric Epilepsy Academic Consortium on Extrapolation 
(PEACE) concerning whether efficacy and safety data established in adults for adjunctive 
POS can be extrapolated to establish efficacy and safety in children as young as 4 years of 
age.  This extrapolation approach is also consistent with criteria outlined in the draft 
European Medicines Agency (EMA) Concept paper on extrapolation of efficacy and safety in 
medicine development (EMA/129698/2012, June 2012).
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The Dec 2014 FDA Draft Guidance algorithm, outlined in the EMA Concept paper, provides 
an assumptions-based framework to evaluate if the extrapolation of efficacy from adults to 
the pediatric population is supported by available data.  Based on this algorithm, the pediatric 
study decision tree allows extrapolation if there is sufficient similarity of both disease 
progression and response to intervention between source and target population.  If the 
exposure-response relationship of the medicinal product is assumed to be similar, only 
pharmacokinetics (PK) studies for dose determination and safety studies are required.  
Similar principles are discussed in the EMA guidelines ‘ICH E11 Clinical Investigation of 
medicinal products in the pediatric population (CPMP/ICH/2711/99)’ and ‘Role of 
Pharmacokinetics in the development of medicinal products in the Pediatric Population 
(CHMP/EWP/147013/2004).’
Due to the challenges inherent in performing clinical trials in children, a systematic review of 
published clinical trials was performed to determine whether the efficacy of antiepileptic 
drugs (AEDs) in adults can be used to predict the efficacy of AEDs in the pediatric 
population.  This systematic review supports the extrapolation and efficacy results in adults 
to predict a similar adjunctive treatment response in 2 to 18 year old pediatric patients with 
POS (Pellock, et al., 2012).  Therefore, AEDs that are shown to be effective in adults with 
partial seizures also can be expected to be effective in children 4 years and older. 
There is a growing body of data indicating that AEDs used in pediatric populations have 
similar exposure-response profiles to those used in adults.  The FDA Algorithm of the 
Dec 2014 guidance offers the structure to assess when extrapolation is appropriate.  As part 
of the PEACE initiative and supported by the FDA Critical Path Project, FDA has been 
analyzing exposure-response similarity between adults and pediatric patients using the data 
of those marketed AEDs.  In November 2015, FDA communicated with Eisai as a sponsor of 
several approved AEDs that they have determined it is acceptable to extrapolate to pediatric 
patients 4 years of age and older the effectiveness of drugs approved for the treatment of POS 
in adults.
Existing data on the efficacy and safety of perampanel as treatment of POS and PGTC in 
adults and adolescents support exposure-response similarity in adolescents and adults.  These 
data include characterization of the PK data of perampanel in treatment of pediatric epilepsy 
patients from Study 232 (ages ≥2 to <12), as well as a consistent pattern of data 
demonstrating exposure-response similarity between adults and pediatrics among AEDs as a 
class.
Eisai considers that placebo-controlled efficacy and safety studies of perampanel in POS and 
PGTC therapy in children equal or greater than 4 to less than 12 years old may pose 
difficulties with regard to placebo use and recruitment challenges and proposed that the 
registration of perampanel for pediatric use be replaced with study designs consistent with 
the data extrapolation model.
The study will also address the potential concerns that a new AED could induce an 
aggravation of the clinical picture and/or have a negative impact on neuropsychological 
functioning, and growth and development.  One-hour (minimum) to 2-hour continuous EEG 
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recording at baseline and during treatment will be collected and all types of seizures that 
subjects experience prior and during the study will be recorded in patient seizure diary.  
Neuropsychological functioning and growth and development assessments will be included.
Study E2007-G000-311 is a multi-center, open-label study followed by an Extension Phase 
(Extension A) designed to evaluate the safety, tolerability, PK, and PK/pharmacodynamics 
(PD) of perampanel as an adjunctive therapy for POS or PGTC or both.  The Core Study 
consists of a Pretreatment and Treatment Phase.  The Pretreatment Phase will consist of a 
Screening/Baseline Period, which may last for up to 4 weeks ±3 days outside of Japan.  
Subjects in Japan are required to complete 4 full weeks ±3 days of the Screening/Baseline 
Period.  However, subjects outside of Japan may begin treatment as soon as baseline 
procedures have been completed and documentation of eligibility (such as a documented 
seizure diary entry for a qualifying seizure during the preceding 12 weeks prior to Visit 2 or a 
qualifying seizure during the prospective Screening/Baseline Period) has been established. 
(revised per Amendment 02) During this phase, subjects will be assessed for eligibility to 
participate in the study.  The Treatment Phase will consist of 3 periods:  Titration (up to 11 
weeks), Maintenance (up to 12 weeks), and Follow-up (up to 4 weeks; only for those subjects 
not rolling over into Extension A). Extension A will consist of a Maintenance Period (up to 
29 weeks) and a Follow-up Period (up to 4 weeks; only for those subjects not entering into 
Extension B [Japan and countries where an extended access program (EAP) cannot be 
implemented]).  (revised per Amendments 01, 02, 03, and 04)  Subjects in Japan and in 
countries where an EAP cannot be implemented, after having completed Extension A, will be 
eligible to participate in an Extension B.  (revised per Amendments 03 and 04)  Subjects will 
be stratified by age groups (≥4 to <7 years, ≥7 to <12 years) with at least 30% of the subjects 
enrolled in the equal or greater than 4 to less than 7 years age group.
The primary objective of this study is to determine the safety and tolerability of perampanel 
oral suspension when administered as an adjunctive therapy in children equal or greater than
4 to less than 12 years old with POS or PGTC.  Plasma PK sampling will be optimized to 
confirm that the PK profile in children is characterized.  Clinical efficacy data will be 
collected to confirm the PK/PD relationship for both POS and PGTC.
Since many other seizure types may coexist in children presenting with PGTC, seizure 
diaries will collect all types of seizures to evaluate whether perampanel contributes to the 
deterioration of other seizure types.  
In addition to other safety parameters, EEGs will be recorded at awake and sleep states to 
evaluate whether perampanel could induce an aggravation of the clinical picture, which was 
incorporated per recommendation by the Committee for Medicinal Products for Human Use
(CHMP) Scientific Advice.
The effect of perampanel on neuropsychological parameters, including cognition, behavior, 
visuomotor skills, and growth and development will also be evaluated per recommendation 
by the CHMP Scientific Advice. 
The A-B neuropsychological assessment schedule 
(ABNAS), a measure of patient-perceived cognitive effects of AEDs.  The Child Behavior 
Checklist (CBCL) obtains reports from the parent/caregiver regarding the subject’s 
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competencies and behavioral/emotional problems.  Visuomotor skills will be assessed using
the Lafayette Grooved Pegboard Test (LGPT), which is a manipulative dexterity test. 
The EuroQol 5 Dimensions-Youth (EQ-5D-Y) questionnaire will be administered to assess 
how perampanel impacts patients’ health-related quality of life (HRQL).  HRQL assessment 
is a requirement for reimbursement submissions both as a qualitative assessment of the net 
impact of a drug’s clinical benefit and AE profile on patients as well as to quantitatively 
adjust incremental life-year estimates in economic models by the quality of those life-years 
gained.  The EQ-5D is a well-accepted instrument for assessing HRQL for these purposes.  
The EQ-5D-Y been developed by EuroQol to assess HRQL in children ages 15 and younger.  
The same five concepts of mobility, self-care, ability to participate in usual activities, pain, 
and anxiety/depression are assessed; only the language utilized to elicit this information has 
been modified to be child-appropriate (eg, simpler vocabulary and child-appropriate 
examples of usual activities).  A proxy version of the EQ-5D-Y is available for children aged
4 to 7 so that caregivers may complete the questionnaire for children whose literacy level 
may be insufficient.
During the Core Study, no change of concomitant AEDs is allowed.  However, during the 
Extension Maintenance Period, addition, deletion, and dose changes to the concomitant 
AEDs are allowed.  Conversion to monotherapy on perampanel is also permitted at the 
discretion of the investigator, if it is considered appropriate to control the seizures.
7.3
Dosing Rationale
Support for the dosing regimen was based on the population PK analysis of the pooled data 
including the data from the clinical study in subjects 2 to 12 years of age with epilepsy 
(E2007-G000-232).  A PK analysis of data from Study 232 comparing dose-normalized 
perampanel concentrations in 42 pediatric epilepsy subjects (aged ≥2 to <12 years) with 
dose-normalized perampanel concentrations from adolescent subjects (aged ≥12 to 
<18 years) in Studies 304, 305, and 306 was conducted.  Of the 42 subjects with wide range 
of body weights (ie, 12.2 to 90.9 kg) analyzed to date, 20 were aged equal or greater than 2 to 
less than 7 years and 22 were aged equal or greater than 7 to less than 12 years.  A total of 
28 subjects were without any concomitant enzyme inducing co-medications (carbamazepine, 
phenytoin, and oxcarbazepine) and 14 subjects were receiving one of these inducers.  
Subjects in Study 232 were administered perampanel suspension (0.5 mg/mL) according to a 
weight-based regimen compared to tablets in Studies 304, 305, and 306.
The results of the analysis demonstrated that perampanel PK was linear as there was no dose 
or time-dependency to oral clearance (CL/F).  The CL/F was not significantly affected by 
age, body weight, gender, race, hepatic function markers (alanine aminotransferase [ALT] or 
aspartate aminotransferase [AST]), renal function marker (creatinine CL/F) or the use of the 
oral suspension formulation in this population.  The predicted perampanel average steady 
state plasma concentration dose normalized to 0.12 mg/kg in pediatrics (intended to 
correspond to 8 mg/70 kg in adults/adolescents) for Study 232 were lower than that at 8 mg 
dose in adolescents from previous Phase 2 and 3 studies.  Since predicted CL/F was 
comparable among the 3 categorical groups (age ≥2 to <7, ≥7 to <12, and ≥12 to <18 years) 
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independent of weight, the lower steady state concentration was deemed to be due to the 
lower total dose (mg/person) administered in pediatric subjects.  The results of the analysis 
suggested that a flat dosing approach will be more appropriate in patients within the age 
range of 2 to less than 12 years.
In Study 311, subjects will be stratified by concomitant use of enzyme inducing antiepileptic 
drugs (EIAED) and will be titrated as per a dosing schedule (Section 9.4) based on individual 
clinical response and tolerability no more frequently than at weekly intervals to up to 
8 mg/day for non-EIAED subjects or 12 mg/day for EIAED subjects.  With the exception of 
subjects enrolled in Japan, EIAED subjects may go beyond 12 mg/day and up to 16 mg/day
if they tolerate 12 mg/day and are deemed likely to benefit from a higher dose.  Non-EIAED 
subjects may go beyond 8 mg/day and up to 12 mg/day if they tolerate 8 mg/day and are 
deemed likely to benefit from a higher dose.  Regardless of EIAED status, subjects enrolled 
in Japan may not receive doses higher than 12 mg/day.
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to evaluate the safety and tolerability of perampanel 
oral suspension when administered as an adjunctive therapy in children (ages 4 to <12 years) 
with inadequately controlled POS or PGTC.
8.2
Secondary Objective(s)
The secondary objectives of the study are:
1. To characterize the PK of perampanel and the relationship between perampanel 
plasma concentrations, efficacy, and safety using population PK/PD modeling.
2. To evaluate the effects of perampanel on cognition, behavior, visuomotor skills, and 
growth and development in children during short-term (23 weeks) and long-term (up 
to 52 weeks) treatment.
3. To evaluate the frequency of EEG abnormalities during awake and sleep state during 
52 weeks of treatment.
4. To evaluate suicidal ideation and suicidal behavior in children 6 years to less than 
12 years as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) 
during 52 weeks of treatment.
5. To evaluate the efficacy of perampanel as measured by the median percent change 
per 28 days in seizure frequency, by the proportion of responders (≥25%, ≥50%, and 
≥75%), and by the proportion of subjects who are seizure-free for POS, PGTC, and 
Generalized Tonic-Clonic (GTC) seizures.
6. To evaluate, in Japanese subjects, the efficacy of perampanel on POS in the present 
study as compared with placebo in Study E2007-J000-335.
7. To assess the effects of perampanel on the Clinical Global Impression (CGI), as 
measured by CGI of Change (CGIC). (revised per Amendment 04)
8.3
Exploratory Objective
To assess the impact of perampanel on the health utility of children using the 
EuroQol 5 Dimensions-Youth (EQ-5D-Y) scale.
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, open-label single-arm study in children (ages 4 to <12 years) with 
inadequately controlled POS or PGTC. The study will consist of a Core Study and Extension 
Phase (Extension A, for all countries in the study) with Extension Phase (Extension B) 
available for subjects enrolled in Japan and in countries where an EAP cannot be 
implemented, after having completed Extension A.
(revised per Amendments 03 and 04)  
Subjects will be stratified by age (≥4 to <7 years, 7 to <12 years) with at least 30% of 
subjects enrolled in the equal or greater than 4 to less than 7 year age group for each seizure 
type (ie, at least 36 with POS and at least 12 with PGTC). 
Core Study
The Core Study will consist of the following 2 phases: Pretreatment and Treatment Phase.
The Pretreatment Phase will consist of a Screening/Baseline Period that lasts up to 4 weeks
±3 days outside of Japan. Subjects in Japan are required to complete 4 full weeks ±3 days of 
the Screening/Baseline Period. However, subjects outside of Japan may begin treatment as 
soon as baseline procedures have been completed and documentation of eligibility (such as a 
documented seizure diary entry for a qualifying seizure during the preceding 12 weeks prior 
to Visit 2 or a qualifying seizure during the prospective Screening/Baseline Period) has been 
established.  (revised per Amendment 02) During this phase, subjects will be assessed for 
eligibility to participate in the study. 
Efforts should be made to perform all clinical 
laboratory and screening tests on the scheduled day of Visit 1, or as close as possible to that 
day, within the 4 week period prior to Visit 2.  (revised per Amendment 01)
The Treatment Phase will consist of 3 periods:  Titration (up to 11 weeks), Maintenance (up 
to 12 weeks), and Follow-up (up to 4 weeks; only for those subjects not rolling over into 
Extension A).  (revised per Amendments 01, 02, and 03)
Extension A
Extension A will consist of a Maintenance Period (up to 29 weeks) and a Follow-up Period 
(up to 4 weeks; only for those subjects not entering into Extension B).  (revised per 
Amendments 02, 03, and 04)
An overview of the study design is presented in Figure 1.
Extension B
Extension B will be available to subjects enrolled in Japan and in countries where an EAP 
cannot be implemented.  Extension B will consist of an open-label Treatment Phase.  In 
Japan, treatment will continue as long as clinically appropriate according to the judgment of 
the investigator.  However, treatment of subjects in Extension B will be completed when the 
subject reaches 12 years of age or when perampanel is commercially available in Japan for 
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treatment of POS in pediatric subjects (4 to less than 12 years of age).  In countries where an 
EAP cannot be implemented, participation in Extension B will continue as long as clinically 
appropriate according to the judgment of the investigator, until the subject reaches 12 years 
of age or perampanel oral suspension is commercially available.  Subjects who discontinue or 
choose not to switch to the commercial product will require a Follow-up Visit which will be 
conducted 4 weeks (±7 days) after the Discontinuation Visit.  (revised per Amendments 03
and 04)
Figure 1
Study Design for Study E2007-G000-311
Note:  (revised per Amendments 02 and 03)
Follow-up can occur during the Core Study (if the subject discontinued during the Core 
Study), or during Extension A or Extension B, after the termination of study treatment.
EIAED = enzyme inducing antiepileptic drug, S = stratified, wks = weeks.
a:
Subjects will have a Follow-up Visit 4 weeks (±7 days) after the end of the treatment and 
a final assessment completed if they are not rolling over into Extension A.
b:
Subjects who are enrolled in Japan and in countries where an EAP cannot be 
implemented, and have completed the Extension A, will be eligible to enroll in Extension
B, as detailed in Appendix 2.  (revised per Amendments 03 and 04)  Subjects in Japan are 
required to complete 4 full weeks ±3 days of the Screening/Baseline Period.  (revised per 
Amendment 02)
Period:
Screening/Baseline
S
perampanel – 16 mg/day 
(12 mg in Japan) (EIAED)
Up to 4 wks ±3 days outside of Japan
4 wks ±3 days in Japanc
Day 1
27 wks
56 wks
Core Study
Titration
Maintenance
11 wks
23 wks
Phase:
S
Subjects ≥4 to 
<7 years old
Subjects 7 to 
<12 years old
Pretreatment
Treatment
Follow-Upa
Extension Ab
perampanel – 12 mg/day 
(Non-EIAED)
Perampanel – 16 mg/day 
(12 mg in Japan) (EIAED)
perampanel – 12 mg/day 
(Non-EIAED)
52 wks
Follow-
up
Maintenance
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9.1.1
Pretreatment Phase
The Pretreatment Phase will consist of a Screening/Baseline Period that last up to 4 weeks 
±3 days outside of Japan.  Subjects in Japan are required to complete 4 full weeks ±3 days of 
the Screening/Baseline Period. However, subjects outside of Japan may begin treatment as 
soon as baseline procedures have been completed and documentation of eligibility (such as a 
documented seizure diary entry for a qualifying seizure during the preceding 12 weeks prior 
to Visit 2 or a qualifying seizure during the prospective Screening/Baseline Period) has been 
established.  (revised per Amendment 02) During this phase, subjects will be assessed for 
eligibility to participate in the study.  Subjects will be stratified by age (≥4 to <7 years, 7 to 
<12 years) with at least 30% of subjects enrolled in the equal or greater than 4 to less than 
7 year age group for each seizure type (ie, at least 36 with POS and at least 12 with PGTC).  
The purpose of the Screening Period is to obtain informed consent and to establish protocol 
eligibility.  Informed consent will be obtained after the study has been fully explained to each 
subject and before the conduct of any screening procedures or assessments.  Procedures to be 
followed when obtaining informed consent are detailed in Section 5.3.
Subjects must have a diagnosis of epilepsy with partial seizures, with or without secondary 
generalized seizures, or PGTC, according to International League Against Epilepsy’s (ILAE) 
Classification of Epileptic seizures and confirmed by EEG and clinical history.  
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable.
During the 12-week period preceding Visit 2 (up to 8 weeks prior to Visit 1 and up to 
4 weeks prior to Visit 2, inclusive), subjects must have had 1 or more POS or PGTC.  
(revised per Amendments 01 and 02)  The POS should include simple partial seizures with 
motor signs, complex POS, and complex POS with secondary generalization.  Subjects must 
be on stable doses of 1 to a maximum of 3 approved AEDs.  Only 1 EIAED out of the 
maximum of 3 AEDs is allowed.  (revised per Amendment 01)
Subjects who complete the Screening/Baseline Period and meet the criteria for 
inclusion/exclusion (Sections 9.3.1 and 6) will begin the Treatment Phase.
9.1.2
Treatment Phase
The duration of the Treatment Phase will be up to 27 weeks and will include 3 periods:  
Titration, Maintenance,
and Follow-up
(only for those subjects not entering into 
Extension A). (revised per Amendments 02 and 03) Subjects whose screening assessments 
and evaluations are completed and reviewed by the PI and who continue to meet all of the 
inclusion/exclusion criteria will enter the Treatment Phase.
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9.1.2.1
Titration Period
During the Titration Period, subjects will be stratified by the presence or absence of 
concomitant EIAEDs and will be titrated using the dosing schedule based on individual 
clinical response and tolerability no more frequently than at weekly intervals, up to 8 mg/day 
for non-EIAED subjects or 12 mg/day for EIAED subjects.  With the exception of subjects 
enrolled in Japan, EIAED subjects may titrate beyond 12 mg/day and up to 16 mg/day if they 
tolerate 12 mg/day and are deemed likely to benefit from a higher dose.  Non-EIAED 
subjects may go beyond 8 mg/day and up to 12 mg/day if they tolerate 8 mg/day and are 
deemed likely to benefit from a higher dose.  Subjects will be flexibly dosed based on 
individual tolerability.  Regardless of EIAED status, subjects enrolled in Japan may not 
received doses higher than 12 mg/day.  The Titration Period is a duration of up to 11 weeks,
during which multiple dose adjustments are allowed in order to identify each subject’s 
optimum dose. All visits are to be done within ±3 days of the schedule.  Each study visit is 
based on the actual prior visit (eg, Visit 3 is completed 2 weeks ±3 days of Visit 2, Visit 4 is 
completed 3 weeks ±3 days of Visit 3, Visit 5 is completed 3 weeks ±3 days of Visit 4).  
(revised per Amendment 02) Subjects will remain on their optimum dose once it is achieved 
during the Titration Period.  (revised per Amendment 01)  The dosing schedule is illustrated 
in Table 1.
According to the investigator’s clinical judgment, subjects experiencing intolerability at any 
dose may remain at the same dose or have their dose decreased 1 dose level down to the 
previously tolerated dose.  If the subject continues to present significant intolerable AEs at 
the decreased dose and the investigator deems it is necessary, the dose can be decreased 
further to the next dose level down.  Dose decreases can be done via telephone.  Subjects 
whose dose has been decreased can have their dose increased again if tolerability improves; 
this can be done at the next clinic visit after the investigator has deemed it is appropriate in 
view of resolution of the AE(s).  Multiple dose adjustments will be allowed during the 
Titration Period.  Only upon completion of the 11 weeks Titration Period, subjects will enter 
the Maintenance Period.  (revised per Amendment 01)
9.1.2.2
Maintenance Period
During the Maintenance Period of the Core Study (up to 12-week), subjects will continue 
taking perampanel oral suspension once daily at the dose level they achieved at the end of the 
Titration Period.  (revised per Amendment 02)  Multiple dose adjustment is allowed if a 
subject is experiencing intolerable AE(s) or a higher dose is deemed to be beneficial. All 
visits are to be done within ±7 days of the schedule.  Each study visit is based on the actual 
prior visit (eg, Visit 6 is completed 3 weeks ±7 days of Visit 5, Visit 7 is completed 4 weeks 
±7 days of Visit 6, Visit 8 is completed 4 weeks ±7 days of Visit 7, Visit 9 is completed 
4 weeks ±7 days of Visit 8).  (revised per Amendment 02)
During the Titration and Maintenance Periods, all dose adjustments will be done via 1 dose 
level up or down.  Those who cannot tolerate a minimum of 2 mg dose must discontinue 
from the study.
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9.1.2.3
Follow-Up Period
Follow-up Visit should be conducted 4 weeks (±7 days) after the last dose of study drug for 
all subjects, except for subjects entering into Extension A.  (revised per Amendment 03)
9.1.3
Extension Phase (Extension A)
Extension A will consist of a Maintenance Period (up to 29 weeks) and a Follow-up Period 
(up to 4 weeks; only for those subjects not entering into Extension B).  Visit 10 is completed 
5 weeks ±6 days of Visit 9.  (revised per Amendments 02, 03, and 04)
All subjects who complete all scheduled visits up to and including Visit 9 in the Treatment 
Phase will be eligible to participate in Extension A of the study.  (revised per 
Amendment 03)
See Appendix 1 for a full description of the Extension A.  (revised per Amendment 03)
9.1.3.1
Maintenance Period
During the Maintenance Period of Extension A, all subjects will continue with their optimal 
perampanel dose (ie, that dose level that they completed on during the Core Study).  (revised 
per Amendment 03)  Multiple dose adjustment is allowed if a subject is experiencing 
intolerable AE(s) or a higher dose is deemed to be beneficial.  The maximum dose is up to 
12 mg/day for non-EIAED subjects or up to 16 mg/day for EIAED subjects, except that 
subjects enrolled in Japan may not receive doses higher than 12 mg/day regardless of EIAED 
status.  Addition, deletion, and dose changes to the concomitant AEDs are allowed during 
Extension Maintenance Period.  Conversion to monotherapy on perampanel is also permitted 
at the discretion of the investigator, if it is considered appropriate to control the seizures.
9.1.3.2
Follow-Up Period
Follow-up Visit should be conducted 4 weeks (±7 days) after the last dose of study drug for 
all subjects, except for subjects in Japan or in countries where an EAP cannot be 
implemented, who are entering into Extension B.  (revised per Amendments 03 and 04)
9.1.4
Extension Phase B
9.1.4.1
Treatment Phase
Subjects in Japan and in countries where an EAP cannot be implemented, after having
completed Extension A, will be eligible to participate in Extension B.  Extension B will 
consist of a Treatment Phase which will continue as long as clinically appropriate according 
to the judgment of the investigator.  In Japan, treatment of subjects in Extension B will be 
completed when the subject reaches 12 years of age or when perampanel is commercially 
available in Japan for treatment of POS in pediatric subjects (4 to less than 12 years of age).  
In countries where an EAP cannot be implemented, participation in Extension B will 
continue as long as clinically appropriate according to the judgment of the investigator, until 
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the subject reaches 12 years of age or perampanel oral suspension is commercially available. 
(revised per Amendment 04)
Subjects will enter Extension B with their optimal perampanel dose (ie, the same dose of 
perampanel that they were maintained on at the end of Extension A).  During the course of 
the Extension B, doses of perampanel and concomitant AEDs can be adjusted (concomitant 
AEDs can be used in accordance with the approved dosage and indication) based on clinical 
judgment. In Japan, the maximum dose of perampanel is 12 mg/day.  (revised per 
Amendment 04)
In countries where an EAP cannot be implemented, the maximum dose of perampanel is 
12 mg/day in subjects not taking any concomitant EIAEDs, or 16 mg/day in subjects taking a 
concomitant EIAED. (revised per Amendment 04) 
Tolerability at a minimum perampanel dose of 2 mg/day is required to continue in the
program.  Subjects who do not tolerate the minimum perampanel dose of 2 mg/day during 
the study will be discontinued from the study. (revised per Amendment 04)
Conversion to monotherapy on perampanel is also permitted at the discretion of the 
investigator, if it is considered appropriate to control the seizures.  
See Appendix 2 for a full description of Extension B.  (revised per Amendment 03)
9.1.4.2
Follow-up Period
Subjects who discontinue or choose not to switch to the commercial product will require a 
Follow-up Visit which will be conducted 4 weeks (±7 days) after the Discontinuation Visit.  
(revised per Amendment 04)
9.2
Discussion of Study Design, Including Choice of Control Groups
Study E2007-G000-311 is a multi-center, open-label study followed by an Extension Phase
designed to evaluate the safety, tolerability, PK, and PK/PD of perampanel as an adjunctive 
therapy for POS and PGTC.
To maintain seizure control in subjects with POS or PGTC during studies of investigational 
AEDs, the investigational AEDs are administered as adjunctive treatment while maintaining 
the subject’s existing AED regimen.
9.3
Selection of Study Population
At least 160 subjects at approximately 60 to 80 sites in the US, EU, and Asia Pacific will be 
enrolled.  (revised per Amendment 02)  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.
The study population of at least 160 subjects who will be enrolled and treated will include up 
to 40 subjects with PGTC and the balance with POS. (revised per Amendment 02) A 
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minimum of 30% of the subjects for each seizure type will be enrolled in the younger age 
group (4 to <7 years) (ie, at least 36 with POS and at least 12 with PGTC)
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Have a diagnosis of epilepsy with POS with or without secondarily generalized seizures 
or PGTC according to the ILAE Classification of Epileptic Seizures (1981).  Diagnosis 
should have been established at least 6 months prior to Visit 1 by clinical history and an 
EEG that is consistent with the diagnosis; normal interictal EEGs will be allowed 
provided that the subject meets the other diagnosis criterion (ie, clinical history).
2. Male or female subject, from age 4 to less than 12 years at the time of informed 
consent/assent.
3. Have a minimum weight of 16 kg (35 lb).
4. Have had a brain imaging (eg, magnetic resonance imaging [MRI] scan or computed 
tomography [CT]) before Visit 1 that ruled out a progressive cause of epilepsy.
5. During the 12 weeks ±3 days (4 weeks ±3 days in Japan only) prior to Visit 2, subjects 
must have had equal or greater than 1 POS or 1 PGTC seizure.  (revised per 
Amendments 01 and 02)  Only simple POS with motor signs, complex POS, and 
complex POS with secondary generalization are counted toward this inclusion for POS.  
6. Are currently being treated with stable doses of 1 to a maximum of 3 approved AEDs. 
(revised per Amendment 01) Doses must be stable for at least 4 weeks before to Visit 1; 
in the case where a new AED regimen has been initiated for a subject, the dose must be 
stable for at least 8 weeks prior to Visit 1.  Only 1 EIAED (defined as carbamazepine, 
phenytoin, oxcarbazepine, or eslicarbazepine) out of the maximum of 3 AEDs is allowed 
(A vagal nerve stimulator [VNS] will be counted as one of the 3 allowed AEDs).
(revised per Amendment 01)
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by 
a positive beta-human chorionic gonadotropin [β-hCG] or human chorionic 
gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of 
β-hCG [or hCG]).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the 1st dose of study drug.
2. Females of childbearing potential who:

Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study period 
or for 28 days after study drug discontinuation.  If a highly effective method is not 
appropriate or acceptable for the subject, then the subject may use a medically 
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effective method (eg, a double barrier method such as condom plus diaphragm with 
spermicide).

Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexually active during the study period or for 28 days after 
study drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use 
the same contraceptive during the study or for 28 days after study drug 
discontinuation.
3. Current or history of pseudo-seizures (psychogenic nonepileptic seizures) within 
approximately 5 years before Visit 1.
4. Have a history of status epilepticus that required hospitalization during the 6 months 
before to Visit 1.
5. Have an unstable psychiatric diagnosis that may confound subjects’ ability to participate 
the study or that may prevent completion of the protocol specified tests (eg, significant 
suicide risk, including suicidal behavior and ideation within 6 months before Visit 1,
current psychotic disorder, acute mania).
6. Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 
(ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS) 
in subjects aged 6 and above.
7. Are scheduled or confirmed or both to have epilepsy surgery within 6 months after 
Visit 1; however, those who have previously documented “failed” epilepsy surgery will 
be allowed.
8. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments.
9. Evidence of moderate or severe renal insufficiency as defined by estimated glomerular 
filtration rates (eGFRs) of 31 to <60 mL/min and <30 mL/min, respectively.  (revised 
per Amendment 01)
10. Evidence of significant active hepatic disease.  Stable elevation of liver enzymes, ALT
and AST due to concomitant medication(s), will be allowed if they are less than 3 times 
the upper limit of normal (ULN).
11. Evidence of significant active hematological disease; white blood cell (WBC) count 
equal or less than 2500/µL (2.50 1E+09/L), or an absolute neutrophil count equal or less 
than 1000/µL (1.00 1E+09/L).
12. Clinically significant ECG abnormality, including prolonged corrected QT interval 
(QTc) defined as greater than 450 msec.
13. Have a progressive central nervous system (CNS) disease, including degenerative CNS 
diseases and progressive tumors.
14. Multiple drug allergies or a severe drug reaction to an AED(s), including dermatological 
(eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
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15. Concomitant use of felbamate as an AED for less than 2 years or where the dose has not 
been stable for at least 8 weeks before Visit 1.  They must not have a history of WBC 
count below equal or less than 2500/μL (2.50 1E+09/L), platelets below 100,000, liver 
function tests (LFTs) above 3 times the ULN, or other indication of hepatic or bone 
marrow dysfunction while receiving felbamate.  If subjects received felbamate in the 
past, it must have been discontinued 8 weeks before Visit 1 to be eligible for study 
participation.
16. Concomitant use of vigabatrin:  Subjects who took vigabatrin in the past must be off 
vigabatrin for at least 5 months before Visit 1 and with documentation showing no 
evidence of a vigabatrin associated clinically significant abnormality in a visual 
perimetry test.
17. Concomitant use of cannabinoids.  (revised per Amendment 01)
18. Used benzodiazepines for epilepsy during which the dose has not been stable for greater 
than 4 weeks prior to Visit 1.
Benzodiazepines use as rescue medication for seizure 
control is allowed; however, intermittent use of benzodiazepines for any other indication 
(eg, anxiety/sleep disorders) is prohibited.  (revised per Amendment 01)
19. A VNS implanted less than 5 months before Visit 1 or changes in parameter less than 
4 weeks before Visit 1 (or thereafter during the study).
20. On a ketogenic diet for which the diet is not stable regimen for at least 4 weeks before to 
Visit 1.
21. History of or a concomitant medical condition that in the opinion of the investigator(s) 
would preclude the subject’s participation in a clinical study or compromise the 
subject’s ability to safely complete the study.
22. Have previously exposed to perampanel in a clinical trial or by prescription for more 
than 2 months or discontinued for AEs.
23. Have participated in a study involving administration of an investigational drug or 
device within 4 weeks before Visit 1, or within approximately 5 half-lives of the 
previous investigational compound, whichever is longer.
24. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption.  (revised per Amendment 01)
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
In the event a subject discontinues the study early for any reason after Visit 2 in Core Study, 
an Early Discontinuation Visit will be performed.  The subject should also return 4 weeks 
(±7 days) after Visit 9 or the last dose of study drug to complete the Follow-up Visit 
procedures.  In the event a subject discontinues the study early for any reason before Visit 12 
in Extension A, an Early Discontinuation Visit and a Follow-up visit 4 weeks (±7 days) after 
the last dose of study drug will be performed. (revised per Amendment 03)  The Subject 
Disposition CRF will be completed indicating the primary reason for discontinuation and all 
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other reasons contributing to the subject’s discontinuation from treatment.  In addition, the 
date of last dose of study drug will be recorded on the Study Drug Dosing CRF.
9.4
Treatment
Test drug for this study will be perampanel, oral solution, 0.5 mg/mL.  Dosing will be 
administered orally and daily.  Dosing will occur at bedtime.
9.4.1
Treatment(s) Administered
Core Study
Pretreatment Phase:
The Pretreatment Phase will consist of a Screening/Baseline Period that lasts up to 4 weeks
±3 days outside of Japan. Subjects in Japan are required to complete 4 full weeks ±3 days of 
the Screening/Baseline Period before they may enter the Treatment Phase (ie, Visit 2).  
However, subjects outside of Japan may begin treatment as soon as baseline procedures have 
been completed and documentation of eligibility (such as a documented seizure diary entry 
for a qualifying seizure during the preceding 12 weeks prior to Visit 2 or a qualifying seizure 
during the prospective Screening/Baseline Period) has been established. 
(revised per 
Amendment 02) During this phase, subjects will continue to take their baseline AEDs 
regimen as allowed per inclusion/exclusion criteria.  No study drug will be administered to 
subjects during this phase.
Treatment Phase:
The treatment phase will consist of 3 periods:  Titration (up to 11 weeks), Maintenance (up to 
12 weeks), and Follow-up (up to 4 weeks; only for those subjects not rolling over into 
Extension A).  (revised per Amendments 01, 02, and 03)

Titration Period
During the Titration Period, subjects will be stratified by the presence or absence of 
concomitant EIAEDs and will be titrated using the dosing schedule presented in Table 1
(Global) and Table 2 (Japan only) based on individual clinical response and tolerability no 
more frequently than at weekly intervals, up to 8 mg/day of perampanel for non-EIAED 
subjects or 12 mg/day for EIAED subjects.  (revised per Amendment 01)  EIAED subjects 
who are not enrolled in Japan may titrate beyond 12 mg/day and up to 16 mg/day if they 
tolerate 12 mg/day and are deemed likely to benefit from a higher dose.  Subjects enrolled in 
Japan and receiving EIAEDs may not receive doses higher than 12 mg/day.  Non-EIAED 
subjects may go beyond 8 mg/day and up to 12 mg/day if they tolerate 8 mg/day and are 
deemed likely to benefit from a higher dose.  Subjects will be flexibly dosed based on 
individual tolerability.  The Titration Period is a duration of up to 11 weeks during which 
multiple dose adjustments are allowed in order to identify each subject’s optimum dose. 
(revised per Amendment 02) Subjects will remain on their optimum dose once it is achieved 
during the Titration Period.  (revised per Amendment 01)
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Table 1
Dosing Schedule (Global)
(revised per Amendment 01)
Week
Subjects on Concomitant EIAEDs
(mg/day)
Subjects NOT on Concomitant 
EIAEDs
(mg/day)
0
4
2
1
6
4
2
8
6
3
10
6
4
10
8
5
12
8
6
12
10
7
14
10
8
14
12
9
16
12
10
16
—
EIAED = enzyme inducing antiepileptic drug.
For subjects not on concomitant EIAEDs, titration above 8 mg/day doses is contingent on subject tolerability.
Table 2
Dosing Schedule (Japan Only)
(revised per Amendment 01)
Week
Subjects on Concomitant EIAEDs
(mg/day)
Subjects NOT on Concomitant 
EIAEDs
(mg/day)
0
2
2
1
4
4
2
6
6
3
6
6
4
8
8
5
8
8
6
10
10
7
10
10
8
12
12
9
12
12
10
—
—
EIAED = enzyme inducing antiepileptic drug.
For subjects not on concomitant EIAEDs, titration above 8 mg/day doses is contingent on subject tolerability.
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According to the investigator’s clinical judgment, subjects experiencing intolerability at any 
dose may remain at the same dose or have their dose decreased 1 dose level down to the 
previously tolerated dose.  If the subject continues to present significant intolerable AE(s) at 
the decreased dose and the investigator deems it is necessary, the dose can be decreased 
further to the next dose level down.  Dose decreases can be done via telephone.  Subjects 
whose dose has been decreased can have their dose increased again if tolerability improves; 
this can be done at the next clinic visit after the investigator has deemed it is appropriate in 
view of resolution of the AE(s).  Multiple dose adjustments will be allowed during the 
Titration Period.  Upon completion of the Titration Period, subjects will enter the 
Maintenance Period.

Maintenance Period
During the Maintenance Period of the Core Study (up to 12 week), subjects will continue 
taking perampanel oral suspension once daily at the dose level they achieved at the end of the 
Titration Period.  Multiple dose adjustment is allowed if a subject is experiencing intolerable 
AE(s) or a higher dose is deemed to be beneficial.  All visits are to be done within ±7 days of 
the schedule.  Each study visit is based on the actual prior visit (eg, Visit 6 is completed 
3 weeks ±7 days of Visit 5, Visit 7 is completed 4 weeks ±7 days of Visit 6, Visit 8 is 
completed 4 weeks ±7 days of Visit 7, Visit 9 is completed 4 weeks ±7 days of Visit 8.  
(revised per Amendment 02)
During the Titration and Maintenance Periods, all dose adjustments will be done via 1 dose 
level up or down.  Those who cannot tolerate a minimum of 2 mg dose must discontinue 
from the study.
Extension A
Details on treatments administered during Extension A are provided in Appendix 1.  (revised 
per Amendment 03)
Extension B
Details on treatments administered during Extension B are provided in Appendix 2.  (revised 
per Amendment 03)
9.4.2
Identity of Investigational Product(s)
Perampanel oral suspension will consist of the active ingredient, perampanel, and assorted 
excipients (all of which are considered appropriate for use in a pediatric population) 
suspended in a water-based medium.  The resulting suspension is opaque and practically 
white.  The formulation of perampanel 0.5 mg/mL oral suspension will be provided by Eisai 
according to current Good Manufacturing Practices.
Perampanel is a Schedule III Controlled Drug Substance in the US.  Investigators in the US
must have valid Drug Enforcement Administration (DEA) registrations and adequate storage 
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facilities to handle Schedule III controlled substances as required per DEA regulations.  All 
shipments to US sites will comply with the DEA regulations.
Perampanel oral suspension will be provided by Eisai to an Eisai-approved vendor in 400 mL 
polyethylene terephthalate (PET) bottles containing 340 mL of oral suspension.  The 
approved vendor will label the bottles and ship them to local country depots or the study 
sites.
A detailed pharmacy manual will be provided to each investigational site.  The PET bottles 
for dispensing the test drug will be, if necessary, fitted with appropriately sized press-in 
bottle adaptors to aid in accurate aliquotting.  Dosing devices (eg, oral syringes) will also be 
provided for subject use.
9.4.2.1
Chemical Name, Structural Formula of E2007

Test drug code:  E2007

Generic name:  perampanel

Chemical name:  IUPAC:  2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) 
benzonitrile hydrate (4:3)

Molecular formula:  C23H15N3O • 3/4H2O

Molecular weight:  362.90 (3/4 hydrate), 349.38 (anhydrous)

Structural formula:  
N
N
O
CN
3/4H2O
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Study drug will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and is translated into the required language(s) for each of those 
countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions and, where 
required per local controlled substance requirements, kept in a locked cabinet.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
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within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
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 receive 
0.5 mg/mL perampanel suspension.  There is no randomization in this study.
9.4.4
Selection of Doses in the Study
See Section 7.3 for selection of doses in the study.
9.4.5
Selection and Timing of Dose for Each Subject
Perampanel will be administered orally and daily. Dosing should occur at bedtime.
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent) will be recorded on the 
Prior & Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  The 
investigator will record on the AE
CRF any AE
for which the concomitant 
medication/therapy was administered.  If the concomitant medication/therapy is being 
administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
Other than carbamazepine, oxcarbazepine, phenytoin, and eslicarbazepine, concomitant use 
of medications known to be inducers of cytochrome (CYP) 3A including, but not limited to:
rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, glucocorticoids (other than 
topical usage), modafinil, pioglitazone, and rifabutin will not be permitted and are to be 
discontinued within 28 days before Visit 1. VNS implanted less than 5 months before Visit 1 
or changes in parameter less than 4 weeks before Visit 1 (or thereafter during the study) will 
be prohibited.
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9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 
1572, where applicable

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current
medical license or medical registration number on the CV

A signed and dated clinical studies agreement

A copy of the regulatory authority approval for the country in which the study is being 
conducted, and the Import License

For US Sites only:  A copy of the Controlled Substance Registration Certificate (DEA 
Form 223), which must be current (ie, not expired) and have the appropriate controlled 
substance schedule listed for the study drug
The investigator and the study staff 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.
In the US, Federal regulations require that registrants notify the DEA Field Division Office in 
their area, in writing, of the theft or significant loss of any controlled substance within 
1 business day of discovery of such loss or theft.  The registrant shall also complete and 
submit to the Field Division Office in their area, DEA Form 106, “Report of Theft or Loss of 
Controlled Substances” regarding the theft or loss.  Additionally, registrants may have local 
or state level reporting requirements to conform with.
Under no circumstances will the investigator allow the study drug to be used other than as 
directed by this protocol.  Study drug will not be dispensed to any individual who is not 
enrolled in the study.  The subject’s parent/guardian will be dispensed the study drugs.
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The site must maintain an accurate and timely record of the following:  receipt of all study 
drug, dispensing of study drug to the subject, collection and reconciliation of unused study 
drug that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drug to the sponsor or (where applicable) destruction of 
reconciled study drug at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drug, (b) study drug dispensing/return reconciliation 
log, (c) study drug accountability log, (d) all shipping service receipts, and (e) 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 drug 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, 
FDA, Medicines and Healthcare Products Regulatory Agency [MHRA]).  As applicable, all 
unused study drug and empty and partially empty containers from used study drug are to be 
returned to the investigator by the subject and, together with unused study drug 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 drug and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drug 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 drug 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 drug may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drug is 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.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity.
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9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All medical and surgical history within 2 years must be noted in the Medical History 
and Current Medical Conditions CRF.
Physical examinations (comprehensive or symptom directed) will be performed as designated 
in the Schedule of Procedures/Assessments (Table 4).  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest 
(including heart and lungs), abdomen, limbs, skin, and a complete neurological examination, 
which will consist of assessment of mental status, sensory systems, cranial nerves, motor 
function, deep tendon reflexes, and cerebellar functions. A urogenital examination will only 
be required in the presence of clinical symptoms related to this region.  Documentation of the 
physical examination will be included in the source documentation at the site.  Significant 
findings at the Screening Visit will be recorded on the Medical History and Current Medical 
Conditions CRF.  Changes from screening physical examination findings that meet the 
definition of an AE will be recorded on the AEs CRF.
9.5.1.2.2
EPILEPSY MEDICAL HISTORY
In addition to standard medical history, epilepsy history will be documented for each subject 
at the Screening/Baseline Visit.  For subjects ≥4 years but <12 years of age, lifetime AED 
history will be collected.
9.5.1.3
Efficacy Assessments
Efficacy will be assessed by seizure counts and types as recorded on the diary.  Diaries will 
be dispensed to all subjects at each visit as described in Table 4.  The diary is to be 
completed daily, by the parent/guardian.  All seizures will be recorded.  At each visit the 
parent/guardian will be instructed by the site personnel as to how to complete the diary and 
reminded that they must return the diary at their next scheduled clinic visit and at the Early 
Discontinuation and Follow-up Visits (if applicable).  To ensure correct seizure classification, 
the medically qualified investigator should review the diary with the parent/guardian at all 
visits.  Parents/guardians must be counseled if diary compliance is not satisfactory (ie, 
missed three or more consecutive daily diary entries).
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Plasma concentrations of perampanel will be determined via collection of blood samples 
during the Maintenance Phase using a sparse sampling technique at specified visits for 
subsequent population PK analysis.
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Participation in the PK assessment portion of the protocol will be mandatory for all sites with 
appropriately trained staff and adequate equipment for procuring and processing the 
specimens.  (revised per Amendment 01)  Blood samples (1 mL each) will be collected at
specified time points for all subjects (Table 4).  (revised per Amendment 01)  Information for 
the collection, handling, and shipping procedures of the samples will be described in a 
manual provided to the sites.
Samples from all subjects receiving active treatment will be analyzed.  Plasma concentrations 
of analytes will be quantified by liquid chromatography coupled with tandem mass 
spectrometry (LC-MS/MS) methodology using a previously validated assay.
Additional blood for PK analysis will be drawn where possible at the 1st report of a serious 
adverse event (SAE) or severe unexpected AE and at its resolution.  (revised per 
Amendment 01)
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Not Applicable.
9.5.1.5
Safety Assessments
Safety will be assessed by monitoring and recording all AEs and SAEs, regular monitoring of 
hematology, blood chemistry, and urine values, periodic measurement of vital signs and 
ECGs, and performance of physical and neurological examinations, as detailed in Table 4.
Growth and development will be assessed by weight, height, thyroid, and insulin-like growth 
factor-1 (IGF-1).  Cognitive testing ABNAS, behavioral questionnaires (CBCL), and 
visuomotor skills testing using the LGPT will be administered.
An assessment of suicidal ideation and behavior using the C-SSRS will be performed 
throughout the study for subjects aged 6 years and older at the time of consent/assent.  
Suicidal ideation and behavior will be monitored in subjects less than 6 years at the time of 
consent/assent based upon clinical impression. An EEG will be performed over a minimum 
of 1-hour up to a 2-hour period in an awake and sleep state.
9.5.1.5.1
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 (IP).  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drugs 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 IP, whether or not 
considered related to the IP (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
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
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

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 and for 28 days following study drug 
discontinuation. 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 AE CRF. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.7 for a description of the C-SSRS). 
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes 1st.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
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
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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 from those used for seriousness (see
Section 9.5.1.5.2 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

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?  
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
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 AE 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)
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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 
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 “AE” (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
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the 1st report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 3.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 4) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study (Core Study).
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Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils) (revised per Amendment 01)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, cholesterol, globulin, glucosea, lactate 
dehydrogenase, phosphorus, total protein, triglyceridesa, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs, Urine drug 
screenb (revised per Amendment 01)
RBC = red blood cell, WBC = white blood cell.
a:
Fasting samples to be taken at baseline and at end of treatment or early discontinuation, with fasting 
window (interval) between 2 and 4 hours.
b:
To be performed only at baseline.  (revised per Amendment 01) 
Clinical laboratory tests during the Core Study and Extension A will be performed by a 
central laboratory.  (revised per Amendment 03)  All blood and urine samples will be 
collected and sent to the central laboratory on the day of collection unless otherwise 
instructed.  In cases of a safety concern, blood samples will be split (or 2 samples drawn) to 
allow a local laboratory analysis in addition to the central laboratory.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the AE CRF.
9.5.1.5.4
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]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 4) 
by a validated method.  BP and pulse will be measured after the subject has been supine for 
5 minutes.  All BP measurements should be performed on the same arm, preferably by the 
same person.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as 
designated in 
the Schedule of 
Procedures/Assessments (Table 4).  Documentation of the physical examination will be 
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included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the AEs CRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
ECGs will be obtained as designated in the Schedule of Procedures/Assessments (Table 4).
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the AEs CRF.
9.5.1.5.7
OTHER SAFETY ASSESSMENTS
C-SSRS
An assessment of suicidality using the C-SSRS will be performed for subjects aged 6 years 
and older at the time of consent/assent at Screening/Baseline, Day 1 postdosing, every visit, 
including after the last dose of study drug, and at the Termination Visit, as designated in the 
Schedule of Procedures/Assessments (Table 4).
Pregnancy Test
A serum β-hCG test will be performed for female subjects age 8 years old and above, or of 
child-bearing potential, only.  A sample of blood will be taken at screening; at all other time 
points a urine pregnancy test will be performed as specified in the Schedule of 
Procedures/Assessments (Table 4).  If urine can not be obtained for pregnancy testing after 
screening, a serum pregnancy test will be performed.  (revised per Amendment 01)
EEG
An EEG will be performed over a minimum of 1-hour and up to a 2-hour period in awake 
and sleeping states at the visits designated in Table 4.
ABNAS
The ABNAS assessment measures 5 aspects of cognitive function:
fatigue, memory, 
concentration, motor speed, and reading, using a 4-point scale. The assessment is a measure 
of patient-perceived cognitive effects of AEDs. 
This instrument aimed at assessing patient perceived drug-related cognitive impairment.  It 
will be assessed at designated time points as specified in the Schedule of 
Procedures/Assessments (Table 4). 
CBCL
The CBCL is a questionnaire to assess behavioral and emotional problems in children as 
reported by the primary caregiver.  It is standardized to evaluate maladaptive behavioral and 
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emotional problems in ages 2 to 18 years.  It will be assessed at designated time points as 
specified in the Schedule of Procedures/Assessments (Table 4).
LGPT
The LGPT is a manipulative dexterity test requiring complex visual-motor coordination and 
will be assessed at designated time points as specified in the Schedule of 
Procedures/Assessments (Table 4).
9.5.1.6
Other Assessments
EQ-5D-Y
A health related quality of life questionnaire (EQ-5D-Y) will be administered.  For patients 
with mental disabilities and patients ages 4 to 7, caregivers, or parents will complete the 
proxy EQ-5D-Y.  For ages 8 to 11 with no mental disabilities, patients will self-complete the 
EQ-5D-Y.  Patients ages 8 to 11 with physical disabilities but no mental disabilities may 
have the EQ-5D-Y read to them and their responses recorded by a caregiver, parent, or study 
coordinator.  EQ-5D-Y will be administered at the visits designated in Table 4.
CGI
The CGI, Clinical Global Impression of Severity (CGIS), and CGIC will be administered at 
the visits designated in Table 4.  Telephone interviews with the subjects and/or caregiver will 
be conducted to ensure that subjects are completing their seizure diaries regularly and to 
assess AEs, study drug compliance, and concomitant medications, including AEDs.
Details for all assessments in the Extension A and Extension B can be found in Appendix 1
and Appendix 2, respectively.  (revised per Amendment 03)
9.5.2
Schedule of Procedures/Assessments – Core Study
9.5.2.1
Schedule of Procedures/Assessments
Table 4 presents the schedule of procedures/assessments for the Core Study.
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Table 4
Schedule of Procedures/Assessments in Study E2007-G000-311:  Core Study
Phase
Pre-Treatment
Treatment Phase
Screening/Baseline
Titrationa
Maintenanceb
Follow-upb,c
Visit
1
2
3
4
5
6
7
8
9
Early 
Discontinuationd
Unscheduled
Week
From up to -4 weeks 
±3 days to Week 0
(outside of Japan)
-4 weeks ±3 days to 
Week 0 (Japan only) 
(revised per 
Amendment 02)
0
2
5
8
11
15
19
23
27
Procedures/Assessments
Demography
X
Informed consent/assent
X
Inclusion/exclusion criteria
X
X
Medical history
X
Epilepsy medical history
X
Prior/concomitant medication(s)
X
X
X
X
X
X
X
X
X
X
X
X
Prior/concomitant AED(s)
X
X
X
X
X
X
X
X
X
X
X
X
Neurological examinatione
X
X
X
X
Physical examinatione
X
X
X
X
Vitalsf and weightg
X
X
X
X
X
X
X
X
X
X
X
X
Heightg
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Study drug compliance
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
Xh
Xi
Retrieve unused study drug
X
X
X
X
X
X
X
X
Xi
Dispense subject’s diary
X
X
X
X
X
X
X
X
Xh
X
Retrieve and review diary
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory testsj
Xk
X
Xk
X
X
X
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Table 4
Schedule of Procedures/Assessments in Study E2007-G000-311:  Core Study
Phase
Pre-Treatment
Treatment Phase
Screening/Baseline
Titrationa
Maintenanceb
Follow-upb,c
Visit
1
2
3
4
5
6
7
8
9
Early 
Discontinuationd
Unscheduled
Week
From up to -4 weeks 
±3 days to Week 0
(outside of Japan)
-4 weeks ±3 days to 
Week 0 (Japan only) 
(revised per 
Amendment 02)
0
2
5
8
11
15
19
23
27
Procedures/Assessments
Thyroid (TSH, fT3, fT4) and IGF-1 
testing
X
X
X
Serum β-hCG (or hCG) testl
X
Urine pregnancy testl
X
X
X
X
X
X
X
X
X
X
X
C-SSRSm
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGn
X
X
X
X
Xo
EEGp
X
X
X
Xo
Perampanel PK sampling (plasma)q,r
X
X
X
X
X
Telephone calls
X
X
X
X
X
X
X
ABNASt
Xu
X
X
X
Xv
Lafayette Grooved Pegboard Test
Xu
X
X
X
Xv
Child Behavior Checklist
X
X
X
EQ-5D-Y
X
X
X
Clinical Global Impression
X
X
X
Disposition
X
X
X
IxRS
X
X
X
X
X
X
X
X
X
X
X
X
ABNAS = A-B neuropsychological assessment schedule, AE = adverse event, AED(s) = antiepileptic drug(s), β-hCG = beta-human chorionic gonadotropin (or hCG = human 
chorionic gonadotropin), C-SSRS = Columbia-Suicide Severity Rating Scale, eCRF = electronic case report form, EQ-5D-Y = EuroQol 5 Dimensions-Youth, fT3 = free 
triiodothyronine, fT4 = free thyroxine, IGF-1 = insulin-like growth factor-1, IxRS = interactive and response system, PK = pharmacokinetics, TSH = thyroid-stimulating hormone. 
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Table 4
Schedule of Procedures/Assessments in Study E2007-G000-311:  Core Study
Phase
Pre-Treatment
Treatment Phase
Screening/Baseline
Titrationa
Maintenanceb
Follow-upb,c
Visit
1
2
3
4
5
6
7
8
9
Early 
Discontinuationd
Unscheduled
Week
From up to -4 weeks 
±3 days to Week 0
(outside of Japan)
-4 weeks ±3 days to 
Week 0 (Japan only) 
(revised per 
Amendment 02)
0
2
5
8
11
15
19
23
27
Procedures/Assessments
a:
All visits to be done within 3 days of the schedule.  Each study visit is based on the actual prior visit (eg, Visit 3 is completed 2 weeks 3 days of Visit 2, Visit 4 is 
completed 3 weeks 3 days of Visit 3, Visit 5 is completed 3 weeks 3 days of Visit 4).  (revised per Amendment 02)
b:
Visit to be done within ±7 days of the schedule.  Each study visit is based on the actual prior visit (eg, Visit 6 is completed 3 weeks 7 days of Visit 5, Visit 7 is completed 
4 weeks 7 days of Visit 6, Visit 8 is completed 4 weeks 7 days of Visit 7, Visit 9 is completed 4 weeks 7 days of Visit 8).  (revised per Amendments 02 and 03)
c:
The Follow-up Visit only applies to those subjects who complete the Core Study (or who discontinue the study early), but do not roll-over into Extension A and is to occur
4 weeks (±7 days) after Visit 9 or last dose of study drug.
d:
These assessments will be conducted for subjects who discontinue the study early for any reason after Visit 2.
e:
Physical and neurological examinations will only be performed at Visit 1 and Visit 9 and at the Follow-up Visit, and at the Early Discontinuation Visit (if applicable).  For all 
other clinic visits during the study, the physical and the neurological exams will only be performed when there is a complaint from the subject.  Clinically significant 
abnormal findings from the physical or the neurological examinations will be reported as AEs.
f:
Blood pressure and pulse will be taken.
g:
Weight and Height (without shoes) will be measured.  Three measurements should be taken at each visit.  Each measurement should be recorded as a separate entry on the 
Vital Sign eCRF.
h:
Only for those subjects who continue into Extension A.
i:
Unused study drug to be retrieved and study drug dispensed only for subjects requiring dose increases at Unscheduled Visits.
j:
Clinical laboratory tests include hematology, blood chemistry including lipid panel, and urinalysis.
k:
Fasting lipid and glucose samples to be taken at baseline and at end of treatment or early discontinuation, with fasting window (interval) between 2 and 4 hours.
l:
Female subjects age 8 years old and above, or of childbearing potential, only.  If urine can not be obtained for pregnancy testing after screening, a serum pregnancy test will 
be performed. (revised per Amendment 01)
m:
Only for subjects aged 6 years and older at the time of consent/assent.
n:
If subject has a normal ECG baseline reading, but during any visit thereafter, the QT is measured as greater than 450 ms, 3 consecutive ECGs separated by 5 to 10 minutes 
will be performed to confirm the abnormality.
o:
During Unscheduled Visits, ECG or EEG will only be done if the results from the previous visit were deemed clinically significant by the investigator.
p:
EEG will be performed at awake and sleep state for all subjects.
q:
One blood sample (approximately 1 mL) for determination of perampanel plasma concentrations will be collected at any time during each of the specified visits.
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Table 4
Schedule of Procedures/Assessments in Study E2007-G000-311:  Core Study
Phase
Pre-Treatment
Treatment Phase
Screening/Baseline
Titrationa
Maintenanceb
Follow-upb,c
Visit
1
2
3
4
5
6
7
8
9
Early 
Discontinuationd
Unscheduled
Week
From up to -4 weeks 
±3 days to Week 0
(outside of Japan)
-4 weeks ±3 days to 
Week 0 (Japan only) 
(revised per 
Amendment 02)
0
2
5
8
11
15
19
23
27
Procedures/Assessments
r:
Additional blood (approximately 1 mL/sample) will be drawn at the 1st report (where possible) of a serious adverse event or severe unexpected AE and at its resolution.  
(revised per Amendment 01)
s:
Telephone interviews with the subjects and/or caregiver will be conducted 1 week after Visit 2, Visit 3, Visit 4, Visit 5, Visit 6; and at the midpoint (3 days) between each 
visit from Visit 7, Visit 8 and Visit 9 to ensure that subjects are completing their seizure diaries regularly and to assess AEs, study drug compliance, and concomitant 
medications, including AEDs.  Subjects whose dose was decreased before the scheduled telephone interview will be strongly encouraged to return to the clinic (instead of the 
scheduled telephone interview) for further consultation with regard to study drug administration.  The site will contact IxRS to receive further dispensing instructions.  
Subjects will then return for their regularly scheduled visit.
t:
ABNAS to assess patient-perceived cognitive effects of AED treatment, measuring 5 aspects of cognitive function: fatigue, memory, concentration, motor speed, and 
reading, using a 4-point scale. 
u:
To be administered twice at Visit 1 (for training purposes only).
v:
Subjects who discontinue after Week 12 must have assessments performed at the Early Discontinuation Visit.
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Table 5 and Table 6 present the Schedule of Procedures/Assessments for Extension A and 
Extension B of the study, respectively.  (revised per Amendment 03)
9.5.2.2
Description of Procedures/Assessments Schedule
The schedule of procedures/assessments for the Core Study, Extension A, and Extension B of 
the study are presented in Table 4, Table 5, and Table 6, respectively.  (revised per 
Amendment 03)
A brief description of the C-SSRS is provided in Section 9.5.1.5.7.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of Phase 3 
studies of epilepsy in pediatric subjects.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, radiologic studies, and assessment of AEs, are standard 
evaluations to ensure subject safety.
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 24 hours from when the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the last visit (through 
the last visit in the Treatment Phase and for 28 days after the subject’s last dose).  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, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
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.
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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.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
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 SAEs [Section 9.5.4.1]).
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 Investigator Study File.  
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
AEs 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 
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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 AE 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 AE CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Not applicable.
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 
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
AEs will be reported by the sponsor or a 3rd 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 GCP
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 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 4 and Table 5).
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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 one of these primary 
reasons: AE(s), lost to follow-up, subject choice, 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
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.
AEs associated with abuse or diversion will be appropriately reported as AEs and monitored 
per Section 9.5.1.5.1.  Abuse is always to be captured as an AE.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
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 
may be conducted 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.
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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 as identified on Form FDA 
1572 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 3rd 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 and a snapshot of the database is obtained 
and released.  Statistical analyses will be performed using Statistical Analysis System (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 Core 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.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
Safety and tolerability, which include incidence of treatment-emergent adverse events 
(TEAEs) and SAEs, laboratory parameters, vital signs, and ECG parameters, of perampanel 
oral suspension in children (ages 4 to <7 years and ≥7 years to <12 years) with POS or PGTC
9.7.1.1.2
SECONDARY ENDPOINTS
The following endpoints will be analyzed:
1. The relationship between plasma levels of perampanel and efficacy endpoints (ie, 
change in average seizure frequency over 28 days, responder probability, and the 
proportion of subjects who are seizure-free in the Maintenance Period of the Core 
Study) separately for each seizure type
2. The relationship between plasma levels of perampanel and cognition endpoints 
including change from baseline in ABNAS, CBCL, and LGPT.  In addition, depending 
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on the AE data, the relationship between plasma levels of perampanel and select AEs
will be assessed.
3. Change from baseline at Week 23 and Week 52 in ABNAS, CBCL, and LGPT
4. Changes from baseline at Week 23 and Week 52 in growth and development parameters 
(height, weight, thyroid, and IGF-1)
5. Change from baseline in EEG and the frequency of EEG abnormalities during awake 
and sleep state
6. Proportion of subjects (aged 6 or older at time of consent/assent) with any 
treatment-emergent reports of suicidal ideation and behavior on the C-SSRS and 
intensity of these behaviors assessed using C-SSRS scores
7. The median percent change in seizure frequency per 28 days during Treatment Phase 
(Titration Period and Maintenance Period) of the Core Study, and during the long-term
treatment (up to 52 weeks) relative to the Pretreatment Phase.  Seizure frequency will be 
based on the 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. 
8. Proportion of responders (25% responders defined as a decrease in 28-day seizure 
frequency of equal or greater than 25% compared to baseline seizure frequency; 
50% responders defined as a decrease in 28-day seizure frequency of equal or greater 
than 50% compared to baseline seizure frequency; 75% responders defined as a decrease 
in 28-day seizure frequency of equal or greater than 75% compared to baseline seizure 
frequency) during Maintenance Period of Core Study, and during the long term 
treatment (up to 52 weeks)
9. Proportion of subjects who are seizure-free during Maintenance Period of Core Study, 
and during the long-term treatment (up to 52 weeks)
10. CGI of Change
9.7.1.1.3
EXPLORATORY ENDPOINT
Change from baseline at Week 23 and Week 52 in EQ-5D-Y.
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 (FAS) is the group of subjects who received at least 1 dose of study 
drug and had at least 1 postdose primary efficacy measurement.
PK Analysis Set is the group of subjects receiving perampanel and with at least 1 
quantifiable perampanel concentration at one of the visits during the Maintenance Period of 
the Core Study and with adequately documented dosing history.
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PK/PD Analysis Set is the group of subjects receiving perampanel who have seizure 
frequency, cognition, or AE data with documented dosing history.  Subjects receiving 
perampanel should have at least 1 quantifiable perampanel concentration at one of the visits 
during the Maintenance Period of the Core Study as per the PK Analysis Set.
9.7.1.3
Subject Disposition
Reasons for discontinuation will be recorded for all entered subjects.  The frequencies of 
occurrence of each reason for discontinuation will be summarized.  The data will be 
described using incidence rate (number of subjects and percentage).
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the safety analysis set will be summarized 
using descriptive statistics.  Continuous demographic and baseline variables include age, 
weight, height, and body mass index (BMI); categorical variables include sex, age group, 
race, and ethnicity.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by Anatomical Therapeutic Chemical (ATC) class and WHO DD 
preferred term (PT).  Prior medications will be defined as medications that stopped before the 
1st dose of study drug.  Concomitant medications will be defined as medications that 
(1) started before the 1st dose of study drug and were continuing at the time of the 1st dose of 
study drug, or (2) started on or after the date of the 1st dose of study drug 4 weeks after the 
subject’s last dose.  All medications will be presented in subject data listings.
9.7.1.6
Efficacy Analyses
The percent change in seizure frequency per 28 days will be summarized using descriptive 
statistics (n, mean, median, minimum and maximum) by age cohorts (4 to <7 years, ≥7 to 
<12 years), by disease cohorts (POS, PGTC, and GTC), and by the presence or absence of 
concomitant EIAED in the FAS. 
The proportion of subjects who are seizure-free and the proportion of responders based on 
decrease from baseline in 28-day seizure frequency of equal or greater than 25%, equal or 
greater than 50%, and equal or greater than 75% will be summarized using frequency count 
(number and percentage) by age cohorts (4 to <7 years, ≥7 to <12 years), by disease cohorts 
(POS, PGTC, and GTC), and by the presence or absence of concomitant EIAED in the FAS.
The CGIC will be summarized using frequency count (number and percentage) by age 
cohorts (4 to <7 years, ≥7 to <12 years), by disease cohorts (POS, PGTC, and GTC), and by 
the presence or absence of concomitant EIAED in the FAS.
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For purposes of registration in Japan, perampanel will be determined to be efficacious if, in 
subjects enrolled in Japan, the upper limit of the 95% CI for the median percent change in 
POS frequency per 28 days is below the pre-specified threshold.  This prespecified threshold 
consists of the median percent reduction in seizure frequency (ie, 10.5%) in subjects who 
received placebo during the Randomization Phase of Study E2007-J000-335.  For example, if 
the 95% CI limits for the median percent reduction in seizure frequency are 65.0% and 
25.0%, respectively, success would be declared because the upper bound of the CI falls 
below the prespecified threshold.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Pharmacokinetic Analysis
Population PK analysis will be performed to characterize the PK of perampanel by pooling 
the concentration data with other studies, including 19 Phase 1 studies, 2 Phase 2 studies 
(232 and 235), and 5 Phase 3 studies (304, 305, 306, 332, and 335).  A 2-compartment PK 
model will be fit to the data and the effect of intrinsic and extrinsic factors, including body 
weight and age, on the PK of perampanel will be evaluated.  The post-hoc estimates of both 
maximum observed concentration (Cmax) and area under the curve (AUC) from the final PK 
model will be derived for all subjects.  In addition, average steady-state drug concentration 
(Css,av) will be calculated.  Subsequently, the dose-normalized derived exposure parameters 
will be summarized descriptively by age group (≤4 years, >4 to ≤8 years, >8 to <12 years, 
≥12 to <18 years, and ≥18 years) for subjects with and without inducing AEDs, and also 
presented in box-plots.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD analysis will be conducted for the relationship between model-predicted 
average exposure to perampanel at steady-state (Css,av) vs responder rate and percent 
reduction in seizure frequency during the Maintenance Phase.  In addition, the relationship 
between Css,av and the cognition endpoints and most frequent AEs will be explored 
graphically.  Any emergent relationship will be subjected to population PK/PD modeling.  
The effect of intrinsic and extrinsic factors (ie, most common concomitant AEDs, 
demographics) on the PK/PD relationship will be evaluated.  Two separate analyses will be 
performed, one for POS, where data from subjects with POS from Study 311 will be pooled 
with data from POS subjects from Studies 304, 305, 306, and 335, and another for PGTC,
where data from subjects with PGTC from Study 311 will be pooled with data from PGTC
subjects from Study 332.
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9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Pharmacodynamic Analysis
PD endpoints to be evaluated as part of PK/PD analyses include endpoints for efficacy 
cognition, and selected safety parameters.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data will be 
summarized on an “as treated” basis using descriptive statistics (eg, n, mean, SD, median, 
minimum, maximum for continuous variables; n [%] for categorical variables) by age cohorts 
(4 to <7 years, ≥7 to <12 years), by disease cohorts (POS, PGTC, and GTC), and by the 
presence or absence of concomitant EIAEDs.  Safety variables include TEAEs, clinical 
laboratory parameters, vital signs, 12-lead ECG results, C-SSRS, growth parameters, CBCL, 
LGPT, and EEG.  Study Day 1 for all safety analyses will be defined as the date of the 1st
dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
The duration of treatment (Titration Period and Maintenance Period of the Core Study) will 
be calculated as the number of days between the date the subject receives their 1st treatment 
dose and the date the subject receives the last dose of treatment.  These values will be used to
summarize the extent of exposure to study medication.
9.7.1.8.2
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).  AEs will be coded to the MedDRA (version 18.1 or higher) lower level term
closest to the verbatim term.  The linked MedDRA 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 TEAEs will be summarized using the Safety Analysis Set.  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
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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]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT.  A subject data listing of all SAEs will be provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to 
discontinuation from study drug will be provided.
The incidence of TEAEs of special interest defined by standardized MedDRA queries
(SMQs) will also be summarized.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, 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.  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.  For each laboratory parameter, shift from baseline (LNH) to each
postbaseline visit and at the end of treatment will be presented.  Similar shift tables from 
baseline (LNH) to the highest/lowest postbaseline value will also be presented.  
Appendix 3 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAV).  Except for phosphate, a TEMAV was defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  The number and 
percentage of subjects with TEMAVs will be presented; each subject will be counted once in 
the laboratory parameter high and low categories, as applicable.  Markedly abnormal 
laboratory values will be flagged in the subject data listings.
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For ALT and AST analysis, the number of subjects with greater than 3 times, but less than 
5 times the ULN and the number of subjects with greater than 5 times the ULN will be 
summarized.  For bilirubin, a summary of the number of subjects with serum concentrations 
greater than 2 times the ULN will be created.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Bazett and QTc Fridericia during the treatment period will be summarized.  
Clinically borderline or abnormal ECG results in QTc Bazett and QTc Fridericia will be 
categorized as follows:
Absolute QTc interval prolongation:

QTc interval 430-450 ms

QTc interval>450 ms

QTc interval>500 ms
Change from baseline in QTc interval:

QTc interval increases from baseline 30-60 ms

QTc interval increases from baseline>60 ms
9.7.1.8.6
OTHER SAFETY ANALYSES
The change from baseline in ABNAS, CBCL, and LGPT will be summarized. 
The change from baseline in growth (height, weight, thyroid, and IGF-1) will be 
summarized.
The change from baseline in EEG parameters and the frequency of EEG abnormalities will 
be summarized.
Proportion of subjects with any treatment-emergent report of suicidal ideation and behavior 
and intensity of these behaviors will be summarized. 
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9.7.1.9
Other Analyses
The change from baseline in EQ-5D-Y, and Global Assessment of Change and its severity 
will be summarized by age and disease cohorts, and by the presence or absence of 
concomitant EIAED, using descriptive statistics.
9.7.2
Determination of Sample Size
A sample size of at least 160 subjects (with up to 40 subjects with PGTC and the balance 
with POS), is deemed sufficient for safety evaluation in this age group (age 4 to <12 years).  
(revised per Amendment 02)  This sample size matches the total number of adolescents who 
were enrolled in the 4 global Phase 3 efficacy and safety studies that support the POS and 
PGTC indications.
For purposes of registration in Japan, it has been determined that a sample size of 65 subjects 
enrolled in Japan will provide 80% power to exclude the possibility that there would be a 
reduction smaller than that observed in the placebo arm of Study E2007-J000-335 (ie, 
10.5%).  Details are provided in the SAP.
9.7.3
Interim Analysis
(revised per Amendments 01 and 02)
An independent data monitoring committee (DMC) will be constructed to monitor the safety 
data.  The responsibilities, membership, and purpose of the DMC, the timing of the 
meeting(s), and an outline of the plan for review of the safety data will be documented in the 
DMC Charter.
Analyses for regional submissions may be performed during the course of the study.  (revised 
per Amendment 02)
9.7.4
Other Statistical/Analytical Issues
Not Applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
Cancer Therapy Evaluation Program, CTCAE version 4.0 [published 28 May 2009 (v4.03: 
June 14, 2010)].  Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_201006-
1 4_QuickReference_8.5x11.pdf.
Columbia-Suicide Severity Rating Scale (C-SSRS).  Columbia University.  Available from:  
http://www.cssrs.columbia.edu/scales_cssrs.html
Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz O. Efficacy of 
antiepileptic drugs in adults predicts efficacy in children: a systematic review. Neurology.
2012;79:1482-89.
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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 or appropriate 
study team member 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).
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
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
Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as interactive and response system
(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 
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.
The Site and PI shall reasonably cooperate with Sponsor to answer critical queries related to 
the study data generated by the Site and PI that may arise after the completion of the study.  
The Site and PI will, upon reasonable notice and during normal business hours, be available 
to provide information requested by Sponsor or its designees regarding such critical queries.  
(revised per Amendment 01)
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.
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11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator or the designated representative 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, Form FDA 1572), 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 IP.
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 permanently retaining the study records.
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 PI (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 review these documents 
along with all other study conduct documents at appropriate intervals once study drug has 
been received by the site.  A laboratory manual will be provided to the study site and will 
contain instructions for the handling and shipment of samples.
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.
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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 Site and PI shall at least 90 
days prior to submitting or presenting a publication to any third party, provide to Sponsor a 
copy of such publication, and allow Sponsor to comment on it within this period.  The Site 
and PI shall remove any confidential information or other proprietary information, requested 
by Sponsor, prior to submitting or presenting a publication and shall incorporate reasonable 
comments made by the Sponsor into the publication.  (revised per Amendment 01)
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.
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).
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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.
11.13 Data Monitoring Committee
An independent DMC will be constructed to monitor the safety data.  The responsibilities, 
membership, and purpose of the DMC, the timing of the meeting(s), and an outline of the 
plan for review of the safety data will be documented in the DMC Charter.
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12 APPENDICES
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Appendix 1
Extension Phase (Extension A)
Study Design and Plan
Extension A will consist of a Maintenance Period (up to 29 weeks) and a Follow-up Period 
(up to 4 weeks; only for those subjects not entering into Extension B).  (revised per 
Amendments 02, 03, and 04)
All subjects who complete all scheduled visits up to and including Visit 9 in the Treatment 
Phase will be eligible to participate in Extension A of the study.
(revised per 
Amendment 03)
During the Maintenance Period of Extension A, all subjects will continue with their optimal 
perampanel dose (ie, that dose level that they completed on during the Core Study).  (revised 
per Amendment 03)  Multiple dose adjustment is allowed if a subject is experiencing 
intolerable AE(s) or a higher dose is deemed beneficial.  The maximum dose is up to 
12 mg/day for non-EIAED subjects or up to 16 mg/day for EIAED subjects, except that 
subjects enrolled in Japan may not receive doses higher than 12 mg/day regardless of EIAED 
status.  Addition, deletion, and dose changes to the concomitant AEDs are allowed during 
Extension Maintenance Period.  Conversion to monotherapy on perampanel is also permitted 
at the discretion of the investigator, if it is considered appropriate to control the seizures. 
The study Follow-up Visit should be conducted 4 weeks (±7 days) after the last dose of study 
drug for all subjects, except for subjects in Japan or in countries where an EAP cannot be 
implemented, who are entering into Extension B.  (revised per Amendments 03 and 04)
Study Drug Supplies
Perampanel is a Schedule III Controlled Drug Substance in the US.  Investigators in the US
must have valid DEA registrations and adequate storage facilities to handle Schedule III 
controlled substances as required per DEA regulations.  All shipments to US sites will 
comply with the DEA regulations.
Schedule of Procedures/Assessments
Table 5 presents the Schedule of Procedures/Assessments for the Extension A (up to 
33 weeks).  (revised per Amendments 02 and 03)
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Table 5
Schedule of Procedures/Assessments in Study E2007-G000-311:  
Extension A (revised per Amendments 03 and 04)
Phase
Extensiona
Period
Maintenance
Follow-
upb
Visit
10c
11
12
Early 
Discontinuation 
Unscheduled 
Week
28
40
52
56
Procedures/Assessments
Prior/concomitant medication(s)
X
X
X
X
X
X
Prior/concomitant AED(s)
X
X
X
X
X
X
Neurological examinationd
X
X
Physical examinationd
X
X
X
Vitalse and weightf
X
X
X
X
X
X
Heightf
X
X
X
Adverse events
X
X
X
X
X
X
IxRS call
X
X
X
X
X
Study drug compliance
X
X
X
X
X
Dispense study drug
X
X
Xg
Retrieve unused study drug
X
X
X
X
Xg
Dispense subject’s diary
X
X
X
Retrieve and review diary
X
X
X
X
X
X
Clinical laboratory testsh
X
Xi
X
Xj
Thyroid (TSH, fT3, fT4) and IGF-1 testing
X
X
Urine pregnancy testk
X
X
X
X
X
X
C-SSRSl
X
X
X
X
X
X
12-lead ECGm
X
X
Xn
EEGo
X
X
Xn
Telephone callp
X
X
X
ABNASq
X
X
Lafayette Grooved Pegboard Test
X
X
CBCL 
X
X
EQ-5D-Y
X
X
Clinical Global Impression
X
X
Disposition
X
X
ABNAS = A-B neuropsychological assessment schedule, AE = adverse event, AED(s) = antiepileptic drug(s),
CBCL = Child Behavior Checklist, C-SSRS = Columbia-Suicide Severity Rating Scale, eCRF = electronic case report form,
EQ-5D-Y = EuroQol 5 Dimensions-Youth, fT3 = free triiodothyronine, fT4 = free thyroxine, IGF-1 = insulin-like growth 
factor-1, IxRS = interactive and response system, QTc = corrected QT interval, TSH = thyroid-stimulating hormone. 
a:
All visits to be done within ±6 days of the schedule. (revised per Amendment 02)
b:
Follow-up Visit should be conducted 4 weeks (±7 days) after the last dose of study drug for all subjects, except for 
those subjects entering into Extension B.  (revised per Amendment 04) .
c:
Subjects should roll-over into Extension A immediately after completion of the Treatment Phase of the Core Study.  
Additional assessments to be done for subjects who choose to roll-over into Extension A.
d:
For any other clinic visits during the study, the physical and the neurological exams will only be performed when there 
is a complaint from the subject.  Clinically significant abnormal findings from the physical or the neurological 
examinations will be reported as adverse events. 
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e:
Blood pressure and pulse.
f:
Weight and Height (without shoes) will be measured.  Three measurements should be taken.  Each measurement should 
be recorded as a separate entry on the Vital Sign eCRF.
g:
Unused study drug to be retrieved and study drug dispensed only for subject requiring dose increases at Unscheduled 
Visits.
h:
Clinical laboratory tests include hematology, blood chemistry including lipid panel, and urinalysis.
i:
Clinical laboratory test will be collected under fasting conditions.
j:
Performed if only an abnormality was noted at previous visit.
k:
Female subjects age 8 years old and above, or of child-bearing potential, only.
l:
Only for subjects aged 6 years and older at the time of consent/assent.
m:
If during any visit the QTc was measured as greater than 450 ms, 3 consecutive ECGs separated by 5 to 10 minutes will 
be performed to confirm the abnormality. 
n:
During the unscheduled visits, ECG or EEG will only be done if the results from the previous visit were deemed 
clinically significant by the investigator.
o:
EEG will be performed in awake and sleep state in all subjects.
p:
Telephone interviews with the subjects and/or caregiver will be conducted 2 weeks (±3 days) after Visit 10 through 12, 
to ensure that subjects are completing their seizure diaries regularly and assess AEs, study drug compliance and 
concomitant medications, including AEDs.  Subjects whose dose was decreased before the scheduled telephone 
interview will be strongly encouraged to return to the clinic (instead of the scheduled telephone interview) for further 
consultation with regard to study drug administration.  The site will contact IxRS to receive further dispensing 
instructions.  Subjects will then return for their regularly scheduled visits.
q:
ABNAS to assess patient-perceived cognitive effects of AED treatment, measuring 5 aspects of cognitive function: 
fatigue, memory, concentration, motor speed, and reading, using a 4-point scale.
Statistical Analyses
Statistical analyses will be performed by the sponsor or designee after the study is completed, 
the database is locked and released, and a snapshot of the database is obtained and released.  
Analyses for regional submissions may be performed during the course of the study.  (revised 
per Amendment 02)  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 SAP.
Analysis Sets
Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least one postdose safety assessment in Extension A.  (revised per Amendment 03)
FAS is the group of subjects who received at least 1 dose of study drug and had at least 
1 postdose seizure measurement in Extension A.  (revised per Amendment 03)
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Efficacy Analyses
The percent change in seizure frequency per 28 days will be summarized using descriptive 
statistics (n, mean, median, minimum, and maximum) by age cohorts (4 to <7 years, ≥7 to 
<12 years), by disease cohorts (POS, PGTC, and GTC), and by the presence or absence of 
concomitant EIAED in the FAS.
The proportion of subjects who are seizure-free and the proportion of responders based on 
the decrease from baseline in 28-day seizure frequency of equal or greater than 25%, equal or 
greater than 50%, and equal or greater than 75% will be summarized using frequency count 
(number and percentage) by age cohorts (4 to <7 years, ≥7 to <12 years), by disease cohorts 
(POS, PGTC, and GTC), and by the presence or absence of concomitant EIAED in the FAS.
The CGIC will be summarized using frequency count (number and percentage) by age 
cohorts (4 to <7 years, ≥7 to <12 years), by disease cohorts (POS, PGTC, and GTC), and by 
the presence or absence of concomitant EIAED in the FAS.
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data that will be 
evaluated include TEAEs, clinical laboratory parameters, vital signs, 12-lead ECG results, 
C-SSRS, growth parameters, CBCL, LGPT, and EEGs.  Safety analyses will be performed 
similarly to the Core Study analyses and all analyses will be on the perampanel treatment 
duration (Core Study and Extension A).  (revised per Amendment 03)
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using MedDRA.  Adverse events will be coded to the 
MedDRA (version 18.1 or higher) lower level term closest to the verbatim term.  The linked 
MedDRA PT and primary 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.
Adverse events will be summarized using the Safety Analysis Set.  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 
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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 (related or not related).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT.  A subject data listing of all SAEs will be provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT.  A subject data listing of all AEs leading to 
discontinuation from study drug will be provided.
The incidence of TEAEs of special interest defined by SMQs will also be summarized.
Laboratory Values
Laboratory results will be summarized using SI units, as appropriate.  For all quantitative 
parameters listed in Section 9.5.1.5.3, 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.  Percentages will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results.
Laboratory test results will be assigned a LNH classification according to whether the value 
was below (L), within (N), or above (H) the laboratory parameter’s reference range.  For 
each laboratory parameter, shift from baseline (LNH) to each postbaseline visit and at the 
end of treatment will be presented.  Similar shift tables from baseline (LNH) to the 
highest/and lowest postbaseline value will also be presented
Appendix 3 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with TEMAVs. Except for phosphate, a TEMAV is defined as a 
postbaseline value with an increase from baseline to a grade of 2 or higher. For phosphate, a 
TEMAV was defined as a postbaseline value with an increase from baseline to a grade of 3 
or higher. The number and percentage of subjects with TEMAVs will be presented; each 
subject will be counted once in the laboratory parameter high and in the laboratory parameter 
low categories, as applicable. Markedly abnormal laboratory values will be flagged in the 
subject data listings.
For ALT and AST analysis, the number of subjects with greater than 3 times, but less than 
5 times the ULN and the number of subjects with greater than 5 times the ULN will be 
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summarized.  For bilirubin, a summary of the number of subjects with serum concentrations 
greater than 2 times the ULN will be created.
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.
ECG
ECG parameters and changes from baseline will be presented by visit.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Bazett and QTc Fridericia during the treatment period will be summarized.  
Clinically borderline or abnormal ECG results in QTc Bazett and QTc Fridericia will be 
categorized as follows:
Absolute QTc interval prolongation:

QTc interval 430-450 ms

QTc interval>450 ms

QTc interval>500 ms
Change from baseline in QTc interval:

QTC interval increases from baseline 30-60 ms

QTC interval increases from baseline>60 ms
Other Safety Analyses
The change from baseline in ABNAS, CBCL, and LGPT will be summarized.
The change from baseline in growth (height, weight, thyroid, and IGF-1) will be 
summarized.
The change from baseline in EEG parameters and the frequency of EEG abnormalities will 
be summarized.
Proportion of subjects with any treatment-emergent report of suicidal ideation and behavior 
and intensity of these behaviors will be summarized.
Other Analyses
The change from baseline in EQ-5D-Y will be summarized by age and disease cohorts, and 
by the presence or absence of concomitant EIAED, using descriptive statistics.
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Appendix 2
Extension Phase B (revised per Amendment 04)
Extension B is only for subjects in Japan or countries where an EAP cannot be implemented,
after having completed Extension A.  (revised per Amendments 03 and 04)
Study Design and Plan
Extension B will consist of a Treatment Period and a Follow-up Period (up to 4 weeks).  
Treatment will continue as long as clinically appropriate according to the judgment of the 
investigator.  In Japan, treatment of subjects in the Extension B will be completed when the 
subject reaches 12 years of age or when perampanel is commercially available in Japan for 
treatment of POS in pediatric subjects (4 to less than 12 years of age).  In countries where an 
EAP cannot be implemented, participation in Extension B will continue as long as clinically 
appropriate according to the judgment of the investigator, until the subject reaches 12 years 
of age or perampanel oral suspension is commercially available. 
(revised per 
Amendment 04)
Subjects eligible for Extension B shall be subjects in Japan or in countries where an EAP 
cannot be implemented, after having completed Extension A of this study, are less than 
12 years of age at the time of entering Extension B, and who in the opinion of the 
investigator continue to benefit from treatment with perampanel.
(revised per 
Amendment 04)
Subjects will enter Extension B with their optimal perampanel dose (ie, the same dose of 
perampanel that they were maintained on at the end of Extension A).  During the course of 
the Extension B, doses of perampanel and concomitant AEDs can be adjusted (concomitant 
AEDs can be used in accordance with the approved dosage and indication) based on clinical 
judgment.  
In Japan, the maximum dose of perampanel is 12 mg/day. (revised per Amendment 04)
In countries where an EAP cannot be implemented, the maximum dose of perampanel is 
12 mg/day in subjects not taking any concomitant EIAEDs, or 16 mg/day in subjects taking a 
concomitant EIAED. (revised per Amendment 04)
Tolerability at a minimum perampanel dose of 2 mg/day is required to continue in the 
program.  Subjects who do not tolerate the minimum perampanel dose of 2 mg/day during 
the study will be discontinued from the study. (revised per Amendment 04)
Conversion to monotherapy on perampanel is also permitted at the discretion of the 
investigator, if it is considered appropriate to control the seizures.
The visit intervals in Extension B will be every 12 weeks.
All visits to be done within 
±6 days of the schedule.
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During Extension B, when a subject reaches 12 years of age, the subject would have to 
switch to the commercial perampanel product promptly, and an End of Study Visit should be 
conducted.  If the subject does not switch to the commercial perampanel product promptly, 
study drug treatment will be discontinued.  A Discontinuation Visit should be conducted, and 
a Follow-up Visit should be conducted 4 weeks (±7 days) later. (revised per Amendment 03)
In Japan, when perampanel is commercially available for treatment of POS in pediatric 
subjects (4 to less than 12 years of age), all subjects will have to switch to perampanel 
commercial product promptly, and an End of Study Visit should be conducted.  If the subject 
does not switch to commercial product promptly, study drug treatment will be discontinued.  
A Discontinuation Visit should be conducted for that subject, and a Follow-up Visit should 
be conducted 4 weeks (±7 days) later. (revised per Amendments 03 and 04)
In countries where an EAP cannot be implemented, participation in Extension B will 
continue as long as clinically appropriate according to the judgment of the investigator, until 
the subject reaches 12 years of age or perampanel oral suspension is commercially available. 
(revised per Amendment 04)
The investigator may discontinue the subject from the study at any time for safety or 
administrative reasons.  When the decision is made to discontinue to subject from the study,
a Discontinuation Visit and a Follow-up Visit 4 weeks (±7 days) later should be conducted
for that subject. (revised per Amendment 03)
Subjects who discontinue or choose not to switch to the commercial product, once 
perampanel is commercially available will require a Follow-up Visit which will be conducted 
4 weeks (±7 days) after the Discontinuation Visit. (revised per Amendment 04)
Subjects who switch to the commercial product, once perampanel is commercially available 
will require an End of Study Visit.  A Follow-up Visit will not be required for subjects who 
switched to the commercial product and attended an End of Study Visit. (revised per 
Amendment 04)
The sponsor reserves the right to terminate the program at any time.  
Study Drug Supplies
Perampanel will be supplied as 0.5 mg/mL oral suspension.  
Schedule of Procedures/Assessments
Table 6 presents the Schedule of Procedures/Assessments for the Extension B.  During 
Extension B, laboratory tests will be performed by the local laboratory.
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Assessments
Safety Assessments
Safety will be assessed by monitoring of AEs, withdrawal from treatment, clinical laboratory 
tests, vital signs, and weight.
Other Assessments
Concomitant medication usage will be monitored.
Statistical Analyses
Analysis Sets
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 in Extension B.
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set. Safety data that will be 
evaluated include TEAEs, clinical laboratory parameters and vital signs. 
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using MedDRA.  Adverse events will be coded to the 
MedDRA (version 18.1 or higher) lower level term closest to the verbatim term.  The linked 
MedDRA PT and primary 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 
•
Re-emerges 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.
Adverse events will be summarized using the Safety Analysis Set.  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 relationship to study drug (related or not related).
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The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  
Laboratory Values
Laboratory results will be summarized using SI units, as appropriate.  For all quantitative 
parameters listed in Section 9.5.1.5.3, 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.  Percentages will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results.
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.
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Table 6
Schedule of Procedures/Assessments in Study E2007-G000-311: Extension B (revised per 
Amendments 03 and 04
Phase
Extension
Period
Treatment
Visit/Timing
At Initial 
Assessmenta
(Day 1, 
Week 1)
Scheduled Visitb
(Every 12 weeks)
Unscheduled
Visitc
End of 
Study
Discontinuation 
Visitd
Follow-Upe
(4 Weeks After 
Discontinuation 
Visit)
Procedures/Assessments
Review risk/benefit of continued therapy with 
perampanel and verify age eligibility
X
X
X
Concomitant medications and Concomitant AED(s)
Xf
X
X
X
X
X
Study drug compliance
Xf
X
X
X
X
Vital signs
Xf
X
X
X
X
X
Weight
Xf
X
Xg
X
X
X
Clinical laboratory evaluations
Xf
X
Xg
X
X
X
Urine pregnancy testh
Xf
X
Xg
X
X
X
Dispense study drug
X
X
Xi
Retrieve unused study drug
X
Xi
X
X
Adverse events
Xf
X
X
X
X
X
AED = antiepileptic drug, POS = partial-onset seizures.
a:
Perform on the final visit of Extension A Maintenance Period (ie, Visit 12).
b:
Visit window ±6 days.
c:
At the unscheduled visit, selected assessments will be performed based on investigator’s judgment of subject’s condition.
d:
Once a subject reaches 12 years of age or perampanel is commercially available, the subject would have to switch to the commercial product promptly. If a subject does not 
switch to the commercial product promptly, a Discontinuation Visit and a Follow-up Visit 4 weeks (±7 days) later should be conducted for the subject.
e:
Follow-up Visit is not required for subjects who will be switching to the commercial product and attend an End of Study Visit.
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Table 6
Schedule of Procedures/Assessments in Study E2007-G000-311: Extension B (revised per 
Amendments 03 and 04
Phase
Extension
Period
Treatment
Visit/Timing
At Initial 
Assessmenta
(Day 1, 
Week 1)
Scheduled Visitb
(Every 12 weeks)
Unscheduled
Visitc
End of 
Study
Discontinuation 
Visitd
Follow-Upe
(4 Weeks After 
Discontinuation 
Visit)
f:
Refer to the data recorded during the final visit of Extension A Maintenance Period (ie, Visit 12).
g:
At the discretion of the investigator.
h:
Female subjects age 8 years old and above, or of childbearing potential, only.
i:
Dispense study drug or Retrieve unused study drug should be done, if necessary.
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Appendix 3
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum-low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL
>27.8 mmol/L
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2007-G000-311
Study Protocol Title:
An Open-Label, Multicenter Study with an Extension Phase to 
Evaluate the Safety, Tolerability, and Exposure-Efficacy 
Relationship of Perampanel Oral Suspension when 
Administered as an Adjunctive Therapy in Pediatric Subjects 
(Age 4 to less than 12 years) with Inadequately Controlled 
Partial-Onset Seizures or Primary Generalized Tonic-Clonic 
Seizures
Investigational Product
Name:
E2007/perampanel
IND Number:
112515
EudraCT Number:
2014-002167-16
SIGNATURES
Authors:
Neurology Business Group
Eisai, Inc.
Date
Neurology Business Group
Eisai, Inc
Date
Neurology Business Group
Eisai Inc.
Date
Neurology Business Group
Eisai Inc.
Date
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2007-G000-311
Study Protocol Title:
An Open-Label, Multicenter Study with an Extension Phase to 
Evaluate the Safety, Tolerability, and Exposure-Efficacy 
Relationship of Perampanel Oral Suspension when 
Administered as an Adjunctive Therapy in Pediatric Subjects 
(Age 4 to less than 12 years) with Inadequately Controlled 
Partial-Onset Seizures or Primary Generalized Tonic-Clonic 
Seizures
Investigational Product
Name:
E2007/perampanel
IND Number:
112515
EudraCT Number:
2014-002167-16
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with ICH and all applicable local GCP guidelines, including 
the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
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SAP_001.pdf: 
Statistical Analysis Plan 
E2007-G000-311 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2007-G000-311 
Study Protocol 
Title: 
An Open-Label, Multicenter Study with an Extension Phase to 
Evaluate the Safety, Tolerability, and Exposure-Efficacy Relationship 
of Perampanel Oral Suspension when Administered as an Adjunctive 
Therapy in Pediatric Subjects (Age 4 to less than 12 years) with 
Inadequately Controlled Partial-Onset Seizures or Primary 
Generalized Tonic-Clonic Seizures 
Date: 
2/AUG/2018 
Version: 
Version 3.0 
 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS .................................................................................................. 2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 4 
3 
INTRODUCTION ............................................................................................................ 6 
3.1 
Study Objectives ..................................................................................................... 6 
3.1.1 
Primary Objective(s) ..................................................................................... 6 
3.1.2 
Secondary Objectives .................................................................................... 6 
3.1.3 
Exploratory Objective ................................................................................... 7 
3.2 
Overall Study Design and Plan ............................................................................... 7 
4 
DETERMINATION OF SAMPLE SIZE ......................................................................... 8 
5 
STATISTICAL METHODS ............................................................................................. 8 
5.1 
Study Endpoints ...................................................................................................... 8 
5.1.1 
Primary Endpoints ........................................................................................ 8 
5.1.2 
Secondary Endpoints .................................................................................... 8 
5.1.3 
Exploratory Endpoint .................................................................................... 9 
5.2 
Study Subjects ....................................................................................................... 10 
5.2.1 
Definitions of Analysis Sets ........................................................................ 10 
5.2.2 
Subject Disposition ..................................................................................... 10 
5.2.3 
Protocol Deviations ..................................................................................... 10 
5.2.4 
Demographic and Other Baseline Characteristics ...................................... 11 
5.2.5 
Prior and Concomitant Therapy .................................................................. 11 
5.2.6 
Treatment Compliance ................................................................................ 11 
5.3 
Data Analysis General Considerations ................................................................. 12 
5.3.1 
Pooling of Centers ....................................................................................... 12 
5.3.2 
Adjustments for Covariates ......................................................................... 12 
5.3.3 
Multiple Comparisons/Multiplicity ............................................................ 12 
5.3.4 
Examination of Subgroups .......................................................................... 12 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .................................... 12 
5.3.5.1 
Efficacy ............................................................................................. 12 
5.3.5.2 
Safety ................................................................................................ 12 
5.3.6 
Other Considerations .................................................................................. 13 
5.4 
Efficacy Analyses ................................................................................................. 13 
5.4.1 
Primary Efficacy Analyses ......................................................................... 13 
5.4.2 
Secondary Efficacy Analyses ..................................................................... 13 
5.4.3 
Other Efficacy Analyses ............................................................................. 14 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses .............................................................................................. 14 
 
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5.5.1 
Pharmacokinetic Analyses .......................................................................... 14 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ... 15 
5.6 
Safety Analyses ..................................................................................................... 15 
5.6.1 
Extent of Exposure ...................................................................................... 15 
5.6.2 
Adverse Events ........................................................................................... 15 
5.6.3 
Laboratory Values ....................................................................................... 17 
5.6.4 
Vital Signs ................................................................................................... 18 
5.6.5 
Electrocardiograms ..................................................................................... 19 
5.6.6 
Other Safety Analyses ................................................................................. 19 
5.7 
Other Analyses ...................................................................................................... 23 
5.8 
Exploratory Analyses ............................................................................................ 23 
5.9 
Extension Phase Analyses ..................................................................................... 23 
6 
INTERIM ANALYSES .................................................................................................. 23 
7 
CHANGES IN THE PLANNED ANALYSES .............................................................. 23 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................. 24 
8.1 
EFFICACY DATA HANDLING ......................................................................... 24 
8.1.1 
Pre-randomization/baseline efficacy ........................................................... 24 
8.1.2 
Treatment Duration for Efficacy Analyses ................................................. 24 
For all efficacy analyses, data reported only during the treatment duration will be 
analyzed. The diary seizure data during the Follow-up will be listed. ....... 24 
8.1.3 
Handling of Replicate Data ......................................................................... 24 
8.2 
SAFETY DATA HANDLING ............................................................................. 25 
8.2.1 
Baseline safety ............................................................................................ 25 
8.2.2 
Treatment Duration for Safety Analyses .................................................... 25 
8.2.3 
Handling of Replicate Data ......................................................................... 26 
9 
PROGRAMMING SPECIFICATIONS ......................................................................... 27 
10 STATISTICAL SOFTWARE ......................................................................................... 27 
11 MOCK TABLES, LISTINGS, AND GRAPHS ............................................................. 27 
12 REFERENCES ............................................................................................................... 27 
13 APPENDICES ................................................................................................................ 28 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results .... 28 
 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ABNAS 
A-B neuropsychological assessment schedule 
AE(s) 
adverse event(s) 
AED 
antiepileptic drug 
 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic class 
BMI 
body mass index 
CBCL 
Child Behavior Checklist 
CGI 
Clinical Global Impression 
CGIC 
Clinical Global Impression of Change 
CGIS 
Clinical Global Impression of Severity 
CRF 
case report form 
Css,av 
average steady-state drug concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
EQ-5D-Y 
EuroQol 5 Dimensions – Youth 
FAS 
Full Analysis Set 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
GTC 
Generalized Tonic-Clonic 
HRQL 
health-related quality of life 
ICF 
informed consent form 
IP 
Invnestigational Products 
LGPT 
Lafayette Grooved Pegboard Test 
LLN 
lower limit of normal 
LNH 
low/normal/high 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
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Abbreviation 
Term 
PD 
Pharmacodynamics 
PGTC 
primary generalized tonic-clonic 
PK 
Pharmacokinetics 
POS 
partial-onset seizures 
PT 
preferred term 
QTc 
corrected QT interval (time from the beginning of the QRS 
complex to the end of the T wave, corrected for heart rate) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Système International 
SMQ 
standardized MedDRA queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
TLG 
tables, listings, and graphs 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for the core phase of Eisai 
Protocol E2007-G000-311. The statistical methods used in the extension phase will be 
described in a separate SAP.  
3.1 
Study Objectives 
3.1.1 
Primary Objective(s) 
To evaluate the safety and tolerability of E2007/perampanel oral suspension when 
administered as an adjunctive therapy in children (ages 4 to <12 years) with inadequately 
controlled partial-onset seizures (POS) or primary generalized tonic-clonic seizures (PGTC) 
3.1.2 
Secondary Objectives 
1. To characterize the PK of perampanel and the relationship between perampanel 
plasma concentrations, efficacy, and safety using population PK/PD modeling 
 
2. To evaluate the effects of perampanel on cognition, behavior, visuomotor skills, and 
growth and development in children during short-term (23 weeks) and long-term (up 
to 52 weeks) treatment 
 
3. To evaluate the frequency of EEG abnormalities during awake and sleep state during 
52 weeks of treatment 
 
4. To evaluate suicidal ideation and suicidal behavior in children 6 years to less than 12 
years as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) during 
52 weeks of treatment 
 
5. To evaluate the efficacy of perampanel as measured by the median percent change per 
28 days in seizure frequency, by the proportion of responders (≥25%, ≥50%, and 
≥75%), and by the proportion of subjects who are seizure-free for POS, PGTC, and 
Generalized Tonic-Clonic (GTC) seizures 
 
6. To evaluate, in Japanese subjects, the efficacy of perampanel on partial onset 
seizures(POS) in the present study as compared with placebo in Study E2007-J000-
335 
 
7. To assess the effects of perampanel on the Clinical Global Impression (CGI), CGI of 
Severity (CGIS) and CGI of Change (CGIC) 
 
 
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3.1.3 
Exploratory Objective 
To assess the impact of perampanel on the health utility of children using the Euroqol 5 
Dimensions-Youth (EQ-5D-Y) scale. 
3.2 
Overall Study Design and Plan 
This was a multicenter, open-label single-arm study in children (ages 4 to <12 years) with 
inadequately controlled POS or PGTC. The study was to consist of a Core Study and 
Extension Phase (Extension A, for all countries in the study) with an Additional Extension 
Phase (Extension B) available for subjects enrolled in Japan only. Subjects were to be 
stratified by age (≥4 to <7 years, 7 to <12 years) with at least 30% subjects enrolled in the 
equal or greater than 4 to less than 7 year age group for each seizure type (ie, at least 36 with 
POS and at least 12 with PGTC). 
Core Study 
The Core Study was to consist of the following 2 phases: Pretreatment and Treatment Phase. 
The Pretreatment Phase was to consist of a Screening/Baseline Period that lasts up to 4 
weeks ±3 days outside of Japan. Subjects in Japan were required to complete 4 full weeks ±3 
days of the Screening/Baseline Period. However, subjects outside of Japan could begin 
treatment as soon as baseline procedures were completed and documentation of eligibility 
(such as a documented seizure diary entry for a qualifying seizure during the preceding 12 
weeks prior to Visit 2 or a qualifying seizure during the prospective Screening/Baseline 
Period) had been established. During this phase, subjects were to be assessed for eligibility to 
participate in the study. 
The Treatment Phase was to consist of 3 periods: Titration (up to 11 weeks), Maintenance 
(up to 12 weeks), and Follow-up (4 weeks; only for those subjects not rolling over into the 
Extension Phase). 
Extension A 
The Extension Phase was to consist of a Maintenance Period (29 weeks) and a Follow-up 
Period (up to 4 weeks; only for those subjects not entering into Extension B [Japan only]). 
An overview of the study design is presented in Figure 1 of the protocol. 
Extension B  
Extension B was to be available to subjects enrolled in Japan and in countries where an EAP 
cannot be implemented. Extension B consisted of an open-label Treatment Phase. In Japan, 
treatment was continued as long as clinically appropriate  according to the judgment of the 
investigator. However, treatment of subjects in Extension B 
was to be completed when the subject reaches 12 years of age or when perampanel is 
commercially available in Japan for treatment of POS in pediatric subjects (4 to less than 
12 years of age). In countries where an EAP cannot be implemented, participation in 
Extension B was continued as long as clinically appropriate according to the judgment of the 
 
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investigator, until the subject reaches 12 years of age or perampanel oral suspension is 
commercially available.  Subjects who discontinue or choose not to switch to the commercial 
product was required a Follow-up Visit which was to be conducted 4 weeks (±7 days) after 
the discontinuation Visit.  
4 
DETERMINATION OF SAMPLE SIZE 
A sample size of 160 subjects (with up to 40 subjects with PGTC and the balance 
with POS), is deemed sufficient for safety evaluation in this age group (age 4 to <12 years). 
This sample size matches the total number of adolescents who were enrolled in the 4 global 
Phase 3 efficacy and safety studies that support the POS and PGTC indications. 
For purposes of registration in Japan, it has been determined that a sample size of 65 subjects 
enrolled in Japan will provide 80% power to exclude the possibility that there would be a 
reduction smaller than that observed in the placebo arm of Study E2007-J000-335 (ie, 
10.5%). 
The sample size calculation was examined based on two scenarios of 10%, 40% and 50% or  
10%, 30% and 60% of subjects receiving E2007 doses of 4mg, 8mg or 12mg respectively, as 
allocation group dose. In addition, the ratio of inducer medication user was assumed to be 
70%. In either scenario, a sample size set 65 subjects is  powered above 80%. The power is 
calculated from the number of counts from 10,000 re-sampling simulation about the upper 
limit of 95% confidence interval below 10.5%. 
 
 
 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects. All summaries will be produced by age cohort (4-<7 and 
7-<12), disease cohort (POS, PGTC, GTC) and inducer status (inducer, non-inducer) except 
TEAE summary by speed of titration. All analysis will be conducted for Japanese POS 
subjects in Japanese sites (Country=Japan). 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
Safety and tolerability, which include incidence of treatment-emergent adverse events 
(TEAEs) and SAEs, laboratory parameters, vital signs, and ECG parameters, of perampanel 
oral suspension in children (ages 4 to <7 years and ≥7 years to <12 years) with POS or PGTC 
 
5.1.2 
Secondary Endpoints 
The following endpoints will be analyzed: 
 
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1. The relationship between plasma levels of perampanel and efficacy endpoints (ie, 
change in average seizure frequency over 28 days, responder probability, and the 
proportion of subjects who are seizure-free in the Maintenance Period of the Core 
Study) separately for each seizure type 
 
2. The relationship between plasma levels of perampanel and cognition endpoints 
including change from baselines in ABNAS, CBCL, and LGPT. In addition, 
depending on the AE data, the relationship between plasma levels of perampanel and 
select AEs will be assessed 
 
3. Change from baseline at Week 23 and Week 52 in ABNAS, CBCL, and LGPT 
 
4. Changes from baseline at Week 23 and Week 52 in growth and development 
parameters (height, weight, thyroid, and IGF-1) 
 
5. Change from baseline in EEG and the frequency of EEG abnormalities during awake 
and sleep state 
 
6. Proportion of subjects (aged 6 or older at time of consent/assent) with any treatment-
emergent reports of suicidal ideation and behavior on the C-SSRS and intensity of 
these behaviors assessed using C-SSRS scores 
 
7. The median percent change in seizure frequency per 28 days during Treatment Phase 
(Titration Period and Maintenance Period) of the Core Study, and during the long-
term treatment (up to 52 weeks) relative to the Pretreatment Phase. Seizure frequency 
will be based on the 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 
 
8.  Proportion of responders (25% responders defined as a decrease in 28-day seizure 
frequency of equal or greater than 25% compared to baseline seizure frequency; 50% 
responders defined as a decrease in 28-day seizure frequency of equal or greater than 
50% compared to baseline seizure frequency; 75% responders defined as a decrease 
in 28-day seizure frequency of equal or greater than 75% compared to baseline 
seizure frequency) during Maintenance Period of Core Study, and during the long 
term treatment (up to 52 weeks) 
 
9.  Proportion of subjects who are seizure-free during Maintenance Period of Core Study, 
and during the long-term treatment (up to 52 weeks) 
 
10. CGI of Change 
 
5.1.3 
Exploratory Endpoint 
Change from baseline at Week 23 and Week 52 in EQ-5D-Y 
 
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5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
The Safety Analysis Set (SAS) 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 (FAS) is the group of subjects who received at least 1 dose of study 
drug and had at least 1 postdose primary efficacy measurement. 
PK Analysis Set is the group of subjects receiving perampanel and with at least 1 
quantifiable perampanel concentration at one of the visits during the Maintenance Period of 
the Core Study and with adequately documented dosing history. 
PK/PD Analysis Set is the group of subjects receiving perampanel who have seizure 
frequency, cognition, or AE data with documented dosing history. Subjects receiving 
perampanel should have at least 1 quantifiable perampanel concentration at one of the visits 
during the Maintenance Period of the Core Study as per the PK Analysis Set. 
5.2.2 
Subject Disposition 
The number of subjects enrolled and the reasons for screen failure will be summarized. The 
frequencies of occurrence of completion, discontinuation and each reason for discontinuation 
of primary and other will be summarized. The data will be described using incidence rate 
(number of subjects and percentage). 
5.2.3 
Protocol Deviations 
The following major protocol deviations will be listed and summarized. 
• Recruitment of a subject who did not satisfy the entry criteria 
• Excluded medication administered 
• Overdose of Investigational Products of 120% or above between two consecutive 
visits 
• Continuation of treatment with investigational product after a treatment related 
withdrawal event  
• IP compliance <80% between two consecutive visits. 
• Unauthorized dose adjustment during Core Study 
• Missing 2 or more PK samples during the Core Study 
• Allowed concomitant AED(s) dose did not remain stable during core phase  
• Other clinically relevant deviations to be decided before database lock 
 
  
 
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5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the SAS will be summarized using 
descriptive statistics. Continuous demographic and baseline variables include age, weight, 
height, and BMI; categorical variables include sex, age group (4-7, 7-12), race and ethnicity. 
MEDICAL HISTORY 
The number (percentage) of subjects in the SAS reporting a history of any medical condition, 
as recorded on the CRF, will be summarized.  A subject data listing of medical and surgical 
history will be provided. 
Epilepsy-specific medical history for the SAS will be summarized using descriptive statistics, 
including time since diagnosis, suspected localization of the epileptogenic region and seizure 
type. 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD). Latest Version before 
databse lock will be used for analysis. The number (percentage) of subjects who took prior 
and concomitant medications will be summarized on the Safety Analysis Set by Anatomical 
Therapeutic Chemical (ATC) class and WHO DD preferred term (PT). Prior medications will 
be defined as medications that stopped before the 1st dose of study drug. Concomitant 
medications will be defined as medications that (1) started before the 1st dose of study drug 
and were continuing at the time of the 1st dose of study drug, or (2) started on or after the 
date of the 1st dose of study drug up until 28 days after the subject’s last dose. All 
medications will be presented in subject data listings.  
The number of baseline AEDs will be summarized and a summary of baseline and 
concomitant AEDs will be produced. A baseline AED is an AED taken at Day1. 
Concomitant AEDs are defined as above for concomitant medications. 
Specifically, the number of subjects who take concomitant enzyme inducing antiepileptic 
drugs (EIAEDs) will be summarized using percentage and frequency. 
5.2.6 
Treatment Compliance 
Percent compliance will be calculated for the treatment phase for the FAS as follows:  
Compliance  
= (Study Med issued in grams 
– 
Study Med Returned in grams)  
x100 
(Number of Days x Prescribed Daily Dose in ml) x Suspension density of 1.07g/ml 
Overall compliance , each period compliance (Titration (Visit2-Visit6), Maintenance(Visit6-
Visit9)) and per visit compliance (Visit2-Visit3, Visit3-Visit4, Visit4-Visit5, Visit5-Visit6, 
Visit6-Visit7, Visit7-Visit8, Visit8-Visit9) with study medication will be summarized using 
 
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descriptive statistics for. Subjects will also be categorized by compliance categories of <80%, 
80%-120% and >120%.  
 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
Not applicable. 
5.3.3 
Multiple Comparisons/Multiplicity 
Not applicable. 
5.3.4 
Examination of Subgroups 
The efficacy endpoints will be summarized by disease cohorts (POS, PGTC, and GTC). 
Within the POS and PGTC disease cohorts, endpoints will also be summarized by age cohort 
(4 to <7 years, ≥7 to <12 years) , and with or without use of concomitant EIAEDs,  
All other endpoints will be summarized by disease cohorts (POS, PGTC, and GTC), age 
cohort (4 to <7 years, ≥7 to <12 years), and the presence or absence of concomitant EIAEDs.  
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
5.3.5.1 Efficacy 
For the last observation carried forward (LOCF) analyses, such as “Maintenance-LOCF” 
analyses of responder rate, if the overall duration of the Maintenance Period is less than 8 
weeks, the diary data up to the last 8 weeks during the Titration and Maintenance Periods 
combined will be used to calculate the seizure frequency per 28 days for Maintenance-LOCF. 
Since data is rank transformed prior to analysis, outliers will have no effect on the calculation 
for confidence interval of percent change in seizure frequency per 28 days. 
5.3.5.2 Safety 
The algorithm on the assumptions used for imputing the missing dates for AEs is given in the 
programming specifications.   
If the day and month are missing, events will be considered treatment-emergent if the year is 
equal to or after the year of the first dose date; if days are missing, events will be considered 
treatment-emergent if the year is after the year of the first dose, or if the year is equal to the 
year of the first dose date and the month is equal to or after the month of the first dose date.  
 
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For the purpose of summarizing maximum severity, if the severity of an adverse event (AE) 
is missing for a subject, then, if this subject has another AE with the same preferred term that 
has “severe” severity, the maximum severity of the AE will be noted as “severe’; otherwise 
the maximum severity will be noted as missing. Similarly, for the purpose of summarizing 
closest relationship, if the relationship of an AE to study drug is missing, the AE will be 
noted to be probably related if there is another probably related AE with the same preferred 
term, otherwise this relationship will be noted as missing.  
For determining treatment emergent markedly abnormal lab values, a missing baseline lab 
value will be assumed to be of grade 0. 
The algorithm to impute missing dates for concomitant medications is given in the 
programming specifications. No special handling of missing data is planned for the analysis 
of any of the other safety variables. 
Data exceptions or outliers will be determined by inspection of the tables, listings, and graphs 
in consultation with the clinical study team. The effect of outliers on analyses may be 
assessed by re-analyzing the data without the outliers. 
All the listings will display the original missing values.  
5.3.6 
Other Considerations 
Not applicable. 
5.4 
Efficacy Analyses 
Only “valid days” and “valid seizure counts” will be used in the calculations of seizure 
frequency per 28 days. A “valid day” is defined as the day where seizure counts information 
is present, that is, either a record with an answer of ‘No’ to the question ‘Did the subject 
experience any seizures?’ or a positive number of seizures for at least one of the seizure types 
collected. “Valid seizure counts” are the seizure counts that are read from the valid seizure 
days. 
5.4.1 
Primary Efficacy Analyses 
Not applicable. 
5.4.2 
Secondary Efficacy Analyses 
The percent change in seizure frequency per 28 days during Treatment Phase (Titration 
Period and Maintenance Period) of the Core Study with respect to during the Pretreatment 
Phase will be summarized using descriptive statistics (n, mean, median, minimum, maximum 
and 95% confidence interval).  The percent change in seizure frequency per 28 days are 
calculated for Total seizure, POS total seizure and total complex partial seizure for POS 
cohort,  for PGTC seizure, absence seizure, myoclonic seizure and total seizure for PGTC 
cohort and for Secondarily Generalized seizures  for GTC cohort. Total Seizures is sum of  
all seizures, including POS, generalized and other seizures. Total POS Seizures is sum of  all 
POS seizures, including simple partial seizures without motor signs, simple partial seizures 
 
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with motor signs, complex partial seizures and complex partial seizures with secondary 
generalization. Secondarily Generalized seizures cohort is a subset of the POS cohort. 
The proportion of subjects who are seizure-free and the proportion of responders based on 
decrease from baseline (during the Pretreatment Phase) in 28-day seizure frequency of equal 
or greater than 25%, equal or greater than 50%, and equal or greater than 75% during 
Maintenance-LOCF Period  of the Core Study will be summarized using frequency count 
(number and percentage). If subjects complete the Core study and have no seizure during the 
Maintenance Period, those will be treated as seizure-free. 
The number of subjects with new seizure types compared to Baseline Period and Seizure 
history will be counted. 
For analysis for the Japanese submission, all of analysis will be conducted for Japanese 
population but the following analysis also will be conducted. 
The percent change in seizure frequency of POS total seizure per 28 days during Treatment 
Phase (Titration Period and Maintenance Period) of the Core Study with respect to the 
Pretreatment Phase will be summarized using descriptive statistics (n, mean, median, 
minimum, maximum and 95% confidence interval) by 4 week periods (1-4week, 5-8week, 9-
12 week , 13-16 week, 17-20 week, 21-23 week, last 4 weeks of treatment). 
The CGI-I and CGI-S will be summarized for each visit using frequency count (number and 
percentage). 
5.4.3 
Other Efficacy Analyses 
The score of EQ-5D-Y each items (Mobility, Looking after myself, Doing usual activities, 
Having pain or discomfort, Feeling worried, sad or unhappy) will be summarized for each 
visit using frequency count (number and percentage). The measurement and the change from 
baseline of EQ-5D-Y VAS at each visit will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum and maximum). 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
Perampanel plasma concentrations were obtained from blood samples drawn at any time 
during the treatment phase (Weeks 15, 19 and 23/EOT). Details of the analysis methods for 
population PK/PD modeling will not be described in this SAP but will be described in a 
separate analysis plan. 
5.5.1 
Pharmacokinetic Analyses 
Population PK analysis will be performed to characterize the PK of perampanel by pooling 
the concentration data with other studies, including 19 Phase 1 studies, 2 Phase 2 studies 
(232 and 235), and 5 Phase 3 studies (304, 305, 306, 332, and 335). A 2-compartment PK 
model will be fit to the data and the effect of intrinsic and extrinsic factors, including body 
weight and age, on the PK of perampanel will be evaluated. The post-hoc estimates of both 
 
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maximum observed concentration (Cmax) and area under the curve (AUC) from the final PK 
model will be derived for all subjects. In addition, average steady-state drug concentration 
(Css,av) will be calculated. Subsequently, the dose-normalized derived exposure parameters 
will be summarized descriptively by age group (≤4 years, >4 to ≤8 years, >8 to <12 years, 
≥12 to <18 years, and ≥18 years) for subjects with and without inducing AEDs, and also 
presented in box-plots. 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
PD endpoints to be evaluated as part of PK/PD analyses include endpoints for efficacy, 
cognition, and selected safety parameters. 
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set(SAS). Safety data will be 
summarized on an “as treated” basis using descriptive statistics (eg, n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables). Safety variables include TEAEs, clinical laboratory parameters, vital signs, 12-
lead ECG results, C-SSRS, growth parameters, CBCL and LGPT. Study Day 1 for all safety 
analyses will be defined as the date of the 1st dose of study drug. 
 
5.6.1 
Extent of Exposure 
The duration of treatment (Titration Period and Maintenance Period of the Core Study) will 
be calculated as the number of weeks between the date the subject receives their 1st treatment 
dose and the date the subject receives the last dose of treatment. These values will be used to 
summarize the extent of exposure to study medication. 
Modal dose , mean daily dose, maximum daily dose and last daily dose will presented using  
summary statistics and frequency using categories of < 4 , 4, >4-<8 , 8-<12 , 12=<.  Number 
and percent of subjects who down-titrated or discontinued study at maximum daily dose exposed will 
be summarized using frequency count (number and percentage). 
5.6.2 
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). AEs will be coded to the MedDRA (version 18.1 or higher) lower level term 
closest to the verbatim term. The linked MedDRA PT and primary system organ class (SOC) 
are also captured in the database. 
A TEAE is defined as an AE that emerges from the date of first dose of study drug  to 28 
days  after last end date of dose in prescribed dose entry , having been absent at pretreatment 
(Baseline) or 
• Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 
 
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• 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 TEAEs will be summarized using the Safety Analysis Set. 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]). 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT. Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT. A subject data listing of all AEs leading to death will be provided.  
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT. A subject data listing of all SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to 
discontinuation from study drug will be provided. 
An overview of TEAEs and the number (percentage) of subjects with TEAEs by speed of 
titration, ‘Fast’ and ‘Other’, will be summarized by MedDRA SOC and PT for safety set. 
‘Fast’ titrators are defined as subjects who spent less time on any one dose prior to attaining 
their maximum dose than was permitted by the protocol and ‘Other’ is defined as all other 
subjects.  
AEs of special Interest 
A listing of subjects with AEs related to suicidality, identified by relevant Standardized 
MedDRA Query (SMQ) terms, will be provided. TEAEs of special interest listed below will 
be summarized by SOC and PT. SMQs will be used to identify relevant terms for the 
following TEAEs. 
• TEAEs suggestive of abuse potential 
• TEAEs related to alertness and cognition 
• TEAEs related to psychosis / psychotic disorders 
• TEAEs related to hostility/aggression 
 
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• TEAEs related to status epilepticus/convulsions 
• TEAEs related to lab abnormalities 
• Cardiac and ECG TEAEs 
• TEAEs related to rash 
 
TEAEs related to rash will be identified by medical review. Falls will be summarized for the 
Pretreatment Phase and Follow-up Period and will be summarized by actual dose of onset for 
the Titration and Maintenance Periods. 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate. 
For all quantitative parameters listed in protocol Section 9.5.1.5.3 Safety Assessments 
(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 protocol 
Section 9.5.1.5.3 Safety Assessments (Laboratory Measurements) 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. For each laboratory parameter, shift from baseline (LNH) to each 
postbaseline visit and at the end of treatment will be presented. Similar shift tables from 
baseline (LNH) to the highest/lowest postbaseline value will also be presented.  
Protocol Appendix 2 (Sponsor’s Grading for Laboratory Values) presents the criteria that 
will be used to identify subjects with treatment-emergent markedly abnormal laboratory 
values (TEMAV). Except for phosphate, a TEMAV was defined as a postbaseline value with 
an increase from baseline to a grade of 2 or higher. For phosphate, a TEMAV was defined as 
a postbaseline value with an increase from baseline to a grade of 3 or higher. The number and 
percentage of subjects with TEMAVs will be presented; each subject will be counted once in 
the laboratory parameter high and low categories, as applicable. Markedly abnormal 
laboratory values will be flagged in the subject data listings. 
For ALT and AST analysis, the number of subjects with greater than 3 times, but less than 5 
times the ULN and the number of subjects with greater than 5 times the ULN will be 
summarized. For bilirubin, a summary of the number of subjects with serum concentrations 
greater than 2 times the ULN will be created. These summaries will also be provided for the 
maximum value in the treatment duration. In addition, the number of subjects who meet the 
criteria for Hy’s Law will be summarized by visit and during the treatment duration. A 
subject will be determined to have met Hy’s Law if AST or ALT is > 3x ULN, bilirubin > 2x 
 
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ULN, and alkaline phosphatase ≤ 2x ULN at a visit. The number of subjects who meet each 
of the criteria for Hy’s Law during treatment (but not all necessarily at the same visit) will 
also be summarized. 
5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.  
In addition, the criteria described in the table below will be used to determine clinically 
notable results for blood pressure and heart rate. The number (percentage) of subjects with 
clinically notable results over all scheduled and unscheduled visits will be summarized. 
Table 1: Criteria for Clinically Notablea Vital Signs 
Variable  
Criterion Value  
Change Relative to Baseline  
Systolic BP  
> 180 mmHg  
Increase of ≥ 20 mmHg  
< 90 mmHg  
Decrease of ≥ 20 mmHg  
Diastolic BP  
>105 mmHg  
Increase of ≥ 15 mmHg  
< 50 mmHg  
Decrease of ≥ 15 mmHg  
Heart Rate  
>120 bpm  
Increase of ≥ 15 bpm  
< 50 bpm  
Decrease of ≥ 15 bpm  
Weight  
  
Increase of > 7%  
  
Decrease of > 7%  
a: Clinically notable means that a value must have met both the criterion value and satisfied 
the magnitude of change relative to baseline. 
The criteria in Table 2 will be used to determine abnormal results for blood pressure and 
heart rate. The number of subjects with abnormal results will be summarized. 
Table 2: Criteria for Abnormal Vital Signs 
Variable  
Change Relative to Baseline  
Systolic BP  
Increase of ≥ 20 mmHg  
Decrease of ≥ 20 mmHg  
 
Increase of ≥ 40 mmHg  
 
Decrease of ≥ 40 mmHg  
Diastolic BP  
Increase of ≥ 10 mmHg  
Decrease of ≥ 10 mmHg  
 
Increase of ≥ 20 mmHg  
 
Decrease of ≥ 20 mmHg  
Pulse  
Increase of ≥ 15 bpm  
 
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Decrease of ≥ 15 bpm  
 
Increase of ≥ 30 bpm  
 
Decrease of ≥ 30 bpm  
5.6.5 
Electrocardiograms 
ECG parameters(QTcB, QTcF, PR interval QRS duration and RR interval) and changes from 
baseline will be presented by visit. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Bazett and QTc Fridericia during the treatment period will be summarized. 
Clinically borderline or abnormal ECG results in QTc Bazett and QTc Fridericia will be 
categorized as follows: 
Absolute QTc interval prolongation: 
• QTc interval 430-450 ms 
• QTc interval >450 ms 
• QTc interval >500 ms 
Change from baseline in QTc interval: 
• QTc interval increases from baseline 30-60 ms 
• QTc interval increases from baseline >60 ms. 
5.6.6 
Other Safety Analyses 
Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS) 
The total ABNAS score (defined as the sum of the individual question scores) and sub-scores for 
fatigue, slowing, memory, concentration, motor-coordination and language (Brooks et al 2001) 
will be listed and summarized by visit. Changes from baseline ABNAS sub-scores will be 
summarized. 
Table 1: Definition between each aspect and question 
Aspect 
# of items 
Range 
Item No 
fatigue  
5 
0-15 
1, 7, 13, 18, 24 
slowing  
5 
0-15 
2, 8, 14, 19, 23 
memory  
4 
0-12 
3, 9, 15, 20 
concentration  
4 
0-12 
4, 10, 16,21 
motor speed  
3 
0-9 
5, 11, 17,  
reading (language)  3 
0-9 
6, 12, 22 
 
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Child Behavior Check List   (CBCL 1.5/5 and CBCL 6/18) 
The CBCL 1.5/5 measures problems in children (1,5 to 5 years old). The data are corrected 
the problems for children from CRF. To measure problems, 100 ‘problem items’ are rated on 
a scale to measure their occurrence.  Higher scores indicate greater problems, as the scale 
ranges from 0, indicating ‘not true,’ to 2, indicating ‘often true.’  67 of the items are then 
summed into seven syndrome scores (Emotionally Reactive, Anxious/Depressed, 
Withdrawn, Somatic Complaints, Attention Problems, Aggressive Behavior syndrome and 
Sleep problems.) The summation of the first four syndrome scores yields the Internalizing 
Syndrome composite score, and the summation of the next two syndrome scores yields the 
Externalizing Syndrome composite score.  The total problems score is the summation of the 
two composite scores, the final three syndrome scores, and the 33 ‘problem items’ that were 
not included in any of the seven syndrome scores. 
The total problems score, the Internalizing Syndromes score, the Externalizing Syndromes 
score, and each of the seven individual syndrome scores of the CBCL 1.5/5 will be evaluated 
using summaries of change from baseline (Week 0) by visit. 
Table 2: Definition CBCL 1.5-5 (Refer to link of CBCL/1 1/2-5 and LDS in profiles at website 
http://www.aseba.org/forms.html) 
Sydrome scale 
#of items 
Range 
Items 
Emotionally Reactive 
9 
(0-18) 
21,46,51,79,82,83,92,97,99 
Anxious/Depressed 
8 
(0-16) 
10,33,37,43,47,68,87,90 
Withdrawn 
8 
(0-16) 
2,4,23,62,67,70,71,98 
Somatic Complaints 
11 
(0-22) 
1,7,12,19,24,39,45,52,78,86,93 
Internalizing 
36 
(0-72) 
sum of 4 previous scores 
Attention Problems 
5 
(0-10) 
5,6,56,59,95 
Aggressive Behavior 
syndrome 
19 
(0-38) 
8,15,16,18,20,27,29,35,40,42,44,53,5
8,66,69,81,85,88,96 
Externalizing 
24 
(0-48) 
sum of 2 previous scores 
Sleep problems 
7 
(0-14) 
22,38,48,64,74,84,94 
Total 
100 
(0-200) 
Sum of all problem items scores, 
including: Internalizing Syndromes, 
Externalizing 
Syndromes, 
Sleep 
problems, and 33 not yet accounted 
for problems 
 
Also the CBCL 6/18 measures competencies and problems in children (6 to 18 years old) .  
To assess competence, sixteen items are scored for each child, with higher scores indicating 
better competence.  The summed scores are grouped into three sub-scores for competence in 
 
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activities, social realms and school.  The total competence score is the summation of all 16 
items. 
To measure problems, 120 ‘problem items’ are rated on a scale to measure their occurrence.  
Higher scores indicate greater problems, as the scale ranges from 0, indicating ‘not true,’ to 
2, indicating ‘often true.’  103 of the items are then summed into eight syndrome scores 
(Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints, Rule-Breaking Behavior, 
Aggressive Behavior, Social Problems, Thought Problems, and Attention Problems.)  The 
summation of the first three syndrome scores yields the Internalizing Syndrome composite 
score, and the summation of the next two syndrome scores yields the Externalizing 
Syndrome composite score.  The total problems score is the summation of the two composite 
scores, the final three syndrome scores, and the 17 ‘problem items’ that were not included in 
any of the eight syndrome scores. 
The total competence score, the three sub-scores for competence, the total problems score, 
the Internalizing Syndromes score, the Externalizing Syndromes score, and each of the eight 
individual syndrome scores of the CBCL 6/18 will be evaluated using summaries of change 
from baseline (Week 0) by visit. 
Table 3: Definition CBCL 6-18 (Refer to link of CBCL/6-18 scored using three differenr societies in 
profiles at website : http://www.aseba.org/forms.html) 
Competency Scores 
Sub-scores 
# of Items 
Score 
Range 
Items 
Activity   
6 
(0-15) 
I.A, B, II.A, B, IV A, B  
Social 
6 
(0-14) 
III.A, B, V.1, 2, VI. A, B 
School 
4 
(0-6) 
VII. 1, 2,3,4 
Total 
16 
(0-35) 
Sum of 3 previous scores 
 
Syndrome/ Problems Scores 
Syndrome scale 
#of items 
Score 
Range 
Items 
Anxious/Depressed 
13 
(0-26) 
14,29,30,31,32,33,35,45,50,52,71,
91,112 
Withdrawn/Depressed 
8 
(0-16) 
5,42,65,69,75,102,103,111 
Somatic Complaints 
11 
(0-22) 
47,49,51,54,56a,56b,56c,56d,56e,
56f,56g 
Internalizing 
32 
(0-64) 
sum of 3 previous scores 
Rule-Breaking Behavior 
17 
(0-34) 
2,26,28,39,43,63,67,72,73,81,82,9
0,96,99,101,105,106 
Aggressive Behavior  
18 
(0-36) 
3,16,19,20,21,22,23,37,57,68,86,8
 
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7,88,89,94,95,97,104 
Externalizing 
35 
(0-70) 
sum of 2 previous scores 
Social Problems 
11 
(0-22) 
11,12,25,27,34,36,38,48,62,64,79 
Thought Problems 
15 
(0-30) 
9,18,40,46,58,59,60,66,70,76,83,8
4,85,92,100 
Attention Problems 
10 
(0-20) 
1,4,8,10,13,17,41,61,78,80 
Total 
120 
(0-240) 
Sum of all problem items scores, 
including: 
Internalizing 
Syndromes, 
Externalizing 
Syndromes, 
Social 
Problem, 
Thought 
Problem, 
Attention 
Problem, 
and 
17 
not 
yet 
accounted for problems 
Additionally, the borh CBCL results for each subject will be converted to a standardized T-
score and classified at baseline and at each evaluation as normal, borderline clinical, or 
clinical, based on the thresholds provided in the CBCL manual. These classifications and 
their change from baseline will be presented in tables. 
Lafayette Grooved Pegboard Test (LGPT) 
Time taken to perform the Lafayette Grooved Pegboard Test correctly (i.e. inserting 25 pegs 
for 8 years or older or 10 pegs for under 8 years old for each hand, ranges up to 300 seconds) 
will be summarized by visit. If the task cannot be completed correctly at 300 seconds, 300 
seconds will be recorded. 
Total number of pegs correctly placed and total number of pegs dropped will also be 
summarized separately for each hand by visit. 
 
Trites) will be calculated as time to complete the test + total 
number of pegs dropped + total number of pegs correctly placed. 
All summaries will be calculated by each age group (for 8 years or older, for under 8 years 
old) separately. 
Growth parameter 
The actual value and change from baseline in growth parameter (height, weight, TSH, fT3, 
fT4 and IGF-1) will be summarized by visit. Height and weight will present summary 
statistics for overall percentile and overall z-score. 
EEG 
The analysis of EEG parameters will be presented in a stand alone report and are covered in a 
separate analysis plan. . 
 
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Columbia Suicide Severity Rating Scale (C-SSRS) 
Scoring of the C-SSRS will be performed as suggested by the C-SSRS Columbia website 
http://www.cssrs.columbia.edu/clinical_trials.html. 
The following summaries will be presented for the treatment duration (defined as the period 
from the date of first dose up to 28 days after the date of last dose, inclusive). 
• Number (percentage) of subjects with any treatment-emergent report of suicidal 
behavior, suicidal ideation, and suicidality (suicidal behavior and/or ideation) will be 
displayed. A treatment-emergent report of suicidal behavior, suicidal ideation, or 
suicidality is an answer of ‘Yes’ to any question in the respective category during the 
treatment duration. 
 
Descriptive statistics and changes from baseline will be presented by visit for the suicidal 
ideation intensity score and the suicidal ideation severity rating (treated as a continuous 
variable) to assess change in suicidal ideation over time. The suicidal ideation intensity score 
ranges from 0 to 25 and is the sum of the 5 intensity items. 
5.7 
Other Analyses 
Not applicable. 
5.8 
Exploratory Analyses 
No exploratory analyses are planned for this study. 
5.9 
Extension Phase Analyses 
The statistical methods used in extension phase will be described in a separate SAP. 
6 
INTERIM ANALYSES 
An independent data monitoring committee (DMC) will be constructed to monitor the safety 
data. The responsibilities, membership, and purpose of the DMC, the timing of the 
meeting(s), and an outline of the plan for review of the safety data will be documented in the 
DMC Charter. 
7 
CHANGES IN THE PLANNED ANALYSES 
The following major changes to the statistical methods in this analysis plan were made after 
version 2.0 of the SAP was approved. 
 
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• The study design was updated with the changes from latest protocol (V9.0). 
• Efficacy analysis of  the percent change in seizure frequency of POS total seizure in the 
subgroups of patients receiving at least 6mg, in the completer population, by age of onset, 
by duration of disease (month) and by CNS concomitant medication (Yes / No) was 
deleted since the overall efficacy analysis was deemed sufficient.    . 
• EEG analysis was defined another document. 
• Overview of TEAE and TEAEs SOC/PT by speed of titration were added . 
 
Other changes were editorial in nature, to add clarification or maintain consistency with the 
latest Eisai SAP template. 
Any future changes to the analysis will be documented separately and will be addressed in 
the Clinical Study Report. 
 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 EFFICACY DATA HANDLING 
8.1.1 Pre-randomization/baseline efficacy 
All diary data prior to first dose date will be used in the computation of Pretreatment Phase 
seizure frequency per 28 days. All subjects should have approximately 4 weeks of diary data 
prior to baseline (Visit 2). The baseline value for other efficacy endpoints will be the last 
nonmissing measurement occurring prior to the first dose of the study drug. 
8.1.2 Treatment Duration for Efficacy Analyses 
The date of first dose of the study drug is considered day 1 in the treatment duration. 
The first dose date is the study drug start date and the last dose date is study drug end date 
from the study medication CRF page. 
The treatment duration for efficacy variables is defined as follows: 
• For diary seizure data: The duration between the day of first dose and the last day of 
study drug in treatment phase, inclusive. 
• For non-diary efficacy data: The duration between the day of first dose and 7  days 
after the last visit of schedule in treatment phase, inclusive. 
For all efficacy analyses, data reported only during the treatment duration will be 
analyzed. The diary seizure data during the Follow-up will be listed. 
8.1.3 Handling of Replicate Data 
For the CGIC and EQ-5D-Y assessment, the last visit, within the treatment duration will be 
used. 
 
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8.2 SAFETY DATA HANDLING 
8.2.1 Baseline safety 
The baseline value for all safety endpoints will be the last non-missing measurement 
occurring prior to the first dose of the study medication. 
8.2.2 Treatment Duration for Safety Analyses 
The treatment duration for non-AE safety variables is same of non-diary efficacy analysis in 
8.1.2 Treatment Duration for Efficacy Analyses. For AEs, the treatment duration is 
considered to begin on Day 1 and ends 28 days after the last dose of treatment phase . 
The post-treatment duration is considered to begin on the day after the treatment duration for 
safety. Since it is not always possible for all study participants to come in for their clinic 
visits on the exact day specified in the protocol schedule, the visit week of a subject’s visit 
will be based on the actual visit occurring during the treatment duration. These visits will be 
used to create by visit summaries for laboratory, vital signs, electrocardiograms and other 
safety analyses data. The end of treatment value is the last non-missing value in the treatment 
duration. 
Any concomitant medication taken within the 14 days after the last dose data will be listed/ 
summarized as part of the concomitant medication listing/table. 
AEs for the subject were collected and reported on CRF starting from the time subject signed 
informed consent to the last visit in the Treatment Phase following subject’s last dose. 
Serious AEs were collected for 28 days after the last dose. 
For summaries of safety by time points, the time points will be relative to date of first dose.  
For standardized reporting, study day windows relative to the first dose (Day 1) in the study 
will be applied to determine into which week the data will be mapped.  Scheduled, 
unscheduled, and early withdrawal visits will be mapped to weeks.  Table 2 below gives the 
mapping of relative day ranges to week for non-AE safety variables. If a subject did not have 
a recorded observation falling within a given range of days in order to be assigned to a  week, 
the subject’s data for that week will be regarded as missing for summarization purposes.  If 
there are two or more assessments in the same window then: 
• if the window is the baseline assessment, then the latest assessment will be used in the 
summary tables; 
• if the window is the follow-up assessment, then the latest assessment will be used in 
the summary tables; 
If the window is not the baseline or the follow-up assessment, then the assessment closest to 
the scheduled assessment will be used in the summary tables.  Note that if two assessments 
are equidistant from the scheduled assessment then the last assessment of the two (within the 
allowable window) will be used. 
 
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Table 1:  Mapping of Study Day Ranges to Week  
 
Windowing Period 
Study Day Range  
(Relative to First Dose) 
Week 
Pretreatment 
Day ≤1a 
0 
Treatment 
2 ≤ Day ≤ 25 
2 
Treatment 
26 ≤ Day ≤ 46 
5 
Treatment 
47 ≤ Day ≤ 67 
8 
Treatment 
68 ≤ Day ≤ 88 
11 
Treatment 
89 ≤ Day ≤ 119 
15 
Treatment 
120 ≤ Day ≤ 147 
19 
Treatment 
148 ≤ Day ≤ 175 
23 
End of Treatment(EOT) of Core 
Study 
- 
b 
Follow up for completer of  Core 
Study 
176 ≤ Day ≤ 203 
c 
Follow up for discontinuation of 
Core Study 
 After the date of discontinuation≤ Day 
≤ last dose of study drug +35 
 
a:  All assessments performed on the same date as the date of first dose were to be 
performed prior to dosing; results from these assessments will be regarded as 
Pretreatment values in the analyses. 
b:  The last non-missing value measured in the Treatment Phase will be handled as the data 
of EOT of the Core Study. The Follow-up visit will not be included in this analysis visit. 
c   For the safety assessment other than AE, the data assessed as the planned visit of the 
Follow-up will be handles as those of Follow-up visit.  AE occurred on or after the date 
of discontinuation will be handles as that of Follow-up period. 
 
8.2.3 Handling of Replicate Data 
A subject having an AE coded to the same preferred term more than once during the study 
will be counted only once in the incidence calculations for that AE. Similarly, if a subject has 
more than one AE in a single body system, the incidence will be counted only once for that 
body system. If a subject has the same AE more than once, the occurrence that is of greatest 
severity will be used in the calculation of the incidence of individual AE by severity. 
Similarly, the AE considered most closely related to study drug will be used in the 
calculation of incidence of individual AE by relationship. 
For the laboratory, vital signs, ECG and other safety variables datasets, the measurement 
noted as the scheduled visit measurement will be used in the analysis. If more than one 
assessment is present at a scheduled visit, then the nearest assessment for evaluation 
 
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visit(day) will be used in the summaries of the actual values and changes from baseline. In 
the event of two assessments being equally close to the scheduled visit day, the last 
assessment will be used. 
Handling of prior/concomitant medication  
If the subject has taken the same concomitant medication (as coded to preferred WHO-drug 
term) more than once, the subject will be counted only once in the tabulation. 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS v 9.3 or later. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
12 REFERENCES 
Cancer Therapy Evaluation Program, CTCAE version 4.0 [published 28 May 2009 (v4.03: 
June 14, 2010)]. Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010- 06-
1 4_QuickReference_8.5x11.pdf. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS). Columbia University. Available 
from: http://www.cssrs.columbia.edu/scales_cssrs.html 
 
Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz O. Efficacy of 
antiepileptic drugs in adults predicts efficacy in children: a systematic review. Neurology. 
2012;79:1482-89. 
 
 
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13 APPENDICES 
13.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results  
The following table is of Sponsor’s Grading for Laboratory Values from the version in the 
protocol, Appendix 1. 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
<LLN – 10.0 g/dL 
<LLN – 100 g/L 
<LLN – 6.2 mmol/L 
<10.0 – 8.0 g/dL 
<100 – 80 g/L 
<6.2 – 4.9 mmol/L  
<8.0 g/dL 
<80 g/L 
<4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated 
Leukocytes (total WBC) 
<LLN – 3.0×109/L 
<LLN – 3000/mm3  
<3.0 – 2.0×109/L 
<3000 – 2000/mm3  
<2.0 – 1.0×109/L 
<2000 – 1000/mm3  
<1.0×109/L 
<1000/mm3  
Lymphocytes  
<LLN – 800/mm3  
<LLN – 0.8×109/L 
<800 – 500/mm3 
<0.8 – 0.5×109/L 
<500 – 200/mm3  
<0.5 – 0.2×109/L 
<200/mm3 
<0.2×109/L 
Neutrophils  
<LLN – 1.5×109/L 
<LLN – 1500/mm3 
<1.5 – 1.0×109/L 
<1500 – 1000/mm3 
<1.0 – 0.5×109/L 
<1000 – 500/mm3  
<0.5×109/L 
<500/mm3  
Platelets 
<LLN – 75.0×109/L 
<LLN – 75,000/mm3  
<75.0 – 50.0×109/L 
<75,000 – 50,000/mm3 
<50.0 – 25.0×109/L 
<50,000 – 25,000/mm3 
<25.0×109/L 
<25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
<LLN – 3 g/dL 
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L 
<2 g/dL 
<20 g/L 
life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase  
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
ALT 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
AST 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5×ULN  
>1.5 – 3.0×ULN 
>3.0 – 10.0×ULN  
>10.0×ULN 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L  
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L  
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L  
>500 mg/dL 
>12.92 mmol/L  
Creatinine 
>ULN – 1.5×ULN 
>1.5 – 3.0×ULN 
>3.0 – 6.0×ULN 
>6.0×ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Glucose, serum-high (hyperglycemia) 
Fasting glucose value: 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L  
Fasting glucose value: 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L  
>250 – 500 mg/dL; 
>13.9 – 27.8 mmol/L; 
hospitalization indicated 
>500 mg/dL; 
>27.8 mmol/L; 
life-threatening 
 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
consequences  
Glucose, serum-low (hypoglycemia) 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
life-threatening 
consequences; 
seizures 
Phosphate, serum-low 
(hypophosphatemia)  
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL 
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
life-threatening 
consequences 
Potassium, serum-high (hyperkalemia) >ULN – 5.5 mmol/L  
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
hospitalization indicated 
>7.0 mmol/L 
life-threatening 
consequences 
Potassium, serum-low (hypokalemia)  
<LLN – 3.0 mmol/L 
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated 
<3.0 – 2.5 mmol/L 
 
<2.5 mmol/L 
life-threatening 
consequences 
Sodium, serum-high (hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
hospitalization indicated 
>160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
N/A 
<130 – 120 mmol/L 
<120 mmol/L 
life-threatening 
consequences 
Triglyceride, serum-high 
(hypertriglyceridemia)  
150 – 300 mg/dL 
1.71 – 3.42 mmol/L 
>300 – 500 mg/dL 
>3.42 – 5.7 mmol/L  
>500 – 1000 mg/dL 
>5.7 – 11.4 mmol/L 
>1000 mg/dL 
>11.4 mmol/L 
life-threatening 
consequences  
Uric acid, serum-high (hyperuricemia) 
>ULN – 10 mg/dL  
≤0.59 mmol/L without 
physiologic 
consequences  
N/A 
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences  
>10 mg/dL 
>0.59 mmol/L  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published:  May 28, 2009 (v4.03:  June 14, 2010). 
 
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SIGNATURE PAGE 
Authors:   
 
 
 
[electronic signature in eDMS] 
 
 
 
 
 
Medicine Develop center 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
 
 
Neurology Business Group 
 
Date 
Approval: 
 
 
 
[electronic signature in eDMS] 
 
 
 
 
 
Neurology Business Group 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
Study Director 
 
 
Neurology Business Group 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
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PPD
PPD
PPD
PPD
PPD
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Eisai Inc. and Eisai Limited 
 
E2007-G000-311 (Extension Phase) 
Date:  6Feb2018 Amendment 1 
Confidential 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2007-G000-311 (Extension Phase) 
Study Protocol 
Title: 
An Open-Label, Multicenter Study with an Extension Phase to 
Evaluate the Safety, Tolerability, and Exposure-Efficacy Relationship 
of Perampanel Oral Suspension when Administered as an Adjunctive 
Therapy in Pediatric Subjects (Age 4 to less than 12 years) with 
Inadequately Controlled Partial-Onset Seizures or Primary 
Generalized Tonic-Clonic Seizures 
Date: 
6 February 2018 
Version: 
Amendment 1 
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Date:  6Feb2018 Amendment 1 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................6 
3.1 
Study Objectives ......................................................................................................6 
3.1.1 
Primary Objective(s) ......................................................................................6 
3.1.2 
Secondary Objectives.....................................................................................6 
3.1.3 
Exploratory Objective ....................................................................................7 
3.2 
Overall Study Design and Plan ................................................................................7 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................7 
5 
STATISTICAL METHODS ..............................................................................................7 
5.1 
Study Endpoints .......................................................................................................8 
5.1.1 
Primary Endpoints .........................................................................................8 
5.1.2 
Secondary Endpoints .....................................................................................8 
5.1.3 
Exploratory Endpoint .....................................................................................9 
5.2 
Study Subjects ..........................................................................................................9 
5.2.1 
Definitions of Analysis Sets...........................................................................9 
5.2.2 
Subject Disposition ......................................................................................10 
5.2.3 
Protocol Deviations ......................................................................................10 
5.2.4 
Demographic and Other Baseline Characteristics .......................................10 
5.2.5 
Prior and Concomitant Therapy ...................................................................10 
5.2.6 
Study Medication Treatment Compliance ...................................................10 
5.3 
Data Analysis General Considerations ..................................................................11 
5.3.1 
Pooling of Centers........................................................................................11 
5.3.2 
Adjustments for Covariates..........................................................................11 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................11 
5.3.4 
Examination of Subgroups ...........................................................................11 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................11 
5.3.6 
Other Considerations ...................................................................................12 
5.3.6.1 
Safety .................................................................................................12 
5.3.6.2 
Efficacy ..............................................................................................12 
5.4 
Efficacy Analyses ..................................................................................................12 
5.4.1 
Primary Efficacy Analyses ..........................................................................13 
5.4.2 
Secondary Efficacy Analyses ......................................................................13 
5.4.3 
Other Efficacy Analyses ..............................................................................13 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................14 
5.5.1 
Pharmacokinetic Analyses ...........................................................................14 
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5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....14 
5.6 
Safety Analyses ......................................................................................................14 
5.6.1 
Extent of Exposure .......................................................................................14 
5.6.2 
Adverse Events ............................................................................................14 
5.6.3 
Laboratory Values ........................................................................................16 
5.6.4 
Vital Signs ....................................................................................................17 
5.6.5 
Electrocardiograms ......................................................................................18 
5.6.6 
Other Safety Analyses..................................................................................19 
5.7 
Exploratory Analyses .............................................................................................23 
6 
INTERIM ANALYSES ...................................................................................................23 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................23 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................23 
8.1 
Efficacy Data Handling..........................................................................................23 
8.1.1 
Pre-randomization/baseline efficacy ............................................................23 
8.1.2 
Treatment Duration for Efficacy Analyses ..................................................23 
8.1.3 
Handling of Replicate Data ..........................................................................23 
8.2 
Safety Data Handling .............................................................................................24 
8.2.1 
Baseline Safety.............................................................................................24 
8.2.2 
Treatment Duration for Safety Variables .....................................................24 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................25 
10 STATISTICAL SOFTWARE ..........................................................................................25 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................26 
12 REFERENCES ................................................................................................................26 
13 APPENDICES .................................................................................................................27 
13.1 
Study Design for E2007-G000-311 .......................................................................27 
13.2 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results .....28 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ABNAS 
A-B neuropsychological assessment schedule 
AE(s) 
adverse event(s) 
AED 
antiepileptic drug 
 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic class 
BMI 
body mass index 
CBCL 
Child Behavior Checklist 
CGI 
Clinical Global Impression 
CGIC 
Clinical Global Impression of Change 
CGIS 
Clinical Global Impression of Severity 
CRF 
case report form 
Css,av 
average steady-state drug concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
EQ-5D-Y 
EuroQol 5 Dimensions – Youth 
FAS 
Full Analysis Set 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
GTC 
Generalized Tonic-Clonic 
HRQL 
health-related quality of life 
ICF 
informed consent form 
IP 
Investigational products 
LGPT 
Lafayette Grooved Pegboard Test 
LLN 
lower limit of normal 
LNH 
low/normal/high 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamics 
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Abbreviation 
Term 
PGTC 
primary generalized tonic-clonic 
PK 
Pharmacokinetics 
POS 
partial-onset seizures 
PT 
preferred term 
QTc 
corrected QT interval (time from the beginning of the QRS 
complex to the end of the T wave, corrected for heart rate) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Système International 
SMQ 
standardized MedDRA queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
TLG 
tables, listings, and graphs 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for the Extension Phase of 
Eisai Protocol E2007-G000-311.  The SAP for the Core Study of Eisai Protocol E2007-
G000-311 is a separate document. 
3.1 
Study Objectives 
3.1.1 
Primary Objective(s) 
To evaluate the safety and tolerability of E2007/perampanel oral suspension when 
administered as an adjunctive therapy in children (ages 4 to <12 years) with inadequately 
controlled partial-onset seizures (POS) or primary generalized tonic-clonic seizures (PGTC) 
3.1.2 
Secondary Objectives 
1. To characterize the PK of perampanel and the relationship between perampanel 
plasma concentrations, efficacy, and safety using population PK/PD modeling 
 
2. To evaluate the effects of perampanel on cognition, behavior, visuomotor skills, and 
growth and development in children during short-term (23 weeks) and long-term (up 
to 52 weeks) treatment 
 
3. To evaluate the frequency of EEG abnormalities during awake and sleep state during 
52 weeks of treatment 
 
4. To evaluate suicidal ideation and suicidal behavior in children 6 years to less than 12 
years as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) during 
52 weeks of treatment 
 
5. To evaluate the efficacy of perampanel as measured by the median percent change 
per 28 days in seizure frequency, by the proportion of responders (≥25%, ≥50%, and 
≥75%), and by the proportion of subjects who are seizure-free for POS, PGTC, and 
Generalized Tonic-Clonic (GTC) seizures 
 
6. To evaluate, in Japanese subjects, the efficacy of perampanel on partial onset 
seizures(POS) in the present study as compared with placebo in Study E2007-J000-
335 
 
7. To assess the effects of perampanel on the Clinical Global Impression (CGI), CGI of 
Severity (CGIS) and CGI of Change (CGIC) 
 
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3.1.3 
Exploratory Objective 
To assess the impact of perampanel on the health utility of children using the Euroqol 5 
Dimensions-Youth (EQ-5D-Y) scale.  
3.2 
Overall Study Design and Plan 
Details regarding the study design and plan for the Core Study and Extension Phase are in the 
Protocol.  For a general overview, see the schema in Section 13.1. 
The Extension Phase will consist of a Maintenance Period (29 weeks) and a Follow-up 
Period (4 weeks).  
All subjects who completed all scheduled visits up to and including Visit 9 in the Core 
Treatment Phase were eligible to participate in the Extension Phase of the study. 
Maintenance Period 
During the Maintenance Period of the Extension Phase, all subjects were to continue with 
their optimal perampanel dose (ie, that dose level that they completed on during the Core 
Study). Multiple dose adjustment was allowed if a subject was experiencing intolerable 
AE(s) or a higher dose was deemed to be beneficial. The maximum dose of perampanel was 
12 mg/day for subjects who were not receiving EIAEDs. For subjects who were receiving 
EIAEDs, the maximum dose was 16 mg except that for subjects enrolled in Japan, the 
maximum dose was 12 mg/day. 
Addition, deletion, and dose changes to the concomitant antiepileptic drugs (AEDs) were 
allowed during Extension Maintenance Period. Conversion to monotherapy on perampanel 
was also permitted at the discretion of the investigator, if it was considered appropriate to 
control the seizures. 
Follow-Up Period 
Follow-up was to be conducted 4 weeks (±7 days) after the last dose of study drug for all 
subjects. 
4 
DETERMINATION OF SAMPLE SIZE 
As this was an extension study, it was not possible to accrue a predetermined number of 
patients; therefore, there was no a priori determination of sample size. The maximum 
possible number of subjects in Extension Phase is the total number of treated subject in Core 
Study. 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects. All summaries will be produced by age cohort (4-<7 and 
7-<12), disease cohort (POS, PGTC, GTC) and inducer status (inducer, non-inducer). All 
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analysis will be conducted for all subjects who have completed the core study and 
participated in the Extension Phase.  
In general, the scope of endpoints and analyses will be based on data collected throughout the 
entire duration of perampanel exposure (i.e., Core and Extension). 
Analysis for CSR in Japan 
For CSR in Japan, all analyses defined in this document will be repeated using all subjects 
enrolled in the study, including those who did not participate in the Extension Phase, and will 
also be repeated using subjects enrolled in Japanese sites only.  
 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
Safety and tolerability, which include incidence of treatment-emergent adverse events 
(TEAEs) and SAEs, laboratory parameters, vital signs, and ECG parameters, of perampanel 
oral suspension in children (ages 4 to <7 years and ≥7 years to <12 years) with POS or PGTC 
 
5.1.2 
Secondary Endpoints 
The following endpoints will be analyzed: 
1. The relationship between plasma levels of perampanel and efficacy endpoints (ie, 
change in average seizure frequency over 28 days, responder probability, and the 
proportion of subjects who are seizure-free in the Maintenance Period of the Core 
Study) separately for each seizure type 
 
2. The relationship between plasma levels of perampanel and cognition endpoints 
including change from baselines in ABNAS, CBCL, and LGPT. In addition, 
depending on the AE data, the relationship between plasma levels of perampanel and 
select AEs will be assessed 
 
3. Change from baseline at Week 23 and Week 52 in ABNAS, CBCL, and LGPT 
 
4. Changes from baseline at Week 23 and Week 52 in growth and development 
parameters (height, weight, thyroid, and IGF-1) 
 
5. Change from baseline in EEG and the frequency of EEG abnormalities during awake 
and sleep state 
 
6. Proportion of subjects (aged 6 or older at time of consent/assent) with any treatment-
emergent reports of suicidal ideation and behavior on the C-SSRS and intensity of 
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these behaviors assessed using C-SSRS scores 
 
7. The median percent change in seizure frequency per 28 days during Treatment Phase 
(Titration Period and Maintenance Period) of the Core Study, and during the long-
term treatment (up to 52 weeks) relative to the Pretreatment Phase. Seizure frequency 
will be based on the 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 
 
8.  Proportion of responders (25% responders defined as a decrease in 28-day seizure 
frequency of equal or greater than 25% compared to baseline seizure frequency; 50% 
responders defined as a decrease in 28-day seizure frequency of equal or greater than 
50% compared to baseline seizure frequency; 75% responders defined as a decrease 
in 28-day seizure frequency of equal or greater than 75% compared to baseline 
seizure frequency) during Maintenance Period of Core Study, and during the long 
term treatment (up to 52 weeks) 
 
9.  Proportion of subjects who are seizure-free during Maintenance Period of Core Study, 
and during the long-term treatment (up to 52 weeks) 
 
10. CGI of Change 
 
5.1.3 
Exploratory Endpoint 
Change from baseline at Week 23 and Week 52 in EQ-5D-Y 
 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
in the Extension Phase and had at least one postdose safety assessment in the Extension 
Phase.  
The Full Analysis Set (FAS) is the group of subjects who received at least 1 dose of study 
drug in the Extension Phase and had at least 1 postdose seizure measurement in the 
Extension Phase. 
The Enrolled Subjects will consist of all subjects who chose to participate in the Extension 
Phase. 
For CSR in Japan, the analysis sets defined in Core Study SAP will be used. 
 
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5.2.2 
Subject Disposition 
The frequencies of completion, discontinuation, ongoing and the primary and other 
discontinuation reasons will be summarized using incidence rate (number of subjects and 
percentage). 
5.2.3 
Protocol Deviations 
Not applicable.  
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized using descriptive statistics. Continuous demographic and baseline variables 
include age, weight, height, and BMI; categorical variables include sex, age group (4-7, 7-12), 
race and ethnicity.  
MEDICAL HISTORY 
The number (percentage) of subjects in the Safety Analysis Set reporting a history of any 
medical condition, as recorded on the CRF, will be summarized.  A subject data listing of 
medical and surgical history will be provided. 
Epilepsy-specific medical history for the Safety Analysis Set will be summarized using 
descriptive statistics, including time since diagnosis, suspected localization of the 
epileptogenic region and seizure type. 
5.2.5 
Prior and Concomitant Therapy 
Concomitant medications are defined as medications that (1) started before the first dose of 
perampanel at Core Study and were continuing at the time of the first dose of perampanel, or 
(2) started on or after the date of the first dose of perampanel (or, started at the time of or 
after the first dose of perampanel) up to 14 days after the subject’s last dose.   
Concomitant medications taken during the study will be coded using the World Health 
Organization Drug Dictionary (WHO-DD) and further coded and summarized by Anatomical 
Therapeutic class, pharmacological class, pharmacological subclass, and WHO drug term.   
A summary of concomitant AEDs, including the number of subjects who take concomitant 
enzyme inducing antiepileptic drugs (EIAEDs), will be produced. A shift table of number of 
AEDs from baseline to the end of treatment will also be produced.  
5.2.6 
Study Medication Treatment Compliance 
In general, study medication treatment compliance (%) for a given period of time will be 
calculated as follows with respect to (i.e., within) the given period of time: 
 
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Study Medication Treatment Compliance (%) =  
(Study Med issued in grams – Study Med Returned in grams)  x100 
(Number of Days x Prescribed Daily Dose in ml) x Suspension density of 1.07g/ml 
Study medication treatment compliance (%) will be presented for the SAS by visit in the 
Maintenance Period of Extension Phase. Subjects will also be categorized by compliance 
categories of <80%, 80%-120% and >120%. 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. For analysis specifically planned for 
Japan subjects, only Japan centers will be pooled.  
5.3.2 
Adjustments for Covariates 
Not applicable. 
5.3.3 
Multiple Comparisons/Multiplicity 
Not applicable. 
5.3.4 
Examination of Subgroups 
The efficacy seizure endpoints will be summarised by disease cohorts (POS, PGTC, and 
GTC). Within the POS and PGTC disease cohorts, endpoints will also be summarized by age 
cohort (4 to <7 years, ≥7 to <12 years) , and the presence or absence of concomitant EIAEDs,  
All other endpoints will be summarised by disease cohorts (POS, PGTC, and GTC), age 
cohort (4 to <7 years, ≥7 to <12 years), and with or without use of concomitant EIAEDs. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
The algorithm on the assumptions used for imputing the missing dates for AEs is given in the 
programming specifications.   
If the day and month are missing, events will be considered treatment-emergent if the year is 
equal to or after the year of the first dose date; if days are missing, events will be considered 
treatment-emergent if the year is after the year of the first dose, or if the year is equal to the 
year of the first dose date and the month is equal to or after the month of the first dose date.  
For the purpose of summarizing maximum severity, if the severity of an adverse event (AE) 
is missing for a subject, then, if this subject has another AE with the same preferred term that 
has “severe” severity, the maximum severity of the AE will be noted as “severe’; otherwise 
the maximum severity will be noted as missing. Similarly, for the purpose of summarizing 
the closest relationship in AE causality, if the relationship of an AE to study drug is missing, 
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the AE will be noted to be probably related if there is another probably related AE with the 
same preferred term, otherwise this relationship will be noted as missing.  
For determining treatment emergent markedly abnormal lab values, a missing baseline lab 
value will be assumed to be of grade 0. 
The algorithm to impute missing dates for concomitant medications is given in the 
programming specifications. No special handling of missing data is planned for the analysis 
of any of the other safety variables. 
Data exceptions or outliers will be determined by inspection of the tables, listings, and graphs 
in consultation with the clinical study team. The effect of outliers on analyses may be 
assessed by re-analyzing the data without the outliers. 
All the listings will display the original missing values. 
5.3.6 
Other Considerations 
5.3.6.1 
Safety 
A subject who has an AE coded to the same preferred term more than once during the 
Extension Phase and the Core Study will be counted only once in the incidence calculations 
for that AE.  Similarly, if a subject has more than one AE in a single system organ class 
(SOC), the incidence will be counted only once for that SOC.  If a subject has the same AE 
more than once, the occurrence that is of greatest severity will be used in the calculation of 
the incidence of individual AE by severity.  The AE considered most closely related to study 
treatment will be used in the calculation of incidence of individual AE by relationship. 
If a subject has taken the same concomitant medication (as coded to preferred WHO-drug 
term) more than once, the subject will be counted only once in the tabulation. 
5.3.6.2 
Efficacy 
If no diary data is observed during a period, then the seizure frequency per 28 days for that 
period will be set to missing.  Missing diary data should not be interpreted as equivalent to a 
non-missing record of zero. 
5.4 
Efficacy Analyses 
Only “valid days” and “valid seizure counts” will be used in the calculations of seizure 
frequency per 28 days. A “valid day” is defined as the day where seizure counts information 
is present, that is, either a record with an answer of ‘No’ to the question ‘Did the subject 
experience any seizures?’ or a positive number of seizures for at least one of the seizure types 
collected. “Valid seizure counts” are the seizure counts that are read from the valid seizure 
days. 
The baseline for a given seizure type (or total) is defined as seizure frequency per 28 days of 
the given type (or total) based on all valid seizure diary data dated before the first dose date 
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of perampanel. This means that the baseline will be based on all valid seizure diary data 
occurring during the Core Study Pretreatment Phase.   
5.4.1 
Primary Efficacy Analyses 
Not applicable. 
5.4.2 
Secondary Efficacy Analyses 
The percent change in seizure frequency per 28 days during the Core Study and Maintenance 
Period of the Extension Phase with respect to baseline assessment collected during the 
Pretreatment Phase of the Core Study will be summarized using descriptive statistics (n, 
mean, median, minimum, maximum and 95% confidence interval). The percent change in 
seizure frequency per 28 days are calculated for total seizure, POS total seizure and total 
complex partial seizure for POS cohort, for PGTC seizure, absence seizure, myoclonic 
seizure and total seizure for PGTC cohort and for Secondarily Generalized seizures  for GTC 
cohort. Total Seizures is sum of all seizures, including POS, generalized and other seizures. 
Total POS Seizures is sum of all POS seizures, including simple partial seizures without 
motor signs, simple partial seizures with motor signs, complex partial seizures and complex 
partial seizures with secondary generalization. Secondarily Generalized seizures cohort is a 
subset of POS cohort. 
The proportion of subjects who are seizure-free and the proportion of responders based on 
decrease from baseline (during the Pretreatment Phase) in 28-day seizure frequency of equal 
or greater than 25%, equal or greater than 50%, and equal or greater than 75% during 
Maintenance Period of the Extension Phase will be summarized using frequency count 
(number and percentage). If subjects complete the Extension Phase and have no seizure 
during the Maintenance Period, those will be treated as seizure-free. 
The number of subjects with new seizure types compared to Baseline Period and Seizure 
history will be summarized. 
The CGIC and CGIS will be summarized for each visit using frequency count (number and 
percentage). 
For Japan submission, all of the analysis will be repeated for Japanese population. 
5.4.3 
Other Efficacy Analyses 
The score of EQ-5D-Y each items (Mobility, Looking after myself, Doing usual activities, 
Having pain or discomfort, Feeling worried, sad or unhappy) will be summarized for each 
visit using frequency count (number and percentage). The measurement and the change from 
baseline of EQ-5D-Y VAS at each visit will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum and maximum). 
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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
Not applicable. 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable. 
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety data will be 
summarized on an “as treated” basis using descriptive statistics (eg, n, mean, standard 
deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables). Safety variables include TEAEs, clinical laboratory parameters, vital signs, 12-
lead ECG results, C-SSRS, growth parameters, CBCL, LGPT, and EEG. Study Day 1 for all 
safety analyses will be defined as the date of the 1st dose of study drug. 
5.6.1 
Extent of Exposure 
Exposure will be evaluated for the Safety Analysis Set. 
Duration of Extension Phase exposure will be calculated as the number of week between the 
date the subject received the first dose of perampanel in the Extension Phase and the date the 
subject received the last dose of perampanel in the Extension Phase.  Total perampanel 
exposure will be calculated as the number of week between the date the subject received the 
first dose of perampanel in Core Study and the date the subject received the last dose of study 
drug in the Extension Phase.   
Modal dose, mean daily dose, maximum daily dose and last daily dose will be presented 
using summary statistics and frequency using categories of <4, 4, >4-<8, 8-<12, 12=<.  
Number and percent of subjects who down-titrated or discontinued study at maximum daily 
dose exposed will be summarized using frequency count (number and percentage). 
5.6.2 
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 (version 18.1or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database. 
A TEAE is defined as an AE that: 
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● Emerges from the date of first dose of study drug in Core Study to 28 days after last 
end date of dose in prescribed dose entry in Extension Phase, having been absent at 
pretreatment (Baseline) in Core Study, or 
● Reemerges during treatment, having been present at pretreatment (Baseline) in Core 
Study but stopped before treatment, or 
● Worsens in severity during treatment relative to the pretreatment state in Core Study, 
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. 
TEAEs will be summarized using the safety analysis set.  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 a SOC and PT, even if the subject experienced more than one 
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 [possibly related, probably related] and No [not related]). 
AEs will be analyzed by the actual dose at AE onset. 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT. Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment. 
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT. A subject data listing of all AEs leading to death will be provided.  
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT. A subject data listing of all SAEs will be provided. 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to 
discontinuation from study drug will be provided. 
 
AEs of special Interest 
A listing of subjects with AEs related to suicidality, identified by relevant Standardized 
MedDRA Query (SMQ) terms, will be provided. TEAEs of special interest listed below will 
be summarized by SOC and PT. SMQs will be used to identify relevant terms for the 
following TEAEs. 
• TEAEs suggestive of abuse potential 
• TEAEs related to alertness and cognition 
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• TEAEs related to hostility/aggression 
• TEAEs related to psychosis/psychotic disorders 
• TEAEs related to status epilepticus/convulsions 
• TEAEs related to lab abnormalities 
• Cardiac and ECG TEAEs 
• TEAEs related to rash 
TEAEs related to rash will be identified by medical review. Falls, regardless of causality, 
will be summarized for the treatment period (including Titration phase and Maintenance 
phase of the Core Study, as well as Maintenance through Follow-up Period of the Extension 
phase) by the actual dose at onset. 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in protocol Section 9.5.1.5.3 Safety Assessments 
(Laboratory Measurements), the actual value and the change from baseline to each post 
baseline 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 protocol 
Section 9.5.1.5.3 Safety Assessments (Laboratory Measurements) will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each post 
baseline visit and to end of treatment will be reported using shift tables. Percentages will be 
based on the number of subjects with both non-missing baseline and relevant post baseline 
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. For each laboratory parameter, shift from baseline (LNH) to each post 
baseline visit and at the end of treatment will be presented. Similar shift tables from baseline 
(LNH) to the highest/lowest post baseline value will also be presented. 
The Sponsor’s Grading for Laboratory Values (Protocol Appendix 2) presents the criteria 
that will be used to identify subjects with treatment-emergent markedly abnormal laboratory 
values (TEMAV).  Except for phosphate, a TEMAV was defined as a postbaseline value with 
an increase from baseline to a grade of 2 or higher. For phosphate, a TEMAV was defined as 
a post baseline value with an increase from baseline to a grade of 3 or higher. The number 
and percentage of subjects with TEMAVs will be presented; each subject will be counted 
once in the laboratory parameter high and low categories, as applicable. Markedly abnormal 
laboratory values will be flagged in the subject data listings.. 
For ALT and AST analysis, the number of subjects with greater than 3 times, but less than 5 
times the ULN and the number of subjects with greater than 5 times the ULN will be 
summarized. For bilirubin, a summary of the number of subjects with serum concentrations 
greater than 2 times the ULN will be created. These summaries will also be provided for the 
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maximum value in the treatment duration. In addition, the number of subjects who meet the 
criteria for Hy’s Law will be summarized by visit and during the treatment duration. A 
subject will be determined to have met Hy’s Law if AST or ALT is > 3x ULN, bilirubin > 2x 
ULN, and alkaline phosphatase < 2x ULN at a visit. The number of subjects who meet each 
of the criteria for Hy’s Law during treatment (but not all necessarily at the same visit) will 
also be summarized. 
5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit. 
In addition, the criteria described in the table below will be used to determine clinically 
notable results for blood pressure and heart rate. The number (percentage) of subjects with 
clinically notable results over all scheduled and unscheduled visits will be summarized. 
Table 1: Criteria for Clinically Notablea Vital Signs 
Variable  
Criterion Value  
Change Relative to Baseline  
Systolic BP  
> 180 mmHg  
Increase of ≥ 20 mmHg  
< 90 mmHg  
Decrease of ≥ 20 mmHg  
Diastolic BP  
>105 mmHg  
Increase of ≥ 15 mmHg  
< 50 mmHg  
Decrease of ≥ 15 mmHg  
Heart Rate  
>120 bpm  
Increase of ≥ 15 bpm  
< 50 bpm  
Decrease of ≥ 15 bpm  
Weight  
  
Increase of > 7%  
  
Decrease of > 7%  
a: Clinically notable means that a value must have met both the criterion value and satisfied 
the magnitude of change relative to baseline. 
The criteria in Table 2 will be used to determine abnormal results for blood pressure and 
heart rate. The number of subjects with abnormal results will be summarized. 
 
 
 
 
 
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Table 2: Criteria for Abnormal Vital Signs 
Variable  
Change Relative to Baseline  
Systolic BP  
Increase of ≥ 20 mmHg  
Decrease of ≥ 20 mmHg  
 
Increase of ≥ 40 mmHg  
 
Decrease of ≥ 40 mmHg  
Diastolic BP  
Increase of ≥ 10 mmHg  
Decrease of ≥ 10 mmHg  
 
Increase of ≥ 20 mmHg  
 
Decrease of ≥ 20 mmHg  
Pulse  
Increase of ≥ 15 bpm  
Decrease of ≥ 15 bpm  
 
Increase of ≥ 30 bpm  
 
Decrease of ≥ 30 bpm  
 
5.6.5 
Electrocardiograms 
ECG parameters(QTcB, QTcF, PR interval QRS duration and RR interval) and changes from 
baseline will be presented by visit. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
In addition, the number (percentage) of subjects with at least one post baseline abnormal 
ECG result in QTc Bazett and QTc Fridericia during the treatment period will be summarized. 
Clinically borderline or abnormal ECG results in QTc Bazett and QTc Fridericia will be 
categorized as follows: 
Absolute QTc interval prolongation: 
 QTc interval 430-450 ms 
 QTc interval >450 ms 
 QTc interval >500 ms 
Change from baseline in QTc interval: 
 QTc interval increases from baseline 30-60 ms 
 QTc interval increases from baseline >60 ms 
 
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5.6.6 
Other Safety Analyses 
Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS) 
The total ABNAS score (defined as the sum of the individual question scores) and sub-scores for 
fatigue, slowing, memory, concentration, motor-coordination and language (Brooks et al 2001) 
will be listed and summarized by visit. Changes from baseline ABNAS sub-scores will be 
summarized. 
Table 3: Definition between each aspect and question 
Aspect 
# of items 
Range 
Item No 
fatigue  
5 
0-15 
1, 7, 13, 18, 24 
slowing  
5 
0-15 
2, 8, 14, 19, 23 
memory  
4 
0-12 
3, 9, 15, 20 
concentration  
4 
0-12 
4, 10, 16,21 
motor speed  
3 
0-9 
5, 11, 17,  
reading (language)  3 
0-9 
6, 12, 22 
 
Child Behavior Check List   (CBCL 1.5/5 and CBCL 6/18) 
The CBCL 1.5/5 measures problems in children (1.5 to 5 years old). To measure problems, 
100 ‘problem items’ are rated on a scale to measure their occurrence.  Higher scores indicate 
greater problems, as the scale ranges from 0, indicating ‘not true,’ to 2, indicating ‘often 
true.’  67 of the items are then summed into seven syndrome scores (Emotionally Reactive, 
Anxious/Depressed, Withdrawn, Somatic Complaints, Attention Problems, Aggressive 
Behavior syndrome and Sleep problems.) The summation of the first four syndrome scores 
yields the Internalizing Syndrome composite score, and the summation of the next two 
syndrome scores yields the Externalizing Syndrome composite score.  The total problems 
score is the summation of all  100 item scores. . 
The total problems score, the Internalizing Syndromes score, the Externalizing Syndromes 
score, and each of the seven individual syndrome scores of the CBCL 1.5/5 will be evaluated 
using summaries of change from baseline (Week 0) by visit. 
 
 
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Table 4: Definition CBCL 1.5-5 (Refer to link of CBCL/1 1/2-5 and LDS in profiles at website 
http://www.aseba.org/forms.html) 
Sydrome scale 
#of items 
Range 
Items 
Emotionally Reactive 
9 
(0-18) 
21,46,51,79,82,83,92,97,99 
Anxious/Depressed 
8 
(0-16) 
10,33,37,43,47,68,87,90 
Withdrawn 
8 
(0-16) 
2,4,23,62,67,70,71,98 
Somatic Complaints 
11 
(0-22) 
1,7,12,19,24,39,45,52,78,86,93 
Internalizing 
36 
(0-72) 
sum of 4 previous scores 
Attention Problems 
5 
(0-10) 
5,6,56,59,95 
Aggressive Behavior 
syndrome 
19 
(0-38) 
8,15,16,18,20,27,29,35,40,42,44,53,5
8,66,69,81,85,88,96 
Externalizing 
24 
(0-48) 
sum of 2 previous scores 
Sleep problems 
7 
(0-14) 
22,38,48,64,74,84,94 
Total 
100 
(0-200) 
Sum of all problem items scores 
 
Also the CBCL 6/18 measures competencies and problems in children (6 to 18 years old).  
To assess competence, sixteen items are scored for each child, with higher scores indicating 
better competence.  The summed scores are grouped into three sub-scores for competence in 
activities, social realms and school.  The total competence score is the summation of all 16 
items. 
To measure problems, 120 ‘problem items’ are rated on a scale to measure their occurrence.  
Higher scores indicate greater problems, as the scale ranges from 0, indicating ‘not true,’ to 
2, indicating ‘often true.’  103 of the items are then summed into eight syndrome scores 
(Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints, Rule-Breaking Behavior, 
Aggressive Behavior, Social Problems, Thought Problems, and Attention Problems.)  The 
summation of the first three syndrome scores yields the Internalizing Syndrome composite 
score, and the summation of the next two syndrome scores yields the Externalizing 
Syndrome composite score.  The total problems score is the summation of the two composite 
scores, the final three syndrome scores, and the 17 ‘problem items’ that were not included in 
any of the eight syndrome scores. 
The total competence score, the three sub-scores for competence, the total problems score, 
the Internalizing Syndromes score, the Externalizing Syndromes score, and each of the eight 
individual syndrome scores of the CBCL 6/18 will be evaluated using summaries of change 
from baseline (Week 0) by visit. 
 
 
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Table 5: Definition CBCL 6-18 (Refer to link of CBCL/6-18 scored using three differenr societies in 
profiles at website : http://www.aseba.org/forms.html) 
Competency Scores 
Sub-scores 
# of Items 
Score 
Range 
Items 
Activity   
6 
(0-15) 
I.A, B, II.A, B, IV A, B  
Social 
6 
(0-14) 
III.A, B, V.1, 2, VI. A, B 
School 
4 
(0-6) 
VII. 1, 2,3,4 
Total 
16 
(0-35) 
Sum of 3 previous scores 
 
Syndrome/ Problems Scores 
Syndrome scale 
#of items 
Score 
Range 
Items 
Anxious/Depressed 
13 
(0-26) 
14,29,30,31,32,33,35,45,50,52,71,
91,112 
Withdrawn/Depressed 
8 
(0-16) 
5,42,65,69,75,102,103,111 
Somatic Complaints 
11 
(0-22) 
47,49,51,54,56a,56b,56c,56d,56e,
56f,56g 
Internalizing 
32 
(0-64) 
sum of 3 previous scores 
Rule-Breaking Behavior 
17 
(0-34) 
2,26,28,39,43,63,67,72,73,81,82,9
0,96,99,101,105,106 
Aggressive Behavior  
18 
(0-36) 
3,16,19,20,21,22,23,37,57,68,86,8
7,88,89,94,95,97,104 
Externalizing 
35 
(0-70) 
sum of 2 previous scores 
Social Problems 
11 
(0-22) 
11,12,25,27,34,36,38,48,62,64,79 
Thought Problems 
15 
(0-30) 
9,18,40,46,58,59,60,66,70,76,83,8
4,85,92,100 
Attention Problems 
10 
(0-20) 
1,4,8,10,13,17,41,61,78,80 
Total 
120 
(0-240) 
Sum of all problem items scores 
Additionally, both CBCL results for each subject will be converted to a standardized T-score 
and classified at baseline and at each evaluation as normal, borderline clinical, or clinical, 
based on the thresholds provided in the CBCL manual. These classifications and their change 
from baseline will be presented in tables. 
Lafayette Grooved Pegboard Test (LGPT) 
Time taken to perform the Lafayette Grooved Pegboard Test correctly (i.e. inserting 25 pegs 
for 8 years or older or 10 pegs for under 8 years old for each hand, ranges up to 300 seconds) 
will be summarized by visit. If the task cannot be completed correctly at 300 seconds, 300 
seconds will be recorded. 
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Total number of pegs correctly placed and total number of pegs dropped will also be 
summarized separately for each hand by visit. 
Total score for each hand (Trites) will be calculated as time to complete the test + total 
number of pegs dropped + total number of pegs correctly placed. 
All summaries will be calculated by each age group (for 8 years or older, for under 8 years 
old) separately. 
Growth parameter 
The actual value and change from baseline in growth parameter (height, weight, TSH, fT3, 
fT4 and IGF-1) will be summarized by visit. Height and weight will be presented using 
summary statistics for overall percentile and overall z-score. 
EEG 
EEG parameters will be summarized and listed as appropriate. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Scoring of the C-SSRS will be performed as suggested by the C-SSRS Columbia website 
http://www.cssrs.columbia.edu/clinical_trials.html. 
The following summaries will be presented for the treatment duration (defined as the period 
from the date of first dose at Core Study up to 28 days after the date of last dose at Extension 
Phase, inclusive). 
 Number (percentage) of subjects with any treatment-emergent report of suicidal 
behavior, suicidal ideation, and suicidality (suicidal behavior and/or ideation) will be 
displayed. A treatment-emergent report of suicidal behavior, suicidal ideation, or 
suicidality is an answer of ‘Yes’ to any question in the respective category during the 
treatment duration. 
 Shift from baseline to the maximum suicidal ideation severity rating (0=no ideation 
present to 5=active ideation with plan and intent) in the treatment duration will assess 
worsening of suicidal ideation. Any score greater than 0 indicates the presence of 
suicidal ideation while a score of 4 (active suicidal ideation with some intent to act) 
or 5 (active suicidal ideation with specific plan and intent) can be used to indicate 
serious suicidal ideation. 
Descriptive statistics and changes from baseline will be presented by visit for the suicidal 
ideation intensity score and the suicidal ideation severity rating (treated as a continuous 
variable) to assess change in suicidal ideation over time. The suicidal ideation intensity score 
ranges from 0 to 25 and is the sum of the 5 intensity items. 
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5.7 
Exploratory Analyses 
The change from baseline in EQ-5D-Y will be summarized by age and disease cohorts, and 
by the presence or absence of concomitant EIAED, using descriptive statistics. 
6 
INTERIM ANALYSES 
An independent data monitoring committee (DMC) will be constructed to monitor the safety 
data. The responsibilities, membership, and purpose of the DMC, the timing of the 
meeting(s), and an outline of the plan for review of the safety data will be documented in the 
DMC Charter. 
7 
CHANGES IN THE PLANNED ANALYSES 
There are currently no changes in the planned analyses. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 Efficacy Data Handling 
8.1.1 Pre-randomization/baseline efficacy 
All diary data prior to first dose date at Core Study will be used in the computation of 
Pretreatment Phase seizure frequency per 28 days. The baseline value for other efficacy 
endpoints will be the last non-missing measurement occurring prior to the first dose of the 
study drug at Core Study. 
8.1.2 Treatment Duration for Efficacy Analyses 
The date of first dose of the study drug is considered day 1 in the treatment duration. 
The first dose date is the study drug start date and the last dose date is study drug end date 
from the study medication CRF page. 
The treatment duration for efficacy variables is defined as follows: 
 For diary seizure data: The duration between the day of first dose at Core Study and 
the last day of study drug at Maintenance Period in Extension Phase, inclusive. 
 For non-diary efficacy data: The duration between the day of first dose at Core Study 
and 7 days after the last day of study drug at Maintenance Period in Extension Phase, 
inclusive. 
For all efficacy analyses, data reported during Core Study and the Maintenance Period in 
Extension Phase will be analyzed. The diary seizure data during the Follow-up will be listed.  
8.1.3 Handling of Replicate Data 
For the CGIC and EQ-5D-Y assessment, the last visit within the treatment duration will be 
used. 
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8.2 Safety Data Handling 
8.2.1 Baseline Safety  
The baseline value for safety endpoints will be the last non-missing measurement occurring 
prior to the first dose of the study medication at Core Study. 
8.2.2 Treatment Duration for Safety Variables 
The treatment duration for non-AE safety variables is the same as non-diary efficacy analysis 
in Section 8.1.2 Treatment Duration for Efficacy Analyses. For AEs, the treatment duration 
is considered to begin on Day 1 at Core Study and ends 14 days after the last dose of 
Maintenance Period in Extension Phase. 
The post-treatment duration is considered to begin on the day after the treatment duration for 
safety. Since it is not always possible for all study participants to come in for their clinic 
visits on the exact day specified in the protocol schedule, the visit week of a subject’s visit 
will be based on the actual visit occurring during the treatment duration. These visits will be 
used to create by visit summaries for laboratory, vital signs, electrocardiograms and other 
safety analyses data. The end of treatment value is the last non-missing value in the treatment 
duration. 
Any concomitant medication taken within the 14 days after the last dose data will be listed/ 
summarized as part of the concomitant medication listing/table. 
AEs for the subject were collected and reported on CRF starting from the time subject signed 
informed consent to the last visit in the Follow-up following subject’s last dose. Serious AEs 
were collected for 28 days after the last dose. 
For summaries of safety by time points, the time points will be relative to date of first dose.  
For standardized reporting, study day windows relative to the first dose (Day 1) in the study 
will be applied to determine into which week the data will be mapped.  Scheduled, 
unscheduled, and early withdrawal visits will be mapped to weeks.  Table 6 below gives the 
mapping of relative day ranges to week for non-AE safety variables. If a subject did not have 
a recorded observation falling within a given range of days in order to be assigned to a week, 
the subject’s data for that week will be regarded as missing for summarization purposes.  If 
there are two or more assessments in the same window then: 
 if the window is the baseline assessment, then the latest assessment will be used in the 
summary tables; 
 if the window is the follow-up assessment, then the latest assessment will be used in 
the summary tables; 
If the window is not the baseline or the follow-up assessment, then the assessment closest to 
the scheduled assessment will be used in the summary tables.  Note that if two assessments 
are equidistant from the scheduled assessment then the last assessment of the two (within the 
allowable window) will be used.   
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Table 6:  Mapping of Study Day Ranges to Week  
 
Windowing Period 
Study Day Range  
(Relative to First Dose) 
Week 
Pretreatment 
Day 1a 
0 
Treatment 
2  Day  25 
2 
Treatment 
26  Day  46 
5 
Treatment 
47  Day  67 
8 
Treatment 
68  Day  88 
11 
Treatment 
89  Day  119 
15 
Treatment 
120  Day  147 
19 
Treatment 
148  Day  175 
23 
Extension 
176  Day  208  
28 
Extension 
209  Day  293 
40 
Extension 
294  Day  378 
52 
End of Treatment(EOT) of 
Extension Phase 
- 
b 
Follow up for discontinuation of 
Extension Phase 
 After the date of discontinuation Day 
 last dose of study drug +35 
c 
a:  All assessments performed on the same date as the date of first dose were to be 
performed prior to dosing; results from these assessments will be regarded as 
Pretreatment values in the analyses. 
b:  The last non-missing value measured in the Maintenance Period will be handled as the 
data of EOT of the Extension Phase. The Follow-up visit will not be included in this 
analysis visit. 
c   For the safety assessment other than AE, the data assessed as the planned visit of the 
Follow-up will be handled as those of Follow-up visit.  AE occurred on or after the date 
of discontinuation will be handled as that of Follow-up period. 
 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All data analyses will be performed by the Sponsor or designee (Symbiance) after the study 
is completed and the database is released. Statistical programming and analyses will be 
performed using SAS® and/or other validated statistical software as required. 
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11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
12 REFERENCES 
Clinical Study Protocol: E2007-G000-311, An Open-Label, Multicenter Study with an 
Extension Phase to Evaluate the Safety, Tolerability, and Exposure-Efficacy Relationship of 
Perampanel Oral Suspension when Administered as an Adjunctive Therapy in Pediatric 
Subjects (Age 4 to less than 12 years) with Inadequately Controlled Partial-Onset Seizures or 
Primary Generalized Tonic-Clonic Seizures, 20 Apr 2017 v5.0 Amendment 01. 
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13 APPENDICES 
13.1 Study Design for E2007-G000-311  
 
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13.2 Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results 
The following table is of Sponsor’s Grading for Laboratory Values from the version in the 
protocol, Appendix 1. 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
<LLN – 10.0 g/dL 
<LLN – 100 g/L 
<LLN – 6.2 mmol/L 
<10.0 – 8.0 g/dL 
<100 – 80 g/L 
<6.2 – 4.9 mmol/L  
<8.0 g/dL 
<80 g/L 
<4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated 
Leukocytes (total WBC) 
<LLN – 3.0109/L 
<LLN – 3000/mm3  
<3.0 – 2.0109/L 
<3000 – 2000/mm3  
<2.0 – 1.0109/L 
<2000 – 1000/mm3  
<1.0109/L 
<1000/mm3  
Lymphocytes  
<LLN – 800/mm3  
<LLN – 0.8109/L 
<800 – 500/mm3 
<0.8 – 0.5109/L 
<500 – 200/mm3  
<0.5 – 0.2109/L 
<200/mm3 
<0.2109/L 
Neutrophils  
<LLN – 1.5109/L 
<LLN – 1500/mm3 
<1.5 – 1.0109/L 
<1500 – 1000/mm3 
<1.0 – 0.5109/L 
<1000 – 500/mm3  
<0.5109/L 
<500/mm3  
Platelets 
<LLN – 75.0109/L 
<LLN – 75,000/mm3  
<75.0 – 50.0109/L 
<75,000 – 50,000/mm3 
<50.0 – 25.0109/L 
<50,000 – 25,000/mm3 
<25.0109/L 
<25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
<LLN – 3 g/dL 
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L 
<2 g/dL 
<20 g/L 
life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase  
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
ALT 
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
AST 
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5ULN  
>1.5 – 3.0ULN 
>3.0 – 10.0ULN  
>10.0ULN 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L  
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L  
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L  
>500 mg/dL 
>12.92 mmol/L  
Creatinine 
>ULN – 1.5ULN 
>1.5 – 3.0ULN 
>3.0 – 6.0ULN 
>6.0ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
Glucose, serum-high (hyperglycemia) 
Fasting glucose value: 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L  
Fasting glucose value: 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L  
>250 – 500 mg/dL; 
>13.9 – 27.8 mmol/L; 
hospitalization indicated 
>500 mg/dL; 
>27.8 mmol/L; 
life-threatening 
consequences  
Glucose, serum-low (hypoglycemia) 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
life-threatening 
consequences; 
seizures 
Phosphate, serum-low 
(hypophosphatemia)  
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL 
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
life-threatening 
consequences 
Potassium, serum-high (hyperkalemia) >ULN – 5.5 mmol/L  
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
hospitalization indicated 
>7.0 mmol/L 
life-threatening 
consequences 
Potassium, serum-low (hypokalemia)  
<LLN – 3.0 mmol/L 
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated 
<3.0 – 2.5 mmol/L 
hospitalization indicated 
<2.5 mmol/L 
life-threatening 
consequences 
Sodium, serum-high (hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
hospitalization indicated 
>160 mmol/L 
life-threatening 
consequences 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
N/A 
<130 – 120 mmol/L 
<120 mmol/L 
life-threatening 
consequences 
Triglyceride, serum-high 
(hypertriglyceridemia)  
150 – 300 mg/dL 
1.71 – 3.42 mmol/L 
>300 – 500 mg/dL 
>3.42 – 5.7 mmol/L  
>500 – 1000 mg/dL 
>5.7 – 11.4 mmol/L 
>1000 mg/dL 
>11.4 mmol/L 
life-threatening 
consequences  
Uric acid, serum-high (hyperuricemia) 
>ULN – 10 mg/dL  
≤0.59 mmol/L without 
physiologic 
consequences  
N/A 
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences  
>10 mg/dL 
>0.59 mmol/L  
life-threatening 
consequences 
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell. 
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published:  May 28, 2009 (v4.03:  June 14, 2010). 
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Eisai Inc. and Eisai Limited 
 E2007-G000-311 (Extension Phase) 
 
 
Date: 6Feb2018 Amendment 1 
Confidential 
Page 30 of 30 
 
SIGNATURE PAGE 
Authors:   
 
 
 
[electronic signature in eDMS] 
 
 
 
 
 
Neurology Business Group 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
 
 
Neurology Business Group 
 
Date 
Approval: 
 
 
 
[electronic signature in eDMS] 
 
 
 
 
 
Neurology Business Group 
 
Date 
 
[electronic signature in eDMS] 
 
 
 
Study Director 
 
 
Neurology Business Group 
 
 
Date 
 
 
 
 
 
 
 
 
 
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