Clinical trial NCT02914314
Conditions: Epilepsy
Keywords: epilepsy refractory partial seizures
Sponsor: Eisai Inc.
Start date: 2017-02-20; Completion date: 2023-04-25
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics (PK) of perampanel during the Maintenance Period of the Core Study following oral suspension administration given as an adjunctive therapy in pediatric participants from 1 month to less than 4 years of age with epilepsy.

Detailed description:
This is a multicenter, open-label study comprised of pretreatment, treatment (core study), and extension phases that is designed to evaluate the PK of an oral suspension of perampanel (maximum dose must not exceed 12 milligrams per day \[mg /day\] for participants taking non-enzyme-inducing antiepileptic drug \[non-EIAED\] or 16 mg/day for participants taking EIAED) when given as an adjunctive therapy in participants ranging from 1 month to less than 4 years of age with epilepsy. The Pretreatment Phase will last up to 2 weeks, during which participants will be assessed for their eligibility to participate in the study. The Treatment Phase will consist of 3 periods: Titration (12 \[for participants taking non-EIAED\] to 16 weeks \[for participants taking EIAED\]), Maintenance (4 weeks), and Follow-Up (4 weeks; only for those participants who complete the Maintenance Period but do not continue into the Extension Phase and those participants who discontinue study participation). Extension Phase: The Extension Phase will consist of 2 periods: Maintenance (32 weeks \[for participants taking EIAED\]; 36 weeks \[for participants taking non-EIAED\]) and Follow-Up (4 weeks).

The maximum total duration of treatment for each participant will be 52 weeks and the maximum total duration of the study for each participant will be 58 weeks (2 weeks Pretreatment+52 weeks of treatment+4 weeks Follow-up).

Arms: arm 1: Pediatric participants, ranging from 1 month to less than 4 years of age, will receive perampanel oral suspension once a day in titration period starting at Week 0 at a dose of 0.50 mg per day (mg/day) titrated up to 4 mg/day (for participants taking non-EIAED) or up to 8 mg/day (for participants taking EIAED). Depending on participants clinical response, tolerability and investigator's decision, dose can be up titrated to 6 mg/day (for participants taking non-EIAED) and up titrated to 8 mg/day (for participants taking EIAED). Dose titration must not exceed 12 mg/day (non-EIAED) and 16 mg/day (EIAED). Participants will continue taking the perampanel oral suspension at dose level achieved at end of titration period through maintenance period of core study and maintenance period of extension phase (Up to Week 52).
Interventions: intervention 1: perampanel
Intervention descriptions: intervention 1: oral suspension.

Protocol documents:
Prot_002.pdf: 
Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page i of x  
 
REVISION HISTORY 
Previous Protocol Version and Date:  v5.0, 08 Jan 2020 
Current Protocol Version:  v6.0 (Amendment 02) 
Date of Revisions:  09 Apr 2020 
Change 
Rationale 
Affected Protocol Section(s) 
For non-EIAED subjects, 
target perampanel dose is 
lowered to 4 mg/day.  
Depending upon individual 
clinical response and 
tolerability, non-EIAED 
subjects could still have their 
perampanel dose up-titrated to 
6 mg/day.  Clarified that the 
maximum dose allowed will 
not change.  
To reflect European Medicines 
Agency/Paediatric Committee 
(EMA/PDCO) final opinion 
(EMEA-000467-PIP01-08-M13 
PIP Modification) dated 
18 MAR 2020. 
• 
Synopsis – Study Design 
• 
Synopsis – Sample Size 
Rationale 
• 
Synopsis – Study 
Treatment(s) 
• 
Section 9.1.2.1 
• 
Section 9.4.1 
• 
Section 9.4.4 
• 
Table 1 
Clarified, in the text, the age 
range of study population 
Editorial update for consistency 
with language in the final 
Paediatric Investigation Plan 
(PIP) PIP Modification #13 
• 
Title Page 
• 
Synopsis – Study Protocol 
Title 
• 
Synopsis – Objectives 
• 
Synopsis – Study Design 
• 
Protocol Signature Page 
• 
Investigator Signature 
Page 
• 
Section 8.1 
• 
Section 8.2 
• 
Section 8.3 
Updated the Protocol Signature 
Page 
Study personnel change 
• 
Protocol Signature Page 
 
 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page ii of x  
 
Previous Protocol Version and Date:  v4.0, 07 Feb 2017 
Current Protocol Version:  v5.0 (Amendment 02) 
Date of Revisions:  08 Jan 2020 
Change 
Rationale 
Affected Protocol Section(s) 
Added a cohort of subjects 
from 2 to less than 4 years of 
age and specified total number 
of subjects required when 
pooled across multiple studies 
Updated the relevant text 
throughout the protocol to 
reflect the inclusion of 2 to less 
than 4 years age cohort 
 
To fulfill regulatory 
requirement 
• 
Title Page 
• 
Synopsis – Study Protocol 
Title 
• 
Synopsis – Study Design 
• 
Synopsis – Objectives and 
Statistical Methods 
• 
Synopsis – Number of 
Subjects 
• 
Synopsis – Inclusion 
Criteria 
• 
Synopsis – Sample Size 
Rationale 
• 
Synopsis – Statistical 
Methods 
• 
Section 7 
• 
Section 7.2 
• 
Section 8.1 
• 
Section 8.2 
• 
Section 8.3 
• 
Section 9.1 
• 
Section 9.2 
• 
Section 9.3 
• 
Section 9.3.1 
• 
Section 9.5.1.4 
• 
Section 9.7.1.1 
• 
Section 9.7.3 
• 
Protocol Signature Page 
• 
Investigator Signature 
Page 
Updated introduction 
To update approved indications 
of Fycompa, and reflect 
academic/regulatory acceptance 
of adult-to-pediatric efficacy 
extrapolation in lieu of 
controlled clinical trials 
• 
Section 7 
Made editorial changes to 
study endpoints 
For correctness  
• 
Synopsis – Statistical 
Methods 
• 
Section 9.7.1.1 
Increased overall study 
duration 
To allow additional time for 
recruitment 
• 
Synopsis –  
Study Period and Phase of 
Development  


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page iii of x  
 
Previous Protocol Version and Date:  v4.0, 07 Feb 2017 
Current Protocol Version:  v5.0 (Amendment 02) 
Date of Revisions:  08 Jan 2020 
Change 
Rationale 
Affected Protocol Section(s) 
Deleted Clinical Global 
Impression of Severity (CGI-S) 
from exploratory objectives 
and endpoints 
To correct error 
• 
Synopsis – Exploratory 
objective 
• 
Section 8.3 
Increased the allowed number 
of concomitant anti-epileptic 
drugs (AEDs) from 3 to 4 
To reflect clinical reality that 
refractory patients are on more 
than 3 concomitant AEDs 
• 
Synopsis – Study Design 
• 
Synopsis – Inclusion 
Criteria 
• 
Synopsis – Concomitant 
Drug/Therapy 
• 
Section 9.1 
• 
Section 9.3.1 
• 
Section 9.4.7 
Lowered the target dose to 
6 mg/day for non-enzyme-
inducing anti-epileptic drug 
(non-EIAED) and to 8 mg/day 
for EIAED subjects  
Specified conditions for further 
up-titrations to maximum 
allowed doses up to 12 mg/day 
for non-EIAED and 16 mg/day 
for EIAED subjects   
Precautionary measure to 
ensure subject’s safety 
• 
Synopsis – Study Design 
• 
Synopsis – Study 
Treatment(s) 
• 
Section 9.1.2.1 
• 
Section 9.2 
• 
Section 9.4.1 
• 
Section 9.4.4 
• 
Table 1 
• 
Table 2 
Updated the discussion of 
study design 
To improve readability and 
clarity 
• 
Section 9.2 
Modified the period during 
which concomitant AED doses 
must have remained stable for 
eligibility determination 
To minimize wait period while 
ensuring the adequate washout 
is achieved before initiating 
study treatment 
• 
Synopsis – Inclusion 
Criteria 
• 
Section 9.3.1 
Modified the period during 
which concomitant central 
nervous system (CNS) drugs 
must have remained stable, and 
specified that these drugs are 
prohibited throughout the 
course of the study 
To minimize wait period, as 
applicable, while ensuring the 
adequate washout is achieved 
before initiating study treatment  
• 
Synopsis – Exclusion 
Criteria 
• 
Synopsis – Concomitant 
Drug/Therapy 
• 
 Section 9.3.2 
• 
Section 9.4.7.2 
Modified exclusion criterion 
related to prior or concomitant 
use of felbamate and vigabatrin 
and specified that these drugs 
are prohibited throughout the 
course of the study 
For clarification 
• 
Synopsis – Concomitant 
Drug/Therapy 
• 
Synopsis – Exclusion 
Criteria 
• 
 Section 9.3.2 
• 
 Section 9.4.7.2 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page iv of x  
 
Previous Protocol Version and Date:  v4.0, 07 Feb 2017 
Current Protocol Version:  v5.0 (Amendment 02) 
Date of Revisions:  08 Jan 2020 
Change 
Rationale 
Affected Protocol Section(s) 
Modified the exclusion 
criterion related to prior use of 
perampanel 
For clarification 
• 
Synopsis – Exclusion 
Criteria 
• 
 Section 9.3.2 
Specified that concomitant use 
of cannabidiol (CBD) products 
is allowed 
For clarification 
• 
Synopsis – Concomitant 
Drug/Therapy 
• 
Section 9.4.7 
Modified concomitant therapy 
section to allow dose 
adjustments of concomitant 
AEDs (non-enzyme inducing 
AEDs only) during the Core 
study.  AED addition or 
deletion will remain prohibited 
during the Core Study. 
To reflect clinical practice in 
the management of patients 
with epilepsy. 
• 
Synopsis – Concomitant 
Drug/Therapy 
• 
Section 9.4.7 
Specified that the subjects who 
immediately switch to 
commercially available 
perampanel after the last dose 
of study drug at the end of 
Core Study or Extension Phase 
need not undergo Follow-up 
Period/Visit 
For clarification 
• 
Synopsis – Study Design 
• 
Synopsis – Study 
Treatment(s) 
• 
Synopsis – Duration of 
Treatment 
• 
Section 9.1 
• 
Section 9.1.2 
• 
Section 9.1.2.3 
• 
Section 9.4.1 
• 
Table 4 
• 
Table 5 
• 
Table 6 
• 
Table 7 
• 
Appendix 3 
Added description of sample 
size calculations for the 2 to 
less than 4 years of age group 
To provide rationale for sample 
size 
• 
Synopsis – Sample Size 
Rationale 
• 
Section 9.7.2 
Lipid and blood glucose tests 
are to be collected under 
fasting conditions, whenever 
practically feasible, at all-time 
points 
Mandatory fasting may not be 
practical in particular in 
pediatric subjects 
• 
Table 4 footnote 
• 
Table 5 footnote 
• 
Table 6 footnote 
• 
Table 7 footnote 
Clarified baseline seizure 
frequency data for efficacy 
endpoint analyses 
For clarification 
• 
Synopsis – Statistical 
Methods 
• 
Section 9.7.1.1 
• 
Section 9.7.1.6 
• 
Appendix 3 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page v of x  
 
Previous Protocol Version and Date:  v4.0, 07 Feb 2017 
Current Protocol Version:  v5.0 (Amendment 02) 
Date of Revisions:  08 Jan 2020 
Change 
Rationale 
Affected Protocol Section(s) 
Added early pharmacokinetic 
(PK) sampling time points at 
predose and 1 to 5 hours 
postdose for subjects of 2 to 
less than 4 years of age and 
adjusted dosing instructions 
around PK visits during 
Maintenance Period.  Also 
updated total blood volumes to 
be taken as applicable 
To support characterization of 
perampanel PK, especially 
during absorption and early 
distribution phases 
• 
Synopsis –Assessments 
• 
Section 9.5.1.4 
• 
Table 4 
• 
Table 5 
• 
Appendix 2 
Added a statement that the 
dose-normalized derived 
exposure parameters will be 
summarized for age groups 
For clarification 
• 
Synopsis – Statistical 
Methods 
• 
Section 9.7.1.7 
Updated the PROTOCOL 
SIGNATURE PAGE 
Added current study director, 
medical monitor, study 
statistician, and clinical 
pharmacologist 
• 
PROTOCOL 
SIGNATURE PAGE 
 
 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page vi of x  
 
Previous Protocol Version and Date: v3.0, 12 May 2016 
Current Protocol Version: v4.0 (Amendment 01) 
Date of Revisions:  07 Feb 2017 
Change 
Rationale 
Affected Protocol Section(s) 
Changed the gestational age 
from 41 to 36 weeks in 
inclusion criterion 1 
Correction 
• 
Synopsis – Inclusion 
Criteria 
• 
Section 9.3.1 
Removed 4-week time frame 
of last seizure occurrence 
prior to Visit 1 from inclusion 
criterion 5 
Changed to increase enrolment • 
Synopsis – Inclusion 
Criteria 
• 
Section 9.3.1 
Changed seizure surgery 
restriction from “before 
Visit 1” to “within 1 year of 
Visit 1” in exclusion 
criterion 4 
Changed to increase enrolment • 
Synopsis – Exclusion 
Criteria 
• 
Section 9.3.2 
Updated the PROTOCOL 
SIGNATURE PAGE 
Added current statistician and 
study director 
• 
PROTOCOL 
SIGNATURE PAGE 
 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page vii of x  
 
Previous Protocol Version and Date: v2.0, 06 Nov 2015 
Current Protocol Version: v3.0 
Date of Revisions:  12 May 2016 
Change 
Rationale 
Affected Protocol Section(s) 
Specify that perampanel oral 
suspension is an adjunctive 
therapy 
For accuracy 
• 
Synopsis – Objectives 
• 
Section 8.2 
• 
Section 8.3 
Revise planned number of 
subjects in specified age 
categories 
Per approved PIP, to ensure 
adequate representation of all 
relevant age groups 
• 
Synopsis – Study Design 
• 
Synopsis -- Number of 
Subjects 
• 
Section 9.1 
• 
Section 9.2 
• 
Section 9.3 
Allow for possible sample 
size increase from 16 to 24 
subjects 
To ensure adequate evaluable 
PK data 
• 
Synopsis—Study Design 
• 
Synopsis – Statistical 
Methods 
• 
Section 9.4.1 
• 
Section 9.7.2 
Revise duration of access to 
oral suspension to allow for 
duration of study treatment 
beyond 52 week 
For flexibility 
• 
Synopsis, Study Design 
• 
Section 9.1 
Clarify that dosing will occur 
before bedtime   
For consistency of dose 
administration across subjects 
 
• 
Synopsis – Study 
Treatment(s) 
• 
Section 9.4.5 
Specify that MTD will be 
based on individual 
tolerability 
For safety of subjects 
• 
Synopsis—Study 
Treatment(s) 
Re-word safety endpoint 
Per approved PIP 
• 
Synopsis – Statistical 
Methods 
Add Clinical Global 
Impression (CGI) to 
assessments 
As advised by PDCO 
• 
Synopsis – Statistical 
Methods 
• 
Synopsis -- Objectives 
• 
Section 8.3 
• 
Section 9.5.1.3 
• 
Table 4 
• 
Table 5 
• 
Section 9.7.1.1 
• 
Section 9.7.1.6 
• 
Appendix 3 
• 
Table 6 
• 
Table 7 
Specify intrinsic and extrinsic 
factors to be used for 
population PK analyses 
As advised by PDCO 
• 
Synopsis – Statistical 
Methods 
• 
Section 9.7.1.7 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page viii of x  
 
Provide further details of 
population PK analysis 
including 2-compartment PK 
model 
As advised by PDCO 
• 
Synopsis – Statistical 
Methods 
• 
Section 9.7.1.7 
Add SAE to safety 
assessments 
For consistency 
• 
Synopsis – Statistical 
Methods 
Clarify that PK comparisons 
will include adult subjects 
For consistency 
• 
Synopsis – Statistical 
Methods 
• 
Section 9.7.2 
Delete IxRS from description 
of study procedures 
The IxRS is not needed for this 
study. 
• 
Section 4 
• 
Section 9.4.2 
• 
Table 4 
• 
Table 5 
• 
Section 11.3 
• 
Appendix 3 
• 
Table 6 
• 
Table 7 
Delete description of titration 
to higher doses in EIAED 
subjects 
For consistency with study 
plan. 
• 
Table 1 
• 
Table 2 
Delete statement that a 
pharmacy manual will be 
provided 
There will be no pharmacy 
manual.  Instructions will be 
sent to the study site. 
• 
Section 9.4.2 
• 
Appendix 3 
Delete band from laboratory 
tests to be conducted 
It is considered unnecessary to 
include this laboratory test. 
• 
Table 3 
Change visit window to ±6 
instead of ±7 days 
Ensure that the shelf life of the 
investigational product is not 
exceeded. 
• 
Section 9.3.3 
• 
Section 9.5.5  
• 
Table 4 
• 
Table 5 
• 
Table 6 
• 
Table 7 
Modify abnormal QTcF 
criteria 
For clarity and consistency 
Section 9.7.1.8 
Appendix 3 
Editorial and formatting 
corrections  
For consistency and quality 
Various locations 
 
 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page ix of x  
 
Previous Protocol Version and Date: v1.0, 28 Apr 2014 
Current Protocol Version: v2.0 
Date of Revisions:  06 Nov 2015 
Change 
Rationale 
Affected Protocol 
Section(s) 
Revised dosing schedule to flat 
dosing, at a starting dose of 
0.5 mg/day, and to allow for 
titrations up to 12 mg/day for 
non-EIAED subjects and 
16 mg/day for EIAED subjects 
As supported by the Study 232 PK 
and safety data  
• Synopsis –  
◦ 
Study Design 
◦ 
Study Treatments 
◦ 
Duration of Treatment 
◦ 
Sample Size Rationale 
• Section 9.1 
• Section 9.1.2 
• Section 9.2 
• Figure 1 
• Section 9.1.2.1 
• Section 9.4.1 
• Table 1, Table 2 
• Table 4 
• Table 5 
•  Appendix 3 
Updated information for relevant 
studies of perampanel (ie, Study 
048, Study 235 and Study 232) 
To provide current study status, 
information on the bioavailability of 
the oral suspension, outcome of 
pharmacokinetic analyses, and the 
supporting rationale for dosing in 
Study 238  
• Section 7.1 
• Section 7.2 
• Section 9.4.4  
• Section 9.7.2 
Revised testing for glucose and 
lipid panel to require fasting at 
baseline and end of treatment or 
early termination 
In response to FDA request per 
persistent signal for weight gain and 
elevated triglycerides 
• Table 3, Table 4, and Table 
5 
• Appendix 3 
Revised how investigational 
product will be provided to the 
sites and subjects 
Due to flat dosing,  
• Section 9.4.2 
• Appendix 3 
Removed the requirement for the 
CGI-C assessment 
Due to the small n in this study and 
the fact that this assessment has not 
demonstrated meaningful results in 
prior studies  
• Synopsis – Assessments 
• Synopsis – Statistical 
Methods 
• Section 9.5.1.3 
• Table 4 
• Section 9.7.1.1 
• Section 9.7.1.8 
• Section 10 
• Appendix 3 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page x of x  
 
Previous Protocol Version and Date: v1.0, 28 Apr 2014 
Current Protocol Version: v2.0 
Date of Revisions:  06 Nov 2015 
Change 
Rationale 
Affected Protocol 
Section(s) 
Revised number of expected sites 
for participation 
Based upon preliminary feasibility 
• Synopsis – Sites 
• Section 6 
• Section 9.3  
Updated various components of 
statistical analysis, and the 
standard safety reporting 
language, and corrected 
formatting and general 
inconsistencies 
To comply with the current Eisai 
template for protocols, the Eisai 
Style Guide, and for general 
consistency throughout the protocol 
• Various 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page 1 of 93  
 
1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E2007-G000-238 
Study Protocol Title: 
An Open-Label Study With an Extension Phase to Evaluate the 
Pharmacokinetics of Perampanel (E2007) Oral Suspension When Given 
as an Adjunctive Therapy in Subjects From 1 Month to Less Than 4 Years 
of Age With Epilepsy  (revised per Amendment 02) 
Sponsor: 
Eisai Inc. 
155 Tice Boulevard 
Woodcliff Lake,  
New Jersey 07677 
US 
Eisai Ltd.  
European Knowledge Centre 
Mosquito Way 
Hatfield, Hertfordshire  
AL10 9SN UK 
Investigational 
Product Name: 
Perampanel 
Indication: 
Epilepsy 
Phase: 
2 
Approval Date:  
v1.0  28 Apr 2014 
v4.0  07 Feb 2017 (Amendment 01) 
 
v2.0  06 Nov 2015 
v5.0  08 Jan 2020 (Amendment 02) 
 
v3.0  12 May 2016 
v6.0  09 Apr 2020  
IND Number: 
112515 
EudraCT Number: 
2013-005391-17 
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 Good Clinical Practice (GCP) 
and regulations.  All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study. 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page 2 of 93  
 
2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No. 
E2007 (perampanel) 
Name of Active Ingredient 
2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate 4:3  
Study Protocol Title 
An Open-Label Study With an Extension Phase to Evaluate the Pharmacokinetics of Perampanel (E2007) Oral 
Suspension When Given as an Adjunctive Therapy in Subjects From 1 Month to Less Than 4 Years of Age 
With Epilepsy  (revised per Amendment 02) 
Sites 
Approximately 15 sites in North America (NA) and the European Union (EU) 
Study Period and Phase of Development 
Total study duration:  Approximately 56 months  (revised per Amendment 02) 
Phase 2 
Objectives 
Primary Objective 
• 
To evaluate the pharmacokinetics (PK) of perampanel during the Maintenance Period of the Core Study 
following oral suspension administration given as an adjunctive therapy in pediatric subjects from 
1 month to less than 4 years of age with epilepsy  (revised per Amendment 02) 
Secondary Objectives 
• 
To evaluate the short- and long-term safety and tolerability of perampanel oral suspension given as an 
adjunctive therapy in subjects from 1 month to less than 4 years of age with epilepsy  (revised per 
Amendment 02) 
• 
To evaluate the long-term effect of perampanel oral suspension, given as an adjunctive therapy, on 
growth from baseline to end of treatment in pediatric subjects from 1 month to less than 4 years of age 
with epilepsy  (revised per Amendment 02) 
Exploratory Objective 
• 
To explore the short- and long-term efficacy of perampanel oral suspension given as an adjunctive 
therapy in subjects from 1month to less than 4 years of age with epilepsy as assessed by:  (revised per 
Amendment 02) 
o 
Percent change in 28-day seizure frequency during the Titration + Maintenance Periods compared 
to baseline and during the Extension Phase compared to baseline 
o 
Proportion of subjects with a 50% decrease in 28-day seizure frequency during the Maintenance 
Period compared to baseline and during the Extension Phase compared to baseline 
o 
Proportion of subjects who are seizure-free during the Maintenance Period and during the Extension 
Phase 
o 
Clinical Global Impression (CGI) of change (CGI-C)  (revised per Amendment 02) 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page 3 of 93  
 
Study Design 
This will be a multicenter, open-label study with an extension phase that will enroll 16 to 24 pediatric subjects 
1 to less than 24 months of age and at least to a maximum of 26 pediatric subjects from 2 to less than 4 years 
of age with epilepsy.  (revised per Amendment 02) 
All subjects must be taking 1 to a maximum of 4 anti-epileptic drugs (AEDs) to participate in the study.  For 
at least 6 but not more than 8 of the subjects in the age group of 1 to less than 24 months and for 13 subjects 
in the age group of 2 to less than 4 years (across studies), only 1 enzyme-inducing AED (ie, EIAEDs; 
carbamazepine [CBZ], oxcarbazepine [OXC], phenytoin [PHT], or eslicarbazepine [ESL]) out of the 
maximum of 4 AEDs will be allowed.  These subjects will be referred to as EIAED subjects.  The remaining 
subjects cannot be taking any EIAEDs and will be referred to as non-EIAED subjects.  (revised per 
Amendment 02) 
For the age group of 1 to less than 24 months, the Sponsor will ensure a reasonable representation of subject 
age (ie, at least 6 subjects in the age range ≥1 to ≤6 months, at least 5 subjects in the age range >6 to 
≤12 months, at least 5 subjects in the age range >12 to <24 months).  (revised per Amendment 02) 
For the age group of 2 to less than 4 years, the required number of subjects (total of 26) can be pooled across 
multiple studies for PK and safety assessments.  Therefore, the target number of subjects to be enrolled in this 
age group ranges from a minimum of 1 to a maximum of 26 subjects.  Enrollment of subjects aged 2 to less 
than 4 years into this study may be stopped upon notification of sponsor when the total number has been 
reached across clinical studies, or when enrollment in the 1 to less than 24 months age group in this study has 
completed (ie, the original purpose of this study has been met).  (revised per Amendment 02) 
This study will consist of 3 phases:  Pretreatment and Treatment (Core Study), and Extension.  The 
Pretreatment Phase will last up to 2 weeks, during which subjects will be assessed for their eligibility to 
participate in the study.  The Treatment Phase will consist of 3 periods:  Titration (12-16 weeks), Maintenance 
(4 weeks), and Follow-up (4 weeks; only for those subjects who complete the Maintenance Period but do not 
continue into the Extension Phase).  The Extension Phase will consist of 2 periods:  Maintenance 
(32-36 weeks) and Follow-up (4 weeks).  (revised per Amendment 02) 
The maximum total duration of treatment for each subject will be 52 weeks and the maximum total duration 
of the study for each subject will be 58 weeks (2 weeks Pretreatment+52 weeks of treatment+4 weeks 
Follow-up).  (revised per Amendment 02) 
Subjects who complete the Extension Phase and who, in the opinion of the investigator, will likely continue to 
demonstrate a positive benefit-to-risk ratio from treatment with perampanel may be enrolled into an extended 
access program (EAP) for perampanel if EAP is implemented for this age group in the country where the 
subject resides.  (revised per Amendment 02) 
Pretreatment Phase (Core Study) 
At the first visit of the Pretreatment Phase, 4 weeks of prescreening (ie, before Visit 1) seizure frequency data 
will be collected for each subject as part of their medical history.  Upon successful completion of the 
Pretreatment Phase, eligible subjects will enter the Treatment Phase.   
Treatment Phase (Core Study) 
During the Treatment Phase, subjects will be dosed with perampanel oral suspension as follows: 
• 
Titration Period:  Subjects will start perampanel treatment at a dose of 0.50 mg/day and follow dose 
titration schemes up to 4 mg/day (non-EIAED subjects) or 8 mg/day (EIAED subjects).  Depending 
on individual subject’s clinical response and tolerability, non-EIAED subjects could still have the 
perampanel dose up-titrated to 6 mg/day.  Perampanel dose should not be further up-titrated beyond 
6 mg/day (non-EIAED subjects) or 8 mg/day (EIAED subjects) unless there is a medical need (for 
example, a subject who tolerated perampanel well but have not reached optimal seizure control).  
Before dose up-titrations beyond 6 mg/day (non-EIAED subjects) or 8 mg/day (EIAED subjects) and 
whenever practically feasible, it is recommended to take a blood sample for the measurement of 
plasma perampanel level as a precautionary measure.  The date and time of the last perampanel dose 


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administration, as well as the date and time of PK blood draw, for these unscheduled PK sample 
collection will be recorded.  Up-titrations of perampanel dose within the range of 0.5 to 6 mg/day will 
be at 1-week intervals; and at doses greater than 6 mg/day will be at 2-week intervals (see Study 
Treatment(s) section).  Dose titrations must not exceed 12 mg/day (non-EIAED subjects) or 
16 mg/day (EIAED subjects).  The decision to up-titrate perampanel dose will be at the investigator’s 
discretion, based on individual subject’s clinical response and/or tolerability to achieve optimal dose 
for a given subject.  Once the optimal dose has been achieved, the subject’s dose will be maintained 
stable for the remaining Titration Period or at least 2 weeks before entering the Maintenance Period.  
(revised per Amendment 02) 
• 
Maintenance Period:  During the Maintenance Period, subjects will continue taking perampanel oral 
suspension at the dose level they achieved at the end of the Titration Period.  The maximum total daily 
dose a subject will be allowed is 12 mg for non-EIAED subjects and 16 mg for EIAED subjects.  
(revised per Amendment 02) 
• 
Follow-Up Period:  Subjects will not receive study drug during this period.  Subjects who do not 
continue into the Extension Phase after completing the Maintenance Period, or those who discontinue 
early from the study will be required to complete the Follow-up Period after their last dose in the 
Treatment Phase.  Subjects who switch to commercially available perampanel or who enter into EAP 
upon completion of study treatment need not to undergo Follow-up Visit; however, sites will conduct 
a telephone contact 28 (+6) days after the last dose of study drug to follow adverse events (AEs) and 
report any serious adverse events (SAEs) that occur within 28 days of the last study drug 
administration.  (revised per Amendment 02) 
After every 4th subject in the age group 1 to less than 24 months completes the Maintenance Period, an interim 
analysis (safety, tolerability, and PK) will be conducted whereby dose-normalized exposure will be compared 
to that observed in other studies in subjects between ≥2 and <18 years of age.  If the exposure of the subjects 
is significantly different from that observed in subjects ages ≥2 to <12 years from other clinical studies or that 
are predicted from PK modeling and simulation, or if non-linear PK is observed, the sample size will be 
increased to at least 24 subjects with evaluable PK data, and the target dose or dosing regimen of those subjects 
may be modified via protocol amendment, depending on the PK of the previous subjects.  PK data collected in 
older age cohort (2 to less than 4 years) will also be examined in the interim PK analyses.  (revised per 
Amendment 02) 
Preliminary PK analysis was performed based on data obtained from 7 subjects (>6 to <24 months of age; 
6 subjects without concomitant EIAED and 1 subject on concomitant EIAED) in this study and pooled with 
existing data from 2336 subjects (aged 2 to 77 years).  Preliminary PK findings suggest that oral clearance in 
subjects aged less than 24 months without concomitant EIAED appears to be approximately 40% of that in 
subjects aged ≥ 2 years.  It is predicted that a daily dose of 6 mg or 8 mg in subjects aged less than 24 months 
without or with concomitant EIAED, respectively, will result in comparable exposure to that in subjects aged 
>2 years receiving a daily dose of 12 mg (non-EIAED subjects) or 16 mg (EIAED subjects), respectively.  
However, European Medicines Agency/Paediatric Committee (EMA/PDCO) recommended that perampanel 
dose should be titrated up to a target dose of 4 mg/day for non-EIAED subjects (EMEA-000467-PIP01-08-
M13), which could be further titrated up to 6 mg/day depending on individual subject’s clinical response and 
tolerability. Therefore, the target dose in this study is revised to 4 mg/day (non-EIAED subjects) and 8 mg/day 
(EIAED subjects) in subjects less than 24 months of age, while the maximum dose allowed remains as 
12 mg/day and 16 mg/day for non-EIAED and EIAED subjects, respectively.  (revised per Amendment 02) 
In subjects 2 to less than 4 years of age, there were very limited PK data (n=4) to allow adequate evaluation of 
effect of age on perampanel PK.  Therefore, the same target dose and dose titration approach will be followed 
for non-EIAED and EIAED subjects aged 2 to less than 4 years as described above for 1 to less than 24 months 
subjects.  (revised per Amendment 02) 
Extension Phase 
Subjects who have completed the last visit of the Core Study Maintenance Period will be eligible to participate 
in the Extension Phase of this study.  For these subjects, the last visit of the Maintenance Period in the Treatment 


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Phase will be considered the first visit of the Extension Phase. 
• 
Maintenance Period:  Subjects will continue taking perampanel oral suspension, at the dose level 
achieved at the end of the Treatment Phase.  The maximum total daily dose a subject will be allowed 
is 12 mg for non-EIAED subjects or 16 mg for EIAED subjects. 
• 
Follow-Up Period:  No study drug will be administered during Follow-up Period.  All subjects will 
be required to complete the Follow-up Period after their last dose in the Extension Phase, except for 
subjects who switch to commercially available perampanel or who enter into EAP upon completion 
of study treatment.  For these subjects, sites will conduct a telephone contact 28 (+6) days after the 
last dose of study drug to follow AEs and report any SAEs that occur within 28 days of the last study 
drug administration.  (revised per Amendment 02) 
Data Monitoring Committee 
An independent data monitoring committee (DMC) will be constructed to monitor the safety data of this 
study.   
Number of Subjects 
1 month to <24 months of age:  At least 16 subjects with evaluable PK data, of which at least 6 subjects are in 
the age range ≥1 to ≤6 months, at least 5 subjects are in the age range >6 to ≤12 months, and at least 5 subjects 
are in the age range >12 to <24 months.  The target number of subjects with EIAED are at least 6 but not more 
than 8 subjects across these 3 age subgroups.  (revised per Amendment 02) 
2 years to <4 years of age:  A total of 26 subjects (13 EIAED and 13 non-EIAED) to be enrolled and pooled 
across clinical studies of perampanel with PK data.  Therefore, the target number of subjects to be enrolled in 
this age group in this study ranges from a minimum of 1 to a maximum of 26 subjects.  (revised per 
Amendment 02)  
Inclusion Criteria 
Pretreatment and Treatment Phases (Core Study) 
1. Male or female, from 1 month to less than 4 years of age (and of at least 36 weeks gestational age) at 
the time of consent  (revised per Amendments 01 and 02) 
2. 
Have a minimum weight of 4 kg (8.8 lb) 
3. 
Have a diagnosis of epilepsy with any type of seizure according to the International League Against 
Epilepsy’s (ILAE) Classification of Epileptic Seizures (1981).  Diagnosis should have been established 
at least 2 weeks (≤6 months of age) or 4 weeks (> 6 months of age) before Visit 1, by clinical history 
and an electroencephalogram (EEG) that is consistent with epilepsy; normal interictal EEGs will be 
allowed provided that the subject meets the other diagnosis criterion (ie, clinical history) 
4. 
Have had brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) before 
Visit 1 that ruled out a progressive cause of epilepsy 
5. 
Have had 1 or more seizure(s) before Visit 1  (revised per Amendment 01) 
6. 
Are currently being treated with a stable dose (ie, unchanged for at least 5 half-lives) of 1 to a maximum 
of 4 AEDs.  (At least 6, but not more than 8 subjects, in the age group of 1 to less than 24 months, and 
up to 13 subjects in the age group of 2 to less than 4 years, will be taking 1 enzyme-inducing AED [ie, 
EIAEDs; CBZ, OXC, PHT, or ESL] out of the maximum of 4 AEDs allowed.  The remaining subjects 
cannot be taking any EIAEDs.)  (revised per Amendment 02) 
7. 
Have been on their current concomitant AED(s) with a stable dose for at least 2 weeks or 5 half-lives, 
whichever is longer, before Visit 1  (revised per Amendment 02) 
8. 
Must have discontinued all restricted medications (eg, medications known to be inducers of cytochrome 
P450 3A) at least 2 weeks or 5 half-lives (whichever is longer) before Visit 1 (revised per 
Amendment 02) 
Extension Phase 
1. Have completed the last visit of the Maintenance Period of the Core Study 


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Exclusion Criteria 
Pretreatment and Treatment Phases (Core Study) 
1. Have a history of status epilepticus that required hospitalization during the 3 months before Visit 1 
2. Have seizures due to treatable medical conditions, such as those arising due to metabolic disturbances, 
toxic exposure, or an active infection 
3. Have epilepsy secondary to progressive central nervous system (CNS) disease or any other 
progressive neurodegenerative disease, including tumors  
4. Have had epilepsy surgery within 1 year of Visit 1 (revised per Amendment 01) 
5. Are scheduled and/or confirmed to have epilepsy surgery within 6 months after Visit 1 
6. Used intermittent rescue benzodiazepines (ie, 1 to 2 doses over a 24-hour period considered one-time 
rescue) 2 or more times in the 2 weeks before Visit 1 
7. Current use of felbamate, or any evidence of ongoing hepatic or bone marrow dysfunction associated 
with prior felbamate treatment. (Prior use of felbamate must be discontinued at least 8 weeks before 
Visit 1.)  (revised per Amendment 02) 
8. Current use of vigabatrin or any evidence of clinically significant vision abnormality associated 
with prior vigabatrin treatment. (Prior use of vigabatrin must be discontinued at least 2 weeks before 
Visit 1.)  (revised per Amendment 02) 
9. On ketogenic diet regimen that has not been stable for at least 4 weeks before Visit 1  
10. Concomitant use of other drugs known to influence the CNS (other than AEDs for epilepsy), where 
the dose has not been stabilized for at least 5 half-lives or 2 weeks, whichever is longer, before Visit 1  
(revised per Amendment 02) 
11. Have any concomitant illnesses/co-morbidities that could severely affect the subject’s safety or study 
conduct 
12. Have 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 study conduct 
13. Have clinically significant laboratory abnormalities or any clinically acute or chronic disease 
14. Have 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 ULN 
15. Have clinical evidence of significant active hematological disease; WBC count ≤2500/μL 
(2.50 x 109/L) or an absolute neutrophil count ≤1000/μL (1.00 x 109/L) 
16. Have conditions that may interfere with their participation in the study and/or with the PK of study 
drug 
17. 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 
18. Have recently (within 30 days before Visit 1) been exposed to perampanel in a clinical study or by 
prescription, and/or previous discontinuation from perampanel treatment due to adverse events related 
to perampanel  (revised per Amendment 02) 
19. Have a clinically significant electrocardiogram (ECG) abnormality, including prolonged corrected QT 
interval (QTc) defined as > 450 msec 
20. Have had 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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Study Treatment(s) 
Test drug 
Perampanel will be provided as 0.5 mg/mL oral suspension stock.  Dosing should occur once daily before 
bedtime in the evening, unless otherwise specified. 
Study treatments are to be administered as follows: 
Pretreatment and Treatment Phase (Core Study) 
Pretreatment Phase:  Subjects will not receive study drug during this phase. 
Treatment Phase: 
• 
Titration Period (12-16 weeks):  Subjects will start perampanel treatment at a dose of 0.50 mg/day 
and follow dose titration schemes up to 4 mg/day (non-EIAED subjects) or 8 mg/day (EIAED 
subjects).  Depending on individual subject’s clinical response and tolerability, non-EIAED subjects 
could still have the perampanel dose up-titrated to 6 mg/day.  Perampanel dose should not be further 
up-titrated beyond 6 mg/day (non-EIAED subjects) or 8 mg/day (EIAED subjects) unless there is a 
medical need (for example, a subject who tolerated perampanel well but have not reached optimal 
seizure control).  Before dose up-titrations beyond 6 mg/day (non-EIAED subjects) or 8 mg/day 
(EIAED subjects) and whenever practically feasible, it is recommended to take a blood sample for 
the measurement of plasma perampanel level as a precautionary measure.  The date and time of the 
last perampanel dose administration, as well as the date and time of PK blood draw, for these 
unscheduled PK sample collection will be recorded.  Up-titrations of perampanel dose within the 
range of 0.5 to 6 mg/day will be at 1-week intervals; and at doses greater than 6 mg/day will be at 
2-week intervals (see Study Treatment(s) section) Dose titrations must not exceed 12 mg/day (non-
EIAED subjects) or 16 mg/day (EIAED subjects)). The decision to up-titrate perampanel dose will be 
at the investigator’s discretion, based on individual subject’s clinical response and/or tolerability to 
achieve optimal dose for a given subject.  Once the optimal dose has been achieved, the subject’s dose 
will be maintained stable for the remaining Titration Period or at least 2 weeks before entering the 
Maintenance Period.  (revised per Amendment 02) 
According to the investigator’s clinical judgment subjects experiencing intolerability at any dose may 
remain at the same dose or have their dose decreased one 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 must be done at the next clinic visit after the 
investigator has deemed it is appropriate in view of the resolution of the AE(s).  Multiple dose 
adjustments will be allowed during the Titration Period.  Every effort should be made to have subjects 
achieve their optimal dose, not to exceed a maximum dose of 12 mg/day (non-EIAED subjects) or 
16 mg/day (EIAED subjects) during the Titration Period.  (revised per Amendment 02) 
• 
Maintenance Period (4 weeks):  During this period, subjects will continue taking perampanel oral 
suspension at the dose level they achieved at the end of the Titration Period. 
Adjustment of the dose level during the Maintenance Period should be discouraged; however, 
according to the investigator’s clinical judgment, subjects experiencing intolerable AE(s) will be 
allowed to have their dose decreased to the previously tolerated dose.  During the Maintenance Period, 
subjects whose dose has been decreased cannot have their dose increased again.  A subject may not 
decrease their dose more than once during Maintenance Period unless there is a significant medical 
reason and with approval from the Medical Monitor. 
During the entire Titration and Maintenance Periods, all dose adjustments will be done via 1 dose 
titration level up or down (relevant to where the subject is within the study).  Subjects who do not 
tolerate a dose of 0.50 mg/day will be discontinued from the study.  The maximum total daily dose a 
subject will be allowed is 12 mg (non-EIAED subjects) or 16 mg (EIAED subjects). 


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Dosing Modifications 
After every 4th subject in the age group 1 to less than 24 months completes the Maintenance Period, 
an interim analysis (safety, tolerability, and PK) will be conducted and reviewed by the Eisai study 
team to decide if dosing modifications are required for additional subjects who enroll in the study.  If 
the exposure of the subjects is significantly different from that observed in subjects ages ≥2 to <12 
years from other clinical studies or that are predicted from PK modeling and simulation, or if non-
linear PK is observed, the target dose or dosing regimen of those subjects may be modified via a 
protocol amendment, depending on the PK of the previous subjects.  PK data collected in older age 
cohort (2 to less than 4 years) will also be examined in the interim PK analyses.  (revised per 
Amendment 02) 
• 
Follow-Up Period (4 weeks):  Subjects will not receive study drug during this period.   
Subjects Not Receiving Concomitant EIAEDs (ie, non-EIAED Subjects) (revised per 
Amendment 02) 
For all non-EIAED subjects (up to 6 mg/day): 
Treatment Phase/Titration Period 
Visit 
Daily Dose 
Week 0 (starting dose) 
Visit 2 
0.50 mg 
Week 1 (Titration #1) 
- 
1 mg 
Week 2 (Titration #2) 
Visit 3 
2 mg 
Week 3 (Titration #3) 
- 
4 mga 
Week 4 (Titration #4) 
Visit 4 
6 mgb 
For non-EIAED subjects who may require further up-titrations of perampanel dosesc: 
Week 6 (Titration #5) 
- 
8 mgd 
Week 8 (Titration #6) 
Visit 5 
10 mg 
Week 10 (Titration #7) 
- 
12 mg 
Week 12 (no titration) 
Visit 6 
Last dose achieved at Week 10d 
Treatment Phase/Maintenance 
Period 
Last dose achieved in the Titration Period 
a. 
Subjects who have shown good clinical response and tolerability at perampanel daily dosing of up to 
4 mg will continue to receive the same dose throughout the remaining of Titration Period.  (revised 
per Amendment 02)  
b. Up-titration to 6 mg/day in non-EIAED subjects will be allowed if a higher dose (6 mg/day) is 
deemed by the investigator to provide a better clinical benefit and provided that the subject tolerates 
perampanel well.  Subjects who have shown good clinical response and tolerability at perampanel 
6 mg/day will continue to receive the same dose throughout the remaining of the Titration Period.  
(revised per Amendment 02) 
c. 
At the discretion of the investigator; only if medically necessary (eg, inadequate seizure control) and 
provided that the subject has shown good tolerability at 6 mg/day.  (revised per Amendment 02)  
d. Site to contact the parent/guardian during the scheduled telephone interview approximately midpoint 
between Visit 4 and Visit 5 to assess if further dose titration (to 8 mg/day) is medically necessary.  
The subject must return to the clinic for an unscheduled visit for any dose increase.  (revised per 
Amendment 02)  
e. 
Visit is considered the end of the Titration Period and start of the Maintenance Period.   
Subjects Receiving Concomitant EIAEDs (ie, EIAED Subjects) (revised per Amendment 02) 


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Treatment Phase/Titration Period 
Visit 
Daily Dose 
For all EIAED subjects (up to 8 mg/day) 
Week 0 (starting dose) 
Visit 2 
0.50 mg 
Week 1 (Titration #1) 
- 
1 mg 
Week 2 (Titration #2) 
Visit 3 
2 mg 
Week 3 (Titration #3) 
- 
4 mg 
Week 4 (Titration #4) 
Visit 4 
6 mg 
Week 6 (Titration #5) 
- 
8 mga 
For EIAED subjects who may require further titrations of perampanel:b 
Week 8 (Titration #6) 
Visit 5 
10 mg 
Week 10 (Titration #7) 
- 
12 mg 
Week 12 (Titration #8) 
Visit 6 
14 mg 
Week 14 (Titration #9) 
- 
16 mg 
Week 16 (no titration) 
Visit 7 
Last dose achieved at Week 14c 
Treatment Phase/Maintenance 
Period 
Last dose achieved in the Titration Period 
a. 
Subjects who have shown good clinical response and tolerability at perampanel daily dosing of up to 
8 mg will continue to receive the same dose throughout the remaining of Titration Period. (revised per 
Amendment 02)  
b. At the discretion of the investigator; only if medically necessary (eg, inadequate seizure control) and 
provided that the subject has shown good tolerability at 8 mg/day.  (revised per Amendment 02) 
c. 
Visit is considered the end of the Titration Period and start of the Maintenance Period.    
Extension Phase 
• 
Maintenance Period (32-36 weeks):  Subjects will continue taking perampanel oral suspension, at the 
dose level achieved at the end of the Treatment Phase.  The maximum total daily dose a subject will 
be allowed is 12 mg (non-EIAED subjects) or 16 mg (EIAED subjects) . 
Dose adjustment during this phase is allowed if necessary, per the investigator’s clinical judgment.  
Subjects must return to the clinic for an unscheduled visit for any dose increase.  However, dose 
decreases can be done via telephone. 
All dose adjustments during this phase will be done by going one dose level up or down.  Subjects 
who do not tolerate a dose of 0.50 mg/day will be discontinued from the study. 
• 
Follow-Up Period (4 weeks):  Subjects will not receive study drug during this period.   
Comparator Drug (if applicable) 
Not applicable. 


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Duration of Treatment 
The maximum total duration of treatment for each subject will be 52 weeks and the maximum total duration 
of the study for each subject will be 58 weeks (52 weeks treatment + 2 weeks Pretreatment+ 4 week 
Follow-up). 
• Pretreatment Phase (Core Study):  up to 2 weeks 
• Treatment Phase (Core Study):  16 to 20 weeks (12-16-week Titration + 4-week Maintenance) + 4-week 
Follow-Up for those not entering the Extension Phase, those who discontinue early from the study, or 
those who do not switch to commercially available perampanel or enter into EAP after study completion  
(revised per Amendment 02) 
• Extension Phase:  36 to 40 weeks (32-36-week Maintenance + 4-week Follow-up) 
Concomitant Drug/Therapy 
Subjects will be taking 1 to a maximum of 4 marketed AEDs (see inclusion criteria 6 and 7 and exclusion 
criteria 6 through 8 for further details).  Changes of baseline AEDs (addition, deletion, or adjustment in dose) 
will not be allowed during 5 half-lives or during the 2 weeks, whichever is longer, before Visit 1.  During the 
Core study, dose adjustments will be allowed only for non-EIAEDs.  Dose adjustments of EIAEDs and 
addition/deletion of any concomitant AEDs are not allowed during the Core study.  Use of cannabidiol (CBD) 
products is allowed and is counted as 1 of the 4 maximum allowed concomitant AEDs.  CBD dose and product 
must have remained stable for at least 2 weeks before Visit 1 and is to remain the same throughout the course 
of the Core Study.  (revised per Amendment 02) 
The following medications will not be permitted (revised per Amendment 02): 
• Medications known to be inducers of cytochrome P450 3A (CYP3A) (other than CBZ, OXC, PHT, or 
ESL) including, but not limited to:  rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, 
barbiturates (except for use as an AED), glucocorticoids (other than topical usage), modafinil, 
pioglitazone, and rifabutin within 2 weeks or 5 half-lives, whichever is longer, before Visit 1 and 
throughout the course of the study [Core and Extension]) 
• Felbamate (within 8 weeks before Visit 1 and throughout the course of the study [Core and Extension]) 
• Vigabatrin(within 2 weeks before Visit 1 and throughout the course of the study [Core and Extension]) 
In case of an emergency, subjects may receive other AEDs, including diazepam as well as other appropriate 
AEDs as rescue medications, to treat status epilepticus, uncontrolled seizures, or seizure clusters. 
For any drug known to influence the CNS (other than AEDs for epilepsy), the dose should be kept stable for 
2 weeks or 5 half-lives, whichever is longer, before Visit 1 and throughout the course of the study (Core and 
Extension).  (revised per Amendment 02) 
Subjects are not permitted to participate in another study involving administration of an investigational drug 
or device for the full duration of this study (ie, up to and including the Follow-up Visit). 
Assessments 
Efficacy Assessments 
Efficacy will be assessed by seizure counts and types as recorded on a study specific seizure diary, and by 
CGI-C. 
Pharmacokinetic Assessments (Core Study only) 
Blood samples (1.0 mL) for plasma will be collected from all subjects at prespecified visits for the 
determination of perampanel plasma concentrations.  On the day of PK sampling, subjects will attend the clinic 
any time during the day to provide blood sampling for PK analysis and to enable close monitoring of the 
subjects for safety and tolerability.  The resulting plasma sample will be aliquoted into 2 Microtainer® tubes.   
For subjects aged 1 to less than 24 months, dosing should occur once daily before bedtime in the evening.  The 
dosing date and time of the last 3 doses before each PK visit will be recorded.  (revised per Amendment 02) 
For subjects aged 2 to less than 4 years, dosing should occur once daily before bedtime in the evening, including 


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the evening before the PK visit during Titration Period (Visit 5 for non-EIAED subjects, or Visit 6 for EIAED 
subjects).  The dosing date and time of the last 3 doses before Titration Period PK visit will be recorded.  Note:  
For PK visits during Maintenance Period (ie, Visits 7 and 8 for non-EIAED subjects, or Visits 8 and 9 for 
EIAED subjects), as 2 PK samples (1 predose and 1 early postdose [within 1 to 5 hours after dosing]) are to be 
collected, the following steps are to be followed (revised per Amendment 02): 
• 
Study drug administration in the evening immediately before the PK visits during Maintenance Period 
will be withheld.  All other AEDs should be administered per the subject’s usual AED regimen.   
• 
During each of the Maintenance Period PK visits, collect predose PK sample.  Then administer study 
drug on site, followed by early postdose PK sample collection (within 1 to 5 hours after dose 
administration). 
• 
Bedtime dosing will resume beginning in the evening of the Maintenance Period PK visits. 
• 
The dosing date and time of the study drug dose administered on-site during each Maintenance Period 
PK visit, as well as the last 2 doses before will be recorded.  
Pharmacodynamic Assessments 
Not applicable.  
Pharmacogenomic/Pharmacogenetic Assessments 
Not applicable.  
Safety Assessments 
Safety will be assessed by monitoring and recording of all AEs and SAEs, clinical labs (ie, hematology and 
blood chemistry), vital signs, ECGs, medical history, and physical and neurological examinations.  In addition, 
growth will be assessed for this age population by measurement of height, weight, head circumference, thyroid 
function and insulin-like growth factor-1 (IGF-1) testing. 
Other Assessments 
Not applicable 
Bioanalytical Methods 
Plasma concentrations of perampanel will be quantified using a validated liquid chromatography mass 
spectrometry (LC-MS/MS) analytical method. 
Statistical Methods  
Study Endpoints 
Primary Endpoint 
• 
PK of perampanel during the Maintenance Period of the Core Study  (revised per Amendment 02)  
Secondary Endpoints 
• 
Safety and tolerability during the Core Study and the Extension Phase, which include incidence of 
treatment-emergent adverse events (TEAEs) and SAEs, laboratory parameters, vital signs, and ECG 
parameters, and growth parameters height, weight, head circumference, thyroid function,and IGF-1 
levels)  (revised per Amendment 02)    
Exploratory Endpoints 
The efficacy endpoints are:  
• 
Seizure frequency:  Percent change in 28-day seizure frequency during the Treatment Phaseand during 
the Extension Phase, compared to baseline  (revised per Amendment 02) 
• 
Responder rate:  Proportion of subjects with a 50% or greater reduction in 28-day seizure frequency 
during the Maintenance Period and during the Extension Phase, compared to baseline  (revised per 
Amendment 02) 
• 
Seizure-free rate:  Proportion of subjects who are seizure-free during the Maintenance Period and 


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during the Extension Phase 
• 
CGI-C at the end of the Core Study and the Extension Phase 
Analyses 
Analysis Sets 
The Pharmacokinetic Analysis Set is the group of subjects with at least 1 PK assessment of perampanel during 
the Maintenance Period and who have a documented dosing history. 
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 study drug and had any seizure frequency 
data during the 2 weeks of Pretreatment Phase plus 4 weeks before Pretreatment Phase and during the 
Treatment Phase.   
Efficacy Analyses 
Exploration of efficacy will be performed on the FAS.  Summary statistics will be displayed for all efficacy 
parameters. 
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/ Pharmacogenetic Analyses 
Pharmacokinetic Analyses 
Determination of PK will be performed on the PK Analysis Set.  Perampanel plasma concentrations will be 
listed. 
A population PK approach will be used to characterize the PK of perampanel.  The effect of intrinsic and 
extrinsic factors (age, body weight, gender, race, ALT, AST, creatinine clearance and concomitant therapy 
with carbamazepine, oxcarbazepine, phenytoin, phenobarbital, valproic acid, lamotrigine, topiramate, 
primidone, zonisamide, levetiracetam and primidone) on perampanel PK will be evaluated.  A 2-compartment 
disposition PK model with linear elimination will be parameterized for absorption rate, oral clearance, and 
apparent central and peripheral volumes of distribution.  Derived exposure parameters such as the steady state 
peak concentration (Cmax,ss), area under concentration vs time curve at steady state (AUCss), and average 
steady-state drug concentration (Css,av) will be calculated using the individual posterior estimates of PK 
parameters from the final PK model.  Descriptive statistics of the individual model-predicted PK parameters 
(including but not limited to Cmax,ss) will be provided.   
Due to the small sample size, population PK analysis will be performed using NONMEM with first-order 
conditional estimation with interaction on data from this study pooled with existing rich data from 19 Phase 1 
studies and spare data from 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 fitted 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 AUC from the final PK mode will be derived for all subjects. 
Subsequently, dose-normalized derived exposure parameters will be summarized descriptively by age group 
(≤6 months, > 6 to ≤ 12 months, >12 to < 24 months, ≥24 months to ≤4 years, >4 to ≤ 8 years, >8 to <12 years, 
≥12 to <18 years and ≥18 years) and also presented in box-plots, stratified by subjects taking and not taking 
EIAEDs.  Additionally, dose-normalized derived exposure parameters will be summarized descriptively for 
the following age groups:  1 to 24 months, 2 to ≤ 4 years, >4 to ≤ 8 years, >8 to <12 years, ≥12 to <18 years 
and ≥18 years), and also presented in box-plots, stratified by subjects with EIAED and non-EIAEDs.  (revised 
per Amendment 02) 
The final PK model will be qualified using visual predictive checks and validated using bootstrap analysis. 
Pharmacodynamic and Pharmacogenomic/ Pharmacogenetic Analyses  
Not applicable. 


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Safety Analyses 
Evaluation of safety will be performed on the Safety Analysis Set.  Assessments that will be evaluated include 
AEs, SAEs, clinical laboratory results, vital signs, and 12-lead ECGs.  Treatment-emergent AEs will be 
summarized by presenting the incidence of TEAEs and the overall incidence by age group and EIAED and 
non-EIAED groups.  The incidence of out-of-normal-range laboratory safety tests variables will be 
summarized along with change from baseline in laboratory safety test variables and vital sign measurements.  
Descriptive summary statistics of the laboratory, vital signs, and ECG parameters will also be evaluated.   
Descriptive summary statistics of changes from baseline in growth (ie, height/length, head circumference, 
weight) will be evaluated.  These data may also be compared with normative scores to assess clinical relevance. 
Changes from baseline for thyroid function and IGF-1 testing will be summarized. 
Other Analyses 
Not applicable. 
Interim Analyses 
An interim analysis  (safety, tolerability, and PK) will be performed as follows:  
• 
After every 4th subject in the age group 1 to less than 24 months completes the Maintenance Period 
where dose-normalized exposure will be compared to that observed in other studies in subjects 
between ≥2 and <18 years of age for evidence of systematic deviations potentially warranting dose 
adjustment in this age group or for other subjects enrolled in the study.  PK data collected in older age 
cohort (2 to less than 4 years) will also be examined in the interim PK analyses.  (revised per 
Amendment 02) 
• 
All data from the Pretreatment and Treatment Phases will be analyzed when all subjects have 
completed the Maintenance Period.  In addition, a final analysis of data from the Pretreatment, 
Treatment, and Extension Phases will be analyzed when all subjects have completed the Extension 
Phase.  (revised per Amendment 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. 
Sample Size Rationale 
Similar to Study 232, Study 238 will use population PK modeling to characterize PK in pediatric subjects 1 to 
less than 24 months and 2 to less than 4 years of age, and compare these data to PK in adolescent and adult 
subjects.  In a prior study (Study 232), data were obtained in 42 subjects ≥ 2 to <12 years of age, with 
approximate equal numbers enrolled in the age ranges of ≥2 to ≤6 and ≥7 to <12 years.  (revised per 
Amendment 02) 
Given the narrower age range planned for Study 238 compared with Study 232, and the fact that the PK data 
from this study will be pooled with the data from subjects in ≥2 to <12 years of age, it is proposed that PK data 
obtained in at least 16 subjects ≥ 1 to <24 months of age would be adequate to characterize the PK in this age 
group.  The sample size will be increased to at least 24 subjects if dose-normalized (to 8 mg) exposure in the 
Maintenance Period from the first 16 subjects in this study is not comparable to existing data in subjects aged 
≥2 to 18 years.  (revised per Amendment 02) 
In order to compare the PK of pediatric subjects aged 2 to less than 4 years of age with the PK of pediatric 
subjects aged >4 years of age, a total of 26 subjects with 13 EIAED and 13 non-EIAED subjects will be enrolled 
and pooled across clinical studies of perampanel with PK assessment. This estimate of the required sample 
size assumes the inter-subject variability of 46.8% (CPMS-E2007-015-v1), equivalent to a coefficient of 
variation (CV) on the log scale of 0.445, that provides a sufficient number of subjects to target a 95% 
confidence interval within 60% and 140% of the point estimate for the geometric mean clearance of 


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perampanel (equal to 0.638 L/h; determined using population PK modeling) with at least 80% power.  (revised 
per Amendment 02) 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................15 
LIST OF IN-TEXT TABLES ...........................................................................................18 
LIST OF IN-TEXT FIGURES .........................................................................................18 
LIST OF APPENDICES..................................................................................................18 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................19 
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 ...........................................................................................................25 
7.1 
Study Rationale ......................................................................................................25 
7.2 
Dosing Rationale ....................................................................................................27 
8 
STUDY OBJECTIVES ....................................................................................................30 
8.1 
Primary Objectives .................................................................................................30 
8.2 
Secondary Objective(s) ..........................................................................................30 
8.3 
Exploratory Objective(s) ........................................................................................30 
9 
INVESTIGATIONAL PLAN ..........................................................................................31 
9.1 
Overall Study Design and Plan ..............................................................................31 
9.1.1 
Pretreatment Phase .......................................................................................33 
9.1.2 
Treatment Phase ...........................................................................................33 
9.1.2.1 
Titration Period ..................................................................................34 
9.1.2.2 
Maintenance Period ...........................................................................34 
9.1.2.3 
Follow-Up Period ...............................................................................34 
9.1.3 
Extension Phase ...........................................................................................34 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................35 
9.3 
Selection of Study Population ................................................................................36 
9.3.1 
Inclusion Criteria .........................................................................................36 
9.3.2 
Exclusion Criteria ........................................................................................37 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................38 
9.4 
Treatment(s) ...........................................................................................................38 
9.4.1 
Treatment(s) Administered ..........................................................................38 
9.4.2 
Identity of Investigational Product ...............................................................42 
9.4.2.1 
Chemical Name, Structural Formula of E2007 ..................................43 


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9.4.2.2 
Comparator Drug ...............................................................................43 
9.4.2.3 
Labeling for Study Drug ....................................................................43 
9.4.2.4 
Storage Conditions .............................................................................43 
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 ..........................................45 
9.4.6 
Blinding........................................................................................................45 
9.4.7 
Prior and Concomitant Therapy ...................................................................45 
9.4.7.1 
Drug-Drug Interactions ......................................................................46 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs ...................................46 
9.4.8 
Treatment Compliance .................................................................................46 
9.4.9 
Drug Supplies and Accountability ...............................................................46 
9.5 
Study Assessments .................................................................................................48 
9.5.1 
Assessments .................................................................................................48 
9.5.1.1 
Demography .......................................................................................48 
9.5.1.2 
Baseline Assessments ........................................................................48 
9.5.1.3 
Efficacy Assessments .........................................................................49 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ...........................................................49 
9.5.1.5 
Safety Assessments ............................................................................51 
9.5.2 
Schedule of Procedures/Assessments ..........................................................56 
9.5.2.1 
Description of Procedures/Assessments Schedule .............................63 
9.5.3 
Appropriateness of Measurements ...............................................................63 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................63 
9.5.4.1 
Reporting of Serious Adverse Events ................................................63 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................64 
9.5.4.3 
Reporting of Events Associated with Special Situations ...................64 
9.5.4.4 
Expedited Reporting ..........................................................................65 
9.5.4.5 
Breaking the Blind .............................................................................65 
9.5.4.6 
Regulatory Reporting of Adverse Events ..........................................65 
9.5.5 
Completion/Discontinuation of Subjects .....................................................65 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................66 
9.5.7 
Confirmation of Medical Care by Another Physician .................................66 
9.6 
Data Quality Assurance .........................................................................................66 
9.6.1 
Data Collection ............................................................................................66 
9.6.2 
Clinical Data Management ..........................................................................66 
9.7 
Statistical Methods .................................................................................................67 
9.7.1 
Statistical and Analytical Plans ....................................................................67 


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9.7.1.1 
Study Endpoints .................................................................................67 
9.7.1.2 
Definitions of Analysis Sets ...............................................................67 
9.7.1.3 
Subject Disposition ............................................................................68 
9.7.1.4 
Demographic and Other Baseline Characteristics .............................68 
9.7.1.5 
Prior and Concomitant Therapy .........................................................68 
9.7.1.6 
Efficacy Analysis ...............................................................................68 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses .................................................................69 
9.7.1.8 
Safety Analyses ..................................................................................70 
9.7.2 
Determination of Sample Size .....................................................................72 
9.7.3 
Interim Analysis ...........................................................................................73 
9.7.4 
Other Statistical/Analytical Issues ...............................................................73 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................73 
10 REFERENCE LIST .........................................................................................................74 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......75 
11.1 
Changes to the Protocol .........................................................................................75 
11.2 
Adherence to the Protocol ......................................................................................75 
11.3 
Monitoring Procedures...........................................................................................75 
11.4 
Recording of Data ..................................................................................................76 
11.5 
Identification of Source Data .................................................................................76 
11.6 
Retention of Records ..............................................................................................76 
11.7 
Auditing Procedures and Inspection ......................................................................77 
11.8 
Handling of Study Drug .........................................................................................77 
11.9 
Publication of Results ............................................................................................77 
11.10 Disclosure and Confidentiality ..............................................................................78 
11.11 Discontinuation of Study .......................................................................................78 
11.12 Subject Insurance and Indemnity ...........................................................................78 
12 APPENDICES .................................................................................................................79 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Non-EIAED Subjects:  Dose Adjustments during the Titration and 
Maintenance Periods  (revised per Amendment 02) ....................................................40 
Table 2 
EIAED Subjects:  Dose Adjustments during the Titration and 
Maintenance Periods  (revised per Amendment 02) ....................................................41 
Table 3 
Clinical Laboratory Tests .............................................................................54 
Table 4 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core 
Study – Non-EIAED Subjects .....................................................................................57 
Table 5 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core 
Study - EIAED Subjects ..............................................................................................60 
Table 6 
Schedule of Procedures/Assessments in Study E2007-G000-238:  
Extension Phase – Non-EIAED Subjects ....................................................................84 
Table 7 
Schedule of Procedures/Assessments in Study E2007-G000-238:  
Extension Phase - EIAED Subjects .............................................................................86 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design for Study E2007-G000-238 ...................................................33 
 
LIST OF APPENDICES 
Appendix 1 
Sponsor’s Grading for Laboratory Values .........................................79 
Appendix 2 
Total Blood Volumes  (revised per Amendment 02) .........................81 
Appendix 3 
Extension Phase .................................................................................82 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event  
AED 
anti-epileptic drug 
ALT 
alanine aminotransferase  
AMPA 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
AST 
aspartate aminotransferase  
ATC 
Anatomical Therapeutic Chemical  
AUC0–72 
area under the curve baseline to 72 hours 
AUClast 
area under the plasma concentration-time profile from time zero to the time 
of the last quantifiable concentration 
AUCss 
area under the curve at steady state 
BP 
blood pressure  
CA 
Competent Authority  
CBZ 
carbamazepine  
CFR 
Code of Federal Regulations  
CGI 
Clinical Global Impression 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CHMP 
Committee for Medicinal Products for Human Use  
CL/F 
apparent clearance  
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum observed concenration 
Cmax,ss 
Msximum observed concentration at steady state 
CNS 
central nervous system 
CPMP 
Committee for Proprietary Medicinal Products 
CRA 
Clinical Research Associate 
CRF 
case report form  
CRO 
contract research organization 
Css,av 
average steady-state drug concentration  
CT 
computed tomography  
CTCAE 
Based on Common Terminology Criteria for Adverse Events 
CV 
curriculum vitae  
CYP 
cytochrome P450 
CYP3A 
cytochrome P450 3A 
DBS 
dried blood spot 
DEA 
Drug Enforcement Administration 


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Abbreviation 
Term 
DMC 
independent Data Monitoring Committee  
ECG 
electrocardiogram 
EEG 
electroencephalogram  
EMA 
European Medicines Agency 
ESL 
eslicarbazepine  
EU 
European Union 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration  
fT3 
free triiodothyronine 
fT4 
free thyroxine 
GCP 
Good Clinical Practice  
GGT 
γ-glutamyl transpeptidase 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee  
IGF-1 
insulin-like growth factor-1  
ILAE 
International League Against Epilepsy 
IND 
Investigational New Drug  
IRB 
Institutional Review Board  
LC-MS/MS 
liquid chromatography mass spectrometry  
LLT 
lower level term  
LNH 
low/normal/high 
MedDRA 
Medical Dictionary for Regulatory Activities  
MHRA 
Medicines and Healthcare Products Regulatory Agency  
MRI 
magnetic resonance imaging  
MTD 
maximum tolerated dose 
NA 
North America   
OXC 
oxcarbazepine 
PD 
pharmacodynamics 
PDCO 
Paediatric Committee 
PET 
polyethylene terephthalate  
PGTCS 
primary generalized tonic-clonic seizures 
PHT 
phenytoin  
PI 
principal investigator  
PiBA 
press in bottle adaptors  
PIP 
Paediatric Investigation Plan 
PK 
pharmacokinetics 


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Abbreviation 
Term 
POS 
partial-onset seizures  
PT 
preferred term  
QD 
once daily 
QTc 
time from the beginning of the QRS complex to the end of the T wave, 
corrected for heart rate 
QTcF 
QT interval data corrected using Fridericia's formula (QT/RR1/3) 
RBC 
red blood cell 
SAE 
serious adverse event  
SAP 
statistical analysis plan  
SD 
standard deviation 
SI 
Système International  
SOC 
system organ class  
SUSAR 
suspected unexpected serious adverse reaction 
tmax 
time to reach maximum concentrations following drug administration  
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
UDP 
uridine-5'-diphosphate 
ULN 
upper limits of normal  
US 
United States 
V/F 
apparent volume of distribution  
WBC 
white blood cell 
WHO 
World Health Organization 
WHO DD 
World Health Organization Drug Dictionary  


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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 ICH E6 (Good Clinical 
Practice [GCP]), Section 3, and the European Good Clinical Practice Directive 2005/28/EC 
and Clinical Trial Directive 2001/20/EC, and the United States (US) Code of Federal 
Regulations (CRF), Title 21 CFR Part 56.  Any protocol amendment or revision to the ICF will 
be resubmitted to the IRB/IEC for review and approval, except for changes involving only 
logistical or administrative aspects of the study (eg, change in Clinical Research Associate 
[CRA(s)], change of telephone number[s]).  Documentation of IRB/IEC compliance with the 
ICH E6 and any local regulations regarding constitution and review conduct will be provided 
to the sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (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 (CA) 
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 CA 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 of the sponsor 
(or designee), which are designed to ensure adherence to GCP guidelines as required by the 
following: 


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• Principles of the World Medical Association Declaration of Helsinki (2013) 
• ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products (CPMP), 
International Conference on Harmonisation of Pharmaceuticals for Human Use 
• 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 Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any European Union (EU) country.  All 
Suspected Unexpected Serious Adverse Reactions (SUSAR[s]) will be reported, as 
required, to the Competent Authorities of all involved EU member states.  
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 
parent/guardian 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 guardian/legally authorized representative) should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject (or guardian/legally authorized 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 guardian/legally authorized representative), and after the subject (or 
guardian/legally authorized representative) has verbally 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 (or guardian/legally 
authorized representative) 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. 
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 parent/guardian/legally authorized 
representative 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.   
The subject (or guardian/legally authorized representative) should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness 


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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 15 investigational sites in North America (NA) and the EU. 
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) are listed in the Regulatory 
Binder provided to each site. 
 
 


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7 
INTRODUCTION 
Perampanel (E2007) is an orally active, noncompetitive, and highly selective α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist 
with potential for therapeutic use in patients with various neurological diseases.  Perampanel 
is approved in the US for the treatment (including monotherapy) of partial-onset seizures 
(POS) with or without secondarily generalized seizures in patients with epilepsy aged 4 years 
and older, and as adjunctive therapy of primary generalized tonic-clonic seizures (PGTCS) in 
patients with epilepsy aged 12 years and older.  Perampanel is also approved in the EU as an 
adjunctive treatment of POS and PGTCS in patients with epilepsy aged 12 years and older.  
This study aims to provide pharmacokinetics (PK) and safety data of perampanel in pediatric 
subjects from age ≥1 to <24 months and from age 2 to less than 4 years.  (revised per 
Amendment 02) 
Epilepsy is a common neurological problem in (Hauser, 1992; Hauser, 1994, Bourgeois, 1995).  
Generalized seizures predominate in the first years of life, but by age 5 years, POS are also 
common (Hauser, 1992).  Despite recent advances in drug treatment, one of every 4 patients 
with epilepsy does not achieve long-term seizure freedom (Northam, 2005) and suffers from 
intractable seizures, while many others experience significant treatment-related side effects 
(Fountain, 2007).  Selection of an anti-epileptic drug (AED) for the treatment of pediatric 
patients with epilepsy has been particularly difficult because of the lack of clinical studies in 
this population especially in younger pediatrics (age <4 years) (Piña-Garza, 2005; Ouellet, 
2001).  (revised per Amendment 02) 
Given the inherent challenges in performing clinical studies in children, extrapolation of 
efficacy from adult to pediatric subjects (24 months and above) with partial onset seizures has 
been accepted as an alternative to randomized, double-blind, placebo-controlled Phase 3 
studies in children, as reflected in the September 2019 FDA Guidance “Drugs for Treatment 
of Partial Onset Seizures:  Full Extrapolation of Efficacy from Adults to Pediatric subjects 
24 months of Age and Older”.  To support extrapolation, adequately designed PK and 
tolerability study(ies) with sufficient sample size are required to demonstrate similar exposure 
(blood/plasma levels of active drugs and, as applicable, metabolites) and to evaluate safety 
profile following drug administration in pediatric subjects aged 24 months and above.  This 
efficacy extrapolation approach, however, does not apply to subjects under 24 months of age.  
For this population, well-designed clinical trials are required to determine efficacy, safety and 
tolerability, PK, and appropriate dosages (Northam, 2005).  (revised per Amendment 02) 
7.1 
Study Rationale 
European Union legislation on pediatric medicines came into effect in Jan 2007.  This 
legislation defines the obligations for the conduct of clinical trials in pediatric populations to 
address problems of inadequate dosage information, non-availability of therapeutic advances, 
dose formulations, and routes of administration in pediatric populations. The legislation is 
expected to stimulate research and result in increased numbers of pediatric clinical trials 


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overseen by the new Paediatric Committee (PDCO) within the European Medicines Agency 
(EMA).   
The main directive of the PDCO is to assess the content of Paediatric Investigation Plans (PIPs) 
and adopt opinions on them in accordance with Regulation (EC) 1901/2006 as amended.  This 
includes the assessment of applications and assessing data generated in accordance with agreed 
PIPs and adopting opinions on the quality, safety or efficacy of any medicine for use in the 
pediatric population (at the request of the Committee for Medicinal Products for Human Use 
(CHMP) or a CA).  The original PIP for perampanel was approved by PDCO on 19 Mar 2010.  
Study E2007-G000-238 is part of the approved PIP to which Eisai is committed to perform as 
part of the pediatric program.   
Pediatric study requirements in the United States are legislated under the Pediatric Research 
Equity Act (PREA) (21 U.S.C. 355c), which requires that all applications for new active 
ingredients, new indications, new dosage forms, new dosing regimens or new routes of 
administration contain an assessment of the safety and effectiveness of the product for the 
claimed indication in pediatric patients unless the requirement is waived, deferred, or 
inapplicable.  As part of the approval for perampanel tablets in the US under NDA 202834 as 
adjunctive therapy for the treatment of partial-onset seizures with or without secondarily 
generalized seizures in patients with epilepsy aged 12 years and older, the FDA granted a 
deferral of pediatric studies of perampanel for ages 1 month to less than 12 years.  Study 
E2007-G000-238 is part of a series of deferred pediatric studies that are required postmarketing 
studies under section 505B(a) of the Federal Food, Drug and Cosmetic Act. 
Study E2007-G000-238 has been approved by PDCO; it is required by FDA and will be the 
first study to be conducted in the pediatric population of age ≥1 to <24 months with 
perampanel.  In this youngest age group, the study will evaluate the PK and will generate 
preliminary safety and efficacy of perampanel following the administration of an oral 
suspension.  Below is a summary of 2 studies of perampanel that have been initiated in the 
pediatric age group: 
• Study E2007-G000-235 (Study 235), was the first stand-alone pediatric study for 
perampanel, recruited an adolescent population similar to those examined in the Phase 
3 studies with the same dose range (ie, 2 to 12 mg/day).  The primary objective of this 
study was to evaluate the effect of perampanel on cognition.  In addition to cognition, 
growth and development will also be evaluated including sexual maturation. Although 
no such safety issues have been identified in relation to perampanel to date, Study 235 
has been designed according to the European CHMP guideline (CPMP/EWP/566/98 
Rev. 2) on the need for data “to detect the potential effect on learning, intelligence, 
growth, endocrine function, and puberty”.  The study has been completed.  The study 
met its primary objective and there was no statistically significant or clinically relevant 
overall cognitive impairment detected in the study with perampanel compared to 
placebo. 
• Study E2007-G000-232 (Study 232), in a pediatric population of ages ≥2 to <12 years 
has completed.  The primary objective of this study was to evaluate the 


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pharmacokinetics (PK) of perampanel following oral suspension administration given 
as an adjunctive therapy in pediatric subjects age ≥2 to <12 years with epilepsy.   
Perampanel oral suspension (0.5 mg/mL) will be used in Study 238.  This formulation was 
used in Study 232.  The bioequivalence between the oral suspension formulation and the tablet 
formulation was evaluated in Study E2007-A001-048 under fed and fasted conditions.  The 
results of the study in conjunction with steady state PK simulations of the data confirmed that 
the oral suspension formulation is bioequivalent to the tablet formulation, and can be used 
interchangeably with the tablet formulation.  From a safety point of view, both the oral 
suspension and tablet formulations were well-tolerated  
In support of pediatric development and minimizing the blood volume necessary to complete 
appropriate PK analyses, fully validated dried blood spot (DBS) sampling method was used 
for analysis of perampanel concentrations in Study 232.  However, sites in this study 
encountered sampling challenges with resultant loss of samples.  For this study, a small-volume 
plasma assay requiring only 1-mL blood volume per time point will be used.  (revised per 
Amendment 02) 
Eslicarbazepine (ESL) is structurally and functionally related to oxcarbazepine (OXC) 
(Rogawski, 2004) and was approved for use by the EMA in April 2009.  In vitro, ESL is a 
weak inducer of CYP3A4 and UDP-glucuronyl transferases.  In vivo, ESL showed an inducing 
effect on the metabolism of medicinal products that are mainly eliminated by metabolism 
through CYP3A4 (Zebinix® SmPC).  Therefore, ESL is being included in this study as an 
enzyme-inducing AED (ie, EIAED) to facilitate enrollment of subjects into this subgroup. 
7.2 
Dosing Rationale 
A key objective of AED dosing with perampanel in pediatrics is to identify appropriate doses 
such that plasma levels fall within a concentration range associated with the therapeutic effect 
and acceptable safety previously demonstrated in adults.  Stabilizing plasma drug levels can 
be more difficult in infants and toddlers than in adolescents or adults because of variability in 
absorption and drug metabolism (Ramsey, 2007).  For example, compared to adolescents and 
adults, during the first year of life infants have reduced hepatic metabolism that by the end of 
their first year progresses to substantially greater hepatic metabolism, which can have 
important implications for dosing (Pellock, 1998). 
Perampanel is almost completely absorbed from the gastrointestinal tract and is mostly 
eliminated in the feces (about 70%) following metabolism primarily via the cytochrome (CYP) 
P450 3A4 pathway in the liver.  The possibility exists that the PK profile of perampanel may 
differ between infants and toddlers compared with, adolescents and adults, thus requiring 
age-specific dosage regimens.  Study 238 is designed to evaluate the optimal maintenance dose 
and the dosing regimens to achieve plasma concentrations in infants and toddlers aged 1 month 
to less than 4 years comparable to those in adolescents and adults. 
The clinical development plan for perampanel included Phase 3 studies (Studies E2007 G000-
304, -305 and -306); in addition to enrollment of adults, these studies included adolescent 


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subjects ≥12 to <18 years of age.  Treatment with perampanel for doses ranging from 4 to 
12 mg/day in these Phase 3 studies was significantly more effective than adjunctive treatment 
with placebo in improving seizure control in subjects ≥12 years of age with refractory POS.  
The studies also demonstrated a positive safety and tolerability profile in this population.   
A population PK analysis was completed on data from 74 adolescent (≥12 to <18 years of age) 
subjects only and from 770 adolescent and adult subjects combined from Studies 304, 305 and 
306.  Perampanel clearance increased in the presence of co-administered carbamazepine 
(CBZ), OXC, and phenytoin (PHT) by approximately 3-fold, 2-fold, and 2-fold respectively.  
Perampanel clearance was not affected by baseline seizure frequency, the time during the 
study, dose administered, race, age, renal or liver conditions (estimated from creatinine 
clearance or liver function tests respectively) and concomitant AEDs lamotrigine, 
levetiracetam, topiramate, valproic acid, zonisamide, primidone, clobazam, and phenobarbital.  
A small effect of gender and body mass was found but these were not considered clinically 
important.  Findings from a recent population PK analysis on data from 78 adolescents from 
Study 235 pooled with the data from the 74 adolescents from Studies 304, 305, and 306, were 
in full agreement with those from the previous analysis. 
A corresponding population PK/pharmacodynamic (PD) analysis for the relationship between 
exposure and seizure frequency was also completed on data from 105 adolescent subjects only 
and 1109 adolescent and adult subjects combined from Studies 304, 305, and 306.  On the 
natural logarithm scale, a significant decrease in seizure frequency of 0.000569 for an increase 
of 1 ng/mL in perampanel concentration was found.  There were no differences in response to 
perampanel resulting from gender, race, age, and co-administration of any AEDs.  An 
additional population PK/PD responder analysis on data from the same 105 adolescent subjects 
only and from 1109 adolescent and adult subjects combined showed that the proportion of 
responders increases with the concentration of perampanel.  Again, findings from a recent 
population PK/PD analysis on data from 110 adolescents from Study 235 pooled with the data 
from the 105 adolescents from Studies 304, 305, and 306 were in full agreement with those 
from the previous analysis. 
Overall, perampanel PK was shown to be similar in adolescents and adults, was not affected 
in clinically important ways by body weight, age, gender, race, body mass (across the range of 
adolescents and adults), and not affected by co-administration of AEDs other than inducing 
CYP3A concomitant CBZ, OXC, and PHT.   
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 ≥2 to ≤6 years and 22 were aged ≥7 to <12 years.  A total of 28 
subjects were not receiving any of the EIAEDs (CBX, OXC, or PHT) and 14 subjects were 
receiving one of these EIAEDs.  As noted above, 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.  Whole blood perampanel concentration values from Study 232 


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analyzed using the DBS technique were converted to plasma concentrations, and for 
comparison purposes both plasma perampanel concentrations.  The results of the analysis 
demonstrated that perampanel PK was linear as there was no dose or time-dependency to 
apparent 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 clearance) 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 (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) independent of weight, the lower steady 
state concentration was deemed to be due to the lower total dose (mg/body) administered in 
these.  The results of the analysis suggested that flat dosing approach will be more appropriate 
in subjects within that age range.   
Considering the ontogenic profile of CYP3A enzyme in pediatrics, especially between 1 to less 
than 24 months old, and due to the unknown safety profile in this population, a lower starting 
dose of 0.5 mg/day was selected, with titrations to a dose of 12 mg/day (non-EIAED subjects) 
or 16 mg (EIAED subjects). To date, sparse PK data is available from 3 pediatric subjects 
between age of 4.5 months to 20 months receiving perampanel as part of a Named Patient IND.  
These subjects were dosed with perampanel up to 8 mg/day at steady state. The plasma 
concentration data in the 3 individuals although close to upper end of the range, were still 
within the 2-fold relative to the exposures observed in 2 to <12 year old subjects. Based on 
these findings, the likelihood of starting dose of 0.5 mg achieving unexpectedly high plasma 
exposures in the proposed age population is considered to be low. Furthermore, noting the 
wide variability in hepatic metabolism via CYP3A in pediatric subjects less than 24 months of 
age, the risk of unexpected plasma exposures in number of pediatric subjects is further 
minimized by planned interim PK analysis in the first 4 subjects completing the PK portion of 
Study 238.  These data (dose-normalized to 8 mg) will be compared with data from and 
adolescents (≥2 to <18 years of age) from previous studies for evidence of systematic 
deviations potentially warranting dose adjustment in this age group.   
 
 


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8 
STUDY OBJECTIVES 
8.1 
Primary Objectives 
The primary objective of the study is to evaluate the PK of perampanel during the Maintenance 
Period of the Core Study following oral suspension administration given as an adjunctive 
therapy in pediatric subjects from 1 month to less than 4 years of age with epilepsy.  (revised 
per Amendment 02) 
8.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
• To evaluate the short- and long-term safety and tolerability of perampanel oral 
suspension, given as an adjunctive therapy, in subjects from 1 month to less than 4 years 
of age with epilepsy  (revised per Amendment 02) 
• To evaluate the long-term effect of perampanel oral suspension, given as an adjunctive 
therapy, on growth from baseline to end of treatment in pediatric subjects from 1 month 
to less than 4 years of age with epilepsy  (revised per Amendment 02) 
8.3 
Exploratory Objective(s) 
The exploratory study objective is to explore the short- and long-term efficacy of perampanel 
oral suspension, given as an adjunctive therapy, in subjects from 1 month to less than 4 years 
of age with epilepsy as assessed by:  (revised per Amendment 02) 
• Percent change in 28-day seizure frequency during the Titration + Maintenance Periods 
compared to baseline and during the Extension Phase compared to baseline 
• Proportion of subjects with a 50% decrease in 28-day seizure frequency during the 
Maintenance Period compared to baseline and during the Extension Phase compared to 
baseline 
• Proportion of subjects who are seizure-free during the Maintenance Period and during 
the Extension Phase 
• Clinical Global Impression (CGI)of change (CGI-C) 
 
 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This will be a multicenter, open-label study with an Extension Phase that will enroll 16 to 
24 pediatric subjects 1 to less than 24 months of age and at least to a maximum of 26 pediatric 
subjects from 2 to less than 4 years of age with epilepsy.  (revised per Amendment 02) 
All subjects must be taking 1 to a maximum of 4 AEDs to participate in the study.  For at least 
6 but not more than 8 of the subjects in the age group of 1 to less than 24 months and for 
13 subjects in the age group of 2 to less than 4 years (across studies), only 1 EIAED (ie, CBZ, 
OXC, PHT, or ESL) out of the maximum of 4 AEDs will be allowed.  These subjects will be 
referred to as EIAED subjects.  The remaining subjects cannot be taking any EIAEDs and will 
be referred to as non-EIAED subjects.  (revised per Amendment 02) 
For the age group of 1 to less than 24 months, the Sponsor will ensure a reasonable 
representation of subject age (ie, at least 6 subjects in the age range ≥1 to ≤6 months, at least 
5 subjects in the age range >6 to ≤12 months, and at least 5 subjects in the age range >12 to 
<24 months).  (revised per Amendment 02) 
For the age group of 2 to less than 4 years, the required number of subjects (total of 26) can be 
pooled across multiple studies for PK and safety assessments in pediatric subjects of 2 to less 
than 4 years of age. Therefore, the target number of subjects to be enrolled in this age group in 
this study ranges from a minimum of 1 to a maximum of 26 subjects.  Enrollment of subjects 
aged 2 to less than 4 years into this study may be stopped upon notification of sponsor when 
the total number has been reached across clinical studies, or when enrollment in the 1 to less 
than 24 months age group in this study has completed (ie, the original purpose of this study 
has been met).  (revised per Amendment 02) 
This study will consist of 3 phases:  Pretreatment and Treatment (Core Study), and Extension.  
The Pretreatment Phase will last up to 2 weeks, during which subjects will be assessed for their 
eligibility to participate in the study.  The Treatment Phase will consist of 3 periods:  Titration 
(12-16 weeks), Maintenance (4 weeks), and Follow-up (4 weeks; only for those subjects who 
complete the Maintenance Period but do not continue into the Extension Phase).  The 
Extension Phase will consist of 2 periods:  Maintenance (32-36 weeks) and Follow-up 
(4 weeks).  (revised per Amendment 02) 
The end of the study will be the date of the last study visit for the last subject. 
The maximum total duration of treatment for each subject will be 52 weeks and the maximum 
total duration of the study for each subject will be 58 weeks (2 weeks Pretreatment+52 weeks 
of treatment+4 week Follow-up).  (revised per Amendment 02) 
Subjects who complete the Extension Phase and who, in the opinion of the investigator, will 
likely continue to demonstrate a positive benefit-to-risk ratio from treatment with perampanel 
may be enrolled into an extended access program (EAP) for perampanel if EAP is implemented 
for this age group in the country where the subject resides.  (revised per Amendment 02) 


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An overview of the study design is presented in Figure 1. 


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Phase
Period
Pretreatment
Titration
Study Week
Week
 -2
Noninducers
Week 16/56
Inducers
Week 20/56
Week 
0
a:  Subjects to receive study treatment starting at Week 0 of the Treatment Phase through Week 52 of the Extension Phase.
b:  Follow-up Period Visit is to be completed at the end of the Treatment Phase for those subjects not rolling over to the Extension Phase of the study, for those subjects 
who early terminate from the study, and for all subjects completing the Extension Phase.
c:  Prior to entry into the Maintenance Period, subjects have been maintained on their last Titration Period dose for at least 2 weeks.
Maintenance
Follow-upb
Extensiona
Noninducersc
Week 16
Inducersc
Week 20
Treatmenta
Week 
52
perampanel
Core Study
perampanel
Noninducers
Week 12
Inducers
Week 16
perampanel
 
Figure 1 
Study Design for Study E2007-G000-238  
9.1.1 
Pretreatment Phase 
At the first visit of the Pretreatment Phase, 4 weeks of prescreening (ie, before Visit 1) seizure 
frequency data will be collected for each subject as part of their medical history.  Upon 
successful completion of the Pretreatment Phase, eligible subjects will enter the Treatment 
Phase.   
9.1.2 
Treatment Phase 
The Treatment Phase will consist of 3 periods:  Titration (12-16 weeks), Maintenance 
(4 weeks), and Follow-up (4 weeks; only for those subjects who complete the Maintenance 
Period but do not continue into the Extension Phase, or those who discontinue early from the 
study).  (revised per Amendment 02) 


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9.1.2.1 
Titration Period 
During the Titration Period, subjects will start perampanel treatment at a dose of 0.50 mg/day 
and follow dose titration schemes  (Table 1 and Table 2) up to 4 mg/day (non-EIAED subjects) 
or 8 mg/day (EIAED subjects).  Depending on individual subject’s clinical response and 
tolerability, non-EIAED subjects could still have the perampanel dose up-titrated to 6 mg/day.  
Perampanel dose should not be further up-titrated beyond 6 mg/day (non-EIAED subjects) or 
8 mg/day (EIAED subjects) unless there is a medical need (for example, a subject who 
tolerated perampanel well but have not reached optimal seizure control).  Before dose up-
titrations beyond 6 mg/day (non-EIAED subjects) or 8 mg/day (EIAED subjects) and 
whenever practically feasible, it is recommended to take a blood sample for the measurement 
of plasma perampanel level as a precautionary measure.  The date and time of the last 
perampanel dose administration, as well as the date and time of PK blood draw, for these 
unscheduled PK sample collection will be recorded.  Up-titrations of perampanel dose within 
the range of 0.5 to 6 mg/day will be at 1-week intervals; and at doses greater than 6 mg/day 
will be at 2-week intervals (see Study Treatment(s) section). Dose titrations must not exceed 
12 mg/day (non-EIAED subjects) or 16 mg/day (EIAED subjects); see Study Treatment(s) 
section).  The decision to up-titrate perampanel dose will be at the investigator’s discretion, 
based on individual subject’s clinical response and/or tolerability to achieve optimal dose for 
a given subject.  Once the optimal dose has been achieved, the subject’s dose will be 
maintained stable for the remaining Titration Period or at least 2 weeks before entering the 
Maintenance Period.  (revised per Amendment 02). 
9.1.2.2 
Maintenance Period 
During the Maintenance Period, subjects will continue taking perampanel oral suspension at 
the dose level they achieved at the end of the Titration Period.  
9.1.2.3 
Follow-Up Period 
Subjects who do not continue into the Extension Phase after completing the Maintenance 
Period, or those who discontinue early from the study will be required to complete the 
Follow-up Period after their last dose in the Treatment Phase.  During this period, subjects will 
not receive study drug.  Subjects who switch to commercially available perampanel or who 
enter into EAP upon completion of study treatment would not need to under Follow-up Visit; 
however, sites will conduct a telephone contact 28 (+6) days after the last dose of study drug 
to follow adverse events (AEs) and report any serious adverse events (SAEs) that occur within 
28 days of the last study drug administration.  (revised per Amendment 02) 
9.1.3 
Extension Phase 
Subjects who have completed the last visit of the Core Study Maintenance Period will be 
eligible to participate in the Extension Phase of this study.  For these subjects, upon completion 
of the last visit of the Maintenance Period they will be considered as participating in the 
Extension Phase.   


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See Appendix 3 for a full description of the Extension Phase.  
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This current study (E2007-G000-238) is part of the continuing development of perampanel in 
pediatric subjects. The purpose of the current study is to fulfill both the European and US 
regulatory requirements for the development of AEDs in pediatric age groups.   
The primary objective of the study is to assess PK in order to determine appropriate dosing 
regimens of perampanel in pediatric subjects younger than 24 months of age.  Accordingly, 
this study is designed as open-label, single-arm, uncontrolled study with no placebo or 
active-control treatment groups.  (revised per Amendment 02) 
Considering the ontogenic development of CYP3A (the enzyme responsible for perampanel 
metabolism) during the first 24 months of life, perampanel PK may be affected as the levels of 
CYP3A is changing.  To better characterize perampanel PK over the time course of CYP3A 
maturation, this study will seek to ensure adequate age representation among subjects (ie, at 
least 6 subjects are in the age range 1 to ≤6 months, at least 5 subjects are in the age range >6 
to ≤12 months, and at least 5 subjects are in the age range >12 to <24 months).  Additionally, 
due to the limited PK data collected for perampanel in the age group of 2 to <4 years, this study 
is amended to expand enrollment to include subjects aged 2 to less than 4 years.  (revised per 
Amendment 02) 
In this study, all subjects will be receiving perampanel as an adjunctive treatment.  As with 
dosing regimens studied in Phase 3 studies in adolescents and adults, gradual increase in dose 
(dose titrations) to reach therapeutic dose levels will be employed.  Clinical response and 
tolerability will be used as the criteria to make decision whether to escalate dose at each 
titration step and to define the optimal dose for individual subject.  The dose titration scheme 
and maximum doses (12 mg/kg [non-EIAED subjects] and 16 mg/kg [EIAED subjects]) have 
been evaluated in a Phase 3 study (E2007-G000-311) in 180 pediatric subjects (4 to <12 years) 
with refractory POS with or without secondarily generalized seizures or with PGTCS, and was 
found to be generally safe and well tolerated.  (revised per Amendment 02) 
Given the vulnerability associated with the young age of this study population and the lack of 
safety and PK information in this young age group, precautionary safety measures will be 
employed:  (1) Slightly longer titration intervals (ie, 1-week intervals up to 6 mg/day and then 
2-week intervals from 6 mg/day to maximum dose of 12 mg/day [non-EIAED subjects] or 
16 mg/day [EIAED subjects]), compared to those in the adolescent/adult studies; (2) a 4-fold 
lower starting dose (0.5 mg/day instead of labeled 2 mg/day) will be employed as a 
precautionary safety measure, and (3) periodic interim PK analysis to examine the 
appropriateness of the target doses and dose range employed in this study.  (revised per 
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9.3 
Selection of Study Population 
For the age group of 1 to less than 24 months, at least 16 pediatric subjects who have been 
diagnosed with epilepsy, of which at least 6 subjects are in the age range ≥1 to ≤6 months, at 
least 5 subjects are in the age range >6 to ≤12 months, and at least 5 subjects are in the age 
range >12 to <24 months.  (revised per Amendment 02) 
In addition, up to 26 subjects in the age range of 2 to less than 4 years may be enrolled in this 
study.  As these subjects can be pooled across clinical studies of perampanel with PK data, 
there is no prespecified number of subjects in this age group that must be enrolled in this study.  
(revised per Amendment 02) 
Subjects will be enrolled at approximately 15 sites in NA and the EU.  (revised per 
Amendment 02) 
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
1. Male or female, from 1 month to less than 4 years of age (and of at least 36 weeks 
gestational age) at the time of consent (revised per Amendments 01 and 02) 
2. Have a minimum weight of 4 kg (8.8 lb) 
3. Have a diagnosis of epilepsy with any type of seizure according to the ILAE guidelines: 
International League Against Epilepsy’s Classification of Epileptic Seizures (1981).  
Diagnosis should have been established at least 2 weeks (≤6 months of age) or 4 weeks 
(>6 months of age) before Visit 1, by clinical history and an electroencephalogram (EEG) 
that is consistent with epilepsy; normal interictal EEGs will be allowed provided that the 
subject meets the other diagnosis criterion (ie, clinical history) 
4. Have had brain imaging (computed tomography [CT] or magnetic resonance imaging 
[MRI]) before Visit 1 that ruled out a progressive cause of epilepsy 
5. Have had 1 or more seizure(s) before Visit 1  (revised per Amendment 01) 
6. Are currently being treated with a stable dose (ie, unchanged for at least 5 half-lives) of 
1 to a maximum of 4 AEDs. (At least 6, but not more than 8 subjects, in the age group of 
1 to less than 24 months, and up to 13 subjects in the age group of 2 to less than 4 years, 
will be taking 1 EIAEDs [ie, CBZ, OXC, PHT, or ESL] out of the maximum of 4 AEDs 
allowed.  The remaining subjects cannot be taking any EIAEDs.)  (revised per 
Amendment 02) 
7. Have been on their current concomitant AED(s) with a stable dose for at least 2 weeks 
or 5 half-lives, whichever is longer, before Visit 1 (revised per Amendment 02) 
8. Must have discontinued all restricted medications (eg, medications known to be inducers 
of cytochrome P450 3A) at least 2 weeks or 5 half-lives (whichever is longer) before 
Visit 1  (revised per Amendment 02) 


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Inclusion criteria for the Extension Phase are listed in Appendix 3. 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Have a history of status epilepticus that required hospitalization during the 3 months 
before Visit 1 
2. Have seizures due to treatable medical conditions, such as those arising due to 
metabolic disturbances, toxic exposure, or an active infection 
3. Have epilepsy secondary to progressive central nervous system (CNS) disease or any 
other progressive neurodegenerative disease, including tumors  
4. Have had epilepsy surgery within 1 year of Visit 1 (revised per Amendment 01) 
5. Are scheduled and/or confirmed to have epilepsy surgery within 6 months after Visit 1 
6. Used intermittent rescue benzodiazepines (ie, 1 to 2 doses over a 24-hour period 
considered one-time rescue) 2 or more times in the 2 weeks before Visit 1 
7. Current use of felbamate, or any evidence of ongoing hepatic or bone marrow 
dysfunction associated with prior felbamate treatment.  (Prior use of felbamate must be 
discontinued at least 8 weeks before Visit 1.)  (revised per Amendment 02) 
8. Current use of vigabatrin or any evidence of clinically significant vision abnormality 
associated with prior vigabatrin treatment.  (Prior use of vigabatrin must be 
discontinued at least 2 weeks before Visit 1.)  (revised per Amendment 02) 
9. On a ketogenic diet that has not been stable for at least 4 weeks before Visit 1  
10. Concomitant use of other drugs known to influence the CNS (other than AEDs for 
epilepsy), where the dose has not been stabilized for at least 5 half-lives or 2 weeks, 
whichever is longer, before Visit 1  (revised per Amendment 02) 
11. Have any concomitant illnesses/co-morbidities that could severely affect the subject’s 
safety or study conduct 
12. Have 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 study conduct 
13. Have clinically significant laboratory abnormalities or any clinically acute or chronic 
disease 
14. Have 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 limits 
of normal (ULN) 
15. Have clinical evidence of significant active hematological disease; WBC count 
≤2500/μL (2.50 x 109/L) or an absolute neutrophil count ≤1000/μL (1.00 x 109/L) 


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16. Have conditions that may interfere with their participation in the study and/or with the 
PK of study drug 
17. 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 
18. Have recently (within 30 days before Visit 1) been exposed to perampanel in a clinical 
study or by prescription, and/or previous discontinuation from perampanel treatment 
due to adverse events related to perampanel  (revised per Amendment 02) 
19. Have a clinically significant electrocardiogram (ECG) abnormality, including 
prolonged corrected QT interval (QTc) defined as > 450 msec 
20. Have had multiple drug allergies or a severe drug reaction to an AED(s), including 
dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity 
reactions 
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 study drug, an Early Discontinuation Visit will be 
performed.  The subject should also return 4 weeks (±6 days) after the last dose of study drug 
to complete the Follow-up Visit procedures.  The Subject Disposition case report form (CRF) 
will be completed indicating the primary reason for discontinuation and all 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(s) 
Test drug for this study will be perampanel, oral suspension, 0.5 mg/mL.  Dosing should occur 
once daily before bedtime in the evening, unless otherwise specified (see Section 9.5.1.4 for 
more details). 
9.4.1 
Treatment(s) Administered 
Pretreatment Phase:   
During the Pretreatment Phase subjects will continue to take their baseline AEDs regimen.  No 
study drug will be administered to subjects during this phase. 
Treatment Phase: 
• Titration Period (12-16 weeks):  Subjects will start perampanel treatment at a dose of 0.50 
mg/day and follow dose titration schemes [Table 1 and Table 2], up to 4 mg/day (non-


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EIAED subjects) or 8 mg/day (EIAED subjects).  Depending on individual subject’s 
clinical response and tolerability, non-EIAED subjects could still have the perampanel dose 
up-titrated to 6 mg/day.  Perampanel dose should not be further up-titrated beyond 6 
mg/day (non-EIAED subjects) or 8 mg/day (EIAED subjects) unless there is a medical 
need (for example, a subject who tolerated perampanel well but have not reached optimal 
seizure control).  Before dose up-titrations beyond 6 mg/day (non-EIAED subjects) or 8 
mg/day (EIAED subjects) and whenever practically feasible, it is recommended to take a 
blood sample for the measurement of plasma perampanel level as a precautionary measure.  
The date and time of the last perampanel dose administration, as well as the date and time 
of PK blood draw, for these unscheduled PK sample collection will be recorded.  Up-
titrations of perampanel dose within the range of 0.5 to 6 mg/day will be at 1-week 
intervals; and at doses greater than 6 mg/day will be at 2-week intervals (see Study 
Treatment(s) section).  Dose titrations must not exceed 12 mg/day (non-EIAED subjects) 
or 16 mg/day (EIAED subjects).  The decision to up-titrate perampanel dose will be at the 
investigator’s discretion, based on individual subject’s clinical response and/or tolerability 
to achieve optimal dose for a given subject.  Once the optimal dose has been achieved, the 
subject’s dose will be maintained stable for the remaining Titration Period or at least 2 
weeks before entering the Maintenance Period (revised per Amendment 02) 
According to the investigator’s clinical judgment subjects experiencing intolerability at any 
dose may remain at the same dose or have their dose decreased one 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 must be done at the next clinic visit after the investigator has deemed it is appropriate 
in view of the resolution of the AE(s).  Multiple dose adjustments will be allowed during 
the Titration Period.  Every effort should be made to have subjects achieve their optimal 
dose, not to exceed a maximum dose of 12 mg/day (non-EIAED subjects) or 16 mg/day 
(EIAED subjects) during the Titration Period.  (revised per Amendment 02) 
• Maintenance Period (4 weeks):  During this period, subjects will continue taking 
perampanel oral suspension at the dose level they achieved at the end of the Titration 
Period. 
Adjustment of the dose level during the Maintenance Period should be discouraged; 
however, according to the investigator’s clinical judgment, subjects experiencing 
intolerable AE(s) will be allowed to have their dose decreased to the previously tolerated 
dose.  During the Maintenance Period, subjects whose dose has been decreased cannot have 
their dose increased again.  A subject may not decrease their dose more than once during 
Maintenance Period unless there is a significant medical reason and with approval from the 
Medical Monitor. 
During the entire Titration and Maintenance Periods, all dose adjustments will be done via 
1 dose level up or down (Table 1 and Table 2).  Subjects who do not tolerate a dose of 
0.50 mg/day will be discontinued from the study.  The maximum total daily dose a subject 
will be allowed is 12 mg (non-EIAED subjects) or 16 mg (EIAED subjects). 


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Dosing Modifications 
After every 4th subject in the age group 1 to less than 24 months completes the 
Maintenance Period, an interim analysis (safety, tolerability, and PK) will be conducted 
and reviewed by the Eisai study team to decide if dosing modifications are required for 
additional subjects who enroll in the study.  If the exposure of the subjects is significantly 
different from that observed in subjects ages ≥2 to <12 years from other clinical studies or 
that are predicted from PK modeling and simulation, or if non-linear PK is observed, the 
sample size will be increased to at least 24 subjects with evaluable PK data and the target 
dose or dosing regimen of those subjects may be modified via a protocol amendment, 
depending on the PK of the previous subjects.  PK data collected in older age cohort (2 to 
less than 4 years) will also be examined in the interim PK analyses.  (revised per 
Amendment 02) 
• Follow-Up Period (4 weeks):  Subjects will not receive study drug during this period.  
Subjects who do not continue into the Extension Phase after completing the Maintenance 
Period, or those who discontinue early from the study will be required to complete the 
Follow-up Period after their last dose in the Treatment Phase.  Subjects who switch to 
commercially available perampanel or who enter into EAP upon completion of study 
treatment need not to undergo Follow-up Visit; however, sites will conduct a telephone 
contact 28 (+6) days after the last dose of study drug to follow AEs and report any SAEs 
that occur within 28 days of the last study drug administration. (revised per 
Amendment 02) 
Table 1 
Non-EIAED Subjects:  Dose Adjustments during the Titration and 
Maintenance Periods  (revised per Amendment 02)  
For all non-EIAED subjects (up to 6 mg/day): 
Treatment Phase/Titration Period 
Visit 
Daily Dose 
Week 0 (starting dose) 
Visit 2 
0.50 mg 
Week 1 (Titration #1) 
- 
1 mg 
Week 2 (Titration #2) 
Visit 3 
2 mg 
Week 3 (Titration #3) 
- 
4 mga 
Week 4 (Titration #4) 
Visit 4 
6 mgb 
For non-EIAED subjects who may require further titrations of perampanel doses:c 
Week 6 (Titration #5) 
- 
8 mgd 
Week 8 (Titration #6) 
Visit 5 
10 mg 
Week 10 (Titration #7) 
- 
12 mg 
Week 12 (no titration) 
Visit 6 
Last dose achieved at Week 10d 
Treatment Phase/Maintenance Period 
Last dose achieved in the Titration Period 
EIAED = enzyme-inducing anti-epileptic drug 


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Table 1 
Non-EIAED Subjects:  Dose Adjustments during the Titration and 
Maintenance Periods  (revised per Amendment 02)  
For all non-EIAED subjects (up to 6 mg/day): 
Treatment Phase/Titration Period 
Visit 
Daily Dose 
a. 
Subjects who have shown good clinical response and tolerability at perampanel daily dosing of up to 
4 mg will continue to receive the same dose throughout the remaining of Titration Period.  (revised 
per Amendment 02)  
b. Up-titration to 6 mg/day in non-EIAED subjects will be allowed if a higher dose (6 mg/day) is 
deemed by the investigator to provide a better clinical benefit and provided that the subject tolerates 
perampanel well.  Subjects who have shown good clinical response and tolerability at perampanel 
6 mg/day will continue to receive the same dose throughout the remaining of Titration Period (revised 
per Amendment 02)  
c. 
At the discretion of the investigator; only if medically necessary (eg, inadequate seizure control) and 
provided that the subject has shown good tolerability at 6 mg/day.  (revised per Amendment 02)  
d. Site to contact the parent/guardian during the scheduled telephone interview approximately midpoint 
between Visit 4 and Visit 5 to assess if further dose titration (to 8 mg/day) is medically necessary.  The 
subject must return to the clinic for an unscheduled visit for any dose increase.  (revised per 
Amendment  02) 
e. 
Visit is considered the end of the Titration Period and start of the Maintenance Period. 
  
 
Table 2 
EIAED Subjects:  Dose Adjustments during the Titration and 
Maintenance Periods  (revised per Amendment 02)   
Treatment Phase/Titration Period 
Visit 
Daily Dose 
For all EIAED subjects (up to 8 mg/day) 
Week 0 (starting dose) 
Visit 2 
0.50 mg 
Week 1 (Titration #1) 
- 
1 mg 
Week 2 (Titration #2) 
Visit 3 
2 mg 
Week 3 (Titration #3) 
- 
4 mg 
Week 4 (Titration #4) 
Visit 4 
6 mg 
Week 6 (Titration #5) 
- 
8 mga 
For EIAED subjects who may require further titrations of perampanel:b 
Week 8 (Titration #6) 
Visit 5 
10 mg 
Week 10 (Titration #7) 
- 
12 mg 
Week 12 (Titration #8) 
Visit 6 
14 mg 
Week 14 (Titration #9) 
- 
16 mg 
Week 16 (no titration) 
Visit 7 
Last dose achieved at Week 14c 
Treatment Phase/Maintenance Period 
Last dose achieved in the Titration Period 
EIAED = enzyme-inducing anti-epileptic drug 


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Table 2 
EIAED Subjects:  Dose Adjustments during the Titration and 
Maintenance Periods  (revised per Amendment 02)   
Treatment Phase/Titration Period 
Visit 
Daily Dose 
For all EIAED subjects (up to 8 mg/day) 
a. 
Subjects who have shown good clinical response and tolerability at perampanel daily dosing of up to 
8 mg will continue to receive the same dose throughout the remaining of Titration Period. (revised per 
Amendment 02)  
b. At the discretion of the investigator; only if medically necessary (eg, inadequate seizure control) and 
provided that the subject has shown good tolerability at 8 mg/day (revised per Amendment 02)    
c. 
Visit is considered the end of the Titration Period and start of the Maintenance Period. 
 
Extension Phase 
Details on treatments administered during the Extension Phase are provided in Appendix 3. 
Other Dosing Considerations 
Down-titration of perampanel upon early discontinuation or completion of the study is not 
necessary, because the plasma half-life of perampanel is between ~25 (in the presence of 
EIAED) to 105 (in the absence of EIAED) hours.  As such, plasma concentrations decrease 
gradually following stopping perampanel.  If, in the clinical judgment of the investigator, 
down-titration of perampanel is still deemed necessary, the investigator must discuss the 
down-titration before the early discontinuation with the Medical Monitor. 
9.4.2 
Identity of Investigational Product 
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 United States. 
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, place the bottles, suitably sized dosing devices (ie, oral syringes), 
and appropriately sized bottle adapters for accurate aliquotting (ie, PiBAs) into a tamper-
evident sealed carton, and ship them to the study sites. 
During the Core Study visits, parents/guardians will be provided with a bottle or bottles of 
suspension that can be redispensed or replaced at the next visit.  Each bottle provided will be 
in a tamper-evident sealed carton that will also contain oral syringes and PiBAs.  Detailed 
instructions on increments in dosage during the Titration Period will be provided to the 
subjects/guardians by the site investigator. 


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Details for the identity of the investigational product for the Extension Phase can be found in 
Appendix 3. 
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) 
9.4.2.2 
Comparator Drug 
Not applicable. 
9.4.2.3 
Labeling for Study Drug 
Test 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.  
Perampanel is a Schedule III Controlled Drug Substance in the United States and will be 
labeled as such for US sites. 
9.4.2.4 
Storage Conditions 
Where applicable, test drug will be stored and labeled in accordance with the US FDA Drug 
Enforcement Administration (DEA) Regulations for Scheduled III - V Drugs.  
Temperature monitoring is required at the storage location to ensure that the study drug is 
maintained within an established temperature range.  The investigator 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.  There is no randomization in this study. 
9.4.4 
Selection of Doses in the Study 
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 


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was conducted.  Of the 42 subjects with a wide range of body weights (ie, 12.2 to 90.9 kg) 
analyzed to date, 20 were aged ≥2 to ≤7 years and 22 were aged ≥7 to <12 years.  A total of 
28 subjects were not receiving any of the EIAEDs (ie, CBX, OXC, or PHT) and 14 subjects 
were receiving one of these EIAEDs.  As noted above, subjects in Study 232 were administered 
perampanel oral suspension (0.5 mg/mL) according to a weight-based regimen compared to 
tablets in Studies 304, 305, and 306.  Whole blood perampanel concentration values from 
Study 232 analyzed using the DBS technique were converted to plasma concentrations, and 
for comparison purposes both plasma perampanel concentrations.  The results of the analysis 
demonstrated that perampanel PK was linear as there was no dose or time-dependency to CL/F.  
The CL/F was not significantly affected by age, body weight, gender, race, hepatic function 
markers (ALT or AST), renal function marker (creatinine clearance) 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) independent of weight, 
the lower steady state concentration was deemed to be due to the lower total dose (mg/body) 
administered in pediatric subjects.  The results of the analysis suggested that a flat dosing 
approach will be more appropriate in subjects within that age range.   
Considering the ontogenic profile with CYP3A enzyme in pediatrics, especially between 1 to 
less than 24 months of age, and due to the unknown safety profile in this population, a lower 
starting dose of 0.5 mg/day was selected for this study, with titrations to a maximum dose of 
12 mg/day (non-EIAED subjects) or 16 mg/day (EIAED subjects).  To date, sparse PK data is 
available from 3 pediatric subjects between age of 4.5 months to 20 months receiving 
perampanel through a Named Patient IND.  These subjects were dosed perampanel up to 
8 mg/day at steady state.  The plasma concentration data in the 3 individuals although close to 
upper end of the range, were still within the 2-fold relative to the exposures observed in 2 to 
<12 year old subjects. Based on these findings, the likelihood of starting dose of 0.5 mg 
achieving unexpectedly high plasma exposures in the proposed age population is considered 
to be low. 
Furthermore, noting the wide variability in hepatic metabolism via CYP3A in pediatric 
subjects less than 24 months of age, the risk of unexpected plasma exposures in number of 
pediatric subjects is further minimized by planned interim analysis (safety, tolerability, and 
PK) after every 4th subject completes the Maintenance Period.  Dose-normalized exposures 
will be compared to that observed in other studies in subjects between ≥2 and <18 years of age 
for evidence of systematic deviations potentially warranting dose adjustment in this age group 
or for other subjects enrolled in the study.   
Preliminary PK analysis was performed based on data obtained from 7 subjects (>6 to 
<24 months of age; 6 subjects without concomitant EIAED and 1 subject on concomitant 
EIAED) in this study and pooled with existing data from 2336 subjects (aged 2 to 77 years).  
Preliminary PK findings suggest that oral clearance in subjects aged less than 24 months 
without concomitant EIAED appears to be approximately 40% of that in subjects aged 


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≥2 years.  It is predicted that a daily dose of 6 mg or 8 mg in subjects aged less than 24 months 
without or with concomitant EIAED, respectively, will result in comparable exposure to that 
in subjects aged >2 years receiving a daily dose of 12 mg (non-EIAED subjects) or 16 mg 
(EIAED subjects), respectively.  However, European Medicines Agency/Paediatric Committee 
(EMA/PDCO) recommended that perampanel dose should be titrated up to a target dose of 4 
mg/day for non-EIAED subjects (EMEA-000467-PIP01-08-M13), which could be further 
titrated up to 6 mg/day depending on individual subject’s clinical response and tolerability.  
Therefore, the target dose in this study is revised to 4 mg/day (non-EIAED subjects) and 
8 mg/day (EIAED subjects) in subjects less than 24 months of age, while the maximum dose 
allowed remains as 12 mg/day and 16 mg/day for non-EIAED and EIAED subjects, 
respectively.  Perampanel dosage should not be further up-titrated, unless there is a medical 
need (for example, a subject who tolerated perampanel well but have not reached optimal 
seizure control).  At any time in the study, perampanel dose must not to exceed 12  mg/day 
(non-EIAED subjects) or 16 mg/day (EIAED subjects).  (revised per Amendment 02) 
In subjects 2 to <4 years of age, there were very limited PK data (n=4) to allow adequate 
evaluation of effect of age on perampanel PK.  Therefore, the same target dose and dose 
titration approach will be followed for non-EIAED and EIAED subjects aged 2 to less than 
4 years as described above for 1 to less than 24 months subjects.  (revised per Amendment 02) 
9.4.5 
Selection and Timing of Dose for Each Subject 
Subjects will be instructed to take the study drug, by mouth, and before bedtime in the evening.  
9.4.6 
Blinding 
This is an open-label, single-arm study.  There is no blinding. 
9.4.7 
Prior and Concomitant Therapy 
Any medication (including over the counter medications, or herbals) or therapy administered 
(including AEDs) during the course of the study (starting at the date of informed consent and 
those taken within 4 weeks of Visit 1) will be recorded on the Prior and Concomitant Therapy 
CRF and/or Nonpharmacologic Therapy/Procedure CRF. The investigator will record any AE 
on the Adverse Events CRF for which the concomitant medication/therapy was administered. 
Subjects will be taking 1 to a maximum of 4 marketed AEDs (see inclusion criteria 6 and 7 
and exclusion criteria 6 through 8 for further details).  Changes of baseline AEDs (addition, 
deletion, or adjustment in dose) will not be allowed during 5 half-lives or during the 2 weeks, 
whichever is longer, before Visit 1.  During the Core study, dose adjustments will be allowed 
only for non-EIAEDs.  Dose adjustments of EIAEDs, and addition/deletion of any concomitant 
AEDs are not allowed during the Core study.  Use of CBD products is allowed and is counted 
as 1 of the 4 maximum allowed concomitant AEDs.  CBD dose and product must have 
remained stable for at least 2 weeks before Visit 1 and is to remain the same throughout the 
course of the Core Study.  (revised per Amendment 02) 


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9.4.7.1 
Drug-Drug Interactions 
Not applicable. 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs 
The following medications will not be permitted (revised per Amendment 02): 
• Medications known to be inducers of cytochrome P450 3A (CYP3A) (other than CBZ, 
OXC, PHT, or ESL)  including, but not limited to:  rifampin, troglitazone, St John’s 
Wort, efavirenz, nevirapine, barbiturates (except for use as an AED), glucocorticoids 
(other than topical usage), modafinil, pioglitazone, and rifabutin within 2 weeks or 
5 half-lives, whichever is longer, before Visit 1 and throughout the course of the study 
[Core and Extension])   
• Felbamate (within 8 weeks before Visit 1 and throughout the course of the study [Core 
and Extension]) 
• Vigabatrin (within 2 weeks before Visit 1 and throughout the course of the study [Core 
and Extension]) 
In case of an emergency, subjects may receive other AEDs, including diazepam as well as 
other appropriate AEDs as rescue medications, to treat status epilepticus, uncontrolled 
seizures, or seizure clusters (see exclusion criterion 6). 
For any drug known to influence the CNS (other than AEDs for epilepsy), the dose should be 
kept stable for 2 weeks or 5 half-lives, whichever is longer, before Visit 1 and throughout the 
course of the study (Core and Extension).  (revised per Amendment 02) 
Subjects are not permitted to participate in another study involving administration of an 
investigational drug or device for the full duration of this study (ie, up to and including the 
Follow-up Visit). 
9.4.8 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  The CRA 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 


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• 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 Food and Drug Administration (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. 
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 one 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 drugs to be used other than as 
directed by this protocol.  The subject’s parent/guardian may be dispensed study drugs for 
pediatric subjects.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) documentation 
of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, (c) study drugs 
accountability log, (d) all shipping service receipts, and (e) documentation of returns to the 


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sponsor.  All forms will be provided by the sponsor.  Any comparable forms that the site wishes 
to use must be approved by the sponsor. 
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, FDA, 
Medicines and Healthcare Products Regulatory Agency [MHRA]).  As applicable, all unused 
study drugs and empty and partially empty containers from used study drugs are to be returned 
to the investigator by the subject and, together with unused study drugs that were shipped to 
the site but not dispensed to subjects, are to be returned to the sponsor’s designated central or 
local depot(s) during the study or at the conclusion of the study, unless provision is made by 
the sponsor for destruction of study drugs and containers at the site.  Destruction at the site will 
only occur under circumstances where regulation or supply type prohibits the return of study 
drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and 
reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed, sealed, and shipped back to the central or local depot(s) following 
all local regulatory requirements.  In some regions, study drugs may be removed from the site 
and hand delivered to the central or local depot by sponsor representatives.  Where study drugs 
are approved for destruction at the site, destruction will occur following the site’s standard 
procedures and certificates of destruction will be provided to the sponsor. 
Drug accountability will be reviewed during site visits and at the completion of the study. 
9.5 
Study Assessments 
9.5.1 
Assessments 
Details for all assessment in the Extension Phase can be found in Appendix 3. 
9.5.1.1 
Demography 
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, and race/ethnicity. 
9.5.1.2 
Baseline Assessments 
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS 
Medical history, including and surgical history and current medical conditions, will be 
recorded.  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 and Table 5).  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest (including 


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heart and lungs), abdomen, limbs, skin, and a complete neurological examination.  
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 Adverse Events CRF. 
EPILEPSY MEDICAL HISTORY 
In addition to standard medical history, epilepsy medical history will be documented for each 
subject. 
9.5.1.3 
Efficacy Assessments 
SEIZURE COUNTS 
Efficacy will be assessed by seizure counts and types as recorded on a study specific seizure 
diary.  Diaries will be dispensed to all subjects at each visit as described in Table 4 and Table 
5.  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 physician 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). 
CLINICAL GLOBAL IMPRESSION OF CHANGE 
The CGI will be used to evaluate perceived seizure frequency and severity, the occurrence of 
AEs, and overall functional status of the subject.  The evaluations of CGIS and CGIC both use 
a 7-point scale. For the CGI-S, 1 = normal, not at all ill and 7 = extremely ill, and for the 
CGI-C, 1 = very much improved and 7 = very much worse. 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
PHARMACOKINETIC ASSESSMENTS 
Blood samples (1.0 mL) for plasma will be collected from all subjects at pre-specified visits 
for the determination of perampanel concentrations, as detailed in Table 4. 
For subjects aged 1 to less than 24 months:  Dosing should occur once daily before bedtime in 
the evening (revised per Amendment 02).  On the day of the PK sampling, subjects will have 
to attend the clinic any time during the day to provide blood sampling for PK analysis and to 
enable close monitoring of the subjects for safety and tolerability.  One blood sample (1.0 mL) 
for the determination of perampanel plasma concentrations will be collected during the 
specified visits.  The resulting plasma sample will be aliquoted into 2 Microtainer tubes.  
Plasma samples will be analyzed using a validated small-volume plasma assay method.The 


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date and time of perampanel dosing for 3 days before a PK visit and time of blood PK sampling 
will be recorded. 
For subjects aged 2 to less than 4 years, dosing should occur once daily before bedtime in the 
evening, including the evening before the PK visit during Titration Period (Visit 5 for 
non-EIAED subjects, or Visit 6 for EIAED subjects).  The dosing date and time of the last 3 
doses before Titiration Period PK visit will be recorded.  Note:  For PK visits during 
Maintenance Period (ie, Visits 7 and 8 for non-EIAED subjects, or Visits 8 and 9 for EIAED 
subjects), as 2 PK samples (1 predose and 1 early postdose [within 1 to 5 hours after dosing]) 
are to be collected, the following steps are to be followed (revised per Amendment 02): 
• 
Study drug administration in the evening immediately before the PK visits during 
Maintenance Period will be withheld.  All other AEDs should be administered per the 
subject’s usual AED regimen.   
• 
During each of the Maintenance Period PK visits, collect predose PK sample.  Then 
administer study drug on site, followed by early postdose PK sample collection (within 
1 to 5 hours after dose administration). 
• 
Bedtime dosing will resume beginning in the evening of the Maintenance Period PK 
visits. 
• 
The dosing date and time of the study drug dose administered on-site during each 
Maintenance Period PK visit, as well as the last 2 doses before will be recorded.  
(revised per Amendment 02) 
A population PK approach will be used to characterize the PK of perampanel. 
An approximation of the total blood volume that will be drawn from each subject during the 
study is presented in Appendix 2. 
For all PK samples, including the unscheduled PK samples collected, if any, before dose 
up-titrations beyond 6 mg/day (non-EIAED subjects) or 8 mg/day (EIAED subjects), plasma 
concentrations of perampanel will be quantified by a validated liquid chromatography-tandem 
mass spectrometry (LC-MS/MS) analytical method in sodium heparinized human plasma 
samples.  (revised per Amendment 02) 
Blood also will be drawn where possible at the first report of a serious adverse event (SAE) or 
severe unexpected AE and at its resolution. 
A detailed description of collection, handling, and shipping procedures of PK samples will be 
provided in the Laboratory Manual to be provided to the sites. 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments 
Not applicable. 


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9.5.1.5 
Safety Assessments 
Safety will be assessed by monitoring and recording of all AEs and SAEs, clinical labs (ie, 
hematology and blood chemistry), vital signs, ECGs, medical history, and physical and 
neurological examinations.   
Growth will be assessed for this age population by measurement of height, weight, head 
circumference, thyroid function and insulin-like growth factor-1 (IGF-1) testing.   
Details of the timing of all safety assessments are presented in Table 4. 
Adverse Events and Events Associated With Special Situations 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the medicinal product.  For this study, the study drug is perampanel (E2007).  
The criteria for identifying AEs in this study are: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE) 
• Any new disease or exacerbation of an existing disease 
• Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, 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 


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laboratory abnormality should be classified as an AE.  Any laboratory abnormality considered 
to constitute an AE should be reported on the Adverse Event 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 msec 
and there is an increase of more than 60 msec from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such. 
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  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 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
 Incapacitating, with inability to work or to perform normal daily activity 
The criteria for assessing severity are different than those used for seriousness (see 
Section 9.5.1.5 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 


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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. 
Serious Adverse Events and Events Associated With Special Situations 
A serious adverse event (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) 
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 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 “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care  
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 


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• 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 first report of an SAE or a severe unexpected AE and at its resolution. 
LABORATORY MEASUREMENTS 
Blood collections for clinical laboratory testing, including hematology, and chemistry, are 
summarized in Table 3.  Subjects should be in a supine position during blood collection.  In 
addition, blood samples for the determination of thyroid function (thyroid stimulating hormone 
[TSH], free triiodothyronine [fT3], free thyroxine [fT4]), and IGF-1 levels will be collected 
The Schedule of Procedures/Assessments (Table 4) shows the visits and timepoints at which 
blood for all clinical laboratory tests will be collected in the study (Core Study).  An 
approximation of total blood volume that will be drawn for each subject during the study is 
presented in Appendix 2.  (revised per Amendment 02) 
Table 3 
Clinical Laboratory Tests   
 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, and WBC count with differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
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, thyroid (TSH, fT3, fT4) and 
IGF-1 tests 
fT3 = free triiodothyronine, fT4 = free thyroxine, IGF = insulin-like growth factor, RBC = red blood cell, TSH = 
thyroid stimulating hormone, WBC = white blood cell. 
a. 
Samples for glucose and triglycerides will be taken under fasted conditions, whenever practically feasible.  
(revised per Amendment 02) 
 
Clinical laboratory tests during the study will be performed by a central laboratory.  All clinical 
laboratory tests are to be performed at the central laboratory.  At Screening/Baseline (Visit 1), 
use of local laboratory test results (hematology, clinical chemistry, thyroid function and IGF-1 
test), if obtained within 4 weeks before Visit 1, may be allowed in lieu of blood draw for central 
laboratory analyses, provided that the subject’s local laboratory tests were performed at a 
Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.  In these cases, 


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to enable safety evaluation (eg, to assess whether there are treatment-emergent shifts in 
laboratory values from baseline), all post-baseline labs must be conducted at the same local 
laboratory using same assays as those used at Screening/Baseline.  In other cases where 
unscheduled laboratory samples need to be taken and immediately analyzed to address a safety 
concern, blood samples will be split (or 2 samples drawn) to allow for a local laboratory 
analysis in addition to the central laboratory.  Laboratory certification, as well as normal assay 
range for each of local laboratory tests run, will be collected as available and will be included 
in the clinical study report for this protocol.  (revised per Amendment 02) 
For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.5), the site must 
fax or email the SAE report including the laboratory report (as regionally required) to the 
sponsor using the SAE form (see Section 9.5.4.1). 
VITAL SIGNS WEIGHT, HEIGHT, AND HEAD CIRCUMFERENCE 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 growth 
parameters including measurement of height, weight (kg), head circumference, will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 4).  Blood 
pressure and pulse will be measured after the subject has been sitting or supine, for 5 minutes.  
All BP measurements should be performed on the same arm, preferably by the same person.  
PHYSICAL EXAMINATIONS 
Physical 
examinations 
will 
be 
performed 
as 
designated 
in 
the 
Schedule of 
Procedures/Assessments (Table 4).  Documentation of the physical examination will be 
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 Adverse Events 
CRF. 
ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in the Schedule of Procedures/Assessments 
(Table 4).   
ECGs should preferably be recorded prior to blood draws when both are scheduled at the same 
visit.  However, if for any reason blood draws occur before ECG recording, then the ECG must 
be recorded at a minimum of 30 minutes after the blood draw.  The subject should be relaxed 
and must be in a supine position at least 5 minutes prior to recording an ECG.  The ECG will 
be reviewed by the investigator (paper or electronic tracing) and will be available for 
comparison with subsequent ECGs by the investigator.   
If the subject has a normal ECG baseline reading, but during any visit thereafter there is any 
clinically significant ECG abnormality (as determined by the investigator), 3 consecutive 
ECGs separated by 5 to 10 minutes will be performed to confirm the abnormality at that visit. 


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ECGs will be transmitted the same day they are taken to the central ECG laboratory for 
evaluation.  The ECG will be interpreted by a Central ECG laboratory cardiologist.  The results 
of this over-read will be transmitted to the investigator.  The cardiologist at the central ECG 
laboratory will be available to consult with the investigator(s) on the interpretation of 
individual subject ECG recordings, as needed.  The corrected interval, as reported to the 
investigator by the Central ECG laboratory, will be QTc Fridericia (QTcF).  
An ECG abnormality may meet the criteria of an AE as described in this protocol (see Section 
9.5.1.5) and the CRF Completion Guidelines.  In these instances, the AE corresponding to the 
ECG abnormality will be recorded on the Adverse Events CRF. 
OTHER SAFETY ASSESSMENTS 
Not applicable. 
9.5.2 
Schedule of Procedures/Assessments  
Table 4 and Table 5 present the schedule of procedures/assessments for the Core Study. 


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Table 4 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core Study – Non-EIAED Subjects 
Phase 
Pretreatment 
Treatment 
Early 
Discontinuation 
Unscheduled 
Period 
Titration 
Maintenance 
Follow-
Upa 
Visit 
1 
2b 
3b 
4c 
5c 
6c,d,e 
7c 
8c,f 
 
Week 
-2 
0 
2 
4 
8 
12 
14 
16 
20 
 
 
Days 
-14 
1  
15 
29 
57 
85 
99 
113 
141 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Epilepsy medical history 
X 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological examinationg 
X 
 
 
 
 
 
 
X 
X 
X 
 
Physical examinationh 
X 
 
 
 
 
 
 
X 
X 
X 
 
Vitals and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height/lengthh 
X 
X 
 
 
 
 
 
X 
 
X 
 
Head circumference 
X 
X 
 
 
 
 
 
X 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
Xi 
 
 
Xj 
Retrieve unused study drug 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Xj 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Dispense subject’s diary 
Xk 
X 
X 
X 
X 
X 
X 
X 
 
X 
Xl 
Retrieve and review subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Clinical laboratory testsm, n 
X 
 
 
 
 
X 
 
X 
X 
X 
Xo 
Thyroid function (TSH, fT3, fT4) and IGF-1 tests 
X 
 
 
 
 
 
 
X 
 
X 
 
12-lead ECGp 
X 
 
 
X 
 
X 
 
X 
X 
X 
Xq 
Perampanel PK blood samplingr 
 
 
 
 
X 
 
X 
X 
 
X 
Xl 
Telephone calls 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-C, CGI-St 
 
X 
 
 
 
 
 
X 
 
X 
 
Disposition 
X 
X 
 
 
 
 
 
X 
 
X 
 


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Table 4 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core Study – Non-EIAED Subjects 
Phase 
Pretreatment 
Treatment 
Early 
Discontinuation 
Unscheduled 
Period 
Titration 
Maintenance 
Follow-
Upa 
Visit 
1 
2b 
3b 
4c 
5c 
6c,d,e 
7c 
8c,f 
 
Week 
-2 
0 
2 
4 
8 
12 
14 
16 
20 
 
 
Days 
-14 
1  
15 
29 
57 
85 
99 
113 
141 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
AE = Adverse event, AED = Anti-epileptic drug, CGI-C = Clinical Global Impression of Change, CGI-S = Clinical Global Impression of Severity, CLIA = Clinical Laboratory 
Improvement Amendments, CRF = case report form, EAP = extended access program, ECG = electrocardiogram, EOT = end of treatment, fT3 = free triiodothyronine, fT4 = 
free thyroxine, IGF-1 = insulin-like growth factor-1, PK = pharmacokinetics, SAE = serious adverse event,TSH = thyroid-stimulating hormone. 
a: 
To be done within ±6 days of the scheduled visit.  Visit applies only to those subjects who complete the Treatment Phase but do not roll-over into the Extension Phase and those subjects 
who discontinue the study early for any reason after Visit 2 and before Visit 8. 
b: 
To be done within ±2 days of the scheduled visit. 
c: 
Visits should be done within ± 3 days of the scheduled visit.  There must be at least 10 days of treatment between Visits 3 and 4, 4 and 5, and 5 and 6.  
d: 
Upon successful completion of Visit 6, subjects will begin the Maintenance Period of the study. 
e: 
No dose titration is allowed at this visit or future visits.   
f: 
Visit 8 will be considered the first visit of the Extension Phase for subjects who choose to continue into the Extension Phase. 
g: 
For clinic visits other than those specified, physical and complete neurological exams, including evaluation of the cranial nerves, motor, sensory, brainstem, cerebellar, and autonomic 
functions, will only be performed when there is a complaint from the parent/guardian. 
h: 
Two measurements of height/length should be taken.  Each measurement should be recorded as a separate entry on the Vital Sign CRF.  
i: 
Only for those subjects who roll-over into the Extension Phase. 
j: 
Unused study drug to be retrieved and study drug dispensed only for subject requiring dose increases at Unscheduled Visits. 
k: 
To include the number and type of seizures for the 4 weeks before the Pretreatment Phase. 
l: 
As needed. 
m: Lipid and blood glucose tests to be conducted under fasting conditions, whenever practically feasible.  (revised per Amendment 02) 
n: 
All clinical laboratory tests are to be performed at the central laboratory.  At Screening/Baseline (Visit 1), use of local laboratory test results (hematology, clinical chemistry, thyroid 
function and IGF-1 test) may be allowed if the subject’s local laboratory tests are obtained from a CLIA-certified laboratory within 4 weeks before Visit 1.  In these cases, to enable safety 
evaluation (eg, to assess whether there are treatment-emergent shifts in laboratory values from baseline), all post-baseline labs must be conducted at the same local laboratory using same 
assays as those used at Screening/Baseline.  (revised per Amendment 02) 
o: 
During the unscheduled visits, clinical laboratory tests will only be done if an abnormality was noted at the previous visit or per the discretion of the investigator.  (revised per Amendment 
02) 
p: 
If the subject has a normal ECG baseline reading, but during any visit thereafter if there is any clinically significant ECG abnormality (as determined by the investigator), 3 consecutive 
ECGs separated by 5 to 10 minutes will be performed at that visit to confirm the abnormality.  
q: 
During the unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the investigator. 
r: 
Blood samples (1.0 mL each) will be collected from all subjects for the determination of perampanel concentrations.  The date and time of PK sample collection will be recorded on the 
CRF, as well as the date and time of the last 3 perampanel doses administered before the PK sample collection.  Subjects aged 1 to less than 24 months will have 1 PK sample taken at 
anytime after the last perampanel dose per PK visit.  Subjects aged 2 to less than 4 years will have 2 PK samples taken (1 predose and 1 postdose between 1 and 5 hours after dose 
administration) per PK visit.  See Section 9.5.1.4 for details.  After centrifugation, plasma sample harvested will be aliquoted onto 2 Microtainer tubes (1 primary and 1 back-up sample).  
(revised per Amendment  02) 


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Table 4 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core Study – Non-EIAED Subjects 
Phase 
Pretreatment 
Treatment 
Early 
Discontinuation 
Unscheduled 
Period 
Titration 
Maintenance 
Follow-
Upa 
Visit 
1 
2b 
3b 
4c 
5c 
6c,d,e 
7c 
8c,f 
 
Week 
-2 
0 
2 
4 
8 
12 
14 
16 
20 
 
 
Days 
-14 
1  
15 
29 
57 
85 
99 
113 
141 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
s: 
Telephone interviews with the parent/guardian will be conducted approximately 1 week after Visit 2 and 3, and approximately at the midpoint between each subsequent visit, 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 strongly be encouraged to return to the clinic (instead of the scheduled telephone interview) for further consultation with regard to study 
drug administration.  Subjects will then return for their regularly scheduled visit.  Subjects not continuing into the Extension phase will have a telephone interview at approximately the 
midpoint between Visit 8 and the Follow-up Visit after finishing the Maintenance Period when drug has been stopped.  Subjects that discontinue the study at any time will have a telephone 
interview at approximately the midpoint between the EOT Visit and the Follow-up Visit.  For subjects who will not need to undergo Follow-up Visit (eg, when switching to commercially 
available Fycompa or entering EAP after the last study drug administration) will have a telephone interview 28 (+6) days after the last study drug administration.  AEs/SAEs that occurred 
within 28  days after the last study drug administration will be reported.  (revised per Amendment 02) 
t: 
CGI-S to be administered at Visit 2, CGI-C to be administered at Visit 8 or early discontinuation. 
 
 
 
 


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Table 5 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core Study - EIAED Subjects 
Phase 
Pretreatment 
Treatment 
Early 
Discontinuation 
Unscheduled  
Period 
Titration 
Maintenance 
Follow-
Upa 
Visit 
1 
2b 
3b 
4c 
5c 
6c 
7c,d,e 
8c 
9c,f 
 
Week 
-2 
0 
2 
4 
8 
12 
16 
18 
20 
24 
 
 
Days 
-14 
1  
15 
29 
57 
85 
113 
127 
141 
169 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Epilepsy medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant medication(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant AED(s) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological examinationg 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Physical examinationh 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
Vitals and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height/lengthh 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Head circumference 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
X 
Xi 
 
 
Xj 
Retrieve unused study drug 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Xj 
Study drug compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Dispense subject’s diary 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Xl 
Retrieve and review subject diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Clinical laboratory testsm,n 
X 
 
 
 
 
X 
X 
 
X 
X 
X 
Xo 
Thyroid function (TSH, fT3, fT4) and IGF-1 tests 
X 
 
 
 
 
 
 
 
X 
 
X 
 
12-lead ECGp 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
Xp,q 
Perampanel PK blood samplingr 
 
 
 
 
 
X 
 
X 
X 
 
X 
Xo 
Telephone calls 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CGI-C, CGI-St 
 
X 
 
 
 
 
 
 
X 
 
X 
 


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Table 5 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core Study - EIAED Subjects 
Phase 
Pretreatment 
Treatment 
Early 
Discontinuation 
Unscheduled  
Period 
Titration 
Maintenance 
Follow-
Upa 
Visit 
1 
2b 
3b 
4c 
5c 
6c 
7c,d,e 
8c 
9c,f 
 
Week 
-2 
0 
2 
4 
8 
12 
16 
18 
20 
24 
 
 
Days 
-14 
1  
15 
29 
57 
85 
113 
127 
141 
169 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Disposition 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
AE = Adverse event, AED = Anti-epileptic drug, CGIC = Clinical Global Impression of Change, CGI-S = Clinical Global Impression of Severity, CLIA = Clinical Laboratory Improvement Amendments, 
CRF = case report form, EAP = extended access program, ECG = electrocardiogram, EOT = end of treatment, fT3 = free triiodothyronine, fT4 = free thyroxine, IGF-1 = insulin-like growth factor-1, PK 
= pharmacokinetics, SAE = serious adverse event, TSH = thyroid-stimulating hormone. 
a: 
To be done within ±6 days of the scheduled visit.  Visit applies only to those subjects who complete the Treatment Phase but do not roll-over into the Extension Phase,  those who discontinue 
early from the study for any reason after Visit 2 and before Visit 9.  (revised per Amendment 02) 
b: 
To be done within ±2 days of the scheduled visit. 
c: 
Visits should be done within ± 3 days of the scheduled visit.  There must be at least 10 days of treatment between Visits 3 and 4, 4 and 5, 5 and 6, and 6 and 7 
d: 
Upon successful completion of Visit 7, subjects will begin the Maintenance Period of the study. 
e: 
No dose titration is allowed at this visit or future visits.   
f: 
Visit 9 will be considered the first visit of the Extension Phase for subjects who choose to continue into the Extension Phase. 
g: 
For clinic visits other than those specified, physical and complete neurological exams, including evaluation of the cranial nerves, motor, sensory, brainstem, cerebellar, and autonomic functions, 
will only be performed when there is a complaint from the parent/guardian. 
h: 
Two measurements of height/length should be taken.  Each measurement should be recorded as a separate entry on the Vital Sign CRF.  
i: 
Only for those subjects who roll-over into the Extension Phase. 
j: 
Unused study drug to be retrieved and study drug dispensed only for subject requiring dose increases at Unscheduled Visits. 
k: 
To include the number and type of seizures for the 4 weeks before the Pretreatment Phase. 
l: 
As needed. 
m: Lipid and blood glucose tests must be conducted under fasting conditions, whenever practically feasible.  (revised per Amendment 02) 
n: 
All clinical laboratory tests are to be performed at the central laboratory.  At Screening/Baseline (Visit 1), use of local laboratory test results (hematology, clinical chemistry, thyroid function 
and IGF-1 test) may be allowed if the subject’s local laboratory tests are obtained from a CLIA-certified laboratory within 4 weeks before Visit 1.  In these cases, to enable safety evaluation 
(eg, to assess whether there are treatment-emergent shifts in laboratory values from baseline), all post-baseline labs must be conducted at the same local laboratory using same assays as those 
used at Screening/Baseline.  (revised per Amendment 02) 
o: 
During the unscheduled visits, clinical laboratory tests will only be done if an abnormality was noted at the previous visit or per the discretion of the investigator. 
p: 
If the subject has a normal ECG baseline reading, but during any visit thereafter if there is any clinically significant ECG abnormality (as determined by the investigator), 3 consecutive ECGs 
separated by 5 to 10 minutes will be performed at that visit to confirm the abnormality.  
q: 
During the unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the investigator. 


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Table 5 
Schedule of Procedures/Assessments in Study E2007-G000-238:  Core Study - EIAED Subjects 
Phase 
Pretreatment 
Treatment 
Early 
Discontinuation 
Unscheduled  
Period 
Titration 
Maintenance 
Follow-
Upa 
Visit 
1 
2b 
3b 
4c 
5c 
6c 
7c,d,e 
8c 
9c,f 
 
Week 
-2 
0 
2 
4 
8 
12 
16 
18 
20 
24 
 
 
Days 
-14 
1  
15 
29 
57 
85 
113 
127 
141 
169 
 
 
Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
r: 
Blood samples (1.0 mL each) will be collected from all subjects for the determination of perampanel concentrations.  The date and time of PK sample collection will be recorded on the CRF, 
as well as the date and time of the last 3 perampanel doses administered before the PK sample collection.  Subjects aged 1 to less than 24 months will have 1 PK sample taken at anytime after 
the last perampanel dose per PK visit.  Subjects aged 2 to less than 4 years will have 2 PK samples taken (1 predose and 1 postdose between 1 and 5 hours after dose administration) per PK 
visit.  See Section 9.5.1.4 for details.  After centrifugation, plasma sample harvested will be aliquotted onto 2 Microtainer tubes (1 primary and 1 back-up sample).  (revised per Amendment 02) 
s: 
Telephone interviews with the parent/guardian will be conducted approximately 1 week after Visit 2 and Visit 3, and at approximately the midpoint between each subsequent 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 strongly be encouraged to return to the clinic (instead of the scheduled telephone interview) for further consultation with regard to study drug 
administration.  Subjects will then return for their regularly scheduled visit.  Subjects not continuing into the Extension phase will have a telephone interview at approximately the midpoint 
between Visit 9 and the Follow-up Visit after finishing the maintenance period when drug has been stopped.  Subjects that discontinue the study at any time will have a telephone interview at 
approximately the midpoint between the EOT Visit and the Follow-up Visit.  For subjects who will not need to undergo Follow-up Visit (eg, when switching to commercially available 
Fycompa or entering EAP after the last study drug administration), sites will conduct a telephone contact 28 (+6) days after the last dose of study drug to follow AEs and report any SAEs that 
occur within 28 days of the last study drug administration.  (revised per Amendment 02) 
t: 
CGI-S administered at Visit 2, CGIC administered at Visit 9 or early discontinuation.  (revised per Amendment 02) 
 


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9.5.2.1 
Description of Procedures/Assessments Schedule 
For a description of the procedures and assessments see Table 4. 
9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in Phase 2 studies of 
epilepsy in pediatric subjects. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, 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. 
Serious adverse events, 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. 
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. 
Any follow-up information received on SAEs should be forwarded within 24 hours 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. 


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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 
Not applicable. 
9.5.4.3 
Reporting of Events Associated with Special Situations 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, MISUSE, ABUSE, 
OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer 
to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose  
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol. Intentional and inappropriate use of study drug not in 
accordance with the prescribed or authorized dose, route of 
administration, or indication(s) or use of prescription-only study drug 
without a prescription  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site 
personnel or the subject.   
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of Serious 
Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse is always 
to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or medication 
error does not meet serious criteria, it must still be reported using the SAE form and in an 
expedited manner but should be noted as nonserious on the SAE form and the Adverse Event 
CRF. 
REPORTING OF STUDY-SPECIFIC EVENTS 
Not applicable. 


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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 
Adverse events will be reported by the sponsor or a third party acting on behalf of the sponsor 
to regulatory authorities in compliance with local and regional law and established guidance.  
The format of these reports will be dictated by the local and regional requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All SUSARs 
will be reported, as required, to the competent authorities of all involved European member 
states. 
9.5.5 
Completion/Discontinuation of Subjects 
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  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 are to return 
for a Follow-up Visit 4 weeks (±6 days) after the last dose of study drug.   
The investigator will promptly explain to the parent/guardian 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, or 
administrative/other.  In addition to the primary reason, the subject may indicate one 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. 


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9.5.6 
Abuse or Diversion of Study Drug 
During the course of 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. 
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.1.5. 
9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects’ parent(s)/guardian(s) to inform site personnel when they 
are planning to receive medical care by another physician.  At each visit, the investigator will 
ask the subjects’ parent(s)/guardian(s) whether the subject has received medical care from 
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.  
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 third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 


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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 SAS software or other validated 
statistical software as required.  Details of the statistical analyses will be included in a separate 
statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock. 
9.7.1.1 
Study Endpoints 
PRIMARY ENDPOINT 
• PK of perampanel during the Maintenance Period of the Core Study  (revised per 
Amendment 02)  
SECONDARY ENDPOINTS 
• Safety and tolerability during the Core Study and the Extension Phase, which include 
incidence of treatment-emergent adverse events (TEAEs) and SAEs, laboratory 
parameters, vital signs, and ECG parameters, and growth parameters (height, weight, 
head circumference, thyroid function,and IGF-1 levels)  (revised per Amendment 02)   
EXPLORATORY ENDPOINTS 
The efficacy endpoints are:  
• Seizure frequency:  Percent change in 28-day seizure frequency during the Treatment 
Phase and during the Extension Phase, compared to baseline  (revised per 
Amendment 02) 
• Responder rate:  Proportion of subjects with a 50% or greater reduction in 28-day seizure 
frequency during the Maintenance Period and during the Extension Phase, compared to 
baseline (revised per Amendment 02) 
• Seizure-free rate:  Proportion of subjects who are seizure-free during the Maintenance 
Period and during the Extension Phase 
• CGI-C at the end of the Core Study and the Extension Phase  
Details on endpoints for the Extension Phase can be found in Appendix 3. 
9.7.1.2 
Definitions of Analysis Sets 
The Pharmacokinetic Analysis Set is the group of subjects with at least 1 PK assessment of 
perampanel during the Maintenance Period with a documented dosing history. 


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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 study drug and had any 
seizure frequency data during the 2 weeks of Pretreatment Phase plus 4 weeks before the 
Pretreatment Phase and during the Treatment Phase.  
9.7.1.3 
Subject Disposition 
A disposition or reason 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 
The demographics and baseline characteristics of the Safety Analysis Set will be summarized 
using descriptive statistics (n, mean, SD, median, minimum, and maximum) for the continuous 
variables such as age, and using numbers and percentages for categorical variables which 
includes sex, age group, and race. 
9.7.1.5 
Prior and Concomitant Therapy 
Prior and concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary (WHO DD) drug codes.  Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification. Concomitant medications by drug and drug class will be tabulated 
and included in the clinical study report for this protocol. 
9.7.1.6 
Efficacy Analysis 
This study is designed to assess PK and preliminary safety, tolerability and efficacy.  No formal 
statistical analysis will be performed.  Summary statistics will be displayed for the following 
efficacy parameters in the FAS. 
Treatment Phase: 
• Seizure Frequency:  Percentage change in 28-day seizure frequency during the Treatment 
Phase and the Extension Phase, compared to Baseline.  The primary analysis will use data 
prospectively collected during the 2-week Pretreatment Phase to calculate baseline 28-day 
seizure frequency.  A secondary analysis will use data prospectively collected during the 
2-week Pretreatment Phase plus data retrospectively collected during the 4 week period 
before Visit 1 to calculate baseline 28-day seizure frequency.  Seizure frequency per 28 
days will be calculated as the number of seizures over the entire time interval divided by 
the number of days in the interval and multiplied by 28.  (revised per Amendment 02) 
• Responder Rate:  A responder is defined as a subject with atleast 50% decrease in 28-day 
seizure frequency while on treatment when compared to Baseline.  Analyses using the 2 
different baseline definitions above will be performed. For subjects who discontinue the 


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study with less than 8 weeks of seizure data in the Maintenance Period, the last 8 weeks of 
data after the first dose (or entire treatment duration if <8 weeks of data are available) will 
be used in lieu of Maintenance Period. 
• Seizure-free status:  The proportion of subjects who are seizure-free during the 
Maintenance Period  
• CGI-C  
Details on efficacy analyses for the Extension Phase can be found in Appendix 3. 
 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
PHARMACOKINETIC ANALYSES 
Determination of PK will be performed on the PK Analysis Set.  Perampanel plasma 
concentrations will be listed. 
A population PK approach will be used to characterize the PK of perampanel.  The effect of 
intrinsic and extrinsic factors (age, body weight, gender, race, ALT, AST, creatinine clearance, 
and concomitant therapy with carbamazepine, oxcarbazepine, phenytoin, phenobarbital, 
valproic acid, lamotrigine, topiramate, primidone, zonisamide, levetiracetam and primidone) 
on perampanel PK will be evaluated.  A 2-compartment disposition PK model with linear 
elimination will be parameterized for absorption rate, oral clearance (CL/F) and apparent 
central and peripheral volumes of distribution (V1/F and V2/F).  Derived exposure parameters 
such as the steady state peak concentration (Cmax,ss), area under concentration vs time curve at 
steady state (AUCss), and average steady-state drug concentration (Css,av) will be calculated 
using the individual posterior estimates of PK parameters from the final PK model.  Descriptive 
statistics of the individual model-predicted PK parameters including but not limited (Cmax,ss 
will be provided. 
Due to the small sample size, population PK analysis will be performed using NONMEM with 
first-order conditional estimation with interaction on data from this study pooled with existing 
rich data from 19 Phase 1 studies and sparse data from two Phase 2 studies (232 and 235), and 
5 Phase 3 Studies (304, 305, 306, 332 and 335).  A 2-compartment PK model will be fitted 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 AUC from the final PK mode will be derived for all subjects.  
Subsequently, dose-normalized derived exposure parameters will be summarised descriptively 
by age group (≤ 6 months, > 6 to ≤ 12 months, >12 to < 24 months, ≥ 24 months to ≤4 years, 
>4 to ≤ 8 years, > 8 to < 12 years, ≥12 to < 18 years and ≥18 years) and also presented in 
box-plots, stratified by subjects taking and not taking EIAEDs.  Additionally, dose-normalized 
derived exposure parameters will be summarized descriptively for the following age groups:  
1 to 24 months, 2 to ≤ 4 years, >4 to ≤ 8 years, >8 to <12 years, ≥12 to <18 years and ≥18 


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years), and also presented in box-plots, stratified by subjects with EIAEDs and non-EIAEDs.  
(revised per Amendment 02) 
The final PK model will be qualified using visual predictive checks and validated using 
bootstrap analysis. 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable. 
9.7.1.8 
Safety Analyses 
Evaluation of safety will be performed on the Safety Analysis Set. 
EXTENT OF EXPOSURE 
Duration of Treatment Phase (Titration Period + Maintenance Period) exposure will be 
calculated as the number of days between the date the subject received the first dose of study 
drug and the date the subject received the last dose of study drug in the Treatment Phase.  
Overall study compliance rate for each subject will be calculated as the mean compliance rate 
over all the visits.  
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 16.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database. 
A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment 
(Baseline) or  
• Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized by age group and by EIAED and non-EIAED.  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) and 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 treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe). 
Adverse events of special interest will also be summarized by SOC and PT using MedDRA 
SMQ terms. 
A subject data listing will be produced for all deaths, SAEs, and discontinuation due to an AE. 
Adverse events will be summarized using the Safety Analysis Set.   
LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.7.1.8, 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 and by age group using descriptive statistics.  Qualitative 
parameters listed in Section 9.7.1.8 will be summarized using frequencies (number and 
percentage of subjects), and changes from baseline to each postbaseline visit and to end of 
treatment will be reported using shift tables.  Percentages will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during 
the treatment period. 
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values (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.  When displaying the incidence 
of TEMAVs, each subject may be counted once in the laboratory parameter high and in the 
laboratory parameter low categories, as applicable. 
VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP [mmHg], pulse 
[beats per minute], respiratory rate [per minute], body temperature [in centigrade]), and growth 


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parameters including measurement of height, weight (kg) changes from baseline, head 
circumference) will be presented by visit and by age group. 
ELECTROCARDIOGRAMS 
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit 
and by age group. 
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 QTcF during the treatment period will be summarized.  Clinically borderline and 
abnormal ECG results in QTcF will be categorized as follows: 
Absolute QTc interval prolongation: 
• QTc interval 430-450 msec 
• QTc interval >450 msec 
• QTc interval >500 msec 
Change from baseline in QTc interval: 
• QTC interval increases from baseline 30-60 msec 
• QTC interval increases from baseline >60 msec 
OTHER SAFETY ANALYSES 
Growth 
Descriptive summary statistics of changes from baseline in height, weight, and head 
circumference will be evaluated for each cohort and overall.  This data will be compared with 
normative scores to assess clinical relevance. 
Changes from baseline for thyroid function and IGF-1 testing will be summarized. 
9.7.2 
Determination of Sample Size 
Study E2007-G000-238 will use population PK modeling to determine PK in pediatrics ≥1 to 
<24 months and from 2 to less than 4 years of age and compare these data to PK in adolescents 
and adults.  In Study E2007-G000-232, data were obtained in 42 pediatric subjects ≥2 to 
<12 years of age, with approximate equal numbers enrolled in the age ranges of ≥2 to ≤6 and 
≥7 to <12 years.  (revised per Amendment 02) 
Given the narrower age range planned for Study 238 compared with Study 232, and the fact 
that the PK data from this study will be pooled with the data from subjects ≥2 to <12 years of 
age, it is proposed that PK data obtained in at least 16 subjects ≥1 to <24 months of age would 


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be adequate to characterize the PK in this age group.  The sample size will be increased to at 
least 24 subjects if dose-normalized (to 8 mg) exposure in the Maintenance Period from the 
first 16 subjects in this study is not comparable to existing data in subjects aged ≥2 to 18 years. 
In order to compare the PK of pediatric subjects aged 2 to <4 years of age with the PK of 
pediatric subjects aged >4 years of age, a total of 26 subjects with 13 EIAED subjects and 
13 non-EIAED subjects will be enrolled and pooled across clinical studies of perampanel with 
PK assessment. This estimate of the required sample size assumes the inter-subject variability 
of 46.8% (CPMS-E2007-015-v1), equivalent to a coefficient of variation (CV) on the log scale 
of 0.445, that provides a sufficient number of subjects to target a 95% confidence interval 
within 60% and 140% of the point estimate for the geometric mean clearance of perampanel 
(equal to 0.638 L/h; determined using population PK modeling) with at least 80% power.  
(revised per Amendment 02) 
9.7.3 
Interim Analysis 
After every 4th subject in the age group 1 to less than 24 months completes the Maintenance 
Period an interim analysis (safety, tolerability, and PK) will be conducted where dose-
normalized exposure will be compared to that observed in other studies in subjects between ≥2 
and <18 years of age for evidence of systematic deviations potentially warranting dose 
adjustment in this age group or for other subjects enrolled in the study.  PK data collected in 
older age cohort (2 to less than 4 years) will also be examined in the interim PK analyses.  
(revised per Amendment 02) 
All data from the Pretreatment and Treatment Phases (Core Study) will be analyzed when all 
subjects have completed the Maintenance Period.  In addition, a final analysis of data from the 
Pretreatment, Treatment, and Extension Phases will be analyzed when all subjects have 
completed the Extension Phase. 
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. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the statistician determines that the analysis plan needs to be revised after this study starts, 
the person in charge of the analysis plan and the study director will examine the validity of the 
revision and the impact of the revision against the evaluation of this study and determine if the 
revision should be made.  The details of revision will be described in the clinical study report 
for this protocol. 


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10 REFERENCE LIST 
Bourgeois BF. Antiepileptic drugs in pediatric practice. Epilepsia. 1995;36:S34-S45. 
Fountain NB, Conry JA, Rodrıguez-Leyva I, Gutierrez-Moctezuma J, Salas E, Coupez R, et 
al. Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 
12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate. 
Epilepsy Research. 2007;74:60-9. 
Hauser WA. Seizure disorders: the changes with age. Epilepsia. 1992;33(Suppl 4):S6 S14. 
Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia. 
1994;35:S1-S6. 
ILAE guidelines.  Proposal for revised clinical and electrographic classification of epileptic 
seizures. From the Commission on Classification and Terminology of the International League 
Against Epilepsy. Epilepsia 1981;22(4):489-501. 
Northam RS, Hernandez AW, Litzinger MJ, Minecan DN, Glauser TA, Mangat S, et al. 
Oxcarbazepine in infants and young children with partial seizures. Pediatr Neurol. 
2005;33:337-44. 
Ouellet D, Bockbrader HN, Wesche DL, Shapiro DY, Garofalo E. Population 
pharmacokinetics of gabapentin in infants and children. Epilepsy Research. 2001;47:229-41. 
Pellock JM. Drug treatment in children. In: Engel J. Jr, Pedley TA, editors. Epilepsy: A 
Comprehensive Textbook. Philadelphia, PA: Lippincott-Raven Publishers; 1998; 1205 10. 
Piña-Garza JE, Espinoza R, Nordli D, Bennett DA, Spirito S, Stites TE, et al. Oxcarbazepine 
adjunctive therapy in infants and young children with partial seizures. Neurology. 
2005;65:1370-5. 
Ramsey RE, Shields WD, Shinnar S. Special issues in the management of young children, 
older adults, and the developmentally disabled. J Child Neurol. 2007;22(5 Suppl):53S-60S.  
Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nature Reviews 
Neuroscience. 2004;5(7):553–64. 
Zebinix® Summary of Product Characteristics. 


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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 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 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. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.   
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the investigator 
is responsible for retaining all study documents, including but not limited to the protocol, 
copies of CRFs, the Investigator's Brochure, and regulatory agency registration documents (eg, 
Form FDA 1572, ICFs, and IRB/IEC correspondence.  The site should plan to retain study 


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documents, as directed by the sponsor, for at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 3 years have elapsed since the formal discontinuation 
of clinical development of the investigational product. 
It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department may conduct 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. 
11.8 Handling of Study Drug 
Perampanel is a Schedule III Controlled Drug Substance in the United States. 
All study drug(s) will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and 
stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of the 
study drug in a drug accountability ledger, a copy of which must be given to the sponsor at the 
end of the study.  An accurate record of the date and amount of study drug dispensed to each 
subject must be available for inspection at any time.  The CRA will visit the site and review 
these documents along with all other study conduct documents at appropriate intervals once 
study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form to 
the sponsor’s CRA. 
11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission pursuant 
to the terms and conditions set forth in the executed Clinical Trial Agreement between the 
sponsor/CRO and the institution/investigator.  The review is aimed at protecting the sponsor's 
proprietary information existing either at the date of the commencement of the study or 
generated during the study. 


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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). 
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. 


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12 APPENDICES 
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 – 3.0 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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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), GGT = γ-glutamyl transpeptidase, N/A = not applicable, 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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Appendix 2 
Total Blood Volumes  (revised per Amendment 02) 
Non-EIAED Subjects 
 
Minimum Blood Volumes Required (mL)a 
 
Core Study  
(Pretreatment Phase + Treatment Phase) 
Extension Phase 
 
V1 
V2 V3 V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 F/U 
Chemistry  
0.5 
 
 
 
 
0.5 
 
0.5 
0.5 
0.5 
0.5 
0.5 
Hematology 
0.5 
 
 
 
 
0.5 
 
0.5 
0.5 
0.5 
0.5 
0.5 
TSH, fT3, fT4 
0.5 
 
 
 
 
 
 
0.5 
0.5 
 
0.5 
 
IGF-1 
0.5 
 
 
 
 
 
 
0.5 
0.5 
 
0.5 
 
Perampanel PK 
 
 
 
 
1.0 
 
1.0b/2.0c 1.0b/2.0c 
 
 
 
 
Approximate total blood 
volume sampled during 
each visit (mL) 
2.0 
 
 
 
1.0 
1.0 1.0b/2.0c 3.0b/4.0c 2.0 
1.0 
2.0 
1.0 
Approximate total blood 
volume per subject (mL) 
~14.0b to 16.0c 
fT3 = free triiodothyronine; fT4 = free thyroxine; F/U = follow-up; IGF-1 = insulin-like growth factor-1; PK = 
pharmacokinetics; TSH = thyroid-stimulating hormone; V = visit. 
a: 
Assumes no retesting. 
b: 
For subjects aged 1 to less than 24 months.  (revised per Amendment 02) 
c: 
For subjects aged 2 to less than 4 years.  (revised per Amendment 02) 
 
EIAED Subjects 
 
Minimum Blood Volumes Required (mL)a 
 
Core Study  
(Pretreatment Phase + Treatment Phase) 
Extension Phase 
 
V1 V2 V3 V4 V5 
V6 
V7 
V8 
V9 
V10 V11 V12 F/U 
Chemistry  
0.5 
 
 
 
 
0.5 
0.5 
 
0.5 
0.5 
0.5 
0.5 
0.5 
Hematology 
0.5 
 
 
 
 
0.5 
0.5 
 
0.5 
0.5 
0.5 
0.5 
0.5 
TSH, fT3, fT4 
0.5 
 
 
 
 
 
 
 
0.5 
0.5 
 
0.5 
 
IGF-1 
0.5 
 
 
 
 
 
 
 
0.5 
0.5 
 
0.5 
 
Perampanel PK 
 
 
 
 
 
1.0 
 
1.0b/2.0c 1.0b/2.0c 
 
 
 
 
Approximate total blood 
volume sampled during 
each visit (mL) 
2.0 
 
 
 
 
1.0 
1.0 1.0b/2.0c 3.0b/4.0c 2.0 
1.0 
2.0 
1.0 
Approximate total blood 
volume per subject (mL) 
~14.0b to 16.0c 
fT3 = free triiodothyronine; fT4 = free thyroxine; F/U = follow-up; IGF-1 = insulin-like growth factor-1; PK = 
pharmacokinetics; TSH = thyroid-stimulating hormone; V = visit. 
a: 
Assumes no retesting. 
b: 
For subjects aged 1 to less than 24 months.  (revised per Amendment 02) 
c: 
For subjects aged 2 to less than 4 years.  (revised per Amendment 02) 
 
 


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Appendix 3 
Extension Phase 
Eligibility Criteria 
Subjects who meet the following will be eligible to participate in the Extension Phase of this 
study: 
• Have completed the last visit of the Maintenance Period of the Core Study 
Study Design and Plan 
During the 32-36-week Maintenance Period of the Extension Phase, subjects will continue 
taking perampanel oral suspension, at the dose level achieved at the end of the Treatment Phase.  
The maximum total daily dose a subject will be allowed is 12 mg for non-EIAED subjects and 
16 mg for EIAED subjects. 
Study Drug Supplies 
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 Substance in the United States and will be labeled as 
such for US sites. 
Perampanel oral suspension will be provided by Eisai to an Eisai-approved vendor in 400-mL 
PET bottles containing 340 mL of oral suspension. The approved vendor will label the bottles, 
place the bottles, suitably sized dosing devices (ie, oral syringes), and appropriately sized bottle 
adapters for accurate aliquotting (ie, PiBAs) into a tamper-evident sealed carton, and ship them 
to the study sites. During the Extension Phase, parents/guardians will be provided with a bottle 
or bottles of suspension that can be redispensed or replaced at the next visit.  Each bottle 
provided will be in a tamper-evident sealed carton that will also contain oral syringes and 
PiBAs.  Instructions regarding routine dosages during the Extension Phase will be provided by 
the site. 
Treatments Administered 
• 
Maintenance Period (32-36 weeks):  Subjects will continue taking perampanel oral 
suspension, at the dose level achieved at the end of the Treatment Phase.  The maximum 
total daily dose a subject will be allowed is 12 mg for non-EIAED subjects or 16 mg 
for EIAED subjects. 
Dose adjustment during this phase is allowed if necessary, per the investigator’s clinical 
judgment.  Subjects must return to the clinic for an unscheduled visit for any dose 
increase.  However, dose decreases can be done via telephone. 


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All dose adjustments during this phase will be done by going one dose level up or 
down.  Subjects who do not tolerate a dose of 0.5 mg/day will be discontinued from the 
study. 
Changes of concomitant AEDs (addition, deletion or adjustment in dose) will be 
allowed. However, if changes do occur subjects should be carefully monitored, 
especially when switching between an EIAED and a non-EIAED. 
• Follow-Up Period (4 weeks):  No study drug will be administered during Follow-up 
Period.  All subjects will be required to complete the Follow-up Period after their last 
dose in the Extension Phase, except for subjects who switch to commercially available 
perampanel or who enter EAP upon completion of study treatment. For these subjects, 
sites will conduct a telephone contact 28 (+6) days after the last dose of study drug to 
follow adverse events (AEs) and report any serious adverse events (SAEs) that occur 
within 28 days of the last study drug administration.  (revised per Amendment 02) 
The Schedule of Procedures/Assessments for the 36 - 40-week Extension Phase of the study is 
presented in Table 6 and Table 7. 
 


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Table 6 Schedule of Procedures/Assessments in Study E2007-G000-238:  Extension Phase – 
Non-EIAED Subjects 
Phase 
Extensiona 
 
 
Period 
Maintenance 
Follow-Upb 
Visit 
9 
10 
11 
 
Early 
Discontinuation 
Unscheduled  
Week 
28 
40 
52 
56 
 
 
Days 
197 
281 
365 
393 
 
 
Procedures/Assessments 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Study drug compliance 
X 
X 
X 
 
X 
X 
Dispense study drug 
X 
X 
 
 
 
Xc 
Retrieve unused study drug 
X 
X 
X 
 
X 
Xc 
Dispense subject’s diary 
X 
X 
X 
 
X 
Xd 
Retrieve and review subject diary 
X 
X 
X 
X 
X 
Xd 
Physical examinatione 
X 
 
X 
 
X 
 
Neurological examinatione 
X 
 
X 
 
X 
 
Vitals and weight 
X 
X 
X 
 
X 
X 
Height/lengthf 
X 
 
X 
 
X 
 
Head circumference  
X 
 
X 
 
X 
 
Clinical laboratory testsg 
X 
X 
Xh 
X 
Xh 
Xi 
Thyroid function (TSH, fT3, fT4) and IGF-1 tests 
X 
 
X 
 
X 
 
12-lead ECGj 
X 
 
X 
 
X 
Xk 
CGI-C 
 
 
X 
 
X 
 
Telephone calll 
X 
X 
X 
 
 
 
Disposition 
 
 
X 
 
X 
 


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Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page 85 of 93  
 
AE = Adverse event, AED = Anti-epileptic drug, CGI-C = Clinical Global Impression of Change, CRF = case report form, EAP = extended access 
program, ECG = electrocardiogram, EOT = End of Treatment, fT3 = free triiodothyronine, fT4 = free thyroxine, IGF-1 = insulin-like growth 
factor-1, SAE = serious adverse event, TSH = thyroid-stimulating hormone. 
a: 
All visits to be done within ± 6 days of the schedule.  
b: 
The Follow-up Visit (4 weeks ± 6 days after the last dose of study medication) applies to those subjects who complete the entire study and 
those who discontinue early during the Extension Phase.  Subjects who switch to commercially available perampanel or who enter into EAP 
upon completion of study treatment will not need to undergo Follow-up Visit; however, sites will conduct a telephone contact 28 (+6) days 
after the last dose of study drug to follow AEs and report any SAEs that occur within 28 days of the last study drug administration.  (revised 
per Amendment 02) 
c: 
Unused study drug to be retrieved and study drug dispensed only for subjects requiring dose increases at Unscheduled Visits. 
d: 
As needed. 
e: 
For clinic visits other than those specified, physical and complete neurological exams, including evaluation of the cranial nerves, motor, 
sensory, brainstem, cerebellar, and autonomic functions, will only be performed when there is a complaint from the parent/guardian.  Clinically 
significant abnormal findings from the physical or the neurological examinations must be reported as AEs.  
f: 
Two measurements of height/length should be taken.  Each measurement should be recorded as a separate entry on the Vital Sign CRF.  
g: 
Clinical laboratory tests include hematology and blood chemistry. 
h: 
Lipid and blood glucose tests must be conducted under fasting conditions, whenever practically feasible.  (revised per Amendment 02) 
i: 
During the unscheduled visits, clinical laboratory tests will only be done if an abnormality was noted at the previous visit or per the discretion 
of the investigator. 
j: 
If the subject has a normal ECG baseline reading, but during any visit thereafter if there is any clinically significant ECG abnormality (as 
determined by the investigator), 3 consecutive ECGs separated by 5 to 10 minutes will be performed at that visit to confirm the abnormality.  
k: 
During the unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the 
investigator.  
l: 
Telephone interviews with the parent/guardian will be conducted approximately 6 weeks following Visit 8 through Visit 11 to ensure that 
subjects are completing their seizure diaries regularly and assess AEs, study drug compliance and concomitant medications, including AEDs 
and to remind the subjects that they are to complete their seizure diary.  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.  Subjects will then return for their regularly scheduled visits.  All subjects will have a telephone interview at 
approximately the midpoint between Visit 11 and the Follow-up Visit when drug has been stopped.  Subjects who discontinue the study at any 
time will have a telephone interview at approximately the midpoint between the EOT Visit and the Follow-up Visit.  For subjects who will not 
need to undergo Follow-up Visit (eg, when switching to commercially available Fycompa or enetering EAP after the last study drug 
administration), sites will conduct a telephone contact 28 (+6) days after the last dose of study drug to follow AEs and report any SAEs that 
occur within 28 days of the last study drug administration.  (revised per Amendment 02) 
 


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Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
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Table 7 Schedule of Procedures/Assessments in Study E2007-G000-238:  Extension Phase - 
EIAED Subjects 
Phase 
Extensiona 
 
 
Period 
Maintenance 
Follow-Upb 
Visit 
10 
11 
12 
 
Early 
Discontinuation 
Unscheduled  
Week 
32 
44 
52 
56 
 
 
Days 
225 
309 
365 
393 
 
 
Procedures/Assessments 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Concomitant AEDs 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Study drug compliance 
X 
X 
X 
 
X 
X 
Dispense study drug 
X 
X 
 
 
 
Xc 
Retrieve unused study drug 
X 
X 
X 
 
X 
Xc 
Dispense subject’s diary 
X 
X 
X 
 
X 
Xd 
Retrieve and review subject diary 
X 
X 
X 
X 
X 
Xd 
Physical examinatione 
X 
 
X 
 
X 
 
Neurological examinatione 
X 
 
X 
 
X 
 
Vitals and weight 
X 
X 
X 
 
X 
X 
Height/lengthf 
X 
 
X 
 
X 
 
Head circumference  
X 
 
X 
 
X 
 
Clinical laboratory testsg 
X 
X 
Xh 
X 
Xh 
Xi 
Thyroid function (TSH, fT3, fT4) and IGF-1 tests 
X 
 
X 
 
X 
 
12-lead ECGj 
X 
 
X 
 
X 
Xk 
CGI-C  
 
 
X 
X 
X 
 
Telephone calll 
X 
X 
X 
 
 
 
Disposition 
 
 
X 
 
X 
 
 
 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
Confidential 
Page 87 of 93  
 
AE = Adverse event, AED = Anti-epileptic drug, CGI-C = Clinical Global Impression of Change, CRF = case report form, EAP = extended access 
program, ECG = electrocardiogram, EOT = End of Treatment, fT3 = free triiodothyronine, fT4 = free thyroxine, IGF-1 = insulin-like growth factor-
1, SAE = serious adverse event, TSH = thyroid-stimulating hormone. 
a: 
All visits to be done within ± 6 days of the schedule.  
b: 
The Follow-up Visit (4 weeks ± 6 days after the last dose of study medication) applies to those subjects who complete the entire study and 
those who discontinue early during the Extension Phase.  Subjects who switch to commercially available perampanel or who enter into EAP 
upon completion of study treatment would not need to undergo Follow-up Visit; however, sites will conduct a telephone contact 28 (+6) days 
after the last dose of study drug to follow AEs and report any SAEs that occur within 28 days of the last study drug administration.  (revised 
per Amendment 02) 
c: 
Unused study drug to be retrieved and study drug dispensed only for subjects requiring dose increases at Unscheduled Visits. 
d: 
As needed. 
e: 
For clinic visits other than those specified, physical and complete neurological exams, including evaluation of the cranial nerves, motor, 
sensory, brainstem, cerebellar, and autonomic functions, will only be performed when there is a complaint from the parent/guardian.  Clinically 
significant abnormal findings from the physical or the neurological examinations must be reported as AEs.  
f: 
Two measurements of height/length should be taken.  Each measurement should be recorded as a separate entry on the Vital Sign CRF.  
g: 
Clinical laboratory tests include hematology and blood chemistry. 
h: 
Lipid and blood glucose tests must be conducted under fasting conditions, whenever practically feasible.  (revised per Amendment 02). 
i: 
During the unscheduled visits, clinical laboratory tests will only be done if an abnormality was noted at the previous visit or per the discretion 
of the investigator. 
j: 
If the subject has a normal ECG baseline reading, but during any visit thereafter if there is any clinically significant ECG abnormality (as 
determined by the investigator), 3 consecutive ECGs separated by 5 to 10 minutes will be performed at that visit to confirm the abnormality.  
k: 
During the unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the 
investigator. 
l: 
Telephone interviews with the parent/guardian will be conducted approximately 6 weeks following Visit 9 through Visit 11 and at 
approximately the midpoint between Visit 11-12 to ensure that subjects are completing their seizure diaries regularly and assess AEs, study 
drug compliance and concomitant medications, including AEDs and to remind the subjects that they are to complete their seizure diary.  
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.  Subjects will then return for their regularly 
scheduled visits.  All subjects will have a telephone interview at approximately the midpoint between Visit 12 and the Follow-up Visit when 
drug has been stopped.  Subjects that discontinue the study at any time, will have a telephone interview at approximately the midpoint between 
the EOT Visit  and the Follow-up Visit.  For subjects who will not need to undergo Follow-up Visit (eg, when switching to commercially 
available Fycompa or enetering EAP after the last study drug administration), sites will conduct a telephone contact 28 (+6) days after the last 
dose of study drug to follow AEs and report any SAEs that occur within 28 days of the last study drug administration.  (revised per 
Amendment 02) 
 


Clinical Study Protocol 
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E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
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EXTENSION PHASE STATISTICAL ANALYSES 
All statistical analyses will be performed by the sponsor or designee. Statistical programming 
and analyses will be performed using SAS and/or other validated software. 
DEMOGRAPHICS 
Demographic and Baseline characteristics will be summarized.  For continuous variables (eg, 
age, weight) the number of non-missing values, median, mean, standard deviation (SD), and 
minimum and maximum will be displayed. For categorical variables (eg, gender, ethnicity) the 
counts and proportions of each value will be tabulated. 
ANALYSIS OF EFFICACY 
Efficacy will be assessed in the Extension Phase with the following: 
• Seizure Frequency:  Percentage change in 28-day seizure frequency in the Extension Phase 
compared to baseline.  The primary analysis will use data prospectively collected during 
the 2-week Pretreatment Phase to calculate baseline 28-day seizure frequency.  A 
secondary analysis will use data prospectively collected during the 2-week Pretreatment 
Phase plus data retrospectively collected during the 4 week period before Visit 1 to 
calculate baseline 28-day seizure frequency.  (revised per Amendment 02) 
• Responder Rate:  A responder is defined as a subject with a 50% decrease in 28-day seizure 
frequency during the Extension Phase when compared to baseline.  The responder rate will 
be summarized.  Analyses using the 2 different baseline definitions above will be 
performed. 
• Seizure-free status:  The proportion of subjects who are seizure-free will be summarized 
during the Extension Phase 
• CGI-C 
PHARMACOKINETIC ANALYSES 
Not applicable. 
PHARMACODYNAMIC ANALYSES 
Not applicable. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
Not applicable. 
PHARMACOGENOMIC ANALYSES 
Not applicable. 


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ANALYSIS OF SAFETY 
The safety of the study population exposed to perampanel will be examined based on nature, 
frequency, and severity of AEs, chemistry and hematology laboratory test results, vital signs, 
and 12-lead ECG abnormalities over the treatment period.  Any potential safety signal will be 
explored by analysis of safety data by dose achieved in the study. 
EXTENT OF EXPOSURE 
Duration of Extension Phase exposure will be calculated as the number of days between the 
date the subject received the first dose of study drug and the date the subject received the last 
dose of study drug in the Extension Phase. 
Overall Extension Phase compliance rate for each subject will be calculated as the mean 
compliance rate over all the visits.  
ADVERSE EVENTS 
Adverse events will be classified into standardized medical terminology from the verbatim 
description (investigator term) using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be presented by preferred term nested within SOC.  Verbatim 
description and MedDRA level terms, for all AEs will be contained in the data listings of the 
clinical study report for this protocol.  
The TEAEs will be summarized by age group and by EIAED and non-EIAED groups.  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) and by relationship to study drug (Yes [related] and No [not related]). 
Adverse events of special interest will also be summarized by SOC and PT using MedDRA 
SMQ terms. 
A subject data listing will be produced for all deaths, SAEs, and discontinuation due to an AE. 
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 treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe). 
Treatment-emergent adverse events are defined as: 
• Adverse events that emerge during treatment, having been absent at pretreatment 
(Baseline) 
• Reemerge during treatment, having been present at Baseline but stopped prior to 
treatment 


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• Worsen in severity during treatment relative to the pretreatment state, when the AE is 
continuous 
LABORATORY VALUES 
Clinical laboratory values will be evaluated for each laboratory parameter by subject.  
Descriptive summary statistics (eg, mean, standard deviation, median, minimum, maximum) 
for the laboratory parameters and changes from baseline (Visit 1) to the last visit in the 
Extension Phase (Follow-up Visit, Week 56) will be summarized by cohort and overall. 
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.  Shift tables will be used to compare the baseline (Visit 1) LNH classification to the 
LNH classification at end of study. 
Clinical laboratory results post-baseline will be evaluated for markedly abnormal values. 
Appendix 1 presents the Sponsor’s Grading for Laboratory Values that will be used to identify 
subjects with markedly abnormal laboratory values. For the incidence of markedly abnormal 
laboratory values, each subject may be counted once in the laboratory parameter value high 
and in the laboratory parameter low categories as applicable. 
VITAL SIGNS 
Vital sign values will be evaluated on an individual basis by subject.  Abnormal vital sign 
values will be identified as those outside (above or below) the reference range, where 
appropriate.  Reference ranges for vital sign parameters will be included in the clinical study 
report for this protocol.  Descriptive summary statistics (eg, mean, standard deviation, median, 
minimum, maximum) for vital sign parameters and changes from baseline (Visit 2) to each 
visit and to the last visit in the Extension Phase (Follow- up Visit, Week 56) will be evaluated 
for each cohort and overall. 
ECG RESULTS 
For 12-lead ECG parameters, changes from baseline (Visit 1) to the last visit in the Extension 
Phase (Follow-up Visit, Week 56) will be summarized for each cohort and overall. 
QTc (QTcF) and PR variables will also be analyzed to include a summary of the following: 
• Number of subjects with QTc in the borderline or abnormal category (430-450 msec, 
>450 msec, and >500 msec) during treatment, and 
• Number of subjects with an increment of 30-60 msec and > 60 msec from baseline (Visit 1). 


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Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
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OTHER ANALYSES 
Growth 
Descriptive summary statistics of changes from baseline in height and weight will be evaluated 
for each cohort and overall.  This data will be compared with normative scores to assess clinical 
relevance. 
Changes from baseline for thyroid function and IGF-1 testing will be summarized. 


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
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Page 92 of 93  
 
PROTOCOL SIGNATURE PAGE 
Study Protocol Number: 
E2007-G000-238 
Study Protocol Title: 
An Open-Label Study With an Extension Phase to Evaluate the 
Pharmacokinetics of Perampanel (E2007) Oral Suspension When 
Given as an Adjunctive Therapy in Subjects From 1 Month to Less 
Than 4 Years of Age With Epilepsy  (revised per Amendment 02) 
Investigational Product 
Name: 
E2007  
IND Number: 
112515 
EudraCT Number: 
2013-005391-17 
 
SIGNATURES 
 
 
Authors: 
 
 
 
 
 
 
 
 
 
 
 
 
Neurology Business Group 
Eisai Inc. 
 
Date 
 
 
 
 
 
 
 
 
 Neurology 
Business Group 
Eisai Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
Eisai Inc. 
 
Date 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol 
(Amendment 02) 
E2007-G000-238 
 
 
 
Eisai 
FINAL:  v6.0, 09 Apr 2020 
 
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Page 93 of 93  
 
INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E2007-G000-238 
Study Protocol Title: 
An Open-Label Study With an Extension Phase to Evaluate the 
Pharmacokinetics of  Perampanel (E2007) Oral Suspension 
When Given as an Adjunctive Therapy in Subjects From 
1 Month to Less Than 4 Years of Age With Epilepsy  (revised 
per Amendment  02) 
Investigational Product 
Name: 
E2007 
IND Number: 
112515 
EudraCT Number: 
2013-005391-17 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki. 
 
 
 
<Name of institution> 
Medical Institution 
<Name, degree(s)> 
  
  
Investigator 
 Signature 
 Date 
 
 

SAP_003.pdf: 
Statistical Analysis Plan
E2007-G000-238
Eisai
Final Version 2.0, 13 Feb. 2023
Confidential
Page 1 of 26
STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2007-G000-238
Study Protocol 
Title:
An Open-Label Study with an Extension Phase to Evaluate the 
Pharmacokinetics of Perampanel (E2007) Oral Suspension When 
Given as an Adjunctive Therapy in Subjects From 1 Month to Less 
Than 4 years of Age with Epilepsy
Date:
13 February 2023
Version:
Version 2.0


Statistical Analysis Plan
E2007-G000-238
Eisai
Final Version 2.0, 13 Feb. 2023
Confidential
Page 2 of 26
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 ......................................................................................6
3.1.2
Secondary Objectives .................................................................................6
3.1.3
Exploratory Objective ................................................................................6
3.2
Overall Study Design and Plan.............................................................................7
4
DETERMINATION OF SAMPLE SIZE.......................................................................8
5
STATISTICAL METHODS..........................................................................................8
5.1
Study Endpoints...................................................................................................9
5.1.1
Primary Endpoint .......................................................................................9
5.1.2
Secondary Endpoints..................................................................................9
5.1.3
Exploratory Endpoints................................................................................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
Medical History........................................................................................10
5.2.6
Prior and Concomitant Therapy................................................................11
5.2.7
Treatment Compliance .............................................................................11
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...........................................................12
5.3.4
Examination of Subgroups........................................................................12
5.3.5
Handling of Missing Data, Dropouts, and Outliers....................................12
5.4
Exploratory Efficacy Analyses...........................................................................12
5.4.1
Primary Exploratory Efficacy Analyses....................................................13
5.4.2
Secondary Exploratory Efficacy Analyses ................................................13
5.4.3
Other Exploratory Efficacy Analyses........................................................13
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................13
5.5.1
Pharmacokinetic Analyses........................................................................13
5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses....14


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5.6
Safety Analyses..................................................................................................14
5.6.1
Extent of Exposure...................................................................................14
5.6.2
Adverse Events.........................................................................................14
5.6.2.1
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events...............................................................................15
5.6.2.2
AEs of Special Interest....................................................................15
5.6.3
Laboratory Values ....................................................................................16
5.6.4
Vital Signs................................................................................................16
5.6.5
Electrocardiograms...................................................................................16
5.6.6
Other Safety Analyses ..............................................................................17
5.7
Other Analyses...................................................................................................17
5.8
Exploratory Analyses.........................................................................................17
5.9
Extension Phase Analyses..................................................................................17
6
INTERIM ANALYSES...............................................................................................17
7
CHANGES IN THE PLANNED ANALYSES ............................................................18
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................18
8.1
EFFICACY DATA HANDLING.......................................................................18
8.1.1
Baseline efficacy Data..............................................................................18
8.1.2
Handling of Missing Efficacy Data, Drop-outs, and Outliers ....................18
8.2
SAFETY DATA HANDLING...........................................................................19
8.2.1
Baseline safety Data .................................................................................19
8.2.2
Visit Windows for Safety Data .................................................................19
8.2.3
Handling of Replicate Data.......................................................................20
9
PROGRAMMING SPECIFICATIONS .......................................................................21
10
STATISTICAL SOFTWARE......................................................................................21
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................21
12
REFERENCES............................................................................................................22
13
APPENDICES.............................................................................................................23
13.1
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results.....23
13.2
Age and Sex Specific Percentile Calculation for Weight and Height ..................25


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE(s)
adverse event(s)
AED
antiepileptic drug
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomical therapeutic class
BMI
body mass index 
BP 
blood pressure 
CGI
Clinical Global Impression
CGIC
Clinical Global Impression of Change
CGIS
Clinical Global Impression of Severity
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
electronic case report form
EIAED
enzyme-inducing antiepileptic drugs
EOT
End of treatment 
FAS
Full Analysis Set
IGF-1
insulin-like growth factor-1
LLN
lower limit of normal
LNH
low/normal/high
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamics
PK
Pharmacokinetics
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
SAS
Safety Analysis Set
SD
Standard Deviation 


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Abbreviation
Term
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 DD
World Health Organization Drug Dictionary


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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 study of Eisai 
Protocol E2007-G000-238 in pediatric subjects from 1 month to less than 4 years of age with 
epilepsy. The statistical methods for the Extension Phase will be described in a separate SAP.
3.1
Study Objectives
3.1.1
Primary Objective
To evaluate the pharmacokinetics (PK) of perampanel during the Maintenance Period of the 
Core Study following oral suspension administration given as an adjunctive therapy in 
pediatric subjects from 1 month to less than 4 years of age with epilepsy.
3.1.2
Secondary Objectives

To evaluate the short- and long-term safety and tolerability of perampanel oral 
suspension, given as an adjunctive therapy, in subjects from 1 month to less than 4
years of age with epilepsy 

To evaluate the long-term effect of perampanel oral suspension, given as an 
adjunctive therapy, on growth from baseline to end of treatment in pediatric subjects 
from 1 month to less than 4 years of age with epilepsy 
3.1.3
Exploratory Objective
The exploratory study objective was to explore the short- and long-term efficacy of 
perampanel oral suspension, given as an adjunctive therapy, in subjects from 1 month to less 
than 4 years of age with epilepsy as assessed by:

Percent change in 28-day seizure frequency during the Titration + Maintenance 
Periods compared to baseline and during the Extension Phase compared to baseline

Proportion of subjects with a 50% decrease in 28-day seizure frequency during the 
Maintenance Period compared to baseline and during the Extension Phase compared 
to baseline

Proportion of subjects who are seizure-free during the Maintenance Period and during 
the Extension Phase

Clinical Global Impression (CGI) of change (CGI-C)


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3.2
Overall Study Design and Plan
This was a multicenter, open-label study with an extension phase that was planned to enroll
16 to 24 pediatric subjects 1 to less than 24 months of age and at least 1 to a maximum of 26 
pediatric subjects from 2 to less than 4 years of age with epilepsy.  All subjects had been 
taking 1 to a maximum of 4 antiepilepsy drugs (AEDs) to participate in the study.  For at 
least 6 but not more than 8 of the subjects in the age group of 1 to less than 24 months and 
for 13 subjects in the age group of 2 to less than 4 years (across studies), only 1 enzyme 
inducing antiepilepsy drug (EIAED) (ie, carbamazepine [CBZ], oxcarbazepine [OXC], 
phenytoin [PHT], or eslicarbazepine [ESL]) out of the maximum of 4 AEDs was allowed.  
These subjects were referred to as EIAED subjects.  The remaining subjects were not taking 
any EIAEDs were referred to as non-EIAED subjects.  For the age group of 1 to less than 24 
months, the Sponsor aimed to ensure a reasonable representation of subject age (ie, at least 
6 subjects in the age range ≥1 to ≤6 months, at least 5 subjects in the age range 6 to ≤12 
months and at least 5 subjects in the age range 12 to <24 months).  For the age group of 2 to 
less than 4 years, the required number of subjects (total of 26) can be pooled across multiple 
studies for PK and safety assessments in pediatric subjects of 2 to less than 4 years of age.
This study consisted of 3 phases:  Pretreatment and Treatment (Core Study), and Extension.  
The Pretreatment Phase lasted up to 2 weeks, during which subjects were assessed for their 
eligibility to participate in the study.  The Treatment Phase consisted of 3 periods:  Titration 
(12-16 weeks), Maintenance (4 weeks), and Follow-Up (4 weeks; only for those subjects 
who completed the Maintenance Period but did not continue into the Extension Phase).  The 
Extension Phase consisted of 2 periods:  Maintenance (32-36 weeks) and Follow-Up 
(4 weeks). The end of the study was the date of the last study visit for the last subject.
The maximum total duration of treatment for each subject was 52 weeks and the maximum 
total duration of the study for each subject was 58 weeks.  
An overview of the study design was presented in Figure below.


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4
DETERMINATION OF SAMPLE SIZE
Study E2007-G000-238 used population PK modeling to determine PK in pediatrics ≥1 to 
<24 months of age and from 2 to less than 4 years of age and compared these data to PK in 
adolescents and adults.  In Study E2007-G000-232, data were obtained in 42 pediatric 
subjects ≥2 to <12 years of age, with approximate equal numbers enrolled in the age ranges 
of ≥2 to ≤6 and ≥7 to <12 years.  
Given the narrower age range planned for Study 238 compared with Study 232, and the fact 
that the PK data from this study would be pooled with the data from subjects ≥2 to <12 years 
of age, it was proposed that PK data obtained in at least 16 subjects ≥1 to <24 months of age
would be adequate to characterize the PK in this age group.  In addition, Study 238 PK data 
in at least 16 subjects in this age group would account for more than 25% of the data 
obtained for perampanel overall in subjects ≥1 month to <12 years of age, confirming 
appropriate assessment and representation of this age group in the overall assessment of PK 
and safety in the pediatric population.  The sample size was to be increased to at least 
24 subjects if dose-normalized (to 8 mg) exposure in the Maintenance Period from the first 
16 subjects in this study was not comparable to existing data in subjects aged ≥2 to 18 years.
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 performed by age cohort (1 to ≤ 6 
months, > 6 to ≤ 12 months, >12 to < 24 months, and ≥24 to <48 months) and overall, unless 
stated otherwise.


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5.1
Study Endpoints
5.1.1
Primary Endpoint
The primary endpoint of this study is to evaluate PK of perampanel during the Maintenance 
Period of the Core Study following oral suspension administration given as an adjunctive 
therapy in pediatric subjects from 1 month to less than 4 years of age with epilepsy, using a 
population PK approach. Details regarding PK analysis will not be described in this SAP but 
will be described in a separate analysis plan.
5.1.2
Secondary Endpoints
Secondary endpoints are safety and tolerability endpoints including incidence of treatment-
emergent adverse events (TEAEs) and serious adverse events (SAEs), clinical laboratory 
parameters, vital signs, ECG parameters, and growth parameters (height, weight, head 
circumference, thyroid function, and IGF-1 levels).
5.1.3
Exploratory Endpoints
The efficacy endpoints are:
•
Seizure frequency:  Percent change in 28-day seizure frequency during the Treatment 
Phase and during the Extension Phase, compared to baseline.  
•
Responder rate:  Proportion of subjects with a 50% decrease in 28-day seizure frequency 
during the Maintenance Period and during the Extension Phase, compared to baseline.  
•
Seizure-free rate:  Proportion of subjects who are seizure-free during the Maintenance 
Period and during Extension Phase.
•
Clinical Impression of change (CGI-C) at the end of core and extension phase.
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 study drug, had seizure 
frequency >0 during baseline period and had any seizure frequency data during the Treatment 
Phase.
The Modified Full Analysis Set (Modified FAS) is the group of subjects who received study 
drug and had any seizure frequency data during the Treatment Phase.


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5.2.2
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed
screening and the reasons for screen failure will be summarized, based on data reported on 
the Screening Disposition electronic case report form (eCRF). The distribution of the number 
of subjects enrolled by each site will be summarized.
The number (percentage) of treated subjects who completed the Core Study and who
discontinued early from the Core Study will be summarized according to the primary reason 
for early discontinuation and other reason(s) for early discontinuation, based on data reported 
on the core study disposition eCRF.
5.2.3
Protocol Deviations
The number (percentage) of subjects with major protocol violations will be summarized.
Major protocol deviation criteria include the following:

Subject is less than 1 month or over 4 years of age at the time of consent/assent.

Incorrect diagnosis of epilepsy according to the International League Against
Epilepsy’s Classification of Epileptic Seizures (1981).

Subject was on more than 1 inducer AED (i.e., carbamazepine, oxcarbazepine,
phenytoin) out of the maximum of 4 AEDs allowed.

Subject stops or interrupted any approved AEDs the subject was on at baseline
OR was on >4 AEDs.

Non-compliance with study drug defined as overall compliance of <80% or >120%. 
For subjects where treatment compliance cannot be calculated, major deviations as 
recorded in the protocol deviation log for compliance will be used.

Subjects with missing PK data at all PK timepoints, except when a subject was 
discontinued early from the study before reaching the first PK visit.
5.2.4
Demographic and Other Baseline Characteristics
The demographics and other baseline characteristics of the Safety Analysis Set will be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and maximum) for 
continuous variables, and using numbers and percentages for categorical variables. Continuous 
demographic and baseline variables include age, weight, height, body mass index (BMI) and 
body surface area; categorical variables include sex, race, and ethnicity. 
5.2.5
Medical History 
The number (percentage) of subjects in the SAS reporting a history of any medical condition, 
as recorded on the eCRF, will be summarized.


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Clinical Global Impression of Severity at baseline will be summarized. 
Epilepsy-specific medical history (etiology, time from diagnosis to Visit 1, seizure type) will 
be summarized. A subject data listing of medical history will be provided. 
5.2.6
Prior and Concomitant Therapy
Prior and concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary (WHO DD) drug codes.  Concomitant medications will be 
further coded to the appropriate Anatomical-Therapeutic-Chemical (ATC) code indicating 
therapeutic classification. 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 (i.e., therapeutic class), and WHO DD preferred term. Prior 
medications are defined as medications that stopped before the first dose of study drug. 
Concomitant medications are defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or 
after the date of the first dose of study drug up to 14 days after the subject’s last dose.
Prior failed AEDs and AEDs taken at baseline, including the number of AEDs, will also be 
summarized on the Safety Analysis Set.
5.2.7
Treatment Compliance
Compliance with study medication during the Treatment Phase will be summarized using
descriptive statistics. Overall percent compliance will be calculated as follows:
	

= 
(Wt. t of Study Drug Dispensed [g] −Wt. of Study Drug Returned [g])' 0.5 *
+
(No. of Days x Prescribed Daily dose [mg])x1.07 g
mL
7 ' 100%
where 0.5 mg/mL is the perampanel concentration in Fycompa oral suspension and 
1.07 g/mL is the density of Fycompa oral suspension
Overall study medication compliance will also be summarized using the categories <80%, 
80% to 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.


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5.3.3
Multiple Comparisons/Multiplicity
Not applicable.
5.3.4
Examination of Subgroups
All analyses will be provided by age cohort (1 to ≤ 6 months, > 6 to ≤ 12 months, >12 to < 24 
months, and 24 to <48 months). Summaries of demography, seizure data, and TEAEs may be 
further presented by inducer/non-inducer subgroup. Growth parameters (height, weight, 
thyroid and insulin-like growth factor-1 [IGF-1] parameters) may also be summarized by sex.
5.3.5
Handling of Missing Data, Dropouts, and Outliers
Analysis of percent change and responder rate for the seizure frequency per 28 days during 
the Maintenance Period will use a last observation carried forward (LOCF) type of
imputation. If the overall duration of the Maintenance Period is less than 4 weeks, the diary 
data from the last 4 weeks during the Core Treatment Phase (Titration Period + Maintenance 
Period) will be used to calculate the seizure frequency per 28 days for Maintenance-LOCF.  
Subjects who didn’t enter the Core Treatment Maintenance Period would be counted as non-
responders in the maintenance period.
The seizure-free status during the Maintenance Period will only be counted for subjects who 
complete the Maintenance Period (i.e., those who complete the Core Study). A subject who 
dropped out early would be counted as ‘No’ for seizure-free status in the Maintenance 
period.
5.4
Exploratory Efficacy Analyses 
This study is designed to assess PK and provide safety, tolerability and efficacy data in 
children with epilepsy aged 1 month to less than 4 years. Given the small sample size and 
lack of placebo or comparator, it will not be possible to draw definitive conclusions 
regarding the efficacy of perampanel oral suspension for the population in this study. As
such, no formal statistical tests will be performed. Summary statistics will be displayed for 
all efficacy parameters in the Full Analysis Set unless stated otherwise.
The primary analysis will use data from the Pretreatment Phase to calculate baseline 28-day 
seizure frequency.  A secondary analysis will use data from the Pretreatment Phase plus data 
from the 4 weeks prior to Visit 1 to calculate baseline 28-day seizure frequency. Seizure 
frequency will be based on the number of seizures per 28 days, calculated as the number of 
seizures over the time interval multiplied by 28 and divided by the number of days in the 
interval. Seizure frequency will refer to the overall seizure type, unless stated otherwise, 
obtained by combining across all seizure types.
Post-baseline data reported only during the on-treatment duration will be analyzed. The on-
treatment duration is defined as follows: 

For diary data: The duration between the day of first study drug dose and the last


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day of study drug dose, inclusive.

For CGIC data: The duration after the day of first study drug dose up to 7 days
after the last study drug dose, inclusive.
5.4.1
Primary Exploratory Efficacy Analyses
The efficacy seizure endpoints are the percent change in 28-day seizure frequency during the 
Treatment Phase compared to baseline, responder rate during the Maintenance Period, and 
seizure-free status during the Maintenance Period. The baseline 28-day seizure frequency for 
the primary analyses will use seizure data from the Pretreatment Phase.
The percent change and responder rate analyses will be based on a subset of FAS including 
subjects with baseline seizure data from the Pretreatment Phase. The seizure-free status will 
be performed on FAS and modified FAS including subjects who received study drug and had 
any seizure frequency data during the Treatment Phase.
5.4.2
Secondary Exploratory Efficacy Analyses
Secondary analyses for the percent change and responder rate endpoints in seizure frequency 
will use seizure data from the Pretreatment Phase plus the data from the 4 weeks prior to Visit 
1 to calculate baseline 28-day seizure frequency.
5.4.3
Other Exploratory Efficacy Analyses
The percent change in 28-day seizure frequency during the Titration Period (no imputation) 
and Maintenance Period (using LOCF-type imputation described in Section 5.3.5) will also be 
summarized.
Percent change, seizure free and responder rate in 28-day seizure frequency analyses will also 
be repeated for each seizure type, as appropriate for subjects who have that seizure type during 
the baseline. Subjects who develop new seizure types during the study will be summarized by 
seizure type separately.
CGI-C scores at EOT compared to baseline will be summarized using frequency table. The 
EOT value is the last non-missing value while on treatment. 
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
Perampanel plasma concentrations were obtained from blood samples drawn during treatment. 
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
Not applicable. 


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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 using descriptive statistics (e.g., n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n [%] for categorical variables). Safety variables include 
treatment-emergent adverse events (TEAEs), clinical laboratory parameters, vital signs, 12-
lead ECG parameters, growth parameters (height, weight, thyroid and insulin-like growth 
factor-1 [IGF-1] parameters). Study Day 1 for all safety analyses is defined as the date of the 
first dose of study drug.
5.6.1
Extent of Exposure
The duration of Treatment Phase (Titration Period and Maintenance Period) exposure to study 
drug will be defined as the number of days between the date of the first dose and the date of 
last dose of study drug, inclusive. The duration of exposure will be summarized as a continuous 
variable and by duration categories (>1 day, >1 week, >2 weeks, >4 weeks, >8 weeks, >12
weeks, >16 weeks). The dates of first and last dose of study drug will be determined from the 
Study eCRF.
The mean daily dose, maximum dose received, last dose, and modal dose for each subject over 
the Treatment Phase and for each period (Titration, Maintenance) will be summarized. The 
mean daily dose will be calculated by taking the average of all the doses taken during the time 
period weighted by the number of days on each dose (i.e., sum of [days on each 
dose*dose]/during the time period). 
5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (Version 25.1 or 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 treatment-emergent AE (TEAE) is defined as an AE that emerged during treatment, having 
been absent at pretreatment (Baseline) or

Re-emerged during treatment, having been present at pre-treatment (Baseline) but
stopped before treatment, or

Worsened in severity during treatment relative to the pre-treatment state, when the
AE was 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.


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Treatment-emergent AEs (TEAEs) will be summarized by age group and by EIAED and non-
EIAED. 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 (related, and not related). The number (percentage) of subjects with TEAEs will 
also be summarized by the onset periods of Titration, Maintenance, and Follow-up.
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 treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
5.6.2.1
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT. A subject data listing of all SAEs will be
provided. A subject data listing of all AEs leading to death 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.
5.6.2.2
AEs of Special Interest
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 psychiatric disorders
•
TEAEs related to hostility/aggression
•
TEAEs related to status epilepticus/convulsions
•
TEAEs related to lab abnormalities
•
Cardiac and ECG TEAEs
TEAEs related to rash will be identified by medical review and summarized. Falls will be 
listed by actual dose of onset for the Titration and Maintenance Periods.


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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 9.7.1.8, 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 and by age group using descriptive statistics.  
Qualitative parameters listed in protocol Section 9.7.1.8 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 non-missing baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during 
the treatment period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) in Section 13.1 presents the criteria 
that will be used to identify subjects with treatment-emergent markedly abnormal laboratory 
values (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.  When displaying 
the incidence of TEMAVs, each subject may be counted once in the laboratory parameter high 
and in the laboratory parameter low categories, as applicable.
5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP [mmHg], pulse 
[beats per minute], respiratory rate [per minute], body temperature [in centigrade]) will be 
presented by visit and by age group.
5.6.5
Electrocardiograms
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit 
and by age group.
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 QTcF during the treatment period will be summarized.  Clinically borderline and 
abnormal ECG results in QTcF will be categorized as follows:
Absolute QTc interval prolongation:


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•
QTc interval 430-450 msec
•
QTc interval >450 msec
•
QTc interval >500 msec
Change from baseline in QTc interval:
•
QTC interval increases from baseline 30-60 msec
•
QTC interval increases from baseline >60 msec
5.6.6
Other Safety Analyses
GROWTH
Descriptive summary statistics of changes from baseline in height, weight, and head 
circumference will be evaluated for each age cohort and overall.  This data will be compared 
with normative scores to assess clinical relevance.
Absolute and percentile changes from baseline in height and weight will be presented by visit 
and to EOT. The sex and age specific percentiles are calculated from z-scores based on the 
2000 Center for Disease Control Growth Charts for the United States. 
Some calculation details are provided in Section 13.2. The average of the 2 height 
measurements from a visit will be used for these summaries. Changes from baseline to EOT 
in thyroid function and IGF-1 testing will be summarized.
5.7
Other Analyses
Not applicable.
5.8
Exploratory Analyses
Other exploratory analyses may be conducted as appropriate. Any exploratory analyses that
are performed will be appropriately titled/labelled as exploratory and will be clearly 
distinguished from planned analyses when results are reported in the Clinical Study Report.
5.9
Extension Phase Analyses
The statistical methods for the Extension Phase will not be described in this SAP but will be 
described in a separate SAP.
6
INTERIM ANALYSES
After every 4th subject completes the Maintenance Period an interim analysis (safety, 
tolerability, and PK) will be conducted where dose-normalized exposure will be compared to 
that observed in other studies in subjects between ≥2 and <18 years of age for evidence of 


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systematic deviations potentially warranting dose adjustment in this age group or for other 
subjects enrolled in the study. 
All data from the Pretreatment and Treatment Phases (Core Study) will be analyzed when all 
subjects have completed the Maintenance Period.  In addition, data from the Pretreatment, 
Treatment, and Extension Phases will be analyzed when all subjects have completed the 
Extension Phase.
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 are documented in the DMC Charter.
7
CHANGES IN THE PLANNED ANALYSES
There are no major changes in the planned analyses from the protocol at the time of the
finalization of this SAP.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
8.1
EFFICACY DATA HANDLING
8.1.1 Baseline efficacy Data
Baseline seizure frequency per 28 days will be calculated two ways. 
For the primary analysis of seizure endpoints, baseline seizure frequency per 28 days will be 
calculated using seizure data from the 2-week Pretreatment Phase. Seizures per 28 days
during these 2-week pretreatment phase will be calculated as the number of seizures during 
this interval divided by the number of days during this interval multiplied by 28. 
Data is also collected over the 4-week interval prior to visit 1 for the days when subject 
experienced seizures. For the secondary analysis of seizure endpoints, baseline seizure 
frequency per 28 days during the 2-week Pretreatment Phase plus the 4 weeks prior will be 
used. Baseline seizure frequency for this analysis will be calculated by taking the average of 
seizure per 28 days from the 2-week Pretreatment Phase and seizures per 28 days from the 4 
weeks interval prior to Visit 1. Seizures per 28 days during the 4-week prior interval will be 
calculated by summing the number of reported seizures during the 4-week (28-day) interval 
prior to visit 1. 
8.1.2 Handling of Missing Efficacy Data, Drop-outs, and Outliers
Only days with valid seizure counts will be used in the calculations of seizures frequency per 
28 days. A day is said to have a valid seizure count if either (1) “No” was the answer to the 
one of questions “Did the subject experience any <seizure category> seizures?” in the 
Seizures Diary Log or (2) other seizure counts were reported for that day. 


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In subjects where dose tapering was done before discontinuation, safety data for the entire   
exposure to study drug will be included in the safety analyses.  However, seizure data during 
tapering will be excluded from the efficacy analyses.
Details on handling efficacy data for early dropouts is provided in section 5.3.5.
8.2
SAFETY DATA HANDLING
8.2.1 Baseline safety Data
The baseline value for all safety endpoints will be the last non-missing measurement prior to 
the first dose of study drug.
8.2.2 Visit Windows for Safety Data
For the by-visit summaries of clinical laboratory data, vital signs, ECG, and growth
parameters, visit windows will be applied to determine into which study week scheduled, 
unscheduled, and early discontinuation data were actually recorded, relative the first dose of 
study drug (Day 1). The aim of using windows for visits is to include the maximum amount 
of data; hence windows will split at the midpoint between visits. It gives the mapping of 
relative day ranges to study week, as well as the target day of a given study week. Mappings 
of relative day ranges to study week will be done for clinical laboratory data, vital signs,
ECG data and growth parameter. Tables 1&2 below provide the mapping of relative day 
ranges to study week for non-AE safety variables. The on-treatment duration for laboratory, 
vital signs, and ECG data is considered to begin on the day of the first dose of study drug and 
ends 14 days after the last dose of study drug, inclusive.
Table 1. Visit Windows – Non-EIAED Subjects
Study Period 
Study Week
Study Day Range 
(Relative to First Dose of 
Study Drug)
Target Day
Pretreatment
Baseline
Day 1a
1
Treatment (Titration)
Week 2
 2 ≤ Day ≤ 21
15
Treatment (Titration)
Week 4
22 ≤ Day ≤ 42
29
Treatment (Titration)
Week 8
43 ≤ Day ≤ 70
57
Treatment (Titration)
Week 12
71 ≤ Day ≤ 91
85
Treatment (Maintenance)
Week 14
92 ≤ Day ≤ 105
99
Treatment (Maintenance)
Week 16
106 ≤ Day ≤ 119
113
Treatment (Follow-Up)
Week 99
120 or LD ≤ Day ≤ 999b
141


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a:  All assessments at Visit 2 were to be performed prior to first dose of study drug; results 
from these assessments will be regarded as Pretreatment values in the analyses.
b:  The last non-missing value measured in the treatment duration will be handled as the data 
of EOT of the core study. 
LD = Last Dose (whichever occurs first)
Table 2. Visit Windows – EIAED Subjects
Study Period 
Study Week
Study Day Range 
(Relative to First Dose of 
Study Drug)
Target Day
Pretreatment
Baseline
Day 1a
1
Treatment (Titration)
Week 2
 2 ≤ Day ≤ 21
15
Treatment (Titration)
Week 4
22 ≤ Day ≤ 42
29
Treatment (Titration)
Week 8
43 ≤ Day ≤ 70
57
Treatment (Titration)
Week 12
71 ≤ Day ≤ 98
85
Treatment (Titration)
Week 16
99 ≤ Day ≤ 119
113
Treatment (Maintenance)
Week 18
120 ≤ Day ≤ 133
127
Treatment (Maintenance)
Week 20
134 ≤ Day ≤ 154
141
Treatment (Follow-Up)
Week 99
155 or LD ≤ Day ≤ 999b
169
a:  All assessments at Visit 2 were to be performed prior to first dose of study drug; results 
from these assessments will be regarded as Pretreatment values in the analyses.
b:  The last non-missing value measured in the treatment duration will be handled as the data 
of EOT of the core study. 
LD = Last Dose (whichever occurs first)
8.2.3 Handling of Replicate Data
For the clinical laboratory data, vital signs, ECG, growth data analyses, when there are 
repeated laboratory tests that occur within the same visit windows (Section 8.2.2), the 
following rules will be used in the by-visit summary tables:
The scheduled visit assessment will be used if there are multiple assessments.

If there are multiple scheduled visit assessments, the scheduled assessment closest

to the target day of the visit will be used.


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
If there are 2 scheduled assessments within the same visit window that are equally

close to the target visit data, the earlier assessment will be used.

If there are 2 scheduled assessments on the same visit, the average will be used for 
that visit. 
If a subject did not have a recorded observation falling within a given range of days in order 
to be assigned a study week, the subject’s data for that study week will be regarded as 
missing for summarization purposes.
A subject having a TEAE coded to the same PT more than once during the study will be
counted only once in the incidence calculations for that TEAE. Similarly, if a subject has 
more than 1 TEAE in a single SOC, the incidence will be counted only once for that SOC.
For summaries by closest relationship to study drug, if a subject had a single incident of a
TEAE with a missing relationship to study drug, the subject will be counted in the ‘Missing’ 
category for that PT. If a subject had two or more TEAEs in the same SOC (or with the same 
PT) with different relationships to study drug, then the event with the closest relationship will 
be used for that subject. Subjects with missing relationship to study drug for the TEAE are 
counted under 'Missing' category unless the subject already has another TEAE classified as 
Related, in which case the subject is counted under 'Related' category.
For summaries by maximum severity, if a subject had a single incident of a TEAE with a
missing severity, the subject will be counted in the ‘Missing’ category for that PT. If a 
subject had two or more TEAEs in the same SOC (or with the same PT) with different 
severities, then the event with the maximum severity will be used for that subject. Subjects 
with missing severity for the TEAE are counted under 'Missing' category unless the subject 
already had another AE with severe intensity, in which case subject is counted under 
‘Severe’ category.
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
10 STATISTICAL SOFTWARE
All statistical analyses and summaries 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.


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12 REFERENCES
ILAE guidelines.  Proposal for revised clinical and electrographic classification of epileptic 
seizures. From the Commission on Classification and Terminology of the International 
League Against Epilepsy. Epilepsia 1981;22(4):489-501.
2000 Center for Disease Control Growth Charts for the United States. CDC. Available from: 
http://www.cdc.gov/growthcharts.


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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 study 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;


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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
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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13.2
Age and Sex Specific Percentile Calculation for Weight and Height
The following information is from US CDC website: http://www.cdc.gov/growthcharts.
To obtain the z-score (Z) and corresponding percentile for a given measurement (X), use the
following equation:
Z=((X/M) ^L – 1)/LS when L≠0;
or
Z = ln(X/M)/S when L=0;
where X is the physical measurement (e.g. weight, length, or calculated BMI value) and L, M
and S are the values from the appropriate table corresponding to the age in months of the child
(or length/stature). (X/M) ^L means raising the quantity (X/M) to the L-th power.
For example, to obtain the weight-for-age z-score of a 9-month-old male who weighs 9.7 kg, we
would look up the L, M and S values from the WTAGEINF table found at
http://www.cdc.gov/growthcharts/percentile_data_files.htm, which are L=-0.1600954,
M=9.476500305, and S=0.11218624. Using the equation above, we calculate that the z-score for
this child is 0.207. This z-score corresponds to the 58th percentile.


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SIGNATURE PAGE
Author:  
[electronic signature in eDMS]
,
.
 
Alzheimer’s Disease and Brain Health
Date
Approval:
[electronic signature in eDMS]
,
, 
.
Alzheimer’s Disease and Brain Health
Date
[electronic signature in eDMS]
,
 
Alzheimer’s Disease and Brain Health 
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD