Conditions: Lennox-Gastaut Syndrome (LGS)
Keywords: Lennox-Gastaut Syndrome (LGS) Inadequately controlled seizures
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
This study is being conducted to demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in reducing the number of drop seizures in participants with inadequately controlled seizures associated with Lennox-Gastaut Syndrome (LGS).

Detailed description:
This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study of perampanel as adjunctive therapy in participants with inadequately controlled seizures associated with LGS. The study will consist of 3 phases: Prerandomization (4 to 8 weeks), Randomization (18 weeks), and an Extension A (52 weeks). An additional Extension B with open-label treatment will be available for optional participation to participants who reside in Japan and in countries where an expanded access program (EAP) cannot be implemented or has not yet been implemented.

Arms:
arm 1: During the Randomization Phase, participants will receive perampanel at a starting dose of 2 milligrams per day (mg/day). Thereafter, the dose will be increased to a maximum target dose of 8 mg/day according to individual tolerability and efficacy for up to 18 weeks. Participants who enter into Extension A will continue to receive perampanel at the dose last received during randomization phase. Participants can be titrated up to 12 mg/day (at 2-week intervals) per the investigator's discretion.

Participants who continue in Extension B will continue to receive perampanel at the dose last received at the end of Extension A. arm 2: During the Randomization Phase, participants will receive matching placebo for up to 18 weeks.

During the Extension A, participants who received placebo during the Randomization Phase will begin treatment with perampanel in a blinded manner in double-blind Conversion Period, starting at 2 mg/day and then up-titrated to a maximum target dose of 8 mg/day according to individual tolerability and efficacy. After the Conversion Period, participants can be titrated up to 12 mg/day (at 2-week intervals) per the investigator's discretion.

Interventions: intervention 1: Placebo intervention 2: Perampanel
Intervention descriptions: intervention 1: Participants will receive matching placebo in Randomization phase. intervention 2: Participants will receive perampanel in Randomization phase, open-label Extension A, and open-label Extension B.

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol
incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
Page i of xxiv
CONFIDENTIAL
REVISION HISTORY
Revisions to Version 10.0
New version/Date: Final, v11.0, 19 Nov 2018 (per Amendment 05)
Change
Rationale
Affected Protocol Sections
Adjust timing of Visit 8 from Week 
20 to Week 21, and Visit 9 from 
Week 22 to Week 23.  Update Study 
Day numbering for these two visits 
accordingly.
To align study visit intervals 
with study product dispensing 
(every 2 weeks during 
Extension A Conversion 
period).
Table 7
Table 8
Editorial corrections.
To improve clarity.
Synopsis – Assessments 
Section 9.5.1.5
Table 5
Table 5Appendix 2
Table 8


Clinical Study Protocol
incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
Page ii of xxiv
CONFIDENTIAL
Revisions to Version 9.0
Amended version/Date: FINAL:  v10.0, 19 Oct 2018 (per Amendment 04)
Change
Rationale
Affected Protocol Sections
Added an additional extension phase 
(Extension B) for subjects in Japan or 
subjects in countries where an extended 
access 
program 
(EAP) 
cannot 
be 
implemented or has not yet been 
implemented
To provide managed access to 
perampanel for subjects in Japan
or subjects in countries where an 
EAP cannot be implemented or 
has not yet been implemented
Synopsis – Study Design
Synopsis – Study Treatments
Synopsis 
–
Duration 
of 
Treatment
Synopsis – Safety Assessments 
Synopsis – Statistical Methods
Section 9.1
Section 9.1.2
Figure 1
Section 9.1.3
Section 9.1.4
Section 9.5.1.3
Section 9.5.1.5
Section 9.7.1
Section 9.7.1.6
Section 9.7.1.10
Section 9.7.1.11
Appendix 2
Appendix 4
Clarified Inclusion Criterion No. 4 that 
subjects must have an average of at least 
2 drop seizures per week during the 
Baseline Period.
To clarify that the total number 
of drop seizures will be summed 
and then averaged over this 
4-week period
Synopsis – Inclusion Criteria
Section 9.1.1.2
Section 9.3.1
Revised Inclusion Criterion No. 5 that 
subjects must have been receiving 1 to 4
(changed from “1 to 3”) concomitant anti-
epileptic drugs (AEDs) at a stable dose 
for at least 30 days before Visit 1
To reflect current clinical reality 
(that most refractory subjects 
with Lennox-Gastaut Syndrome 
(LGS) are often receiving at 
least 4 concomitant AEDs).
Synopsis – Number of Subjects
Synopsis – Inclusion Criteria
Section 9.1.1.2
Section 9.3.1
Modification of Exclusion Criterion No. 
28
and Inclusion Criterion No. 5
(concomitant use of cannabinoids) and 
current therapeutic options
To reflect approved AED 
medications
Synopsis – Inclusion Criteria
Synopsis – Exclusion Criteria
Synopsis 
–
Concomitant 
Drug/Therapy
Section 7.1.1
Section 9.3.2
Section 9.4.7.2
Table 5
Section 10
Added Exclusion Criterion No. 29 that 
subjects with rare hereditary problems of 
galactose intolerance, the Lapp lactase 
deficiency 
or 
glucose-galactose 
malabsorption will be excluded.
Per South Korea Ministry of 
Food and Drug Safety (MFDS)
request
Synopsis – Exclusion Criteria
Section 9.3.2


Clinical Study Protocol
incorporating Amendment 05
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FINAL:  v11.0, 19 Nov 2018
Page iii of xxiv
CONFIDENTIAL
Added 
early 
pharmacokinetic 
(PK)
sampling time points predose and 1 to 
5 hours 
postdose; 
adjust 
dosing 
instructions around Visit 5 and Visit 6
accordingly
To support characterization of  
perampanel PK, especially 
during absorption and early 
distribution phase
Synopsis – Study Treatments
Synopsis 
–
Pharmacokinetic 
Analyses
Table 1
Table 5
Table 6
Section 9.1.2.2
Section 9.4.1
Section 9.7.1.7
Added that subjects 12 or older may 
receive 
perampanel 
oral 
suspension, 
0.5 mg/mL as medically necessary , at the 
discretion of the investigator
To ensure appropriate study drug 
formulation is to be administered 
based on individual subject 
conditions
Synopsis – Study Treatments
Section 9.1.2.1
Section 9.4.1
Section 9.4.4
Synopsis – Assessments 
Section 9.5.1.5
Table 5
Appendix 2
Clarification of safety analysis set and 
analyses for Core and Extension A
Clarification
Synopsis – Statistical Methods
Appendix 2
Clarification of language and dosing 
throughout study periods 
Clarification
Synopsis – Study Design 
Synopsis – Study Treatments
Figure 1
Section 9.1.2.1
Updated 
subject 
information 
and 
informed consent language
To align with sponsor updated 
protocol language
Section 5.3
Update and simplification of
clinical 
experience section
To refer to Investigator’s 
Brochure, which contains the 
most up-to-date clinical efficacy 
and safety information (updated 
on an annual basis)
Section 7.1.2.2
Section 7.1.2.3 (removed)
Clarified that Extension A conversion 
period is double-blind and Maintenance 
Period is open-label
Clarification
Table 7
Editorial corrections as needed
Document quality
throughout
Updated names of signatories
Administrative 
Protocol 
(sponsor) 
signature 
page
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Clinical Study Protocol
incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
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CONFIDENTIAL
Revisions to Version 8.0
Amended version/Date: FINAL:  v9.0, 24 Feb 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Sections
Added that subjects with laboratory 
results that include elevated aspartate 
aminotransferase
(AST) 
or 
alanine 
aminotransferase (ALT) greater than or 
equal to 3 × upper limit of normal (ULN) 
and elevated total bilirubin (TBIL) greater 
than or equal to 2 × ULN with an alkaline 
phosphatase (ALP) laboratory value that 
is less than 2 × ULN, ie, that meet criteria 
for Hy’s law will be withdrawn from the 
study
Per VHP request
Section 9.3.3
Added that subjects who appear to have a 
high risk of suicidal behavior according 
to results of the
Columbia Suicide 
Severity Rating Scale (C-SSRS) and/or 
clinical impression will be withdrawn 
from the study.
Added that subjects who will reach the 
age of 8 years during the double-blind 
phase of the study will also be assessed 
using the C-SSRS starting at Baseline. 
The description in Section 9.5.4.3 and 
9.5.4.4 was consolidated into a new 
Section 9.5.4.3.
Per VHP request
Synopsis - Safety Assessments –
Core Study and Extension Phase
Section 9.3.3
Section 9.5.1.5
Section 9.5.2, Table 5
Section 9.5.4.3
Editorial corrections as needed
document quality
throughout


Clinical Study Protocol
incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
Page v of xxiv
CONFIDENTIAL
Revisions to Version 7.0
Amended version/Date: Final, v8.0, 04 Jan 2017 (per Amendment 02)
Change
Rationale
Affected Protocol Sections
Corrected misspelling of tiagabine
Editorial quality
Synopsis – Exclusion Criteria; 
Concomitant Drug Therapy
Section 7.2
Section 9.3.2
Section 9.7.2
Added suicidal ideation to the list of 
exclusion criteria in the Synopsis
For consistency with body of 
protocol
Synopsis – Exclusion Criteria
Added 
instructions 
for 
laboratory 
abnormalities that might meet criteria for 
Hy’s Law (elevated AST or ALT greater 
than or equal to 3 × ULN and elevated 
total bilirubin greater than or equal to 2 ×
ULN with an alkaline phosphatase 
laboratory value that is less than 2 ×
ULN).  Stated that these laboratory results
should always be reported as serious.
Per VHP request to clarify 
laboratory 
abnormalities 
that 
may meet criteria for Hy’s Law.
Synopsis – Assessments
Section 9.5.1.5
Section 9.5.4.3
Section 9.7.1.8
Appendix 2
Added language allowing for 
discontinuation  if the C-SSRS and/or 
clinical impression indicates a high risk 
of suicidal behavior
Per VHP request
Synopsis – Assessments
Section 9.5.1.5
Deleted text describing side effects 
associated with other antiepileptic drugs
This text repeats text in Section 
7.1.1
Section 7.2
Deleted laboratory abnormalities and 
events of aggression and anger from 
events associated with special situations
Events 
of 
aggression 
and 
significant 
laboratory 
abnormalities are defined in the 
preceding paragraph
Section 9.5.1.5
Revised window for Maintenance Period 
visits from 7 days to 6.
For consistency
Table 5
Corrected numbering of study weeks 
during Conversion Period of Extension 
Phase 
To allow sufficient time for 
titration
Table 7
Corrected numbering of study weeks 
during Conversion Period of Extension 
Phase
To correct an error
Appendix 2, Table 7 and Table 8
Editorial style
Appendix 2, Table 8
Corrected table cross-referencing errors
For accuracy
Appendix 2
Appendix 3
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incorporating Amendment 05
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FINAL:  v11.0, 19 Nov 2018
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Revisions to Version 6.0
Amended version/Date: Final, v7.0, 06 Dec 2016 (per Amendment 01)
Change
Rationale
Affected Protocol Sections
Revised description of regions where the 
study will be conducted
Allow additional sites to be 
included in study
Synopsis – Investigators
Section 6
Added text to define the end of the study
Per VHP request
Synopsis, Study Design
Section 9.1.3
Revised exclusion criterion #17 to remove 
double-barrier contraception from set of 
acceptable methods, and to add recently 
updated safety language
Per VHP request
and for 
compliance with Eisai standard 
language
Synopsis – Exclusion Criteria
Section 9.3.2
Added assessment of criteria for Hy’s Law
Per VHP request
Synopsis – Assessments
Section 9.5.1.5
Section 9.5.3
Section 9.7.1.8
Appendix 2
Added C-SSRS and language pertaining to 
suicidal behavior
Per VHP request
Synopsis – Assessments
Section 9.3.2
Section 9.5.1.5
Section 9.5.1.5
Appendix 2
Per VHP request
Synopsis --  Assessments
Section 9.5.1.5
Table 5
Appendix 2
Stated that secondary endpoints (other than 
key secondary endpoints) and exploratory 
endpoints will not be analyzed statistically 
but will be summarized
Per VHP request
Synopsis --- Statistical Methods
Section 9.7.1.1
Per VHP request
Synopsis – Statistical Methods
Section 9.7.1.1
Added statement that treatment effect 
(efficacy) will be assessed using odds 
ratios.
Per VHP request
Synopsis – Statistical Methods
Section 9.7.1.1
Revised introductory text
and deleted 
references which were made redundant
Per VHP request
Section 7
Section 10
Corrected statement pertaining to number 
of Phase 2 and 3 studies completed
Update and for consistency 
with Investigators Brochure
Section 7.1.2.2
Added statement that any reaction with a 
fatal 
outcome 
will 
be 
considered 
unexpected
Per VHP request
Section 7.1.2.3 (removed)
Per VHP request
Section 7.2
Revised start and end dates of study 
Updated information
Section 9.1
Corrected description of study phase
To correct an error
Section 9.4.1
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FINAL:  v11.0, 19 Nov 2018
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Corrected description of dose packs
For accuracy
Section 9.4.2
Inserted “78” in table cell specifying the 
study day corresponding to Visit 6
To correct an error
Table 5
Updated visit window (6 days rather than 
7) 
For consistency
Table 5
Stated that height of adult subjects is to be 
obtained only at Screening
Per VHP request
Table 5
Appendix 2, Table 8
Added information and table stating 
volumes of blood to be drawn during the 
core study
and the Extension Phase.  
Inserted 
new 
table 
and 
corrected 
numbering 
of 
tables 
occurring 
subsequently in text.
Per VHP request
Section 9.5.2
Table 6
Appendix 2, Table 8
Appendix 3
Added aggression and status epilepticus as 
study-specific events
As per clinical findings
Section 9.5.4.3
Revised numbering of study weeks during 
extension 
phase
and 
corrected 
the 
numbering of the study day at the end of 
Week 74
For clarity and consistency
Appendix 2, Table 7


Clinical Study Protocol
incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
Page viii of xxiv
CONFIDENTIAL
Revisions to Version 5.0
New version/Date: Final, v6.0, 26 Aug 2016
Change
Rationale
Affected Protocol Sections
Synopsis -- Exploratory Objectives
Synopsis -- Exploratory Endpoints
Section 8.3
Section 9.7.1.1
Specified that in Japan, doses of 
perampanel 
may 
not 
exceed 
8 mg/day
For subject safety as per 
PMDA request
Synopsis --Study Design
Synopsis -- Treatments
Figure 1
Table 1
Appendix 2
Editorial correction
Per Eisai style
Section 7.1.2.3 (removed)
Section 9.4.4
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incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
Page ix of xxiv
CONFIDENTIAL
Revisions to Version 4.0
New version/Date: Final, v5.0, 06 May 2016
Change
Rationale
Affected Protocol Sections
Increased number of study sites from 
50 to 70
To accelerate study completion

Synopsis – Sites

Section 6

Section 9.3

Synopsis –Secondary Objectives

Synopsis – Exploratory Objectives

Synopsis – Statistical Methods

Section 8.2

Section 8.3

Section 9.7.1.1

Synopsis – Exploratory Objectives

Synopsis – Assessments

Synopsis – Statistical Methods

Section 4

Section 8.3

Section 9.5.1.6

Table 3and Table 5

Section 9.7.1.1

Section 9.7.1.9

Section 10

Synopsis – Exploratory Objectives

Synopsis – Assessments

Synopsis – Statistical Methods

Section 4

Section 8.3

Section 9.5.1.6

Table 4 and Table 5

Section 9.7.1.1

Section 9.7.1.9

Section 10
Added 
inclusion 
criterion 
that 
weight must be at least 8 kg
To 
ensure 
subjects 
are 
of 
adequate weight to participate in 
a clinical study

Synopsis – Inclusion Criteria

Section 9.3.1
Added 
exclusion 
criterion 
for 
cannabinoids
Cannabinoids 
may 
influence 
study results

Synopsis – Exclusion Criteria

Section 7
Deleted country and added region 
and age group as independent 
variables
Likely that there will be too few 
subjects per country; therefore 
group by region instead.  Age 
group is considered an important 
variable.

Synopsis – Statistical Methods

Section 9.4.3

Section 9.7.1.6
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For subjects who do not roll over 
into the Extension Phase, added a 
visit at 7±2 days after the last dose 
of study drug and provided that a PK 
sample will be drawn at this visit.
The PK sample is to be drawn
for correlation of  potential 
withdrawal symptoms and signs 
with perampanel plasma levels.  
This sample will not be used for 
population PK analyses.

Synopsis—Statistical Methods

Section 9.5.1.4

Table 5

Section 7

Section 9.7.1.7
Modified literature reference style
To conform with changes in 
Eisai style 

Section 7.1.1

Section 7.2

Section 9.5.1.6

Section 10
Added statement that sites should 
enroll 
subjects 
throughout 
the 
allowed age range
To allow for representation of 
younger 
as 
well 
as 
older 
children in the study

Section 9.3
Provided that lifetime AED history 
be collected
To aid in interpretation of 
efficacy and safety findings

Section 9.5.1.2

Table 5
Added details of the handling and 
assay of PK samples
For clarity and completeness

Section 9.5.1.4
 
 
 

Section 9.5.1.6

Section 9.7.1.9
Clarified 
that 
Follow-up 
Visit 
intervals will have a window of ±2 
days
To allow sufficient flexibility in 
scheduling visits

Table 5
Clarified that the minimum interval 
of 10 days between visits does not 
apply to Visit 3
For accuracy, as Visit 3 is to 
occur less than 10 days after 
Visit 2. 

Table 5
Allowed a window of ±10 days for 
Follow-up Visits
To allow sufficient flexibility

Table 5
Deleted reporting of study-specific 
events
Not applicable as there are no 
criteria for study-specific events

Section 9.5.4.3
Editorial corrections
For quality and consistency

Various locations
Changed visit window to ±6 instead 
of ±7 days in the Maintenance 
Period of the Extension Phase
Ensure that the shelf life of the 
investigational product is not 
exceeded.

Table 8
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Revisions to Version 3.0
New version/Date: v4.0, 22 Nov 2015
Change
Rationale
Affected Protocol Sections
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 2, Table 5, and Table 8


Clinical Study Protocol
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FINAL:  v11.0, 19 Nov 2018
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Revisions to Version 2.0
New version/Date: v3.0, 27 Oct 2014
Change
Rationale
Affected Protocol Sections
Revisions to grammar, spelling, etc.
Compliance with current 
company style guide and for 
general consistency

Throughout protocol
Revisions made per new company 
protocol template
Alignment with current Eisai 
template

Title 
page
Synopsis 
-
Safety 
Analyses

Synopsis - Inclusion/Exclusion 
Criteria

Section 9.3.1

Section 7

Section 9.5.1.5

Section 9.5.4

Section 9.5.4.1

Section 9.5.4.2

Section 9.5.4.3
Revised dosing to reduce frequency 
of titrations and overall titration 
period
Per recommendation by FDA
●Synopsis
○
Study Design
○
Study Treatments
●Section 9.1
●Figure 1
●Section 9.1.2
●Section 9.1.2.1
●Section 9.4.1
●Section 9.4.2
●Section 9.4.4
●Appendix 2
●Table 5
●Table 8
Per recommendation by FDA
●Synopsis
○
Objectives
○
Statistical Methods
●Section 8.2
●Section 8.3
●Section 9.7.1.1
●Section 9.7.1.6
Revised list of permitted AEDs
Per FDA feedback on inclusion 
of inducers
●Synopsis
○
Inclusion Criteria
○
Exclusion Criteria
○
Concomitant Drugs/Therapies
○
Statistical Methods
●Section 7.1.2.3 (removed)
Section 9.3.1
●Section 7
●Section 9.4.7.1
●Section 9.4.7.2
●Section 10
Revised language around dose 
adjustments
Clarification
●Section 9.1.2.1
●Appendix 2
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Revisions to Version 2.0
New version/Date: v3.0, 27 Oct 2014
Change
Rationale
Affected Protocol Sections
Removed all text regarding post 
Screening ECG
Correction as ECGs assessments 
are not performed after 
Screening
●Synopsis
○
Safety Assessments
○
Statistical Methods
●Section 9.5.1.5
●Section 9.5.1.6
●Section 9.7.1
●Section 9.7.1.8
Added text to qualify that 30% of 
subjects will be recruited from the 
United States
Per SPA review request
●Synopsis – Number of Subjects
●Section 9.3
Revised text to indicate subjects who 
become pregnant will not be able to 
continue in the study
For consistency with 
perampanel clinical program
●Section 9.5.4.2
Revised sample size rationale text
Removed reference to the 
felbamate study because the 
endpoint was different (atonic 
seizures) not drop seizures.
Clarified mean decreases in the 
clobazam study; the absolute 
decreases are not comparable 
between studies.
●Synopsis - Sample Size Rationale
●Section 9.7.2
Added vital signs assessments at 
Visit 14
Correction
●Table 5
Revised CGI assessments to include 
CGI-Severity and CGI-Improvement 
scales
Correction
●Synopsis
○
Efficacy Assessments
●Section 9.5.1.3
Removed language stipulating that 
laboratory assessments qualifying 
subjects for study entry will be 
performed by a local laboratory
Correction
●Section 9.5.1.5


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Revisions to Version 1.0
New version/Date: v2.0, 29 May 2014
Change
Rationale
Affected Protocol Sections
Allowed provision for subjects 
≥12 years to be up-titrated to 12 
mg/day perampanel
Although 8 mg/day is the 
selected dose in the Core 
study based on the expected 
efficacy and the low 
percentage of subjects 
expected to be on inducer 
AEDs, some subjects might 
still benefit from a higher 
dose for a better seizure 
control. The option to titrate 
to 12 mg/day, which is limited 
to subjects ≥12 years, will be 
based on the clinical judgment 
of the investigators and the 
subjects' agreement.
●Synopsis
○
Study Design
○
Extension Phase
●Section 9.1
●Appendix 2
○
Study Design and Plan
○
Table 4
○
Study Drug Supplies/Perampanel 
Tablets
Revised text regarding the statistical 
and analytical plan
Clarification
●Section 9.7.1
Added sample size rationale for 71 
subjects in each treatment arm for 
percent change from baseline in drop 
seizure frequency and 50% 
responder rate
Clarification
●Synopsis
●Section 9.7.2
Revised title to include age of 
subjects
Clarification
●Title page
●Synopsis, Study Protocol Title
●Protocol (sponsor) signature page
●Protocol (investigator) signature page
Revised “lactating” to “nursing”; 
populated full list of inclusion and 
exclusion criteria
Clarification
●Synopsis
○
Exclusion criteria
●Section 9.3.2, exclusion criterion #16
Correction
●Table 3
Removed reference to the last visit 
of the Maintenance Period of the 
Core Study having a window of 
±3 days
Correction
●Table 5, footnote b
Replaced IVRS with IxRS
Correction
●Section 9.4.2
●Table 3 abbreviations
●Table 5 abbreviations
Qualified the collection of urine 
Modified to take into account 
●Table 3, footnote g
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Revisions to Version 1.0
New version/Date: v2.0, 29 May 2014
Change
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Affected Protocol Sections
samples
that urine collection in young 
children can be difficult.
●Table 5, footnote g
Removed respiratory rate and body 
temperature from assessments at all 
visits.
These assessments are no 
longer deemed necessary 
given the experience gathered 
from previous trials.
●Section 9.5.1.5
●Section 9.7.1.8
●Table 5
Removed Extension Phase eligibility 
requirement for subjects to be on a 
stable dose of 1 to 3 concomitant 
AEDs
Such requirement is not 
necessary in extension when 
efficacy endpoints are not 
collected.
●Appendix 2
Revised text for classification of 
causality of adverse events
To align with most current 
approved language for AE 
reporting
●Section 9.5.1.5
Revised text pertaining to quantity 
of study drug supplies; noted DEA 
scheduling of perampanel
To accommodate added 
weeks to the Titration Period; 
to adhere to requirements for 
DEA-scheduled drugs
●Section 9.4.2
●Section 9.4.2.3
●Section 9.4.2.4
●Section 9.4.9
●Appendix 2
Revised text for analysis of SAEs 
(removed seriousness)
Redundant text
●Synopsis
○
Safety analyses
●Section 9.7.1.8
Removed daily volumes for dosing 
of oral suspension
Not needed; details will be 
provided to the sites in a 
pharmacy manual.
●Table 1
Added age group to subgroup 
analyses and randomization
To take into consideration 
different titration schedules 
for subjects <12 years
●Synopsis
○
Efficacy analyses
●Section 9.4.3
●Section 9.7.1.6
Added text to monitor anxiety and 
irritability 
Per recommendation of 
CHMP
●Section 9.5.1.5
Qualified conduct of the Extension 
Phase
Clarification
●Synopsis
○
Study Design
●Section 9.1
●Section 9.1.3
●Appendix 2
○
Study Design and Plan
Revised dosing regimens for 
subjects <12 years; extended the 
Preliminary interim PK data 
of perampanel in subjects 2 to 
●Table 1
●Figure 1


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Titration and Conversion Periods of 
the study
<12 years of age with partial 
onset seizures indicated that a 
considerable number of 
plasma exposures when 
normalized to 0.18 mg/kg 
dose, were below the median 
of the 8 mg equivalent 
concentrations in adolescent 
subjects.  The effect appeared 
to be more pronounced in 2 to 
6 year-old subjects relative to 
7 to 11 year-old subjects.  The 
subsequent PK simulations 
indicated that maintenance 
doses up to 0.24 mg/kg in 7 to 
11 year-old subjects and up to 
0.36 mg/kg in 2 to 6 year-old 
subjects is necessary to 
achieve median exposures 
similar to adolescents at an 
8-mg dose. In addition, the 
total daily dose is capped at 
12 mg because of the limited 
experience of perampanel 
safety at doses above 12 mg in 
adults.
●Table 3
●Table 4
●Synopsis
○
Primary Objective
○
Secondary Objectives
○
Exploratory Objectives
○
Study Design
○
Study Treatments
○
Duration of Treatment
●Section 8.1
●Section 8.2
●Section 8.3
●Section 9.1
●Section 9.1.2
●Section 9.1.2.1
●Section 9.1.3
●Section 9.4.1
●Section 9.4.4
●Appendix 2
○
Eligibility Criteria
○
Study Design and Plan
○
Schedule 
of 
Procedures 
and 
Assessments
Extended Maintenance Period of the 
Extension Phase to allow 52 weeks 
of treatment for (Core study) 
placebo subjects 
As specified per CHMP 
request
●Synopsis
○
Study Design
○
Duration of Treatment
●Figure 1
●Section 9.1
●Section 9.1.3
●Appendix 2
○
Study Design and Plan
○
Schedule 
of 
Procedures 
and 
Assessments
○
Table 5
Revised sample size rationale
Clarification
●Synopsis
○
Statistical Methods/Sample Size 
Rationale
●Section 9.7.2
Revised the definition of the FAS 
and added an ITT analysis set
To align the definition of FAS 
back to the company 
definition and added ITT 
●Synopsis
○
Statistical Methods/Analysis Sets
●Section 9.7.1.2


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analysis to address concerns 
of CHMP to include all 
randomized subjects in 
analysis
●Synopsis
○
Statistical Methods/Study 
Endpoints
○
Statistical Methods/Efficacy 
Analyses Core Study
●Section 9.7.1.1
●Section 9.7.1.6
●Synopsis
○
Secondary Objectives
○
Exploratory Objectives
●Section 8.2
●Section 8.3
Removed specifying drop, non-drop, 
and total seizures from the PK and 
PK/PD secondary objective
Not needed; any seizures 
associated with LGS will be 
evaluated for this objective. 
●Synopsis
○
Secondary Objectives 
●Section 8.2
●Synopsis
○
Secondary Objectives
○
Exploratory Objectives
●Section 8.2
●Section 8.3
Specified reference to perampanel as 
‘test drug’
Consistency within the 
protocol
●Section 9.1.2.2
●Section 9.4.2
●Section 9.4.2.4
Revised text regarding up- and 
down- titration of study drug
Consistency within the 
protocol
●Section 9.1.2.1
Revised text regarding site audits
Clarification
●Section 9.6
Integrated like exclusion criteria
Clarification
●Section 9.3.2 (#16 and #18; #25 and 26)
Allowed provision for sub-
investigators to review screening 
assessments and evaluations
The PI is not at every site.
●Section 9.1.2
Revised description of appropriate
local country-specific mechanism
Clarification
●Synopsis
○
Study Design
●Section 9.1
●Section 9.1.3
●Appendix 2
○
Study Design and Plan
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○
Schedule of 
Procedures/Assessments
Removed structural formula
Not needed
●Section 9.4.2.1
Revised study rationale, resulting in 
an additional cross reference (ILAE)
Clarification
●Section 7.2
●Section 10
Revised protocol title to reflect 
open-label Extension Phase
Correction
●Title Page
●Synopsis- Study Protocol Title
●Sponsor Signature Page
●Investigator Signature Page
Revised start/end dates for the study 
and estimated duration
Correction
●Section 9.1
Changed the name of Clinical 
Pharmacology signatory
Administrative 
●Protocol (sponsor) signature page
●Appendix 3
Updated abbreviations
To align with current protocol
●List of Abbreviations and Definition of 
Terms
Removed ethyl alcohol as an 
example of drugs screened for in 
urine
Correction
●Section 9.5.1.2
Redistributed visits in the Titration 
Period of the Core Study and the 
Conversion Period of the Extension 
Phase
To make visit intervals more 
proportional to each other
●Table 1
●Table 3
Removed reference to Table 4 
(Extension Phase schedule) for 
serum pregnancy testing
Correction; serum pregnancy 
testing is not performed in the 
Extension Phase
●Section 9.5.1.5
Specified Screening Visit for 
collection of urine for drug 
screening
Clarification
●Section 9.5.1.2
Noted eslicarbazepine as a 
perampanel inducer
Correction
●Synopsis
○
Inclusion #5
○
Concomitant Drug/Therapy
●Section 9.1.1.2
●Section 9.3.1
●Section 9.3.2
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Affected Protocol Sections
●Section 9.4.7.2
Qualified that ages are that at time of 
consent
Clarification
●Synopsis
○
Study Design
●Section 9.1
Removed analysis of secondary 
efficacy endpoints in the PP 
Analysis Set
Correction
●Synopsis
○
Efficacy Analyses
●Section 9.7.1.6
Specified number of subjects 
randomized
Clarification
●Section 9.3
Revised text for laboratory shift 
tables, out-of-range values, and vital 
signs
Correction
●Synopsis
○
Safety Analyses
●Section 9.7.1.8
Revised text regarding analysis of 
subjects who withdraw from 
treatment
Clarification
●Synopsis
○
Analysis Sets
●Section 9.7.1.2
Specified that all seizure types will 
be collected in the seizure diaries
Clarification
●Synopsis
○
Study Design
○
Efficacy Assessments
●Section 9.1
●Section 9.1.2.2
●Section 9.5.1.3
●Appendix 2
Revised language in subsections on 
the effect of perampanel on oral 
contraceptives and concomitant 
AEDs
Clarifications
●Section 9.4.7.1
Qualified the use of concomitant 
AEDs by allowing carbamazepine, 
oxcarbazepine, and phenytoin
Clarification
●Synopsis
○
Concomitant Drug Therapy
●Section 9.3.2
●Section 9.4.7.2
●
Revised text regarding dose 
adjustment and down-titration
Clarification
●Section 9.1.2.1
Added daily volume for perampanel 
oral suspension
Clarification
●Table 1
Specified both tablet and suspension 
formulations of perampanel
The tablet formulation was 
added for subjects ≥12 years.
●Synopsis
○
Study Design
○
Study Treatments
●Section 9.1


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●Section 9.1.2.1
●Section 9.1.2.2
●Section 9.4.1
●Table 1
●Section 9.4.2
●Section 9.4.4
●Appendix 2
Subjects <12 years of age will be 
treated with suspension formulation 
0.5 mg/mL; subjects ≥12 will be 
treated with the tablet formulation; 
specified that subjects will remain 
on the same formulation throughout 
the study
A suspension formulation for 
those age 12 years and below 
has been introduced for ease 
of use in that age range. 
●Synopsis
○
Study Design
○
Study Treatments
●
Section 9.1
●
Section 9.1.2.1
●
Section 9.1.2.2
●
Section 9.4.1
●
Table 1
●
Section 9.4.4
●
Appendix 2
Revised text to clearly state that 
subjects will be on a stable dose for 
at least 2 weeks during the Core 
Study Titration Period before 
entering the Maintenance Period
Clarification of existing text
●Synopsis
○
Study Design
●Section 9.1
●Figure 1 – footnote b
●Section 9.1.2.1
●Table 1
Revised primary objective and 
secondary objective #1 not to 
include reference to endpoints
Correction; endpoints are 
discussed in another section
●Synopsis
○
Primary Objective
○
Secondary Objectives 
●Section 8.1
●Section 8.2
Added a secondary objective related 
to physicians evaluation of 
symptoms 
To support secondary 
endpoint and related analysis
●Synopsis
○
Secondary Objectives 
●Section 8.2
Revised secondary objective related 
to total and non-drop seizure 
frequency
Clarification
●Synopsis
○
Secondary Objectives 
○
Secondary Endpoints
●Section 8.2
●Section 9.7.1.1
●Synopsis-
○
Exploratory Objectives
●Section 8.3
●Synopsis
○
Exploratory Objectives
●Section 8.3
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Affected Protocol Sections
Clarification
●Synopsis
○
Exploratory Objectives
●Section 8.3
Revised endpoints text by removing 
text related to analysis and moving 
to applicable analysis sections
Clarification
●Synopsis
○
Primary Endpoints
○
Secondary Endpoints
○
Exploratory Endpoints
○
Efficacy Analyses
●Section 9.7.1.1
●Section 9.7.1.6
Combined secondary endpoint 
related to non-drop seizure 
frequency with the endpoint for total 
seizure frequency 
Clarification
●Synopsis
○
Secondary Endpoints
●Section 9.7.1.1
Clarification
●Synopsis
○
Exploratory Endpoints
●Section 9.7.1.1
Clarification
●Synopsis
○
Exploratory Endpoints
●Section 9.7.1.1
Added the secondary endpoint for 
PK
Clarification
●Synopsis
○
Secondary Endpoints
●Section 9.7.1.1
Revised definition of the FAS
Correction
●Synopsis
○
Analysis Sets
●Section 9.7.1.2
Revised definition of the PK 
Analysis Set
Clarification
●Synopsis
○
Analysis Sets
●Section 9.7.1.2
Clarification
●Synopsis
○
Exploratory Endpoint Analysis 
(Core Study)
○
Section 9.7.1.6
Removed description of the PK 
Analysis Set
Not needed; already in 
Section 9.7.1.2
●Section 9.7.1.7
Revised text around performing and 
reporting of pharmacogenomic 
analyses
Clarification
●Synopsis-
○
Pharmacogenomic Analysis (Core 
Study)
●Section 9.7.1.7
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Affected Protocol Sections
Added aggression and anger as other
events of interest
For the safety of subject, 
given the rates of these events 
in other perampanel studies
●Section 9.5.1.5
●Section 9.5.4.3
●Section 9.7.1.8
Revised description of study periods
Clarification
●Section 9.1
●Appendix 2
Added estimated study start/stop 
dates
Clarification
●Section 9.1
Removed “at least” in reference to 
the number of concomitant AEDs
Clarification
●Section 9.1.1.2
Specified viral tests 
Correction
●Table 2
●Table 3
Revised reporting window for SAEs, 
deaths, and life-threatening events
To comply with EC Directive 
2011/C 172/01
●Section 9.5.4.1
Revised PK sampling method and 
information regarding PK analysis 
methodology
A low-volume plasma assay 
for measuring perampanel 
concentrations will be used 
instead of the dried blood spot 
method.
●Synopsis
○
PK and PD Assessments
○
Bioanalytical Methods
●Section 9.5.1.4
●Table 3 – footnote l
●Section 9.7.1.7
Qualified that for inclusion, if the 
subject is under the legal age, a 
parent or legal guardian must 
provide informed consent
Clarification
●Section 9.3.1
Added use of prohibited medications 
to exclusion criteria
For consistency with text 
elsewhere
●Section 9.3.1
Qualified description of females 
who would have pregnancy testing
Clarification
●Section 9.5.1.5
●Table 3
●Table 4
Removed Photosensitivity 
Questionnaire as an assessment
No safety signal was seen in 
Phase 3 POS studies
●Synopsis
○
Safety Assessments
○
Safety Analyses
●Section 9.5.1.5
●Table 3
●Section 9.7.1.8
Correction
●Synopsis
●Section 9.5.1.6
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Change
Rationale
Affected Protocol Sections
Removed CBCL, thyroid hormone, 
and IGF-1 assessments
Correction
●Table 3
Revised text for PK/PD analyses
Clarification
●Synopsis
○
PK and PK/PD Analyses (Core 
Study)
●Section 9.7.1.7
Moved location within protocol, of 
other safety analyses
Correction
●Section 9.7.1.8
Removed caregiver assessment of 
changes in symptoms (CGI-C)
Correction
●Synopsis
○
Efficacy Assessments
○
Secondary Endpoints
○
Efficacy Analyses
●Section 9.5.1.3
●Section 9.7.1.1
●Section 9.7.1.6
Combined inclusion criteria 
formerly numbered #7 and #8 and 
re-numbered subsequent criteria
Related subject matter; 
combined for continuity
●Section 9.3.1
Deleted inclusion criterion #9 
pertaining to male 
sterilization/contraceptive 
techniques (renumbered subsequent 
criteria)
Criterion is redundant to 
inclusion  #8
●Section 9.3.1
Clarify plans for statistical 
analysis
●Section 9.7.1.6
Moved statement that by-subject 
listings would be presented for 
pregnancy tests
Correction
●Section 9.7.1.9
●Synopsis
○
Exploratory Objectives
●Section 8.3
Revised pharmacogenomics-related 
instructions; removed reference to 
biomarker analysis
To conform with regulations 
pertaining to the use of 
subjects’ DNA samples for 
pharmacogenomics
●Appendix 4
Revised version of the Declaration 
of Helsinki to the recently approved 
version
Update
●Section 5.2
Revised name of business unit and 
study Biostatistician
Update
●Protocol Signature page
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Affected Protocol Sections
Editorial/template corrections
For interdocument 
consistency and compliance 
with current template and 
study guide
●Throughout protocol


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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
E2007-G000-338
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial
With an 
Open-Label Extension Phase of Perampanel as Adjunctive Treatment in Subjects at 
Least 2 Years of Age With Inadequately Controlled Seizures Associated With 
Lennox-Gastaut Syndrome
Sponsor:
Eisai Inc.
155 Tice Blvd
Woodcliff Lake, 
New Jersey 07677
US
Eisai Ltd.
European Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd.
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational Product 
Name:
Perampanel
Indication:
Seizures associated with Lennox-Gastaut Syndrome (LGS)
Phase:
3
Approval Date:
v1.0, 11 Feb 2013 (original protocol)
v2.0, 29 May 2014 (revised protocol)
v3.0, 27 Oct 2014 (revised protocol)
v4.0, 22 Nov 2015 (revised protocol)
v5.0, 06 May 2016 (revised protocol)
v6.0, 26 Aug 2016 (revised protocol)
v7.0, 06 Dec 2016 (amended protocol per Amendment 01)
v8.0, 04 Jan 2017 (amended protocol per Amendment 02)
v9.0, 24 Feb 2017 (amended protocol per Amendment 03)
v10.0, 19 Oct 2018 (amended protocol per Amendment 04)
v11.0, 19 Nov 2018 (amended protocol per Amendment 05)
IND Number:
112515
EudraCT Number:
2014-002321-35
GCP Statement:
This study is to be performed in full compliance with International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities.
Confidentiality Statement:
This document is confidential.  It contains proprietary information of Eisai (the sponsor).  Any 
viewing or disclosure of such information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the purpose of reviewing or 
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.
E2007
Name of Active Ingredient
Study Protocol Title
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial With an Open-Label Extension Phase of 
Perampanel as Adjunctive Treatment in Subjects at Least 2 years of Age With Inadequately Controlled Seizures 
Associated With Lennox-Gastaut Syndrome
Investigators
Investigators in North America, Europe, and Asia (revised per Amendment 01)
Sites
Approximately 70 sites
Study Period and Phase of Development
Approximately 36 months
Phase 3
Objectives
Primary Objective
To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in reducing the 
incidence of drop seizures during 18 weeks of treatment in subjects with inadequately controlled seizures 
associated with Lennox-Gastaut Syndrome (LGS)
Secondary Objectives
1.
To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in 
reducing the incidence of all seizures during 18 weeks of treatment in subjects with inadequately 
controlled seizures associated with LGS
2.
To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in the 
50%, 75%, and 100% responder rates for drop seizures during 12 weeks of the Maintenance Period in 
subjects with inadequately controlled seizures associated with LGS
3.
To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in the 
50%, 75%, and 100% responder rates for total seizures during 12 weeks of the Maintenance Period in 
subjects with inadequately controlled seizures associated with LGS
4.
To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in 
reducing the incidence of non-drop seizures during 18 weeks of treatment in subjects with inadequately 
controlled seizures associated with LGS
5.
To evaluate the 50%, 75%, and 100% responder rates in non-drop seizure frequency during 12 weeks of 
the of the Maintenance Period in subjects with inadequately controlled seizures associated with LGS
6.
To evaluate physicians’ global evaluation of subjects’ overall changes in symptoms
7.
To evaluate the safety of perampanel relative to placebo as adjunctive therapy in subjects with 
inadequately controlled seizures associated with LGS during both the Core Study and the Extension Phase
8.
To evaluate the pharmacokinetics (PK) and the pharmacokinetic/pharmacodynamic (PK/PD) relationships
of perampanel as adjunctive therapy in subjects with inadequately controlled seizures associated with 
LGS
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Exploratory Objectives
Study Design
This will be a multicenter, double-blind, randomized, placebo-controlled, parallel-group study of perampanel as 
adjunctive therapy in subjects with inadequately controlled seizures associated with LGS. The study will consist of 
3 phases:  Prerandomization, Randomization, and Extension.
The Core Study will consist of the Prerandomization and Randomization Phases.  The Prerandomization Phase will 
consist of a 4- to 8- week Screening/Baseline Period during which subjects will be assessed for overall eligibility to 
participate in the study, including seizure activity. Baseline seizure count will be assessed using all diary data 
before randomization (at least 4 weeks prospectively).  Following successful completion of this period, subjects 
will be randomized to receive perampanel or placebo in a 1:1 ratio.
The Randomization Phase will consist of 3 periods:  Titration (6 weeks), Maintenance (12 weeks), and Follow-up.
(4 weeks, only for subjects not entering into Extension A). Subjects will start perampanel at a dose of 2 mg/day (or 
matching placebo).  Thereafter, the dose will be increased up to a maximum target dose of 8 mg/day (or matching 
placebo) according to individual subject tolerability and efficacy. Once titrated, all subjects will be kept at a stable 
dose for at least 2 weeks (to reach steady-state) before the start of the Maintenance Period.  The dose of study drug 
during the Maintenance Period will be the last dose achieved at the end of the Titration Period. Upon completion 
of the Titration Period, subjects will begin the Maintenance Period of the study.  Subjects will enter this period on
the study drug dose (or matching placebo) they achieved during the Titration Period.  In general, dose adjustment 
during the Maintenance Period is not recommended; however, the investigator may reduce a subject’s dose if, in 
his/her clinical judgment, the subject experiencing intolerable adverse event(s) [AE(s)] that warrant(s) such an 
action.  Subjects whose dosage has been down-titrated can have their dose increased again, as soon as tolerability 
improves. Changes of baseline anti-epileptic drugs (AEDs, addition, deletion, or adjustment in dose) are not 
allowed during the Randomization Phase. Parents or caregivers will complete seizure diaries throughout the Core 
Study; seizures will be collected as drop seizures or non-drop seizures. Subjects will remain on the same 
formulation of perampanel (or matching placebo) throughout the course of the study.  (revised per Amendment 04)
Subjects who complete the Maintenance Period of the Core Study will have the option to roll over into Extension 
A and will immediately begin the blinded Conversion Period.  During the Conversion Period (6 weeks), subjects 
who received perampanel during the Core Study will continue receiving perampanel in a blinded manner at the 
same dose received during the Core Maintenance Period.  Subjects who received placebo during the Core Study 
will begin treatment with perampanel in a blinded manner, following the same dosing regimen and titration 
schedule as that in the Core Study, starting at 2 mg/day and will then be up-titrated as described above for the Core 
Study, to the optimal dose per the investigator’s discretion, not to exceed a maximum dose of 8 mg/day.  After the 
double-blind Conversion Period, subjects can be titrated up to 12 mg/day (except in Japan, where the maximum 
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allowed dose remains at 8 mg/day), in 2-week intervals during the Extension A Maintenance Period (46 weeks) as 
per the investigator’s discretion.  The total treatment duration in Extension A is 52 weeks for evaluation of long 
term safety and efficacy.  Addition, deletion, and dose changes to the concomitant AEDs are allowed during 
Extension Maintenance Period. (revised per Amendment 04)
After completion of Extension A, an additional Extension Phase (Extension B) with open-label treatment will be
available for optional participation to subjects who reside in Japan or subjects in countries where an extended 
access program (EAP) cannot be implemented, and who in the opinion of the investigator continue to benefit from 
treatment with perampanel.  Participation in Extension B will continue as long as clinically appropriate according 
to the judgment of the investigator until perampanel is commercially available.  (revised per Amendment 04)  
For subjects residing in countries where commercial perampanel is not yet available and EAP can be implemented
(provided that a positive risk/benefit is demonstrated based on analysis of the Core Study data), subjects who have 
completed Extension A and who in the opinion of the investigator continue to benefit from treatment with 
perampanel may opt to enroll into EAP (if activated), or temporarily into Extension B until EAP is activated or 
until perampanel is commercially available, whichever occurs first.  At that point, the subject will complete his/her 
participation in Extension B.  (revised per Amendment 04)  
In the event that a risk-benefit assessment of perampanel for the treatment of LGS is found to be negative, this 
study will be terminated and no EAP will be set up. (revised per Amendment 04)  
Subjects who do not continue in Extension A or those who prematurely discontinue from the study will return to
the study site for Follow-up visits 1 week and 4 weeks after the last study drug administration. Subjects who do 
not enter into Extension B will enter a 4-week Follow-up Period.  At the end of the 4-week Follow-up Period, 
subjects will return to study site to complete the End-of-Study assessments (Follow-Up visit).  (revised per 
Amendment 04)  
The end of the study will be the date of the last visit of the last subject.  (revised per Amendment 01)
Number of Subjects
Approximately 142 male and female subjects with inadequately controlled seizures associated with LGS, receiving 
1 to 4 concomitant anti-epileptic drugs (AEDs).  Approximately 30% of subjects will be recruited from the US.
(revised per Amendment 04)
Inclusion Criteria
1.
Subjects must have diagnosis of LGS as evidenced by:
o
More than one type of generalized seizures, including drop seizures (atonic, tonic, or myoclonic) for 
at least 6 months before Visit 1
o
An electroencephalogram (EEG) reporting diagnostic criteria for LGS at some point in their history 
(abnormal background activity accompanied by slow, spike and wave pattern <2.5 Hz)
2.
Subjects must be at least 2 years old at the time of consent/assent
3.
Subjects must have been <11 years old at the onset of LGS
4.
Subjects must have experienced an average of at least 2 drop seizures per week in the 4-week Baseline 
Period preceding randomization; the Baseline Period within the Prerandomization Phase is (minimum) 
4 weeks (revised per Amendment 04)
5.
Subjects must have been receiving 1 to 4 concomitant AEDs at a stable dose for at least 30 days before
Visit 1 (vagal nerve stimulation [VNS] and ketogenic diet do not count as an AED).  Use of cannabidiol 
(CBD) products is allowed and is counted as one of the 4 maximum allowed concomitant AEDs.  CBD 
dose and product must have remained stable for at least 30 days before Visit 1 and is to remain the same 
throughout the course of the Core Study.  (revised per Amendment 04)
6.
In the investigator’s opinion, parents or caregivers must be able to keep accurate seizure diaries
7.
Body weight at least 8 kg
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1.
Presence of progressive neurological disease
2.
Presence of drop seizure clusters where individual seizures cannot be reliably counted (seizure clusters are 
defined as ≥2 drop seizures with <5 minutes between any two consecutive seizures)
3.
Prior treatment with perampanel with discontinuation due to safety issues (related to perampanel)
4.
Prior treatment with perampanel within 30 days before Visit 1
5.
Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease, hepatic 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or study conduct
6.
Scheduled for epilepsy-related surgery or any other form of surgery during the projected course of the 
study
7.
Ketogenic diet and VNS, unless stable and ongoing for at least 30 days before Visit 1
8.
Treatment with an investigational drug or device within 30 days before Visit 1
9.
Status epilepticus within 12 weeks of Visit 1
10. If felbamate is used as a concomitant AED, subjects must be on felbamate for at least 1 year, with a stable 
dose for 60 days before Visit 1.  They must not have a history of white blood cell (WBC) count below 
≤2500/μL (2.50 1E+09/L), platelets <100,000/μL, liver function tests (LFTs) >3 times the upper limit of 
normal (ULN), or other indication of hepatic or bone marrow dysfunction while receiving felbamate.
11. Concomitant use of vigabatrin:  Subjects who took vigabatrin in the past must be discontinued for at least 
5 months before Visit 1, and must have documentation showing no evidence of a vigabatrin-associated 
clinically significant abnormality in an automated visual perimetry test
12. 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
13. Evidence of significant active hepatic disease.  Stable elevations of liver enzymes, alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST) due to concomitant medication(s) will be 
allowed if they are < 3 times the ULN
14. Adrenocorticotropic hormone within the 6 months before Visit 1
15. Had history of anoxic episodes requiring resuscitation within 6 months before Visit 1
16. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-
human chorionic gonadotropin [ß-hCG] with a minimum sensitivity of 25 IU/L or equivalent units of ß-
hCG or hCG).  A separate baseline assessment is required if a negative screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug.
17. Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, which 
includes any of the following:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device or intrauterine hormone-releasing system (IUS)
o
an oral contraceptive (with additional barrier method if using contraceptive containing levogesterol) 
(Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before 
dosing and throughout the study and for 28 days after study drug discontinuation.)
o
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) throughout 
the entire study period and for 28 days after study drug discontinuation.
For sites outside of the EU, it is permissible that if a highly effective method of contraception is not 
appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of 
contraception, ie, double-barrier methods of contraception such as condom plus diaphragm or cervical/vault 
cap with spermicide (revised per Amendment 01)
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[amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or 
suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
18. Had intermittent use of benzodiazepine of more than 4 single administrations in the month before Visit 1
19. A prolonged QT/QTc interval (QTc >450 ms) as demonstrated by a repeated electrocardiogram (ECG)
20. Hypersensitivity to the study drug or any of the excipients
21. Any history of a medical condition or a concomitant medical condition that in the opinion of the 
investigator(s) would compromise the subject’s ability to safely complete the study
22. Known to be human immunodeficiency virus (HIV) positive
23. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
24. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior 
suicide attempt(s) within approximately the last 2 years
25. History of drug or alcohol dependency or abuse within approximately the last 2 years; use of illegal 
recreational drugs  
26. Concomitant use of medications known to be inducers of cytochrome P450 (CYP3A) including, but not 
limited to: rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, glucocorticoids (other than 
topical usage), modafinil, pioglitazone, and rifabutin
27. Use of AEDs not recommended by Epilepsy Treatment Guidelines for use in LGS including, but not 
limited to carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin
(revised per Amendment 02)
28. Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 (ie, answering 
“Yes” to questions 4 or 5 on the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale
[C-SSRS]) in subjects aged 8 and above.  (revised per Amendment 02)
29. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption.  (revised per Amendment 04)
Study Treatments
Test drug:  Perampanel
Dosing should occur orally once a day before bedtime.
Note: For Visit 5 and Visit 6, predose and early postdose (within 1 to 5 hours after dosing) PK samples are to be 
collected.  For these visits, if due to infeasibility of PK sample collection before and after evening/bedtime dose 
administration, then the following steps are to be followed:

Study drug administration in the evening immediately before Visit 5 and Visit 6 should be withheld (all 
other AEDs should be administered per the subject’s usual AED regimen).  

During Visit 5 and Visit 6, 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 in the evening on the day of Visit 5 and Visit 6.

In these cases, dosing date and time of the previous 3 doses before each PK sampling visit will continued to 
be recorded.
(revised per Amendment 04)  
Perampanel will be supplied as 2-mg oral tablets and 0.5 mg/mL oral suspension. It is recommended that oral 
tablet be used for dosing subjects ≥12 years of age, and oral suspension for subjects <12 years of age.  However, 
the most appropriate formulation may be selected based on the subject’s condition and at the discretion of the 
investigator.  The same formulation should be used for a given subject throughout the course of the study.
Comparator Drug:  Matching-placebo
Core Study:  Subjects will start perampanel at a dose of 2 mg/day (or matching placebo).  Thereafter, the dose will 


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be increased up to a maximum target dose of 8 mg/day (or matching placebo) according to individual subject 
tolerability and efficacy.  Once titrated, all subjects will be kept at a stable dose for at least 2 weeks (to reach 
steady-state) before the start of the Maintenance Period.  The dose of study drug during the Maintenance Period 
will be the last dose achieved at the end of the Titration Period.  See the dosing table for the dosing schedule in the 
Titration Period.  (revised per Amendment 04)
Dosage Schedule in E2007-G000-338 (Randomization Phase –Core Study)
Randomization Phase/
Titration Period
Visit
All Subjects
Week 1 (starting dose)
Visit 2
2 mg/day
Week 2 
Visit 3
4 mg/day
Week 3
-
6 mg/day
Week 4
Visit 4
6 mg/day
Week 5a
-
8 mg/day
Week 6a
-
8 mg/day
Randomization Phase/
Maintenance Period (Week 7/Visit 5)b
Starts the Maintenance Period at the last dose achieved in the 
Titration Period
a:  Subjects will remain on dose for at least 2 weeks before entering the Maintenance Period.
b: Dosing should occur orally once a day before bedtime, except on the evenings immediately before (and the 
evening on the day of) Visits 5 and 6.  Study drug administration in the evening immediately before (and the 
evening on the day of) Visit 5 and Visit 6 should be withheld (all other AEDs should be administered per the 
subject’s usual AED regimen).  Study drug will be given during Visit 5 and Visit 6 at the study site, after 
collection of predose PK sample (within 1 to 5 hours after dose administration).  Bedtime dosing will resume in 
the evening on the day of Visit 5 and Visit 6.  (revised per Amendment 04).
Extension A: During the Conversion Period, subjects who received perampanel during the Core Study will 
continue receiving perampanel in a blinded manner at the same dose last received during the Core Maintenance
Period.  Subjects who received placebo during the Core Study will begin treatment with perampanel in a blinded 
manner, following the same dosing regimen and titration schedule as that in the Core Study, starting at 2 mg/day 
and will then be up-titrated to the optimal dose, not to exceed 8 mg/day, per the investigator’s discretion.  After the 
double-blind Conversion Period, subjects can be titrated up to 12 mg/day (except in Japan, where the maximum 
allowed dose remains at 8 mg/day), at 2-week intervals per the investigator’s discretion.  During the Conversion
and Maintenance Periods, all dose adjustments will be done via 1 dose level up or down. Those who cannot 
tolerate a minimum of 2 mg dose must discontinue from the study. (revised per Amendment 04)  
Extension B:  Perampanel dosing in Extension B will be the last dose the subject received at the end of 
Extension A. During the Treatment Period, all dose adjustments will be done via 1 dose level up or down. Those 
who cannot tolerate a minimum of 2 mg dose must discontinue from the study. (revised per Amendment 04):  
Duration of Treatment (revised per Amendment 04)
Core Study: 

Prerandomization Phase (Screening/Baseline):  4 (minimum) to 8 weeks

Randomization Phase (Titration, Maintenance, Follow-up):  18 weeks (6+12 weeks, respectively, for 
subjects continuing into Extension A) or 22 weeks (6+12+4 weeks, respectively, for subjects not entering 
into Extension A) 
Extension A (Conversion, Maintenance, Follow-up):
52 weeks (6+46 weeks, respectively, for subjects 
continuing into Extension B) or 56 weeks (6+46+4 weeks, respectively, for subjects not entering into Extension B)
Extension B: Until perampanel is available commercially for the treatment of LGS, or accessible via EAP (if 
activated in the country in which a subject resides), unless the sponsor terminates the study or terminates the study 
in a particular country
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Concomitant use of medications known to be inducers of cytochrome P450 (CYP3A) including, but not limited to
rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), modafinil, 
pioglitazone, and rifabutin, will not be permitted and are to be discontinued 30 days before Visit 1. Use of AEDs 
not recommended by Epilepsy Treatment Guidelines for use in LGS (including, but not limited to carbamazepine, 
gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin) is prohibited throughout the study.  
(revised per Amendment 02)  Use of CBD products is allowed and is counted as one of the 4 maximum allowed 
concomitant AEDs).  CBD dose and product must have remained stable for at least 30 days before Visit 1 and is to 
remain the same throughout the course of the Core Study.  (revised per Amendment 04)
Assessments
Efficacy Assessments – Core Study and Extension A
Seizure diaries will be used to collect seizure counts and types.
The Clinical Global Impression of Severity (CGI-S) and CGI-Improvement (CGI-I) scales will be used to evaluate 
overall changes in symptoms by the physician during the Core Study only.
Pharmacokinetic and Pharmacodynamic Assessments – Core Study
Plasma concentrations of perampanel will be determined using sparse sampling collected at prespecified 
timepoints. Efficacy and selected safety endpoints may be correlated against exposure and/or dose.
Pharmacogenomic Assessments – Core Study
Genomic DNA samples may be used to examine the role of genetic variability in subject’s absorption, distribution, 
metabolism, and excretion, or the development of adverse events.  
Variations in perampanel exposure or adverse events (AEs) may be evaluated by correlation of single-nucleotide 
polymorphisms with PK, safety, or PD data.
Safety Assessments – Core Study and Extension A
Safety assessments will consist of monitoring and recording all AEs and serious adverse events (SAEs); regular 
laboratory evaluation for hematology, blood chemistry, including assessment of criteria for Hy’s Law, and
urinalysis values; periodic measurement of vital signs and physical examination.  (revised per Amendment 01)
The investigator is required to evaluate laboratory results related to liver function (AST, ALT, total bilirubin
[TBIL], and alkaline phosphatase [ALP]) that could potentially meet criteria for Hy’s Law.  If these laboratory 
results include an elevated AST or ALT greater than or equal to 3 × ULN and elevated TBIL greater than or equal 
to 2 × ULN with an ALP laboratory value that is less than 2 × ULN, the subject will be discontinued from the 
study and an SAE will be reported. (revised per Amendment 02)
In addition, an assessment of suicidal ideation and behavior using the C-SSRS will be performed throughout the 
study for subjects aged 8 years and older at the time of consent/assent; subjects who will reach the age of 8 years 
during the double-blind phase of the study will also be assessed using the C-SSRS starting at Baseline. (revised 
per Amendment 03) Suicidal ideation and behavior will be monitored throughout the study for subjects less than 8 
years at the time of consent/assent and during the study, based upon clinical impression. (revised per 
Amendments 01 and 03).  Subjects who appear to have a high risk of suicidal behavior according to results from 
the C-SSRS and/or clinical impression will be withdrawn from the study.  (revised per Amendment 02)
 
 
Safety Assessments – Extension B (revised per Amendment 04)
Safety assessments will consist of monitoring of AEs, withdrawal from treatment, clinical laboratory tests, vital 
signs, and weight. Concomitant medication usage will be monitored.
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Bioanalytical Method
Plasma concentrations of perampanel will be analyzed using a validated liquid chromatography coupled with 
tandem mass spectrometry (LC-MS/MS) assay method.
Statistical Methods
Study Endpoints
Primary Endpoints
The primary efficacy endpoint will be the median percent change in drop seizure frequency per 28 days during 
double-blind treatment (Titration Period and Maintenance Period) relative to the Prerandomization Phase in the 
Full Analysis Set (FAS)
Secondary Endpoints
The following key secondary endpoints will be evaluated sequentially using the FAS:
1.
Median percent change in total seizure frequency per 28 days during double-blind treatment (Titration 
Period and Maintenance Period) relative to the Prerandomization Phase 
2.
The 50% responder rate in the Maintenance Period of the double-blind treatment relative to the 
Prerandomization Phase for drop seizures 
3.
The 50% responder rate in the Maintenance Period of the double-blind treatment relative to the 
Prerandomization Phase for total seizures.
Other secondary endpoints are as follows.  These will not be analyzed statistically but will be summarized:  
(revised per Amendment 01)
4.
Median percent change in non-drop seizure frequency per 28 days during double-blind treatment 
(Titration Period and Maintenance Period) relative to the Prerandomization Phase 
5.
Proportion of subjects with 75%, and 100% responder rates for drop, non-drop, and total seizures in the 
Maintenance Period relative to the Prerandomization Phase
6.
Proportion of subjects with 50% responder rate in the Maintenance Period of the double-blind treatment 
relative to the Prerandomization Phase for non-drop seizures
7.
Physicians’ global evaluation of the subject’s overall changes in symptoms (using a 7-point Likert scale 
with 1=very much improved and 7=very much worse) at the end of the double-blind treatment.
8.
Incidence of AEs and SAEs, changes in clinical laboratory values, and vital signs
9.
Model-derived average perampanel concentrations at steady state (Cav,ss) during the Maintenance Period 
of the Core Study
Exploratory Endpoints
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Analysis Sets (revised per Amendment 04)
Safety Analysis Set (Core Study):  The group of subjects who received at least one dose of study drug and had at 
least one post-dose safety assessment.
Full Analysis Set (FAS, Core Study):  The group of randomized subjects who received at least one dose of study 
drug and had at least one postdose seizure measurement
Per Protocol (PP) Analysis Set:  The group of subjects who sufficiently complied with the protocol.  Details of 
the evaluability criteria will be determined before database lock and treatment unblinding and will be specified in 
the Statistical Analysis Plan (SAP).
Pharmacokinetic Analysis Set: The group of subjects receiving perampanel and with at least one quantifiable 
perampanel concentration during the Maintenance Period of the Core Study and adequately documented dosing 
history
Pharmacokinetic-Pharmacodynamic Analysis Set:
The group of subjects receiving either perampanel or 
placebo who have seizure frequency data with documented dosing history.  Subjects receiving perampanel should 
have at least one quantifiable perampanel concentration as per the PK Analysis Set.
Intention to Treat Set (ITT): The group of randomized subjects who received at least one dose of study drug
Safety Analysis Set (Extension A): The group of subjects who received at least one dose of perampanel and had 
at least one post-perampanel safety assessment. 
FAS (Extension A): The group of subjects who received at least one dose of perampanel and had at least one post-
perampanel seizure measurement.
Safety Analysis Set (Extension B):  The group of subjects who received at least one dose of study drug and had at 
least one postdose safety assessment in Extension B.
All subjects who withdraw from treatment will be summarized and their withdrawal reasons will be tabulated.  
Prior and concomitant medication usage and demographics will also be summarized.
Efficacy Analyses:
Core Study
The analysis of the primary endpoint, percentage change in drop seizure per 28 days in the FAS, will be conducted 
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using rank analysis of covariance (ANCOVA) with ranked percentage change from Baseline in drop seizures per 
28 days as the dependent variable; and treatment, region, age group, and ranked baseline drop seizure rate per 
28 days as the independent variables.  Seizure frequency will be based on the number of drop seizures per 28 days, 
calculated as the number of drop seizures over the entire time interval divided by the number of days in the interval 
and multiplied by 28.
The primary endpoint of median percent change will be tested at 0.05 level and if it is significant then the 3 key 
secondary efficacy endpoints will proceed in a sequential manner. 
Median percent change in total seizure frequency per 28 days during double-blind treatment will be tested first. If 
this test is significant at 0.05 level, then the 50% responder rate in the Maintenance Period for drop seizures will be 
tested. If this is significant then the 50% responder rate in the Maintenance Period for total seizures will be tested. 
All tests will be at a 2-sided 5% significance level.
50% responder rates will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusting for region and age 
group.  For subjects who discontinue the 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 double-blind treatment duration if < 8 weeks of data are 
available) will be used in lieu of Maintenance Period. The treatment effect will be assessed using odds ratios.  The 
common odds ratio and 95% CI as well as response rate from each treatment group will be presented.  (revised per 
Amendment 01)
The same ANCOVA model employed for the primary efficacy endpoint will be employed to analyze percentage 
change from baseline in total seizures.
In addition, a sensitivity analysis for the primary efficacy endpoint and the 3 key secondary endpoints will 
performed in the PP and ITT analysis sets.
Physicians’ global evaluations over time will be analyzed using the CMH test.
Extension A
Summary statistics will be provided for the efficacy endpoints in the Extension A.
Pharmacokinetic Analyses (Core Study):  (revised per Amendment 04)
Perampanel concentrations will be listed by subject, dose, and visit.
A population PK approach will be used to characterize the PK of perampanel, utilizing PK sample data collected 
during the Maintenance Phase of the study. The effect of intrinsic (ie, demographics) and extrinsic factors (ie,
most common concomitant AEDs) on perampanel PK will be evaluated. Derived exposure parameters such as area 
under the concentration-time curve at steady-state (AUCss) or the average steady-state drug concentration (Cav,ss) 
will be calculated from the model using the individual posterior estimates of CL/F and dosing history.
Pharmacodynamic Analyses (Core Study): 
Efficacy and selected safety endpoints may be correlated against exposure and/or dose.
Pharmacokinetic Pharmacodynamic Analyses (Core Study):  
The relationship between exposure to perampanel and response will be explored graphically and any emergent 
relationship will be further subjected to population PK/PD modeling.
Pharmacogenomic Analysis (Core Study):
Pharmacogenomics analyses may be performed and reported separately.  Details of these analyses may be 
described in a separate analysis plan.
Other Endpoint Analyses (Core Study):
 
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Safety Analyses: 
Core Study
Safety analyses will be conducted on the Safety Analysis Set (Core). (revised per Amendment 04)
The incidence of treatment-emergent adverse events (TEAEs, defined as AEs occurring from the time of first dose 
through 28 days after the last dose of study medication), SAEs, AEs associated with fatal outcomes or leading to 
discontinuations, and AEs leading to dose adjustment will be summarized by treatment group.  Incidence of 
TEAEs also will be summarized by severity (mild, moderate, or severe), as well as by relationship to treatment (not 
related, possibly related, or probably related).
Changes from Baseline in laboratory values will be summarized by treatment groups for continuous variables.  Lab 
shift tables showing incidence of new or worsening clinically significant findings from Baseline to the last visit 
will be displayed by treatment groups.  Shift from Baseline to the highest lab value and from Baseline to the lowest 
lab value will also be displayed.
Incidence of out-of-normal-range values and markedly abnormal change from Baseline in laboratory safety test 
variables will be tabulated by treatment group. These out-of-normal-range values and markedly abnormal changes 
from Baseline will be obtained from laboratory-defined normal ranges and using modified National Cancer 
Institute (NCI) criteria, respectively.
Laboratory analyses will also include analysis of outliers. For ALT and AST analysis, the number of subjects with 
> 3 times but < 5 times the ULN and the number of subjects with >5 times the ULN will be summarized.  For 
bilirubin, a summary of the number of subjects with serum concentrations >2 times the ULN will be created.
Changes in vital signs from Baseline to each visit and to the last visit of double-blind treatment will be summarized 
by treatment groups.
The duration of double-blind treatment (Titration Period and Maintenance Period) will be calculated as the number 
of days between the date the subject receives their first treatment dose and the date the subject receives the last 
dose of double-blind treatment.  These values will be used to summarize the extent of exposure to study 
medication.
Extension A
Safety analyses will be performed similarly to the Core Study analyses and all analyses will be on the perampanel 
treatment duration (Randomization Phase + Extension A for subjects randomized to perampanel and Extension A 
for subjects randomized to placebo).  TEAEs are defined as AEs occurring from the time of first perampanel 
through 28 days after the last perampanel dose.  Baseline for laboratory and vital sign parameters is the last non-
missing value before first perampanel dose.
Extension B
Safety analyses will be performed similarly to the Core Study analyses and all analyses will be on the perampanel 
treatment duration (Randomization Phase + Extension A + Extension B for subjects randomized to perampanel and 
Extension A + Extension B for subjects randomized to placebo).  TEAEs are defined as AEs occurring from the 
time of first perampanel through 28 days after the last perampanel dose.  Baseline for laboratory and vital sign 
parameters is the last non-missing value before first perampanel dose.
Interim Analyses
Not applicable
Sample Size Rationale
Seventy-one (71) subjects will be randomized to each treatment arm and this sample size will provide adequate 
power for the primary endpoint and the key secondary endpoints.
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Primary endpoint percent change from baseline in drop seizures:
Placebo rates in drop seizures in the rufinamide and clobazam clinical trials were +1.4%, and -12.1%, respectively.  
In the active treatment arm, rufinamide had a median decrease of 42.5% in drop seizures and clobazam had mean 
decreases of 41.2%, 49.4%, and 68.3% for the low, medium, and high doses, respectively.  A standard deviation of 
~63% was observed for both rufinamide and for the medium dose of clobazam for drop seizures.  It is assumed that 
comparable results will be seen in this trial for the placebo and perampanel treatment arms for drop seizures.
A sample size of 71 subjects in each treatment arm in the FAS will have 94% power to detect a treatment 
difference in median percentage seizure frequency change in drop seizures per 28 days of 40% (common SD of 
63%) between placebo and perampanel based on a Wilcoxon rank-sum test at the 0.05 two-sided significance level.
50% responder rate for drop seizures:
A sample size of 71 subjects per treatment arm will have 97% power to detect a 30% difference in responder rate 
proportions between placebo (assuming a placebo response rate of 20%) and perampanel treatment groups at the 
0.05 two-sided significance level in drop seizures per 28 days using a two-group chi-square test.
Percent change in seizure frequency for total seizures:
Decreases in total seizures for placebo, and low, medium, and high doses in the clobazam trial were approximately 
9%, 35%, 45%, and 65% respectively; common standard deviations ranged from 63% to 83%.  It is assumed that 
comparable results will be seen in this trial for the placebo and perampanel treatment arms for total seizures.
A sample size of 71 subjects in each treatment arm in the FAS will have 80% power to detect a treatment 
difference in median percentage seizure frequency change in total-seizures per 28 days of 36% (SD=73%) between 
placebo and perampanel based on a Wilcoxon rank-sum test at the 0.05 two-sided significance level.
50% responder rate in total seizures:
A sample size of 71 subjects per treatment arm (142 total) will have more than 80% power to detect a 22% 
difference in responder rate proportions between placebo (assuming a placebo response rate of 20%) and 
perampanel treatment groups at the 0.05 two-sided significance level in total-seizures per 28 days using a two-
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TABLE OF CONTENTS
REVISION HISTORY
i
1
TITLE PAGE
1
2
CLINICAL PROTOCOL SYNOPSIS
2
3
TABLE OF CONTENTS
14
LIST OF IN-TEXT TABLES
17
LIST OF IN-TEXT FIGURES
17
LIST OF APPENDICES
17
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
18
5
ETHICS
20
5.1
Institutional Review Boards/Independent Ethics Committees
20
5.2
Ethical Conduct of the Study
20
5.3
Subject Information and Informed Consent
21
6
INVESTIGATORS AND STUDY PERSONNEL
22
7
INTRODUCTION
23
7.1
Indication
23
Current Therapeutic Options
23
7.1.1
Perampanel
24
7.1.2
Mechanism of Action
24
7.1.2.1
Clinical Experience with Perampanel
24
7.1.2.2
7.2
Study Rationale
24
8
STUDY OBJECTIVES
25
8.1
Primary Objective
25
8.2
Secondary Objectives
25
8.3
Exploratory Objectives
25
9
INVESTIGATIONAL PLAN
27
9.1
Overall Study Design and Plan
27
Prerandomization Phase
28
9.1.1
Screening Period
28
9.1.1.1
Baseline Period
29
9.1.1.2
Randomization Phase
29
9.1.2
Core Titration Period
29
9.1.2.1
Core Maintenance Period
30
9.1.2.2
Follow-up Period
31
9.1.2.3
Extension A
31
9.1.3
Additional Extension Phase (Extension B)
32
9.1.4
9.2
Discussion of Study Design, Including Choice of Control Groups
32
9.3
Selection of Study Population
32
Inclusion Criteria
32
9.3.1
Exclusion Criteria
33
9.3.2
Removal of Subjects from Therapy or Assessment
35
9.3.3


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9.4
Treatments
36
Treatments Administered
36
9.4.1
Identity of Investigational Products
37
9.4.2
Chemical Name, Structural Formula of E2007
38
9.4.2.1
Comparator Drug
38
9.4.2.2
Labeling for Study Drug
38
9.4.2.3
Storage Conditions
38
9.4.2.4
Method of Assigning Subjects to Treatment Groups
39
9.4.3
Selection of Doses in the Study
39
9.4.4
Selection and Timing of Dose for Each Subject
40
9.4.5
Blinding
40
9.4.6
Prior and Concomitant Therapy
40
9.4.7
Drug-Drug Interactions
41
9.4.7.1
Prohibited Concomitant Therapies and Drugs
41
9.4.7.2
Treatment Compliance
42
9.4.8
Drug Supplies and Accountability
42
9.4.9
9.5
Study Assessments
44
Assessments
44
9.5.1
Demography
44
9.5.1.1
Baseline Assessments
44
9.5.1.2
Efficacy Assessments
45
9.5.1.3
Pharmacokinetic, 
Pharmacodynamic, 
and 
9.5.1.4
Pharmacogenomic/Pharmacogenetic Assessments
45
Safety Assessments
45
9.5.1.5
Other Assessments
51
9.5.1.6
Schedule of Procedures/Assessments Core Study
53
9.5.2
Appropriateness of Measurements
58
9.5.3
Reporting of Serious Adverse Events, Pregnancy, and Events 
9.5.4
Associated with Special Situations
58
Reporting of Serious Adverse Events
58
9.5.4.1
Reporting of Pregnancy and Exposure to Study Drug 
9.5.4.2
Through Breastfeeding
59
Reporting of Events Associated with Special Situations
60
9.5.4.3
Expedited Reporting
60
9.5.4.4
Breaking the Blind
60
9.5.4.5
Regulatory Reporting of Adverse Events
61
9.5.4.6
Completion/Discontinuation of Subjects
61
9.5.5
Abuse or Diversion of Study Drug
61
9.5.6
Confirmation of Medical Care by Another Physician
61
9.5.7
9.6
Data Quality Assurance
62
Data Collection
62
9.6.1
Clinical Data Management
62
9.6.2
9.7
Statistical Methods
62
Statistical and Analytical Plans
62
9.7.1
Study Endpoints
63
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Definitions of Analysis Sets
64
9.7.1.2
Subject Disposition
65
9.7.1.3
Demographic and Other Baseline Characteristics
65
9.7.1.4
Prior and Concomitant Therapy
65
9.7.1.5
Efficacy Analyses
65
9.7.1.6
Pharmacokinetic, 
Pharmacodynamic, 
and 
9.7.1.7
Pharmacogenomic/Pharmacogenetic Analyses
66
Safety Analyses
67
9.7.1.8
Other Analyses
69
9.7.1.9
Extension A Analyses
70
9.7.1.10
Extension B Analyses
70
9.7.1.11
Determination of Sample Size
70
9.7.2
Interim Analysis
71
9.7.3
Other Statistical/Analytical Issues
71
9.7.4
Procedure for Revising the Statistical Analysis Plan
71
9.7.5
10
REFERENCE LIST
72
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES)
74
11.1
Changes to the Protocol
74
11.2
Adherence to the Protocol
74
11.3
Monitoring Procedures
74
11.4
Recording of Data
75
11.5
Identification of Source Data
75
11.6
Retention of Records
75
11.7
Auditing Procedures and Inspection
76
11.8
Handling of Study Drug
76
11.9
Publication of Results
76
11.10 Disclosure and Confidentiality
77
11.11 Discontinuation of Study
77
11.12 Subject Insurance and Indemnity
77
12
APPENDICES
78


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LIST OF IN-TEXT TABLES
Table 1
Dosage Schedule in E2007-G000-338 (Randomization Phase Core Study)
37
Table 2
Clinical Laboratory Tests
50
Table 3
51
Table 4
52
Table 5
Schedule of Procedures/Assessments in Study E2007-G000-338 (Core 
Study)
54
Table 6
Blood Volumes Taken During Core Study
58
Table 7
Dosage Schedule in E2007-G000-338 (Extension A)
82
Table 8
Schedule 
of 
Procedures/Assessments 
in 
Study 
E2007-G000-338 
(Extension A)
85
Table 9
Blood Volumes Taken During Extension A (revised per Amendment 04)
86
Table 10
Schedule 
of 
Procedures/Assessments 
in 
Study 
E2007-G000-338:  
Extension B  (revised per Amendment 04)
94
LIST OF IN-TEXT FIGURES
Figure 1
Study Diagram for Study E2007-G000-338 (revised per Amendment 04)
28
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
79
Appendix 2
Extension A
81
Appendix 3
Pharmacogenomic Information
89
Appendix 4
Additional Extension Phase (Extension B) (revised per Amendment 04)
91
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
anti-epileptic drugs 
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
AMPA
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
ANCOVA
analysis of covariance 
AST
aspartate aminotransferase
ß-hCG
beta-human chorionic gonadotropin 
BP
blood pressure
CA
Competent Authority 
CFR
Code of Federal Regulations
CL/F
apparent clearance
CMH
Cochran-Mantel-Haenszel
CRA
clinical research associate
CRF
case report form 
CRO
contract research organization
CV
curriculum vitae 
EAP
extended access program
ECG
electrocardiogram
EU
European Union
FAS
Full Analysis Set 
FDA
Food and Drug Administration
GCP
Good Clinical Practice 
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board 
IxRS
interactive voice and web response system 
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Abbreviation
Term
LGS
Lennox-Gastaut Syndrome 
LNH
low/normal/high
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PET
polyethylene terephthalate 
PG
pharmacogenomic
PI
principal investigator 
PK
pharmacokinetics
POS
partial-onset seizure 
PP
per protocol
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure 
TBIL
total bilirubin
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values 
ULN
upper limit of normal
VNS
vagal nerve stimulation 
WBC
white blood cell 
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 International Conference on Harmonisation 
(ICH) E6 (Good Clinical Practice [GCP]), Section 3, and any local regulations.  Any protocol 
amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and approval, 
except for changes involving only logistical or administrative aspects of the study (eg, change in 
clinical research associate [CRAs], change of telephone number[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review conduct 
will be provided to the sponsor.  
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study drug to 
the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend 
or terminate the study, the investigator will immediately send the notice of study suspension or 
termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to the 
IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) or the sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice.  Upon completion of the study, the investigator will provide the 
IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority (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:
●
Principles of the World Medical Association Declaration of Helsinki (2013)
●
ICH E6 Guideline for GCP (Committee for Proprietary Medicinal Products 
[CPMP]/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, 
Committee for Proprietary Medicinal Products, ICH of Pharmaceuticals for Human Use


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●
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
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, in accordance with applicable professional 
standards and local laws/regulations, the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, any potential 
discomfort, potential alternative procedure(s) or course(s) of treatment available to the subject, 
and the extent of maintaining confidentiality of the subject’s records.  Each subject must be 
informed that participation in the study is voluntary, that he/she may withdraw from the study at 
any time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.  (revised per Amendment 04)
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to read, 
an impartial witness should be present during the entire informed consent discussion.  In 
countries where specific laws for children are established for informed consent, those local laws 
will be applied.  After the ICF and any other written information to be provided to subjects is 
read and explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the ICF, 
the witness should sign and personally date the consent form.  The subject will be asked to sign 
an ICF at the screening visit before any study-specific procedures are performed.  No subject can 
enter the study before his/her informed consent has been obtained.  (revised per Amendment 04)
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations.  Each subject must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The original, 
signed ICF for each subject will be verified by the sponsor and kept on file according to local 
procedures at the site.  
The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study.  The communication of this information should be 
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 70 investigational site(s) in North America, Europe, and Asia. 
(revised per Amendment 01).
The name and telephone and fax numbers of the medical monitor and other contact personnel 
will be provided to each site.


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7
INTRODUCTION
7.1
INDICATION 
Lennox-Gastaut Syndrome (LGS) is one of the most rare and severe forms of childhood 
epilepsy.  The syndrome usually affects children between the ages of 1 and 8 years (typically 
between 3 and 5 years), but occasionally has its onset in children who are older than 8 years.  
Lennox-Gastaut Syndrome begins in childhood, but continues to manifest into adulthood and has 
a significant morbidity and mortality.  It accounts for approximately 1% of all new cases of 
epilepsy, although LGS may account for as many as 10% of the severe epilepsy cases. 
Current Therapeutic Options 
7.1.1
Treatment options for subjects with LGS are limited because of the resistance of seizures to 
pharmacological treatment.  In addition, as there is no animal model for LGS, progress in our 
understanding and treatment of this disorder is impeded because novel targets for intervention 
cannot be rigorously studied.  The choice of the most appropriate anti-epileptic drugs (AEDs) is 
complex and there is little guidance available for practicing physicians.
Owing to the many seizure types, many drugs are used in combinations that are mostly guided by 
anecdotal evidence or personal experience.  Opinions towards treatment are further complicated 
because an AED might be of some benefit for the control of one seizure type while aggravating 
another type.  Concomitantly, polytherapy increases the potential for AEs (Arzimanoglou et al., 
2009).
Currently, 6 AEDs are approved for the indication of LGS: clobazam, rufinamide, lamotrigine, 
felbamate, topiramate, and epidiolex. Randomized clinical trials with these drugs aimed for a 
reduction of seizures associated with LGS (Devinsky et al., 2018; Thiele et al., 2018; Ng et 
al., 2011; Glauser et al., 2008; Motte et al., 1998; Sachdeo et al., 1999; Anonymous, 1993). 
Some of these drugs are associated with potentially severe adverse reactions, such as severe skin 
rashes (lamotrigine), aphasia in this cognitively impaired population (topiramate), and serious 
hematologic and hepatic toxicity (felbamate).  (revised per Amendments 01 and 04)
Also, treatment options for subjects with LGS are limited because of the resistance of seizures to 
pharmacological treatment. The choice of the most appropriate AEDs is complex and there is 
little guidance available for practicing physician. Owing to the many seizure types, many drugs 
are used in combinations and some AEDs might be of some benefit for the control of one seizure 
type while aggravating another type.
Concomitantly, polytherapy increases the potential for 
AEs.
Perampanel is a novel AED with a unique mechanism of action, which has been 
demonstrated to be effective in the treatment of both partial and primary generalized types of 
seizures, making it a viable opportunity for the treatment of LGS. The benefit of improving the 
seizures associated with LGS, especially the severe drop attacks, outweigh the potential risks 
associated with the use of the drug.  (revised per Amendment 01)


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Perampanel
7.1.2
Mechanism of Action
7.1.2.1
In an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) induced seizure 
model, oral perampanel significantly prolonged seizure latency, suggesting that perampanel is an 
orally active, selective noncompetitive AMPA receptor antagonist.
Clinical Experience with Perampanel
7.1.2.2
Clinical efficacy and safety of perampanel has been established in other epilepsy indications, 
including partial-onset seizures (POS) and PGTC seizures.  Detailed information regarding the 
clinical efficacy and safety of perampanel is provided in the E2007 Global Investigator’s 
Brochure.  (revised per Amendment 04)
7.2
STUDY RATIONALE
(revised per Amendment 02)
The proposed study follows a similar design utilized for the studies of previously approved 
AEDs in this indication.  The primary endpoint of the study is the change in count of seizures 
resulting in drop attacks (tonic, atonic or myoclonic).  Drop seizure is defined as a drop attack or 
spell involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the 
patient’s head hitting a surface or that could have led to a fall or injury, depending on the 
patient’s position at the time of the attack or spell. This endpoint was chosen over the alternative 
endpoint of total seizures count based on review of the relevant publications and input from key 
opinion leaders.  Non-drop seizures are defined according to the International League Against 
Epilepsy guidelines (1981).
Subjects on carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, and 
vigabatrin will not be permitted to participate in Study 338.  (revised per Amendment 02)  This is 
based on the lack of approval of these drugs in any region for this indication, and on the 
recommendation in guidelines against using these AEDs for the treatment of LGS, which are 
based on literature reports of worsening of some types of seizures associated with LGS when 
these AEDs are used (Thomas et al., 2006; Snead and Hosey, 1985; Eldridge et al., 1983; Osorio 
et al., 1989).  
 
 
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8
STUDY OBJECTIVES
8.1
PRIMARY OBJECTIVE
The primary objective of the study is to demonstrate that perampanel given as adjunctive anti-
epileptic treatment is superior compared to placebo in reducing the incidence of drop seizures 
during 18 weeks of treatment in subjects with inadequately controlled seizures associated with 
LGS.
8.2
SECONDARY OBJECTIVES
The secondary objectives of the study are:
1. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in reducing the incidence of all seizures during 18 weeks of treatment in subjects 
with inadequately controlled seizures associated with LGS
2. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in the 50%, 75%, and 100% responder rates for drop seizures during 12 weeks of 
the Maintenance Period in subjects with inadequately controlled seizures associated with 
LGS
3. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in the 50%, 75%, and 100% responder rates for total seizures during 12 weeks of 
the Maintenance Period in subjects with inadequately controlled seizures associated with 
LGS
4. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in reducing the incidence of non-drop seizures during 18 weeks of treatment in 
subjects with inadequately controlled seizures associated with LGS
5. To evaluate the 50%, 75%, and 100% responder rates in non-drop seizure frequency in 
the Maintenance Period
6. To evaluate physicians’ global evaluation of subjects’ overall changes in symptoms
7. To evaluate the safety of perampanel relative to placebo as adjunctive therapy in subjects
with inadequately controlled seizures associated with LGS during both the Core Study
and the Extension Phase 
8. To evaluate the pharmacokinetics and the pharmacokinetic/pharmacodynamic (PK/PD) 
relationships of perampanel as adjunctive therapy in subjects with inadequately
controlled seizures associated with LGS
8.3
EXPLORATORY OBJECTIVES
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9
INVESTIGATIONAL PLAN
9.1
OVERALL STUDY DESIGN AND PLAN
This will be a multicenter, double-blind, randomized, placebo-controlled, parallel-group study of 
perampanel as adjunctive therapy in subjects with inadequately controlled seizures associated 
with LGS.  The study will consist of 3 phases:  Prerandomization, Randomization, and 
Extension.  The Core Study will consist of the Prerandomization and Randomization Phases.
The Prerandomization Phase will consist of a 4- to 8-week Screening/Baseline Period during 
which subjects will be assessed for overall eligibility to participate in the study, including seizure 
activity. Baseline seizure count will be assessed using all diary data before randomization (at 
least 4 weeks prospectively).  Following successful completion of this period, subjects will be 
randomized to receive perampanel or placebo in a 1:1 ratio.  
The Randomization Phase will consist of 3 periods:  Titration (6 weeks), Maintenance 
(12 weeks), and Follow-up (4 weeks, only for subjects not entering into Extension A). As 
required by some regulatory agencies, the following estimates are provided: 
●
The study will begin approximately Jan 2017 and will end approximately Jan 2020.  
(revised per Amendment 01)
●
The maximum estimated period for each subject (except subjects continuing in 
Extension B) on the study is anticipated to be approximately 82 weeks. (revised per 
Amendment 04)
An overview of the study design is presented in Figure 1.


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Figure 1
Study Diagram for Study E2007-G000-338 (revised per Amendment 04)
R = randomization.
a: Subjects who do not continue in Extension A or those who prematurely discontinue from the study will return to
the study site for Follow-up visits 1 week and 4 weeks after the last study drug administration.
b:  Subjects will be up-titrated to optimize efficacy while maintaining good tolerability, up to a maximum dose of 
8 mg/day.  Once titrated, all subjects will be kept at a stable dose for at least 2 weeks (to reach steady-state) before 
the start of the Maintenance Period.  The dose of study drug during the Maintenance Period will be the last dose 
achieved at the end of the Titration Period.
c:  After the double-blind Conversion Period of Extension A, subjects can be titrated (except in Japan, where the 
maximum allowed dose remains at 8 mg/day) up to 12 mg/day in 2-week intervals, as per the investigator’s 
discretion.
Prerandomization Phase
9.1.1
The Prerandomization Phase will last 4 (minimum) to 8 weeks and will include a Screening and 
a Baseline period. (revised per Amendment 04)
Screening Period
9.1.1.1
During this period, subjects will be assessed for overall eligibility to participate in the study, 
including seizure activity.  A minimum of 4 consecutive weeks of diary data before
randomization will be required for study participation. Baseline seizure count will be assessed 
using all diary data before randomization.  Following successful completion of this period, 
subjects will be randomized to receive perampanel or placebo in a 1:1 ratio.
Period:
Screening
Baseline
R
Perampanel
< 8 weeks
Day 1
Week 71
Week 23/75
Core Study
Titrationb
Maintenance
Placebo
Week 7
Week 19
Phase:
Conversion
Period
+
Maintenance
Periodc
Randomization
Prerandomization
Follow-Upa
Extension A


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Screening will occur from up to Day -56 to Day -1.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility.  Informed consent will be obtained 
after the study has been fully explained to each subject and before the conduct of any screening 
procedures or assessments.  Procedures to be followed when obtaining informed consent are 
detailed in Section 5.3.
Subjects must have at least a 6 month diagnosis of LGS as evidenced by more than one type of 
generalized seizures, including drop seizures (atonic, tonic, or myoclonic).  This must be 
confirmed by an electroencephalography (EEG) reporting diagnostic criteria (abnormal 
background activity accompanied by slow, spike and wave pattern < 2.5 Hz) at some point in the 
subject’s history.
Baseline Period
9.1.1.2
During the 4-week Baseline Period, subjects must have an average of at least 2 drop seizures per 
week as computed from a seizure diary.  To satisfy inclusion criterion #4, the total number of 
drop seizures will be summed and then averaged over this 4-week period.  Subjects must also 
demonstrate at least a 30-day stable dosing regimen of 1 to 4 concomitant AEDs before Visit 1. 
(revised per Amendment 04).
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1and 9.3.2) will begin the Randomization Phase.
Randomization Phase
9.1.2
The duration of the Randomization Phase will be either 18 (for subjects continuing into 
Extension A) or 22 weeks (for subjects not continuing into Extension A) and will include 
3 periods:  Titration, Maintenance, and Follow-up (for subjects not rolling over into Extension A
and those who terminate early from the study).  Subjects whose screening assessments and 
evaluations are completed and reviewed by the PI or designee and who continue to meet all of 
the inclusion/exclusion criteria will enter the Core Titration Period.  (revised per Amendment 04)
Subjects will be randomized in 1:1 ratio to receive either perampanel or placebo.  Changes of 
baseline AEDs (addition, deletion, or adjustment in dose) are not allowed during the 
Randomization Phase).  (revised per Amendment 04)
Core Titration Period
9.1.2.1
During the 6-week Titration Period, subjects will be started on 2 mg/day of perampanel tablets
(recommended for ≥12 years at time of consent/assent), oral suspension (recommended for 
<12 years at time of consent/assent), or matching placebo.  However, the most appropriate 
formulation may be selected based on the subject’s condition and at the discretion of the 
investigator.  The same formulation should be used for a given subject throughout the course of 
the study.  Thereafter, the dose will be increased up to a maximum target dose of 8 mg/day (or 
matching placebo) according to individual tolerability and efficacy.  Once titrated, all subjects 
will be kept at a stable dose for at least 2 weeks (to reach steady-state) before the start of the 
Maintenance Period.  The dose of study drug during the Maintenance Period will be the last dose 


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achieved at the end of the Titration Period.  According to the investigators’ clinical judgment, 
subjects experiencing intolerable AEs may remain on the same dose or have their dose reduced 
to the previously tolerated dose during the Titration Period.  Subjects whose dosage has been 
down-titrated can have their dose increased again, as soon as tolerability improves.  This can be 
done at the next clinic visit or at an unscheduled clinic visit after the investigator has deemed it 
adequate in view of the resolution of AE(s).  The decision to down-titrate a subject’s dose can be 
made via telephone. (revised per Amendment 04)
In general, more than one down-titration will be discouraged; however, if the subject continues 
to present significant intolerable AE(s) and the investigator deems it is necessary, the dose may 
be reduced further.
At the end of the Titration Period, all subjects should be at their optimum dose level. Subjects 
who do not tolerate a daily dose of 2 mg/day will be discontinued from the study.
Core Maintenance Period
9.1.2.2
During the 12-week Maintenance Period, subjects will continue treatment with the dose and 
formulation of test drug (perampanel) or placebo achieved during the Titration Period, taking the 
study drug once daily in blinded fashion.  The Maintenance Period will begin with Visit 5, and 
subjects will continue treatment at the last dose (or matching placebo) achieved in the Titration 
Period.  Study drug administration in the evening immediately before (and the evening on the 
day of) Visit 5 and Visit 6 should be withheld (all other AEDs should be administered per the 
subject’s usual AED regimen).  Study drug will be given during Visit 5 and Visit 6 at the study 
site (within 1 to 5 hours after dose administration).  Bedtime dosing will resume in the evening 
on the day of Visit 5 and Visit 6. In these cases, dosing date and time of the previous 3 doses 
before each PK sampling visit will continued to be recorded.  Parents or caregivers will complete 
seizure diaries throughout the Core Study; all seizure types will be collected.  Subjects will 
continue to take their baseline anti-epileptic medications throughout the study.  (revised per 
Amendment 04)  
Dose adjustment during the Maintenance Period is not recommended; however, the investigator 
may down-titrate a subject’s dose if, in his/her clinical judgment, the subject experiencing 
intolerable AE(s) that warrant(s) such an action.  In general, more than one down-titration of a 
subject’s dose will be discouraged; however, if the subject continues to present significant 
intolerable AE(s) and the investigator deems it is necessary, the dose may be reduced further.  
During the Maintenance Period, subjects whose dose has been down-titrated can have their dose 
increased again, as soon as tolerability improves.  This can be done at an unscheduled clinic visit 
or at the next clinic visit after the investigator has deemed it appropriate based on the resolution 
of AE(s). 
Subjects who complete the Maintenance Period will have the option to roll over into Extension A
and will immediately begin the blinded Conversion Period.


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Subjects who do not continue in Extension A or those who prematurely discontinue from the 
study will return to the study site for Follow-up visits 1 week and 4 weeks after the last study 
drug administration.  (revised per Amendment 04)
Follow-up Period
9.1.2.3
Subjects who do not continue in Extension A or those who prematurely discontinue from the 
study will return to the study site for Follow-up visits 1 week and 4 weeks after the last study 
drug administration.  At the end of the 4-week Follow-up Period, subjects will return to study 
site to complete the End-of-Study assessments (Follow-Up visit).  These assessments will also be 
performed if a subject prematurely discontinues from the study, after the Early Discontinuation 
Visit.  (revised per Amendment 04)
Extension A
9.1.3
A subject who completes the Maintenance Period of the Core Study will be eligible to enter 
Extension A, which consists of 3 periods: Conversion Period (6 weeks), Maintenance Period
(46 weeks), and Follow-up (4 weeks; only for those subjects not entering into Extension B). The 
total treatment duration in Extension A is 52 weeks for evaluation of long term safety and 
efficacy.  (revised per Amendment 04)
Subjects will immediately begin the blinded Conversion Period starting at Week 19.  During the 
Conversion Period, subjects who received perampanel during the Core Study will continue 
receiving perampanel in a blinded manner at the same dose received during the Core 
Maintenance Period.  Subjects who received placebo during the Core Study will begin treatment 
with perampanel in a blinded manner, following the same dosing regimen and titration schedule 
as that in the Core Study, starting at 2 mg/day and will then be up-titrated as described above for 
the Core Study, to the optimal dose per the investigator’s discretion, not to exceed a maximum 
dose of 8 mg/day.  After the double-blind Conversion Period, subjects can be titrated up to 
12 mg/day (except in Japan, where the maximum allowed dose remains at 8 mg/day), in 2-week 
intervals during the Extension A Maintenance Period as per the investigator’s discretion.  The 
total treatment duration in Extension A is 52 weeks for evaluation of long term safety and 
efficacy.  Addition, deletion, and dose changes to the concomitant AEDs are allowed during 
Extension Maintenance Period. (revised per Amendment 04)
After completion of Extension A, an additional Extension Phase (Extension B) with open-label 
treatment will be available for optional participation to subjects who reside in Japan or subjects 
in countries where an extended access program (EAP) cannot be implemented or has not yet 
been implemented, and who in the opinion of the investigator continue to benefit from treatment 
with perampanel.  All subjects, except for those entering Extension B, will enter a 4-week 
Follow-up Period, which will have 1 visit during which End-of-Study assessments will be 
performed. (revised per Amendment 04)
Further information regarding Extension A is provided in Appendix 2 .


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Additional Extension Phase (Extension B)
9.1.4
Extension B will be open for subjects who reside in Japan or subjects residing in countries where 
an EAP cannot be implemented, and who in the opinion of the investigator continue to benefit 
from treatment with perampanel.  Participation in Extension B will continue as long as clinically 
appropriate according to the judgment of the investigator until perampanel is commercially 
available.  (revised per Amendment 04)  
For subjects residing in countries where commercial perampanel is not yet available and EAP 
can be implemented (provided that a positive risk/benefit is demonstrated based on analysis of 
the Core Study data), subjects who have completed Extension A and who in the opinion of the 
investigator continue to benefit from treatment with perampanel may opt to enroll into EAP (if 
activated), or temporarily into Extension B until EAP is activated or until perampanel is 
commercially available, whichever occurs first.  At that point, the subject will complete his/her 
participation in Extension B. (revised per Amendment 04)  
In the event that a risk-benefit assessment of perampanel for the treatment of LGS is found to be 
negative, this study will be terminated and no EAP will be set up.  (revised per Amendment 04)  
See Appendix 4 for a full description of Extension B. (revised per Amendment 04)
The end of the study will be the date of the last visit of the last subject.  (revised per 
Amendment 01)
9.2
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL GROUPS
Randomization will be used in this study to avoid bias in the assignment of subjects to treatment, 
to increase the likelihood that known and unknown subject attributes (eg, demographics and 
baseline characteristics) are balanced across treatment groups, and to ensure the validity of 
statistical comparisons across treatment groups.  Blinding to treatment will be used to reduce 
potential bias during data collection and evaluation of endpoints.
9.3
SELECTION OF STUDY POPULATION
Approximately 142 subjects will be randomized at approximately 70 sites in regions that include 
North America, Europe, and Asia.  Approximately 30% of subjects will be recruited from the 
US.  Sites will be encouraged to enroll subjects throughout the allowed age range (2 years and 
older).  Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.
Inclusion Criteria
9.3.1
Subjects must meet all of the following criteria to be included in this study:
1. Subjects must have diagnosis of LGS as evidenced by:
a.
More than one type of generalized seizures, including drop seizures (atonic, tonic, or 
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b. An EEG reporting diagnostic criteria for LGS at some point in their history (abnormal 
background activity accompanied by slow, spike and wave pattern < 2.5 Hz)
2. Subjects must be at least 2 years old at the time of consent/assent
3. Subjects must have been <11 years old at the onset of LGS
4. Subjects must have experienced an average of at least 2 drop seizures per week in the 
4-week Baseline Period preceding randomization; the Baseline Period within the 
Prerandomization Phase is (minimum) 4 weeks. (revised per Amendment 04)
5. Subjects must have been receiving 1 to 4 concomitant AEDs at a stable dose for at least 
30 days before Visit 1 (vagal nerve stimulation [VNS] and ketogenic diet do not count as 
an AED).  Use of cannabidiol (CBD) products is allowed and is counted as one of the 
4 maximum allowed concomitant AEDs.  CBD dose and product must have remained 
stable for at least 30 days before Visit 1 and is to remain the same throughout the course 
of the Core Study.  (revised per Amendment 04)
6. In the investigator’s opinion, parents or caregivers must be able to keep accurate seizure 
diaries
7. Body weight at least 8 kg 
Exclusion Criteria
9.3.2
Subjects who meet any of the following criteria will be excluded from this study:
1. Presence of progressive neurological disease
2. Presence of drop seizure clusters where individual seizures cannot be reliably counted 
(seizure clusters are defined as ≥2 drop seizures with <5 minutes between any 
2 consecutive seizures)
3. Prior treatment with perampanel with discontinuation due to safety issues (related to 
perampanel) 
4. Prior treatment with perampanel within 30 days before Visit 1
5. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease, hepatic disease) that in the opinion of the investigator(s) could affect the 
subject’s safety or study conduct
6. Scheduled for epilepsy-related surgery or any other form of surgery during the projected 
course of the study
7. Ketogenic diet and VNS, unless stable and ongoing for at least 30 days before Visit 1
8. Treatment with an investigational drug or device within 30 days before Visit 1
9. Status epilepticus within 12 weeks of Visit 1
10. If felbamate is used as a concomitant AED, subjects must be on felbamate for at least 
one year, with a stable dose for 60 days before Visit 1.  They must not have a history of 
white blood cell (WBC) count below ≤2500/μL (2.50 1E+09/L), platelets < 100,000/μL, 


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liver function tests >3 times the upper limit of normal (ULN), or other indication of 
hepatic or bone marrow dysfunction while receiving felbamate.
11. Concomitant use of vigabatrin:  Subjects who took vigabatrin in the past must be 
discontinued for at least 5 months before Visit 1, and must have documentation showing 
no evidence of a vigabatrin-associated clinically significant abnormality in an automated 
visual perimetry test
12. 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
13. Evidence of significant active hepatic disease.  Stable elevations of liver enzymes, 
alanine aminotransferase (ALT), and aspartate aminotransferase (AST) due to 
concomitant medication(s) will be allowed if they are < 3 times the ULN
14. Adrenocorticotropic hormone within the 6 months before Visit 1
15. Had history of anoxic episodes requiring resuscitation within 6 months before Visit 1
16. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] with a minimum sensitivity of 
25 IU/L or equivalent units of ß-hCG or hCG).  A separate baseline assessment is 
required if a negative screening pregnancy test was obtained more than 72 hours before 
the first dose of study drug.
17. Females of childbearing potential who:
(revised per Amendment 01)

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
o
Total abstinence (if it is their preferred and usual lifestyle)
o
An intrauterine device or intrauterine hormone-releasing system (IUS)
o
An oral contraceptive (with additional barrier method if using contraceptive 
containing levogesterol) (Subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the study 
and for 28 days after study drug discontinuation.)
o
Have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.  
For sites outside of the EU, it is permissible that if a highly effective method of contraception 
is not appropriate or acceptable to the subject, then the subject must agree to use a medically 
acceptable method of contraception, ie, double-barrier methods of contraception such as 
condom plus diaphragm or cervical/vault cap with spermicide.  (revised per Amendment 01)
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically [ie, 


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bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 
1 month before dosing]).
18. Had intermittent use of benzodiazepine of more than 4 single administrations in the 
month before Visit 1
19. A prolonged QT/QTc interval (QTc >450 ms) as demonstrated by a repeated 
electrocardiogram (ECG)
20. Hypersensitivity to the study drug or any of the excipients 
21. Any history of a medical condition or a concomitant medical condition that in the opinion 
of the investigator(s) would compromise the subject’s ability to safely complete the study 
22. Known to be human immunodeficiency virus (HIV) positive
23. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
24. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years
25. History of drug or alcohol dependency or abuse within approximately the last 2 years; use 
of illegal recreational drugs
26. Concomitant use of medications known to be inducers of cytochrome P450 (CYP3A) 
including, but not limited to: rifampin, troglitazone, St John’s Wort, efavirenz, 
nevirapine, glucocorticoids (other than topical usage), modafinil, pioglitazone, and 
rifabutin.
27. Use of AEDs not recommended by Epilepsy Treatment Guidelines for use in LGS 
including, but not limited to carbamazepine, gabapentin, oxcarbazepine, phenytoin, 
pregabalin, tiagabine, and vigabatrin  (revised per Amendment 02)
28. Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 
(ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS) 
in subjects aged 8 and above.  (revised per Amendment 01)
29. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption.  (revised per Amendment 04)
Removal of Subjects from Therapy or Assessment
9.3.3
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.
Subjects with laboratory results that include elevated AST or ALT greater than or equal to 
3 × ULN and elevated total bilirubin (TBIL) greater than or equal to 2 × ULN with an alkaline 
phosphatase (ALP) laboratory value that is less than 2 × ULN, ie that meet criteria for Hy’s law,
will be withdrawn from the study. (revised per Amendment 03) Subjects who appear to have a 
high risk of suicidal behavior according to results of the C-SSRS and/or clinical impression will 
be withdrawn from the study.  (revised per Amendment 03)


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A subject who discontinues study treatment should be followed for subsequent 
protocol-specified visits and procedures.  If a subject discontinues study drug(s) but remains in 
the study (Core Study), the set of end-of-treatment procedures will be administered, and 
protocol-specified information will be collected.  The primary reason for discontinuation and all 
other reason(s) contributing to the subject’s discontinuation from study drug(s) should be 
collected on the Subject Disposition case report form (CRF) page (or the Early Discontinuation 
from Study Drug CRF page).  In addition, the date of last dose of study drug(s) will be recorded 
on the Study Drug Dosing CRF page.  If a subject discontinues study treatment and the study at 
the same time, the End-of-Study procedures (Final Visit) will be followed.
9.4
TREATMENTS
Treatments Administered
9.4.1
The following treatments will be administered during the Randomization Phase:  

Perampanel: single daily dose of perampanel oral 2-mg tablets with multiple tablets 
dispensed to give a dose of 2 mg/day to 8 mg/day.  (revised per Amendment 04)

Perampanel: single daily dose of perampanel oral suspension 0.5 mg/mL, with the 
volume dispensed adjusted to give a dose of 2 mg/day to 8 mg/day.  (revised per 
Amendment 04)

Placebo matched to perampanel 2-mg tablets

Placebo matched to perampanel oral suspension
It is recommended that oral tablet be used for dosing subjects ≥12 years of age and oral 
suspension be used for subjects <12 years of age (at the time of signing informed consent); 
however, the most appropriate formulation may be selected based on the subject’s condition and 
at the discretion of the investigator.  The same formulation should be used for a given subject 
throughout the course of the study.  Dosing should occur orally once a day before bedtime.  
Before the PK sampling visits, the dosing date and time of the previous 3 doses before each PK 
sampling visit will be recorded.  Study drug administration in the evening immediately before
(and the evening on the day of) Visit 5 and Visit 6 should be withheld (all other AEDs should be 
administered per the subject’s usual AED regimen).  Study drug will be given during Visit 5 and 
Visit 6 at the study site (within 1 to 5 hours after dose administration).  Bedtime will resume in 
the evening on the day of Visit 5 and Visit 6.  (revised per Amendment 04)  
The subject will continue to take their baseline anti-epileptic medication regimen throughout the 
Randomization Phase.  Changes of baseline AEDs (addition, deletion, or adjustment in dose) are 
not allowed during the Randomization Phase.  (revised per Amendment 01)
The following treatments will be administered to subjects in this study (Table 1).  The dosage 
form administered at the start of the Titration Period (tablets or suspension [ie, the most 
appropriate formulation selected based on the subject’s condition and at the discretion of the 
investigator]) will be continued throughout the study (Core and Extension) even if a subject 
reaches 12 years of age during this time. (revised per amendment 04)


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Table 1
Dosage Schedule in E2007-G000-338 (Randomization Phase Core Study)
Randomization Phase/
Titration Period
Visit
All Subjects
Week 1 (starting dose)
Visit 2
2 mg/day
Week 2
Visit 3
4 mg/day
Week 3
-
6 mg/day
Week 4
Visit 4
6 mg/day
Week 5a
-
8 mg/day
Week 6a
-
8 mg/day
Randomization Phase/
Maintenance Period (Week 7/Visit 5)b
Starts the Maintenance Period at the last dose achieved in the 
Titration Period
a:  Subjects will remain on dose for at least 2 weeks before entering the Maintenance Period.
b: Dosing should occur orally once a day before bedtime, except on the evenings immediately before (and the 
evening on the day of) Visit 5 and Visit 6.  Study drug administration in the evening immediately before (and the 
evening on the day of) Visit 5 and Visit 6 should be withheld (all other AEDs should be administered per the 
subject’s usual AED regimen).  Study drug will be given during Visit 5 and Visit 6 at the study site, after 
collection of predose PK sample (within 1 to 5 hours after dose administration).  Bedtime dosing will resume in 
the evening on the day of Visit 5 and Visit 6.  (revised per Amendment 04)
Identity of Investigational Products
9.4.2
E2007 (perampanel) is a US Drug Enforcement Administration (DEA) Scheduled III Drug 
Product (C-III).
PERAMPANEL TABLETS 
Perampanel 2-mg tablets will be provided as orange, 6.6 mm diameter, biconvex film-coated 
tablets for oral administration.  The front and reverse sides of the tablets will be debossed with 
“E274.”  Each tablet will contain 2 mg of perampanel.  The certificate(s) of analysis (CoA) will 
provide manufacturer information.
Perampanel-matched placebo tablets will be provided as orange, 6.6 mm diameter, biconvex 
film-coated tablets for oral administration.  The front and reverse sides of the tablets will be 
debossed with “E274.”  The CoA will provide manufacturer information.
The Eisai-approved vendor will package the study drugs in a double-blind configuration.  Each 
subject’s study drug will consist of either perampanel and/or perampanel-matched placebo and 
will be supplied in a subject medication kit bearing a multilanguage booklet label.
During the Titration Period, subjects will be given blinded 2-week dose packs containing 2 × 28
tablets plus 3 days of additional medication.  During the Maintenance Period, subjects will be 
given blinded 2-week dose packs, each containing 2 x 28 tablets plus 3 days of additional 
medication.  (revised per Amendment 01)
PERAMPANEL SUSPENSION
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 CoA 
will provide manufacturer information.  Placebo solution (for dilution purposes) will consist of 


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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 CoA will provide manufacturer information.
Both the perampanel and placebo oral suspensions will be provided by Eisai Co. Ltd. to an Eisai-
approved vendor in 400-mL polyethylene terephthalate (PET) bottles containing 340 mL of oral 
suspension.  The approved vendor will label the bottles and ship them to the study sites
The PET bottles will be, if necessary, fitted with appropriately sized press-in bottle adaptors 
(PiBA) to aid in accurate aliquoting.  Dosing devices (eg, oral syringes) will also be provided for 
subject use.
During the Titration and Maintenance Periods subjects will be given bottles containing oral 
suspension.  The same bottle can be returned to the subject/caregiver. Instructions regarding 
routine dosage changes during the Titration Period will also be conveyed to the investigator via 
IxRS as described in Section 9.4.3.  
Detailed instructions on weekly/biweekly increments in dosage during the Titration Period will 
be provided to the subject’s caregiver by the site investigator or the designated pharmacy.
Details for the identity of the investigational product for Extension A can be found in
Appendix 2.
Chemical Name, Structural Formula of E2007
9.4.2.1

Test drug code: E2007
Comparator Drug
9.4.2.2
Not applicable
Labeling for Study Drug
9.4.2.3
Perampanel 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.
Storage Conditions
9.4.2.4
Where applicable, test drug (perampanel) will be stored and labeled in accordance with the US 
FDA Drug Enforcement Administration (DEA) Regulations for Scheduled III - V Drugs.
CCI


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Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained within 
an established temperature range.  The investigator or designee is responsible for ensuring that 
the temperature is monitored throughout the total duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
validated data acquisition system, a mechanical recording device, such as a calibrated chart 
recorder, or by manual means, such that minimum and maximum thermometric values over a 
specific time period can be recorded and retrieved as required.
Method of Assigning Subjects to Treatment Groups
9.4.3
Subjects will be assigned to treatments based on a computer-generated randomization scheme 
that will be reviewed and approved by an independent statistician.  The randomization scheme 
and identification for each subject will be included in the final clinical study report for this study.
After the Baseline Period, subjects will be randomized to 1 of 2 treatment groups.  One treatment 
group will receive perampanel and the other treatment group will receive placebo once daily.
Randomization will be performed centrally by IxRS. The IxRS or clinical supply vendor will 
generate randomized identification numbers.  At enrollment (and after successful completion of 
Visit 1), the investigator or designee will access the IxRS to register the subject information.  At 
randomization (Visit 2), the IxRS will assign each subject a unique 6-digit randomization 
number.  At every subsequent dose change, the investigator or a designee will access the IxRS to 
obtain dispensing instructions and register the subject’s visit.
Randomization will be stratified by age group and region.
Selection of Doses in the Study
9.4.4
All subjects will start perampanel at a dose of 2 mg/day (or matching placebo).  Thereafter their 
dose will be increased up to a maximum dose of 8 mg/day (or matching placebo) according to 
individual tolerability and efficacy. See Table 1 for the dosing schedule and titration steps.
It is recommended that oral tablet be used for dosing subjects ≥12 years of age (at the time of 
signing informed consent). It is recommended oral suspension be used for subjects <12 years of 
age (at the time of signing informed consent).  However, the most appropriate formulation may 
be selected based on the subject’s condition and at the discretion of the investigator.  The same 
formulation should be used for a given subject throughout the course of the study.  (revised per 
Amendment 04)
The choice of a maintenance dose up to 8 mg/day was based on the population PK analysis of the 
data from the clinical study in subjects 2 to 12 years of age with epilepsy (E2007-G000-232).  
The analysis included data from a total of 42 subjects with age range between 2 to 11 years and 
wide range of body weights (ie, 12.2 to 90.9 kg). The dataset included 14 females out of 
42 subjects. The results of the analysis demonstrated that perampanel PK was linear as there was 
no dose or time-dependency to oral clearance (CL/F). The CL/F was not significantly affected by 
age, body weight, gender, race, hepatic function markers (ALT or AST), renal function marker 


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(creatinine clearance) or the use of 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. These results suggest that a similar 
dosing approach as in adolescents or adults without presence of enzyme inducing AEDs (ie, flat 
dosing with a target dose of 8 mg would be appropriate for the pediatric subjects between 2 to 
<12 years of age).
Selection and Timing of Dose for Each Subject
9.4.5
Subjects will be instructed to take the study drug once daily, by mouth, and before bedtime.
Blinding
9.4.6
Study drugs will be administered on a double-blind basis.  During the Randomization Phase, 
subjects and all personnel involved with the conduct and interpretation of the study, including 
investigators, site personnel, and sponsor staff will be blinded to the treatment codes.  
Randomization data will be kept strictly confidential, filed securely by an appropriate group with 
the sponsor or contract research organization (CRO) and accessible only to authorized persons 
(eg, Eisai Global Safety) until the time of unblinding, per standard operating procedure (SOP).
A master list of all treatments and the subject numbers associated with them will be maintained 
in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the sponsor.  In the
event that emergency conditions require knowledge of the study treatment given, the blind may 
be broken via the code breaker facility within the IxRS.  Emergency procedures for revealing 
drug codes are given in Section 9.5.4.5.  If possible, before breaking the blind, the investigator 
should consult with the sponsor to ascertain the necessity of breaking the code.
Prior and Concomitant Therapy
9.4.7
Any medication (including over-the-counter medications) or therapy administered to the subject 
during the study (starting at the date of informed consent) will be recorded on the Prior & 
Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  The investigator will 
record on the Adverse Event CRF any AE for which the concomitant medication/therapy was 
administered.
If the concomitant medication/therapy is being administered for a medical condition present at 
the time of entry into the study, the investigator will record the medical condition on the Medical 
History and Current Medical Condition CRF.


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Drug-Drug Interactions
9.4.7.1
Oral Contraceptives
At a dose of 12 mg/day, perampanel reduces levonorgestrel maximum concentration (Cmax) and 
area under the concentration-time curve (AUC) by approximately 40%. The possibility of 
decreased efficacy of contraceptives containing levonorgestrel should be considered for women 
taking perampanel.  Females using hormonal contraceptives containing levonorgestrel must be 
on another form of contraception as well, as specified in Section 7.
Cytochrome P450
Perampanel is considered to be neither a potent inhibitor, nor a potent inducer of cytochrome 
P450 (CYP) enzymes.  A drug-drug interaction study in healthy subjects showed a 3-fold 
increased clearance of perampanel when administered with carbamazepine.  A similar result was 
seen in a population pharmacokinetic analysis of subjects with partial-onset seizures (POS)
receiving perampanel up to 12 mg/day in placebo-controlled clinical trials.  The total clearance 
of perampanel was increased 3-fold when administered with carbamazepine, 2-fold with 
phenytoin, and 2-fold with oxcarbazepine; all of which are known inducers of cytochrome 
P450 3A4 (CYP3A4).  
Effect of Perampanel on Concomitant AEDs
In a population pharmacokinetic analysis of subjects with POS receiving perampanel up to 
12 mg/day in placebo-controlled clinical trials, perampanel did not significantly affect the 
clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, or zonisamide.  
Perampanel had a marginally statistically significant effect on the clearance of carbamazepine, 
clobazam, lamotrigine, and valproic acid, but the effect was of no clinical relevance.
Alcohol 
A pharmacodynamic interaction study in healthy subjects found that the effects of perampanel on 
complex tasks such as driving ability were additive or supra-additive to the impairment effects of 
alcohol.  Multiple dosing of perampanel 12 mg/day also enhanced the effects of alcohol on 
vigilance and alertness and increased levels of anger, confusion, and depression. These effects 
may also be seen when perampanel is used in combination with other central nervous system 
(CNS) depressants.
Prohibited Concomitant Therapies and Drugs
9.4.7.2
Use of prior or concomitant therapies and drugs as dictated by the exclusion criteria (Section 7) 
will preclude a subject’s participation on the study.
Concomitant use of non-AED medications known to be inducers of cytochrome P450 (CYP3A) 
including, but not limited to: rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, 
glucocorticoids (other than topical usage), modafinil, pioglitazone, and rifabutin will not be 
permitted during the study.


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Use of AEDs not recommended by Epilepsy Treatment Guidelines for use in LGS (including, 
but not limited to carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, 
and vigabatrin) is prohibited throughout the study.  (revised per Amendment 02)  Use of CBD 
products is allowed and is counted as one of the 4 maximum allowed concomitant AEDs.  CBD 
dose and product must have remained stable for at least 30 days before Visit 1 and is to remain 
the same throughout the course of the Core Study.  (revised per Amendment 04)
Treatment Compliance
9.4.8
Records of treatment compliance for each subject will be kept during the study.  The CRAs will 
review treatment compliance during site visits and at the completion of the study.
Drug Supplies and Accountability
9.4.9
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
●
A signed and dated confidentiality agreement
●
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
●
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
●
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
●
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
●
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol
●
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 trials agreement
●
A copy of the regulatory authority approval for the country in which the study is being 
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●
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.  Study drug will only be shipped to the exact 
address found on the DEA form 223 registration.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
At US sites, federal regulations require that registrants notify the DEA Field Division Office in 
their area, in writing, of the theft or significant loss of any controlled substance within 1 business 
day of discovery of such loss or theft. The registrant shall also complete and submit to the Field 
Division Office in their area, DEA Form 106, "Report of Theft or Loss of Controlled Substances" 
regarding the theft or loss.  Additionally, registrants may have local or state level reporting 
requirements to conform with.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to any 
individual who is not enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study supplies 
to the sponsor or (where applicable) destruction of reconciled study drugs/study supplies at the 
site.  This includes, but may not be limited to:  (a) documentation of receipt of study drugs/study 
supplies, (b) study drugs/study supplies dispensing/return reconciliation log, (c) study 
drugs/study supplies accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study drugs/study 
supplies that occurs at the site.  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/study supplies 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/study supplies and empty and partially empty containers from used study 
drugs/study supplies are to be returned to the investigator by the subject and together with 
unused study drugs/study supplies 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/study supplies 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/study supplies 
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/study supplies that are to be returned to the sponsor’s designated central or local depot(s) 


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must be boxed and sealed and shipped back to the central or local depot(s) following all local 
regulatory requirements.  In some regions, study drugs/study supplies may be removed from the 
site and hand delivered to the central or local depot by sponsor representatives.  Where study 
drugs/study supplies 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
Assessments
9.5.1
Demography
9.5.1.1
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity.
Baseline Assessments
9.5.1.2
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the 
Screening/Baseline Visit.  All pertinent medical and surgical history must be noted in the 
Medical History and Current Medical Conditions CRF.  The subject’s lifetime AED history will 
also be collected.
Physical examinations (comprehensive or symptom directed) will be performed as designated on 
the Schedule of Procedures/Assessments (Table 5).  A comprehensive physical examination will 
include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), 
abdomen, limbs, skin, and a complete neurological examination.  A urogenital examination will 
only be required in the presence of clinical symptoms related to this region.  Documentation of 
the physical examination will be included in the source documentation at the site.  Significant 
findings at the Screening Visit will be recorded on the Medical History and Current Medical 
Conditions CRF.
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained at Screening / Baseline as designated on the Schedule of 
Procedures/Assessments (Table 5).
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5, Adverse Events and Events Associated with Special Situations) and the CRF 
Completion Guidelines.  In these instances, the AE corresponding to the ECG abnormality wi ll 
be recorded on the Adverse Events CRF.
VIRAL TESTS
A 6-mL sample of blood will be taken for hepatitis B surface antigen and hepatitis C antibodies, 
antibodies at Screening.


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URINE DRUG TEST
A 30-mL urine sample will be collected at Screening.  This sample will be tested for common 
drugs of use/abuse (eg, cocaine, phencyclidine [PCP], opioids [as a group], benzodiazepines, 
barbiturates, and amphetamines).  (revised per Amendment 04)
Efficacy Assessments
9.5.1.3
SEIZURE DIARIES
Seizure diaries will be used to collect seizure counts and types.
CLINICAL GLOBAL IMPRESSION SCALES
The Clinical Global Impression of Severity (CGI-S) and CGI-Improvement (CGI-I) scales will 
be used by the physician to evaluate overall changes in symptoms from baseline during the Core 
Study only.
Information regarding efficacy assessments in Extension A is provided in Appendix 2.
Pharmacokinetic, 
Pharmacodynamic, 
and 
Pharmacogenomic/Pharmacogenetic 
9.5.1.4
Assessments
PHARMACOKINETIC ASSESSMENTS
Blood samples (1 mL) for determination of plasma perampanel concentrations will be collected 
during the Core Study at prespecified timepoints as shown in Table 5.  Samples from subjects 
receiving active treatment will be analyzed.  Plasma concentrations of analytes will be quantified 
by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) methodology 
using a previously validated assay.  A detailed description of collection, handling, and shipping 
procedures of PK samples will be provided in a manual to be supplied to the study sites, or the 
details will be included in the central laboratory manual.  (revised per Amendment 04)
PHARMACODYNAMIC ASSESSMENTS
Efficacy and selected safety endpoints may be correlated against exposure and/or dose.
PHARMACOGENOMIC ASSESSMENTS
Genomic DNA samples may be used to examine the role of genetic variability in subject’s 
absorption, distribution, metabolism, and excretion, or the development of adverse events.  
Variation in perampanel exposure or AEs may be evaluated by correlation of single-nucleotide 
polymorphisms with PK, safety or PD data.
Further information regarding pharmacogenomic assessments is provided in Appendix 3.
Safety Assessments
9.5.1.5
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
laboratory evaluation for hematology, blood chemistry, including assessment of criteria for Hy’s
Law and urine values; and periodic measurement of vital signs as detailed in Table 5. Reports of 


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anxiety and irritability will be closely monitored during the study by both the investigators and 
the Medical Monitor.  (revised per Amendment 01)
The investigator at each site is required to evaluate laboratory results related to liver function 
(AST, ALT, TBIL, andALP), as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.  If these laboratory results include elevated AST or ALT greater 
than or equal to 3 × ULN and elevated TBIL greater than or equal to 2 × ULN with an 
ALPlaboratory value that is less than 2 × ULN, the subject will be discontinued from the study.  
Any laboratory results that are more than 3 times greater than the ULN for ALT or AST will be 
flagged by the central laboratory for investigator review.  These laboratory abnormalities should 
be reported as an SAE. (revised per Amendment 02)
Please note that besides the laboratory abnormalities noted above, the criteria for Hy’s Law
include the stipulation that no other reason can be found to explain the combination of increased 
ALT, AST and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or 
another drug capable of causing the observed injury. 
The investigator should document
causality. (revised per Amendment 02)In addition, assessments of suicidal ideation and behavior 
using the C-SSRS will be performed during the study for subjects aged 8 years and older at the 
time of consent/assent; subjects who will reach the age of 8 years during the double-blind phase 
of the study will also be assessed using the C-SSRS starting at Baseline. 
(revised per 
Amendment 03) Suicidal ideation and behavior will be monitored in subjects less than 8 years at 
the time of consent/assent and during the study, on the basis of clinical impression.  (revised per 
Amendments 01 and 03)  Subjects who appear to have a high risk of suicidal behavior according 
to results from the C-SSRS and/or clinical impression will be withdrawn from the study.  
(revised per Amendment 03)
Information regarding safety assessments in Extension A is provided in Appendix 2.  
Information regarding safety assessments in Extension B is provided in Appendix 4.  (revised per 
Amendment 04)
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the medicinal product.  For this study, the study drug is perampanel. 
The criteria for identifying AEs 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


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●
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
●
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
●
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the last visit in the Treatment Phase after the subject’s last dose. 
Serious AEs will be collected for 28 days after the last dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute an 
AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality considered to 
constitute an AE should be reported on the Adverse Event CRF. 
Seizures, all of which will be captured in the Patient Seizure Diary as part of the efficacy
outcome measure, should not generally also be captured on the AE page of the CRF.  A seizure 
should only be recorded as an AE if it is a new type of seizure experienced by subject or if the 
seizure is greater in intensity or frequency than was experienced by the subject before signing the 
ICF.
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, Serious Adverse Events and Events Associated with Special Situations for the 
definition of an SAE).


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ASSESSING RELATIONSHIP TO STUDY TREATMENT
Items to be considered when assessing the relationship of an AE to the study treatment are:
●
Temporal relationship of the onset of the event to the initiation of the study treatment
●
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
●
Whether the event is known to be associated with the study treatment or with other 
similar treatments
●
The presence of risk factors in the study subject known to increase the occurrence of the 
event
●
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
CLASSIFICATION OF CAUSALITY
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a reasonable 
possibility.
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A SAE is any untoward medical occurrence that at any dose:
●
Results in death
●
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)
●
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Results in persistent or significant disability/incapacity
●
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization but, when based on appropriate medical judgment, may jeopardize the subject or 
may require intervention to prevent one of the outcomes in the definition of SAE listed above 


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should also be considered SAEs.  Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if they do not meet other serious criteria: status epilepticus, laboratory 
results of elevated AST or ALT greater than or equal to 3 × ULN and elevated TBIL greater than 
or equal to 2 × ULN with an ALP laboratory value that is less than 2 × ULN, and reports of 
aggression when the aggressive act resulted in another person requiring medical treatment or the 
aggressive act or threat involved a weapon.  (revised per Amendment 02)
In addition to the above, events associated with special situations include pregnancy or exposure 
to study drug through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or 
medication error. (revised per Amendment 02)  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.
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 post study drug administration)
●
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
●
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for the measurement of study drug blood concentration should be 
drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, are 
summarized in Table 2.  Subjects should be in a seated or supine position during blood 
collection.
The Schedule of Procedures/Assessments (Table 5) shows the visits and timepoints at which 
blood for clinical laboratory tests and urine for urinalysis will be collected in the study (Core 
Study).


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Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
hematocrit, hemoglobin, platelets, RBC count, and WBC count with 
differential (bands, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)
Chemistry
Electrolytes
bicarbonate, chloride, potassium, sodium 
Liver function tests
alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function parameters
blood urea/blood urea nitrogen, creatinine
Other
albumin, calcium, cholesterol, globulin, glucosea, lactate 
dehydrogenase, phosphorus, total protein, lipid panela, uric acid
Urinalysis
bacteria, casts, crystals, epithelial cells, glucose, ketones, occult blood, 
pH, protein, RBCs, specific gravity, WBCs
Viral tests
HbsAg, HepC
HbsAg = Hepatitis B surface antigen; HepC = Hepatitis C; RBC = red blood cell, WBC = white blood cell.
a:
Fasting samples to be taken at Baseline and at Visit 7 (end of Maintenance Period) or Early Discontinuation
Clinical laboratory tests during the study will be performed by a designated laboratory.  All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  In cases of a safety concern, blood samples will be split 
(or two samples drawn) to allow a local laboratory analysis in addition to the central laboratory.  
Laboratory certification as available may be included in the final clinical study report for this 
study.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Section 9.5.1.5, Adverse Events and Events Associated with Special Situations) and the 
CRF Completion Guidelines.  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event CRF.
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats per 
minute], height, and weight (kg) will be obtained at the visits designated on the Schedule of 
Procedures/Assessments (Table 5) by a validated method.  (revised per Amendment 01)  Blood 
pressure and pulse will be measured after the subject has been sitting for 5 minutes.  All BP 
measurements should be performed on the same arm, preferably by the same person. 
OTHER SAFETY ASSESSMENTS
Pregnancy Test
A serum β-hCG test will be performed for postpuberty, premenopausal females and 
postmenopausal females who have been amenorrheic for less than 12 months.  A 6-mL sample of 


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blood will be taken at designated timepoints as specified in the Schedule of 
Procedures/Assessments (Table 5).
Urine pregnancy testing will be conducted at timepoints specified in Table 5.  (revised per 
Amendment 01)
Other Assessments
9.5.1.6
CCI
CCI
CCI


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CCI


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Schedule of Procedures/Assessments Core Study
9.5.2
Table 5 presents the Schedule of Procedures/Assessments for the Core Study.
CCI


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Table 5
Schedule of Procedures/Assessments in Study E2007-G000-338 (Core Study)
(revised per Amendments 01, 04, and 05)
Phase
Prerandomiz-
ation
Randomization
Period
Screening/Base
line
Titrationa
Maintenanceb
Early 
DC
Follow-up
Unsched-
uled
Visit
1a
2c
3
4
5
6
7d
Follow-up, 
1 weeke
Follow-up, 
4 weekse
Week
(up to -8)
1
2
4
7
13
19
20
23
Day
(up to -56)
1
8
22
43
85
127
134
155
Procedures/ 
Assessments
Informed 
consent/assent
X
Inclusion/exclusion 
X
Xf
Randomization
Xf
Physical and 
neurological 
examination
X
Medical historyg
X
Prior/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
Vital signs, height 
and weighth
X
X
X
X
X
X
X
X
X
(X)i
ECG
X
(X)i
C-SSRSk
X
X
X
X
(X)i
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Table 5
Schedule of Procedures/Assessments in Study E2007-G000-338 (Core Study)
(revised per Amendments 01, 04, and 05)
Phase
Prerandomiz-
ation
Randomization
Period
Screening/Base
line
Titrationa
Maintenanceb
Early 
DC
Follow-up
Unsched-
uled
Visit
1a
2c
3
4
5
6
7d
Follow-up, 
1 weeke
Follow-up, 
4 weekse
Week
(up to -8)
1
2
4
7
13
19
20
23
Day
(up to -56)
1
8
22
43
85
127
134
155
Procedures/ 
Assessments
Urine pregnancy 
testl
X
X
X
X
X
X
X
X
(X)i
Serum pregnancy 
testl
X
Clinical laboratory 
testsm
X
Xn
X
Xn
Xn
X
(X)i
Viral tests (HBsAg, 
HepC)
X
Urine drug testingo
X
Dispense/collect 
seizure diary
X
X
X
X
X
X
Xp
X
X
X
(X)i
IxRS
X
X
X
X
X
X
X
X
X
(X)i
Dispense study drug
X
X
X
X
X
X
(X)i
Administer study 
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Table 5
Schedule of Procedures/Assessments in Study E2007-G000-338 (Core Study)
(revised per Amendments 01, 04, and 05)
Phase
Prerandomiz-
ation
Randomization
Period
Screening/Base
line
Titrationa
Maintenanceb
Early 
DC
Follow-up
Unsched-
uled
Visit
1a
2c
3
4
5
6
7d
Follow-up, 
1 weeke
Follow-up, 
4 weekse
Week
(up to -8)
1
2
4
7
13
19
20
23
Day
(up to -56)
1
8
22
43
85
127
134
155
Procedures/ 
Assessments
drug at site
Retrieve unused 
study drug
X
X
X
X
X
X
(X)i
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Perampanel blood 
concentration 
samples
Xr
Xr
Xs
Xs
Xs
(X)i
CGI-S
X
CGI-I
X
X
(X)i
Pharmacogenomic 
blood samplest
X
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Footnotes for Table 5:
AED = antiepileptic drug; CGI-I = Clinical Global Impression of Improvement; CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia Suicide Severity Rating 
Scale; DC = discontinuation; ECG = electrocardiogram; EEG = electroencephalogram;
HBsAg = Hepatitis B surface antigen;
HepC = Hepatitis C;
 PK = pharmacokinetic
a:
Visits will have a window of ±3 days with at least 10 days between visits (with the exception of Visit 3).
b:
Visits will have a window of ±6 days.
c:
There must be at least 4 weeks between Visits 1 and 2.
d:
For those subjects who have completed Visit 7 study assessments and who are rolling over into Extension A, Visit 7 will serve as the End-of-Core Study visit and the 
beginning of the blinded Conversion Period of Extension A. (revised per Amendments 04 and 05)
e:
Only for those subjects not rolling over into Extension A, and for those subjects who prematurely discontinued from the study, the Follow-up visits will take place at 1 week 
and 4 weeks after the last study drug administration (ie, Visit 7 or Early Discontinuation Visit, respectively).  These visits will not be conducted if the subject continues into 
Extension A, in which case, a Follow-up visit will be performed 4 weeks after the last Extension visit.  Visits will have a window of ±6 days. (revised per Amendments 01 and 
04)
f:
Final determination of eligibility and, if eligible, randomization to occur before any study drug administration.  (revised per Amendment 04)
g:
Lifetime AED history will be collected as part of medical history.
h:
Height of adult subjects is to be recorded only at the Screening Visit (Visit 1). (revised per Amendment 01)
i:
j:
k:
Subjects ≥8 years of age at time of informed consent/assent and subjects who will reach the age of 8 years during the double-blind phase of the study will also be assessed 
using the C-SSRS starting at Baseline.  (revised per Amendment 03)
l:
Urine and serum pregnancy testing is for postpuberty, premenopausal females and postmenopausal females who have been amenorrheic for less than 12 months.
m:
Clinical laboratory tests include chemistry, hematology, and urinalysis.  If a urine sample cannot be obtained; the subject will still be eligible for enrollment.  However, every 
effort should be made to collect a sample.
n:
Fasting samples to be taken at indicated time points for glucose and lipid panel.
o:
Drug screen includes cocaine, phencyclidine [(PCP)], opioids ([as a group)], benzodiazepines, barbiturates, and amphetamines.   Positive CBD results in subjects taking CBD 
products will not be exclusionary.  (revised per Amendment 04)
p:
Collect diaries at Visit 7 from subjects not rolling over into Extension A.  Dispense diaries at Visit 7 to subjects rolling over into Extension A.
q:
r:
Two blood samples (1.0 mL each) will be collected at Visit 5 and Visit 6 for the determination of perampanel plasma concentrations. One blood sample will be collected 
before dose administration and the second sample will be collected anytime between 1 to 5 hours postdose. Study drug administration in the evening immediately before (and 
the evening on the day of) Visit 5 and Visit 6 should be withheld (all other AEDs should be administered per the subject’s usual AED regimen).  Study drug will be given 
during Visit 5 and Visit 6 at the study site, after collection of predose PK sample (within 1 to 5 hours after dose administration).  Bedtime dosing will resume in the evening 
on the day of Visit 5 and Visit 6. Each PK sample is to be split into 2 aliquots before storage per instructions provided in the laboratory manual.  (revised per Amendment 
04)
s:
One blood sample (1.0 mL) will be collected for the determination of perampanel plasma concentrations.  The blood sample may be collected at any time during the specified 
visits
t:
A sample will be collected predose on Day 1, or at another visit if it cannot be collected at this time.
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The volume of blood to be taken at each visit in the core study is shown in Table 6.  The total 
volume of blood taken during the core study for subjects who complete all core study visits and 
enter Extension A will be 36 mL.  For subjects who do not enter Extension A after completing 
all core study visits, the total volume of blood taken during the core study will be 43 mL (not 
including unscheduled visits).  (revised per Amendments 01 and 04)
Table 6
Blood Volumes Taken During Core Study
(revised per Amendments 01 and 04)
Visit No.
V1
V2
V4
V 5
V 6
V7
EDC
Follow-
up, 
Wk19
Follow-
up,    
Wk 22
Unsched-
uled 
Visit
Chemistry
X
X
X
X
X
X
X
Serology
X
X
PK sample
X
X
X
X
X
Haematology
X
X
X
X
X
X
X
PGx
X
Total 
Vol.
(mL)
10
9
6
2
2
7
-
1
6
-
EDC = early discontinuation, V = visit, Wk = week
Appropriateness of Measurements
9.5.3
All clinical assessments are standard measurements commonly used in studies of LGS.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, assessment of AEs, and assessment of criteria for Hy’s Law are
standard evaluations to ensure subject safety.  (revised per Amendment 01)
Reporting of Serious Adverse Events, Pregnancy, and Events Associated with 
9.5.4
Special Situations
Reporting of Serious Adverse Events
9.5.4.1
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 and for 28 days after the last dose of study medication.  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 should be reported to the sponsor regardless of the length of time 
that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study File.


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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 1 business day of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor or 
designated CRO to be filed in the sponsor’s Trial Master File.
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
9.5.4.2
Any pregnancy in which the estimated date of conception is either before the last visit or within 
28 days of last study treatment, or any exposure to study drug through breastfeeding during study 
treatment or within 28 days of last study treatment must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or email as 
soon as possible but no later than 1 business day from the date the investigator becomes aware of 
the pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File.
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later than 
1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.


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Reporting of Events Associated with Special Situations
9.5.4.3
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, MISUSE,
ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error refer to 
AEs associated with uses of the study drug outside of that specified by the protocol.  Overdose, 
misuse, abuse, and medication error are defined as follows: 
Overdose
Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with the 
protocol 
Abuse
Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study drug use 
or subject harm while the study drug is in the control of site personnel or the 
subject. 
All AEs associated with an overdose should be captured on the Adverse Event CRF.  Adverse 
events associated with overdose, misuse, abuse, or medication error should be 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
For this study, the following events should always be considered serious and reported as an 
important medical event even if it does not meet other serious criteria: status epilepticus,
laboratory results of elevated AST or ALT greater than or equal to 3 × ULN and elevated TBIL
greater than or equal to 2 × ULN with an ALP laboratory value that is less than 2 × ULN, and 
reports of aggression when the aggressive act resulted in another person requiring medical 
treatment or if the aggressive act or threat involved a weapon.  (revised per Amendments 01 and 
02)
Expedited Reporting
9.5.4.4
The sponsor must inform investigator 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.
Breaking the Blind
9.5.4.5
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code for 


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an individual subject.  In all such cases, the AE necessitating the emergency blind break will be 
handled as an SAE in accordance with the procedures indicated above.  Any broken code will be 
clearly justified and documented.  The medical monitor must be notified immediately of the 
blind break.
Regulatory Reporting of Adverse Events
9.5.4.6
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 GCP 
Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the competent authorities of 
all involved European member states.
Completion/Discontinuation of Subjects
9.5.5
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 5).  (revised per Amendment 01)
The investigator will promptly explain to the subject involved that the study will be discontinued 
for that subject and provide appropriate medical treatment and other necessary measures for the 
subject.  A subject who has ceased to return for visits will be followed up by mail, phone, or 
other means to gather information such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms.  This 
information will be recorded in the CRF.
Subjects who discontinue early from the study will be discontinued for one of these primary 
reasons: AE(s), lost to follow-up, subject choice, or other.  In addition to the primary reason, the 
subject may indicate one or more of secondary reasons 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.
Abuse or Diversion of Study Drug
9.5.6
During the study, the investigator will report any concern about abuse or diversion of study drugs 
by completing the Abuse or Diversion of Study Drug CRF.
Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.4.3.  Abuse is always to be captured as an AE.
Confirmation of Medical Care by Another Physician
9.5.7
The investigator will instruct subjects to inform site personnel when they are planning to receive 
medical care by another physician.  At each visit, the investigator will ask the subject whether 


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he/she has received medical care by another physician since the last visit or is planning to do so 
in the future.  When the subject is going to receive medical care by another physician, the 
investigator, with the consent of the subject, should 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.
Data Collection
9.6.1
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, 
where applicable, 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.
Clinical Data Management
9.6.2
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All data, 
both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
STATISTICAL METHODS
All statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and a snapshot of the database is obtained and released for unblinding.
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).
Statistical and Analytical Plans
9.7.1
The statistical analyses of the Core Study data for the purposes of registration are described in 
this section.  Further details of the analytical plan will be provided in the Core Study SAP, which 
will be finalized before database lock for the Core Study and treatment unblinding.  Separate 


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SAPs will be produced for Extension A and Extension B of the study.  (revised per 
Amendment 04)
Study Endpoints
9.7.1.1
PRIMARY ENDPOINTS
The primary efficacy endpoint will be the median percent change in drop seizure frequency per 
28 days during double-blind treatment (Titration Period and Maintenance Period) relative to the 
Prerandomization Phase in the Full Analysis Set (FAS).  
SECONDARY ENDPOINTS
The following key secondary endpoints will be evaluated sequentially using the FAS:
1. Median percent change in total seizure frequency per 28 days during double-blind 
treatment (Titration Period and Maintenance Period) relative to the Prerandomization 
Phase.  
2. The 50% responder rate in the Maintenance Period of the double-blind treatment relative 
to the Prerandomization Phase for drop seizures 
3. The 50% responder rate in the Maintenance Period of the double-blind treatment relative 
to the Prerandomization Phase for total seizures.
Other secondary endpoints are as follows.  They will not be analyzed statistically but will be 
summarized.  (revised per Amendment 01):
4. Median percent change in non-drop seizure frequency per 28 days during double-blind 
treatment (Titration Period and Maintenance Period) relative to the Prerandomization 
Phase
5. Proportion of subjects with 75%, and 100% responder rates for drop, non-drop, and total 
seizures in the Maintenance Period relative to the Prerandomization Phase
6. Proportion of subjects with 50% responder rate in the Maintenance Period of the double-
blind treatment relative to the Prerandomization Phase for non-drop seizures
7. Physicians’ global evaluation of the subject’s overall changes in symptoms (using a 
7-point Likert scale with 1=very much improved and 7=very much worse) at the end of 
the double-blind treatment.
8. Incidence of AEs and SAEs, changes in clinical laboratory values, and vital signs 
9. Model-derived average perampanel concentrations at steady state (C av,ss) during the 
Maintenance Period of the Core Study
EXPLORATORY ENDPOINTS
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Definitions of Analysis Sets
9.7.1.2
The Safety Analysis Set is the group of subjects who received at least one dose of study drug and 
had at least one post-dose safety assessment.
The FAS is the group of randomized subjects who received at least one dose of study drug and 
had at least one postdose seizure measurement.
The Per Protocol (PP) Analysis Set is the group of subjects who sufficiently complied with the 
protocol.  Details of the evaluability criteria will be determined before database lock and 
treatment unblinding and will be specified in the SAP.
The Pharmacokinetic Analysis Set is the group of subjects who received perampanel and had at 
least one quantifiable perampanel concentration during the Maintenance Period of the Core 
Study and adequately documented dosing history.
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The PK/PD analysis set is the group of subjects who received perampanel or placebo who had 
seizure frequency data with documented dosing history.  Subjects who received perampanel 
should have at least one quantifiable perampanel concentration as per the PK analysis set. 
Intention to Treat (ITT) analysis set is the group of randomized subjects who received at least 
one dose of study drug.
All subjects who withdraw from treatment will be summarized and their withdrawal reasons will 
be tabulated.  Prior and concomitant medication usage and demographics will also be 
summarized.
Subject Disposition
9.7.1.3
Subject disposition summary tables will include the number (percent) of subjects who were:
Randomized into each treatment group
Discontinued early from the study by primary and secondary reasons for discontinuation
Demographic and Other Baseline Characteristics
9.7.1.4
Demographic and other baseline characteristics for the safety and FAS will be summarized for 
each treatment group and for all study drug groups combined using descriptive statistics.
For continuous variables (eg, age, weight), the number of non-missing and missing values, 
median, mean, SD, and minimum and maximum will be displayed. For categorical variables (eg, 
gender, ethnicity), the counts and proportions of each value will be tabulated.
Prior and Concomitant Therapy
9.7.1.5
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number (percentage) of 
subjects who took prior and concomitant medications will be summarized on the safety and full 
analysis set by treatment group, Anatomical Therapeutic Chemical (ATC) class and WHO DD 
PT.  Prior medications will be defined as medications that stopped before the first dose of study 
drug.  Concomitant medications will be 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 28 days after the subject’s last dose.  All 
medications will be presented in subject data listings.
Efficacy Analyses
9.7.1.6
PRIMARY EFFICACY ANALYSIS
The analysis of the primary endpoint, percentage change in drop seizure per 28 days in the FAS,
will be conducted using rank analysis of covariance (ANCOVA), with ranked percentage change 
from baseline in drop seizures per 28 days as the dependent variable and treatment, age group, 
region, and ranked baseline drop seizure rate per 28 days as the independent variables. Seizure 
frequency will be based on the number of drop seizures per 28 days, calculated as the number of 


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drop seizures over the entire time interval divided by the number of days in the interval and 
multiplied by 28.
Treatment effect in different age groups will be investigated.
A 5% (2-sided) level of significance will be used for all analyses.
SECONDARY EFFICACY ANALYSIS
The 3 key secondary efficacy endpoints will proceed in a sequential manner.
Median percent change in total seizure frequency per 28 days during double-blind treatment will 
be tested first. If this test is significant at 0.05 level, then the 50% responder rate in the 
Maintenance Period for drop seizures will be tested. If this is significant then the 50% responder 
rate in the Maintenance Period for total seizures will be tested. All tests will be at a 2-sided 5% 
significance level.
50% responder rates will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusting 
for region and age group.  For subjects who discontinue the 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 
double-blind treatment duration if <8 weeks of data are available) will be used in lieu of 
Maintenance Period. The treatment effect will be assessed using odds ratio.  The common odds 
ratio and 95% CI as well as response rate from each treatment group will be presented.  (revised 
per Amendment 01)
The same ANCOVA model employed for the primary efficacy variable will be employed to 
analyze percentage change from baseline in total seizures.
Physicians’ global evaluations over time will be analyzed using the CMH test.
EXPLORATORY EFFICACY ANALYSIS
Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic/Pharmacogenetic Analyses
9.7.1.7
PHARMACOKINETIC ANALYSES
Perampanel concentrations will be listed by subject, dose, and visit.
Analysis variable(s): Plasma concentrations of perampanel
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Analysis methods:  A population PK approach will utilize PK sample data collected during the 
Maintenance Phase of this study, and will be used to characterize the PK of perampanel.  The 
effect of intrinsic (ie, demographics) and extrinsic factors (ie, most common concomitant AEDs) 
on perampanel PK will be evaluated.  Derived exposure parameters such as area under the 
concentration-time curve at steady-state (AUCss) or the average steady-state drug concentration 
(Cav,ss,) will be calculated from the model using the individual posterior estimates of CL/F and 
dosing history. (revised per Amendment 04)
PHARMACODYNAMIC ANALYSES
Efficacy and selected safety endpoints may be correlated against exposure and/or dose.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
The relationship between exposure to perampanel and response will be modeled using
population PK/PD analysis.
PHARMACOGENOMIC ANALYSES
Pharmacogenomics analyses may be performed and reported separately.  Details of these 
analyses may be described in a separate analysis plan.
Safety Analyses
9.7.1.8
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, n, 
mean, SD, median, minimum, maximum for continuous variables; n [%] for categorical 
variables).  Safety variables include TEAEs, clinical laboratory parameters, and vital signs.  
Study Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
EXTENT OF EXPOSURE
The extent of exposure will be characterized according to the number of subjects exposed, the 
duration of exposure, and the dose to which they were exposed using descriptive statistics.
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 15 or higher) lower level 
term closest to the verbatim term.  The linked MedDRA PT and primary system organ class 
(SOC) are also captured in the database.
A TEAE is defined as an AE that occurs from the time of first dose through 28 days after the last 
dose of study medication, or:
●
Re-emerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 


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●
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that were treatment-emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
TEAEs will be summarized by treatment group.  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), and by relationship to study drug 
(possibly related, probably related, and not related).
The number (percentage) of subjects with TEAEs leading to death, treatment-emergent SAEs, 
and TEAEs leading to discontinuation from study drug will be summarized by MedDRA SOC 
and PT for each treatment group.
Adverse events of special interest (ie, aggression and anger) will also be summarized by 
treatment groups. 
A subject data listing will be produced for all deaths, SAEs, and discontinuation due to an AE. 
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For all 
quantitative 
parameters 
listed 
in 
Section 9.5.1.5,
Safety 
Assessments 
(Laboratory 
Measurements), the actual value and the change from baseline to each postbaseline visit and to 
the end of treatment will be summarized by visit and treatment group using descriptive statistics.  
Incidence of out-of-normal-range values and markedly abnormal change from Baseline in 
laboratory safety test variables will be tabulated by treatment group.  These out-of-normal-range 
values and markedly abnormal changes from Baseline will be obtained from laboratory-defined 
normal ranges and using modified National Cancer Institute (NCI) criteria, respectively.
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 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 (TEMAV).  
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 


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TEMAVs, each subject may be counted once in the laboratory parameter high and in the 
laboratory parameter low categories, as applicable.
Laboratory analyses will also include analysis of outliers.  For ALT and AST analysis, the 
number of subjects with >3 times but <5 times the ULN and the number of subjects with 
>5 times the ULN will be summarized.  For bilirubin, a summary of the number of subjects with 
serum concentrations >2 times the ULN will be created. The number of subjects who meet the 
criteria for Hy’s Law (Section 9.5.1.5) will be summarized by visit and during the treatment 
duration. (revised per Amendment 02)  The number of subjects who meet each of the criteria for 
Hy’s Law during treatment (but not all necessarily at the same visit) will also be summarized.  
(revised per Amendment 01)
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, diastolic and systolic BP, pulse) and changes 
from baseline to each visit and to the last visit of the double-blind treatment will be presented by 
treatment group.
OTHER SAFETY ANALYSES
Pregnancy Test
By-subject listings will be presented for pregnancy tests.
Other Analyses
9.7.1.9
Only subjects with a baseline and at least 1 post-baseline score for a given assessment will be 
included in the analyses of data from that assessment.  Thus, the subject population may vary 
depending on the score that is calculated.
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Extension A Analyses
9.7.1.10
See Appendix 2 for further information.
Extension B Analyses
9.7.1.11
See Appendix 4 for further information. (revised per Amendment 04)
Determination of Sample Size
9.7.2
Randomization of 71 subjects to each treatment arm will provide a sample with adequate power 
for the primary endpoint and the key secondary endpoints.
Primary endpoint percent change from baseline in drop seizures:
Placebo rates in drop seizures in the rufinamide and clobazam clinical trials were +1.4%, 
and -12.1%, respectively.  In the active treatment arm, rufinamide had a median decrease of 
42.5% in drop seizures and clobazam had mean decreases of 41.2%, 49.4%, and 68.3% for the 
low, medium, and high doses, respectively.  A standard deviation of ~63% was observed for both 
rufinamide and for the medium dose of clobazam for drop seizures.  It is assumed that 
comparable results will be seen in this trial for the placebo and perampanel treatment arms for 
drop seizures.
A sample size of 71 subjects in each treatment arm in the FAS will have 94% power to detect a 
treatment difference in median percentage seizure frequency change in drop seizures per 28 days
of 40% (common SD of 63%) between placebo and perampanel based on a Wilcoxon rank-sum 
test at the 0.05 two-sided significance level. 
50% responder rate in drop seizures: 
A sample size of 71 subjects per treatment arm will have 97% power to detect a 30% difference 
in responder rate proportions between placebo (assuming a placebo response rate of 20%) and 
perampanel treatment groups at the 0.05 two-sided significance level in drop seizures per 
28 days using a two-group chi-square test.
Percent change in seizure frequency for total seizures:
Decreases in total seizures for placebo, and low, medium, and high doses in the clobazam trial 
were approximately 9%, 35%, 45%, and 65% respectively; common standard deviations ranged 
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from 63% to 83%.  It is assumed that comparable results will be seen in this trial for the placebo 
and perampanel treatment arms for total seizures.
A sample size of 71 subjects in each treatment arm in the FAS will have 80% power to detect a 
treatment difference in median percentage seizure frequency change in total-seizures per 28 days
of 36% (SD=73%) between placebo and perampanel based on a Wilcoxon rank-sum test at the 
0.05 two-sided significance level.
50% responder rate in total seizures:
A sample size of 71 subjects per treatment arm (142 total) will have more than 80% power to 
detect a 22% difference in responder rate proportions between placebo (assuming a placebo 
response rate of 20%) and perampanel treatment groups at the 0.05 two-sided significance level 
in total-seizures per 28 days using a two-group chi-square test.
Interim Analysis
9.7.3
No interim analysis is planned for this study. 
Other Statistical/Analytical Issues
9.7.4
Not applicable
Procedure for Revising the Statistical Analysis Plan
9.7.5
If the SAP needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision will 
be documented and described in the clinical study report.


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10 REFERENCE LIST
Anonymous. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut 
syndrome). The Felbamate Study Group in Lennox-Gastaut Syndrome. N Engl J Med. 1993 
Jan 7;328(1):29-33.
Arzimanoglou A, French J, Blume WT, Cross JH, Ernst JP, Feucht M, et al. Lennox-Gastaut 
syndrome: a consensus approach on diagnosis, assessment, management, and trial 
methodology. Lancet Neurol. 2009 Jan;8(1):82-93. Review.
 
 
Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of 
cannabidiol on drop seizures in the Lennox–Gastaut Syndrome. N Engl J Med. 
2018;378:1888-97.
Eldridge R, Stern R, Koerber T, Iivanainen M, Wilder BJ. ”Baltic” myclonus epilepsy: 
hereditary disorder of childhood made worse by phenytoin. Lancet. 1983;838-42
 
Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for 
generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008 May 
20;70(21):1950-8. Epub 2008 Apr 9.
Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P. Lamotrigine for 
generalized 
seizures 
associated 
with 
the 
Lennox-Gastaut 
syndrome. 
Lamictal 
Lennox-Gastaut Study Group. N Engl J Med. 1997 Dec 18;337(25):1807-12. Erratum in: N 
Engl J Med 1998 Sep 17;339(12):851-2.
Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA. OV-1012 Study Investigators. 
Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 
2011 Oct 11;77(15):1473-81. Epub 2011 Sep 28.
Osorio I, Burnstine TH, Remler B, Manon-Espillat R, Reed RC.  Phenytoin-induced seizures: 
A paradoxical effect at toxic
concentrations in epileptic patients.  Epilepsia.
1989;30(2):230-4.
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.
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Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G. A double-blind, randomized 
trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology. 
1999 Jun 10;52(9):1882-7.
Snead OC, Hosey LC. Exacerbation of seizures in children with carbamazepine.  New Engl J 
Med. 1985;13(15):916-21.
Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. 
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome 
(GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet. 
2018 Mar391;10125:1085-96.
Thomas P, Valton L, Genton P.  Absence and myoclonic status epilepticus precipitated by 
antiepileptic drugs in idiopathic generalized epilepsy. Brain. 2006; 129:1281-92.


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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 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 (or, if regionally required, the head of the medical institution) 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 IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to the 
following:
1. Clinic, office, or hospital charts
2. Copies or transcribed health care provider notes which have been certified for accuracy 
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3. Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computed tomography (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
4. Pain, 
 or medical history questionnaires completed by subjects
5. Records of telephone contacts
6. Diaries or evaluation checklists
7. Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
8. Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
9. Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
10. 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).  In addition, the sponsor will send a list of treatment 
codes by study subject to the investigator after the clinical database for this study has been 
locked.  The site should plan to retain study documents, as directed by the sponsor, for at least 2 
years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 3 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.
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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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s SOPs 
to evaluate compliance with the principles of ICH GCP and all applicable local regulations.  If a 
government regulatory authority requests an inspection during the study or after its completion, 
the investigator must inform the sponsor immediately.
11.8 HANDLING OF STUDY DRUG
All study drug will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according to 
the conditions specified on the drug labels.  The investigator (or a designated pharmacist) must 
maintain an accurate record of the shipment and dispensing of the study drug in a drug
accountability ledger, a copy of which must be given to the sponsor at the end of the study.  An 
accurate record of the date and amount of study drug dispensed to each subject must be available 
for inspection at any time.  The CRA will visit the site and review these documents along with 
all other study conduct documents at appropriate intervals once study drug has been received by 
the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used
and unused drug containers, drug labels, and a copy of the completed drug disposition form to 
the sponsor’s CRA or, when approval is given by the sponsor, will destroy supplies and 
containers at the site.
11.9 PUBLICATION OF RESULTS
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission pursuant to 
the terms and conditions set forth in the executed Clinical Trial Agreement between the 
sponsor/CRO and the institution/investigator.  The review is aimed at protecting the sponsor's 
proprietary information existing either at the date of the commencement of the study or 
generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.


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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


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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
< LLN – 10.0 g/dL
< LLN – 100 g/L
< LLN – 6.2 mmol/L
< 10.0 – 8.0 g/dL
< 100 – 80 g/L
< 6.2 – 4.9 mmol/L 
< 8.0 g/dL
< 80 g/L
< 4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
< LLN – 3.0 x 109/L
< LLN – 3000/mm3
< 3.0 – 2.0 x 109/L
< 3000 – 2000/mm3
< 2.0 – 1.0 x 109/L
< 2000 – 1000/mm3
< 1.0 x 109/L
< 1000/mm3 
Lymphocytes 
≥2 to ≤6 years
≥7 to <12 years
≥12 years
< LLN – 800/mm3 
< LLN – 0.8 x 109/L
< 800 – 500/mm3
< 0.8 – 0.5 x 109/L
< 500 – 200/mm3
< 0.5 – 0.2 x 109/L
< 200/mm3
< 0.2 x 109/L
Neutrophils 
< LLN – 1.5 x 109/L
< LLN – 1500/mm3
< 1.5 – 1.0 x 109/L
< 1500 – 1000/mm3
< 1.0 – 0.5 x 109/L
< 1000 – 500/mm3 
< 0.5 x 109/L
< 500/mm3 
Platelets
< LLN – 75.0 x 109/L
< LLN – 75,000/mm3
< 75.0 – 50.0 x 109/L
< 75,000 – 50,000/mm3
< 50.0 – 25.0 x 109/L
< 50,000 – 25,000/mm3
< 25.0 x 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 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
ALT
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
AST
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
Bicarbonate, serum-low 
< LLN – 16 mmol/L
< 16 – 11 mmol/L
<11 – 8 mmol/L
< 8 mmol/L 
Bilirubin (hyperbilirubinemia)
> ULN – 1.5 x ULN 
> 1.5 – 3.0 x ULN
> 3.0 – 10.0 x ULN 
> 10.0 x 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 x ULN
> 1.5 – 3.0 x ULN
> 3.0 – 6.0 x ULN
> 6.0 x ULN
GGT (γ-Glutamyl transpeptidase) 
> ULN – 3.0 x ULN
> 3.0 – 5.0 x ULN
> 5.0 – 20.0 x ULN
> 20.0 x ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
> ULN – 160 mg/dL
> ULN – 8.9 mmol/L 
Fasting glucose value:
> 160 – 250 mg/dL
> 8.9 – 13.9 mmol/L 
> 250 – 500 mg/dL;
> 13.9 – 27.8 mmol/L;
hospitalization indicated
> 500 mg/dL;
> 27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
< LLN – 55 mg/dL
< LLN – 3.0 mmol/L
< 55 – 40 mg/dL
< 3.0 – 2.2 mmol/L
< 40 – 30 mg/dL
< 2.2 – 1.7 mmol/L
< 30 mg/dL
< 1.7 mmol/L
life-threatening 
consequences; 
seizures
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 
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
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
Extension A
ELIGIBILITY CRITERIA (revised per Amendment 04)
Subjects who meet the following criteria will continue to be eligible to participate in Extension A
of this study:
1. Have completed Visit 7 of the Core Study E2007-G000-338
2. Be considered reliable, willing to be available for the study duration, willing to comply 
with study procedures, and are able to record seizures in subject diaries and report AEs 
themselves or have a caregiver who can record and report the events for them
3. Continue to abide by concomitant drug/therapy restrictions (Section 9.4.7.2).
Subjects who meet the following will not be eligible to participate in Extension A of this study:
1. Those who, for any reason, discontinued early from the preceding double-blind Core 
Study.
STUDY DESIGN AND PLAN
Extension A will comprise 3 periods:  6-week Conversion, 46-week Maintenance, and 4-week 
Follow-up (except for subjects who are entering into Extension B).  Extension A will last 
approximately 52 weeks overall, or until such time that perampanel is made commercially 
available or accessible to subjects via an EAP if activated in the country in which they reside, 
whichever happens sooner. (revised per Amendment 04)
During the Conversion Period, subjects who received perampanel during the Core Study will 
continue receiving perampanel in a blinded manner at the same dose last received during the 
Core Maintenance Period.  Subjects who received placebo during the Core Study will begin 
treatment with perampanel in a blinded manner, following the same dosing regimen and titration 
schedule as that in the Core Study, starting at 2 mg/day and will then be up-titrated to the optimal 
dose per the investigator’s discretion, not to exceed a maximum dose of 8 mg/day (Table 7).  
After the double-blind Conversion Period, subjects can be titrated up to 12 mg/day (except in 
Japan, where the maximum allowed dose remains at 8 mg/day), at 2-week intervals per the 
investigator’s discretion.  Addition, deletion, and dose changes to the concomitant AEDs are 
allowed during Extension Maintenance Period. (revised per Amendment 04)
The dosing schedule for Extension A is summarized in Table 7 (revised per Amendment 01)


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Table 7
Dosage Schedule in E2007-G000-338 (Extension A)
(revised per Amendments 01, 02, 04, and 05)
Extension A/ 
Double-blind Conversion Period
Visit
All Subjects Converting from Placebo
Week 19 (starting dose)
Visit 7
2 mg/day
Week 20
--
4 mg/day
Week 21
Visit 8
6 mg/day
Week 22
--
6 mg/day
Week 23a
Visit 9
8 mg/day
Week 24
--
8 mg/day
Extension A/
Open-label Maintenance Period 
(beginning Week 25)
Visit 10
Starts Extension A Maintenance Period at the last dose 
achieved in the Conversion Periodb
a.
Subjects will remain on the same dose for at least 2 weeks before entering the Open-label Maintenance 
Period.
b.
After the double-blind Conversion Period, subjects can be titrated up to 12 mg/day (except in Japan, where 
the maximum allowed dose remains at 8 mg/day), in 2-week intervals as per the investigator’s discretion.
Per the investigators’ judgment, all subjects will be allowed to have their dose decreased only if 
they experience intolerance, or their dose increased only if needed for better seizure control until 
the optimal dose is found. Subjects whose dose has been decreased can have their dose 
increased again, as soon as tolerability improves.  Dose decreases can be done at an unscheduled 
clinic visit or via telephone.
After the double-blind Conversion Period, subjects can be titrated up to 12 mg/day (except in 
Japan where the maximum allowed dose remains at 8 mg/day), in 2-week intervals as per the 
investigator’s discretion.
All dose adjustments during this phase will be done by going one dose level up or down.  
Subjects who do not tolerate a daily dose of 2 mg will be discontinued from the study.
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 to 105 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 (or at the end of 
Extension A) with the Medical Monitor.
During Extension A, changes of concomitant AEDs (addition, deletion or adjustment in dose) 
will be allowed. However, if changes do occur subjects should be carefully monitored.
EXTENSION A ASSESSMENTS
Seizure diaries will be used to collect seizure counts and types.
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
laboratory evaluation for hematology, blood chemistry, including assessment of criteria for Hy’s 
Law, urine values; and periodic measurement of vital signs, as detailed in Table 5.  Reports of 


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anxiety and irritability will be closely monitored during the study by both the investigators and 
the Medical Monitor.  (revised per Amendment 01)
SAEs and events of special interest will be reported in the same manner as described for the Core 
Study (see Section 9.5.4.1 and Section 9.5.4.3).  (revised per Amendment 01)
The Follow-up Period of Extension A will have 1 visit during which End-of-Study assessments 
will be performed, except for subjects who are entering into Extension B.  These assessments 
will also be performed if a subject prematurely discontinues from Extension A, after the Early 
Discontinuation Visit. (revised per Amendment 04)
STUDY DRUG SUPPLIES
Where applicable, test drug (perampanel) will be stored and labeled in accordance with the US 
FDA Drug DEA Regulations for Scheduled III - V Drugs.  See Section 9.4.2 and Section 9.4.9
for other information regarding requirements for DEA-scheduled perampanel.
PERAMPANEL TABLETS
Perampanel 2-mg tablets will be provided as orange, 6.6 mm diameter, biconvex film-coated 
tablets for oral administration.  The front and reverse sides of the tablets will be debossed with 
“E274.”  Each tablet will contain 2 mg of perampanel.
Perampanel-matched placebo tablets will be provided as orange, 6.6 mm diameter, biconvex 
film-coated tablets for oral administration.  The front and reverse sides of the tablets will be 
debossed with “E274.”
The Eisai-approved vendor will package the study drugs in a double-blind configuration.  Each 
subject’s study drug will consist of either perampanel and/or perampanel-matched placebo and 
will be supplied in a subject medication kit bearing a multilanguage booklet label.
During the Conversion Period, subjects will be given blinded 2-week dose pack containing 
2 x 28 tablets plus 3 days of additional medication.  (revised per Amendment 01)
During the Maintenance Period, subjects will be given the required quantity of open-label 
4-week dose packs, each containing 4 x 42 tablets plus 7 days of additional medication.
PERAMPANEL ORAL SUSPENSION
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.  
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Perampanel oral suspension will be provided by Eisai Co. Ltd. to an Eisai-approved vendor in 
400-mL PET bottles containing 340 mL of oral suspension.  The approved vendor will label the 
bottles and ship them to the study sites.  
The PET bottles will be, if necessary, fitted with appropriately sized PiBA to aid in accurate 
aliquoting.  Dosing devices (eg, oral syringes) will also be provided for subject use.
During the Conversion and Maintenance Periods subjects will be given bottles containing oral 
suspension.  The same bottle can be returned to the subject/caregiver. Instructions regarding 
routine dosage changes during the Conversion Period will also be conveyed to the investigator 
via IxRS as described in Section 9.4.3.  
Detailed instructions on weekly/biweekly increments in dosage during the Conversion Period 
will be provided to the subject’s caregiver by the site investigator or the designated pharmacy.
SCHEDULE OF PROCEDURES/ASSESSMENTS
Table 8 presents the Schedule of Procedures/Assessments for Extension A of the study.  (revised 
per Amendment 01)  Extension A will last approximately 52 weeks overall, or until such time 
that perampanel is made commercially available or accessible to subjects via an EAP if activated 
in the country in which they reside, whichever happens sooner. 
The assessments to be 
administered are described in Section 9 (Core Study).


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Table 8
Schedule of Procedures/Assessments in Study E2007-G000-338 (Extension A)
(revised per Amendment 01, 02, 04, and 05)
Phase
Extension Aa
Period
Conversionb
Maintenancec
Follow-upc
Visit
8
9
10
11
12
13
14
Early 
DC
F/U
Unscheduled
Week
21
23
25
34
46
58
71
75
Day
141
155
169
232
316
400
491
519
Procedures/Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
(X)e
Urine pregnancy testf
X
X
X
X
X
X
X
X
X
(X)e
Clinical laboratory testsg
Xg
X
X
Xh
Xh
X
(X)e
C-SSRS
X
X
X
X
X
X
X
(X)e
Dispense/collect seizure diary
X
X
X
X
X
X
X
X
(X)e
IxRS
X
X
X
X
X
X
(X)e
Dispense study drug
X
X
X
X
X
X
(X)e
Retrieve unused study drug
X
X
X
X
X
X
X
X
(X)e
Adverse events
X
X
X
X
X
X
X
X
X
Xe
bpm = beats per minute; C-SSRS = Columbia Suicide Severity Rating Scale; DC = discontinuation; EEG = electroencephalogram, F/U = Follow-up; IxRS = 
interactive voice and web response system.
a:
Extension A begins with Week 19 after the completion of end of Core Study Visit (Visit 7) assessments.  That is, for those subjects rolling over into Extension 
A, Visit 7 (Week 19) will mark the end of the Core Study and the beginning of the blinded Conversion Period of Extension A.  (revised per Amendment 04)
b:
Conversion Period visits (Visits 8 and 9 of Extension A) will have a window of ±3 days with at least 10 days between visits 
c:
Visit will have a window of ±6 days
d:
Systolic blood pressure, diastolic blood pressure, heart rate (bpm), height, and weight (kg). Height of adult subjects is to be recorded only at the Screening 
Visit (Visit 1). (revised per Amendment 01).
e:
Unscheduled procedures to be conducted as needed.  (revised per Amendment 04)
f:
Urine pregnancy testing is for postpuberty, premenopausal females and postmenopausal females who have been amenorrheic for less than 12 months.  (revised 
per Amendment 04)
g:
Clinical laboratory tests include chemistry, hematology, and urinalysis.  
h:
Fasting samples to be taken at indicated time points for glucose and lipid panel  Fasting samples to be taken at indicated time points for glucose and lipid panel  
i:
 
 
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Table 9 presents the blood volumes to be collected during Extension A.  The total volume of 
blood taken in Extension A for subjects who complete all visits will be 30 mL.  For subjects who 
complete both the core study and Extension A, the blood volume will be 66 mL (not including 
unscheduled visits).  (revised per Amendment 04)
Table 9
Blood Volumes Taken During Extension A (revised per Amendment 04)
Visit No.
Visit 8
Visit 10
Visit 12
Visit 14
Early Discon-
tinuation
Follow-up 
Visit
Unscheduled Visit
Chemistry
X
X
X
X
X
X
X
Serology
Haematology
X
X
X
X
X
X
X
Total Volume
(mL)
6
6
6
6
-
6
-
PGx = pharmacogenomic (sample)
EXTENSION A STATISTICAL ANALYSES (revised per Amendment 04)
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.
Definitions of Study Populations: 
The Safety Analysis Set (Extension A) is the group of subjects who received at least one dose of 
perampanel and had at least one post-perampanel safety assessment. 
The FAS (Extension A) is the group of subjects who received at least one dose of perampanel
and had at least one post-perampanel seizure measurement.
Demographics
Demographic and Baseline characteristics will be summarized.  For continuous variables (eg, 
age, weight) the number of non-missing values, median, mean, SD, and minimum and maximum 
will be displayed. For categorical variables (eg, gender, ethnicity) the counts and proportions of 
each value will be tabulated.
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Safety Analyses
Safety analyses will be performed similarly to the Core Study analyses (Section 9.7.1.8) and all 
analyses will be on perampanel treatment duration (Randomization Phase + Extension A for 
subjects randomized to perampanel and Extension A for subjects randomized to placebo).  The 
Safety Analysis Set is defined for Extension A as the group of subjects who received at least one 
dose of perampanel and had at least one post-perampanel safety assessment. TEAEs are defined 
as AEs occurring from the time of first perampanel through 28 days after the last perampanel 
dose.  Baseline for laboratory and vital sign parameters will be the last non-missing value before
first perampanel dose.  
Extent of Exposure
Duration of exposure will be calculated as the number of days between the date the subject 
received the first dose of perampanel (Core Study for subjects randomized to perampanel and 
Extension A for subjects randomized to placebo) and the date the subject received the last dose 
of perampanel.
Overall Extension A 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 MedDRA.  Adverse events will be coded to the 
MedDRA (Version 15 or higher) lower level term closest to the verbatim term.  The linked 
MedDRA PT and primary SOC are also captured in the database.
Laboratory Values
Clinical laboratory values will be evaluated for each laboratory parameter by subject.  
Descriptive summary statistics (eg, mean, SD, median, minimum, maximum) for the laboratory 
parameters and changes from Baseline to the last on-treatment visit will be summarized.
Laboratory test results will be assigned a LNH classification according to whether the value was 
below (L), within (N), or above (H) the laboratory parameter’s reference range.  Shift tables will 
be used to compare the baseline 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 modified National Cancer Institute-common toxicity criteria 
(NCI-CTC)criteria 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.


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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.  
Descriptive summary statistics (eg, mean, SD, median, minimum, maximum) for vital sign 
parameters and changes from baseline and to the last on-treatment visit will be evaluated.


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Appendix 3
Pharmacogenomic Information
Subjects enrolled in this clinical study will have biological samples collected for 
pharmacogenomic (PG) analysis. Those samples may be used for discovery and validation to 
identify biomarkers that, for evaluation of response and/or safety-related outcomes as well as for 
use in diagnostic development. 
The PG samples may be used to identify genetic factors that may influence a subject’s exposure 
to the study drug, as well as genetic factors that may have an effect on clinical response or 
potential adverse events related to study treatment and to explore the role of genetic variability in 
response/resistance. Samples may be analyzed to determine subject’s genotypes or sequence for 
a number of genes or non-coding regulatory regions. The research may include the investigation 
of polymorphisms in genes that are likely to influence the study drug pharmacokinetics or 
therapeutic response. 
Collection of the samples for pharmacogenomic analysis will be bound by the same principles 
and processes outlined in the main study protocol.  Sample collection for PG analysis is required 
as per the study protocol unless the collection and use of the samples is prohibited by specific 
country laws.
Sample collection and handling
The pharmacogenomic samples will be collected according to the schedule of assessments. If for 
operational or medical reasons the blood samples for pharmacogenomic analysis cannot be 
obtained at the prespecified visit, the sample can be taken at any study visit at the discretion of 
the investigator and site staff. For anticipated volume of blood samples to be collected during 
this study, please refer to Table 6.  (revised per Amendments 01 and 02)
Security of the samples, use of the samples, retention of the samples
Sample processing, including DNA extraction and genotyping, sequencing, or other analysis will 
be performed by a laboratory under the direction of the Sponsor. Processing, analysis and 
storage will be performed at a secure laboratory facility to protect the validity of the data and 
maintain patient privacy.
Samples will only be used for the purposes described in this protocol by the Sponsor. 
Laboratories contracted to perform the analysis on behalf of the Sponsor will not retain rights to 
the samples beyond those necessary to perform the specified analysis, and will not transfer or sell 
those samples. The Sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report [CSR] to appropriate regulatory agencies). At the end of 
the storage period, samples will be destroyed. Samples may be stored for longer if a Health 
Authority (or medicinal product approval agency) has active questions about the study. In this 
special circumstance, samples will be stored until the questions have been adequately addressed.


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It is possible that future research and technological advances may identify genomic variants of 
interest, or allow alternative types of genomic analysis not foreseen at this time. Because it is not 
possible to prospectively define every avenue of future testing, all samples collected will be 
single or double-coded (according to the ICH15 guidelines) in order to maintain patient privacy.
Right to withdraw
If during the time the pharmacogenomic samples are stored a participant would like to withdraw 
his or her consent for participation in this research, Eisai will destroy the samples. Information 
from any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Patient privacy and return of data
No patient-identifying information (eg, initials, date of birth, government identifying number) 
will be associated with the samples. Samples that are processed for analysis (DNA/RNA 
extracted) may be double-coded. 
Double coding involves removing the initial code and 
replacing with another code such that the subject can be re-identified by use of two code keys. 
The code keys are usually held by different parties. The key linking the sample ID to the subject 
number will be maintained separately from the sample. At this point, the samples will be 
double-coded (the first code being the subject number) as long as the initial tube does not carry 
any personal identifiers or the random code assigned by the central laboratory or biorepository. 
Laboratory personnel performing genetic analysis will not have access to the “key”. Clinical 
data collected as part of the clinical trial will be cleaned of patient identifying information, and 
linked by use of the sample ID “key”.
The Sponsor will take steps to ensure that data are protected accordingly and that confidentiality 
is maintained as far as possible. Data from patients enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The Sponsor, its representatives and agents, may share anonymized data with persons and 
organizations involved in the conduct or oversight of this research. These include:

Clinical research organizations retained by the Sponsor

Independent ethics committees or institutional review boards that have responsibility for 
this research study

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or all 
of the anonymized data, in listing or summary format. Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of study results will only include summaries of the 
population in the study, and no identified individual results will be disclosed.
Given the research nature of the planned analysis, it will not be possible to return individual data 
to subjects participating in the pharmacogenomic analysis.


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Appendix 4
Additional Extension Phase (Extension B) (revised per Amendment 04)
Extension B is planned to be implemented in Japan and in countries where an EAP cannot be 
implemented or has not yet been implemented.
Study Design and Plan
Extension B will consist of a Treatment Period and a Follow-up Period (up to 4 weeks). 
Treatment will continue as long as clinically appropriate according to the judgment of the 
investigator. However, treatment of a subject in the Extension B will be completed when 
perampanel is commercially available or when EAP is activated in the subject’s country of 
residence.
Subjects eligible for Extension B shall be subjects in Japan or subjects in countries where an 
EAP cannot be implemented or has not yet been implemented, who have completed Extension A 
of this study and who, in the opinion of the investigator, continue to benefit from treatment with
perampanel.
Subjects will enter Extension B with their optimal perampanel dose (ie, the same dose of 
perampanel that they were maintained on at the end of Extension A).
During the course of 
Extension B, doses of perampanel and concomitant AEDs can be adjusted (concomitant AEDs 
can be used in accordance with the approved dosage and indication) based on clinical judgment.
A minimum perampanel dose of 2 mg/day is required to continue in the program. The maximum 
dose of perampanel is 8 mg/day (Japan) or 12 mg/day (other countries). Subjects who do not 
tolerate the minimum perampanel dose of 2 mg/day during the study will be discontinued from 
the study.
The visit intervals in Extension B will be every 12 weeks.  All visits are to be done within
±6 days of the schedule.
The investigator may discontinue the subject from the study at any time for safety or 
administrative reasons.  When the decision is made to discontinue to subject from the study, a 
Discontinuation Visit and a Follow-up visit 4 weeks (±7 days) later should be conducted for that 
subject.
Once perampanel is commercially available in the subject’s country of residence:

Subjects who discontinue or choose not to switch to the commercial product will require 
a Follow-up visit which will be conducted 4 weeks (±7 days) after the Discontinuation 
Visit.

Subjects who switch to the commercial product will require an End-of-Study Visit.  A 
Follow-up visit will not be required for subjects who switched to the commercial product 
and attended an End-of-Study Visit.
The sponsor reserves the right to terminate the program at any time.  


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Study Drug Supplies
Perampanel will be supplied as 2-mg oral tablets and 0.5 mg/mL oral suspension.  It is 
recommended that oral tablet be used for dosing subjects ≥12 years of age, and oral suspension 
for subjects <12 years of age.  However, the most appropriate formulation may be selected based 
on the subject’s condition and at the discretion of the investigator.  The same formulation used in 
the Core Study and Extension A for a given subject should be used throughout the course of the 
study, including Extension B, unless a change in formulation is medically indicated.  
Schedule of Procedures/Assessments
Table 10 presents the Schedule of Procedures/Assessments for the Extension B.  During 
Extension B, laboratory tests will be performed by the local laboratory.
Assessments
Safety Assessments
Safety will be assessed by monitoring of AEs, withdrawal from treatment, clinical laboratory 
tests, vital signs, and weight.
Other Assessments
Concomitant medication usage will be monitored. 
Statistical Analyses
Analysis Sets
The Safety Analysis Set (Extension B) is the group of subjects who received at least one dose of 
study drug and had at least one postdose safety assessment in Extension B.
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data that will be 
evaluated include TEAEs, and vital signs. 
Safety analyses will be performed similarly to the Core Study analyses and all analyses will be 
on the perampanel treatment duration (Randomization Phase + Extension A + Extension B for 
subjects randomized to perampanel and Extension A + Extension B for subjects randomized to 
placebo).  TEAEs are defined as AEs occurring from the time of first perampanel through 
28 days after the last perampanel dose.  Baseline for laboratory and vital sign parameters will be 
the last non-missing value before first perampanel dose.
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using MedDRA.  Adverse events will be coded to the 


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MedDRA (version 18.1 or higher) lower level term closest to the verbatim term.  The linked 
MedDRA PT and primary SOC are also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment 
(Baseline) or 
•
Re-emerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
Adverse events will be summarized using the Safety Analysis Set.  The incidence of TEAEs will 
be reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1 TEAE 
within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be 
summarized by relationship to study drug (related or not related).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by SOC 
and PT.  Treatment-related TEAEs include those events considered by the investigator to be 
related to study treatment.  
Laboratory Values
Laboratory results will be summarized using SI units, as appropriate.  For all quantitative 
parameters listed in Section 9.5.1.5, the actual value and the change from baseline to each 
postbaseline visit and to the end of treatment (defined as the last on treatment value) will be 
summarized by visit using descriptive statistics.  Percentages will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results.
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, weight) and 
changes from baseline will be presented by visit.


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Table 10
Schedule of Procedures/Assessments in Study E2007-G000-338:  Extension B (revised per Amendment 04)
Phase
Extension B
Period
Treatment
Visit/Timing
At Initial 
Assessmenta 
(Day 1,
Week 1)
Scheduled Visitb 
(Every 12 weeks)
Unscheduled 
Visitc
End of 
Study
Discontinuation 
Visitd
Follow-Upe
(4 Weeks After 
Discontinuation 
Visit)
Procedures/Assessments
Review risk/benefit of continued therapy 
with perampanel 
X
X
X
Concomitant medications and Concomitant 
AED( )
Xf
X
X
X
X
X
Study drug compliance
Xf
X
X
X
X
Vital signs
Xf
X
(X)g
X
X
X
Weight
Xf
X
(X)g
X
X
X
Clinical laboratory evaluations
Xf
X
(X)g
X
X
X
Urine pregnancy testh
Xf
X
(X)g
X
X
X
Dispense study drug
X
X
(X)g
Retrieve unused study drug
X
(X)g
X
X
Adverse events
Xf
X
X
X
X
X
AED = antiepileptic drug, LGS=Lennox-Gastaut Syndrome
a:
Perform on the final visit of Extension A Maintenance Period (ie, Visit 14).
b:
Visit window ±6 days.
c:
At the unscheduled visit, selected assessments will be performed based on investigator’s judgment of subject’s condition.
d:
Once perampanel is commercially available in the subject’s country of residence, the subject will have to switch to the commercial perampanel product promptly.  If a 
subject does not switch to the commercial product promptly, study drug treatment will be discontinued. A Discontinuation Visit and a Follow-up Visit 4 weeks (±7 days) 
later should be conducted for the subject.
e:
Follow-up visit is not required for subjects who will be switching to the commercial product or rolling over to EAP. 
f:
Data collected during the final visit of Extension A Maintenance Period (ie, Visit 14) will serve to fulfill initial assessments on Study Day 1 in Extension B.
g:
Unscheduled procedures to be conducted as needed.
h:
Female subjects age 8 years old and above, or of childbearing potential, only.


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2007-G000-338
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled 
Trial With an Open-Label Extension Phase of Perampanel as 
Adjunctive Treatment in Subjects at Least 2 Years of Age With 
Inadequately 
Controlled 
Seizures 
Associated 
With 
Lennox-Gastaut Syndrome
Investigational Product 
Name:
Perampanel 
IND Number:
112515
EudraCT Number:
2014-002321-35
SIGNATURES
Authors:
 
Neurology Business Group
Eisai Inc.
Date
Neurology Business Group
Eisai Inc
 
Neurology Business Group
Eisai Inc.
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol
incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
Confidential
Page 96 of 97
Neurology Business Group
Eisai Ltd.
Date
PPD
PPD
PPD


Clinical Study Protocol
incorporating Amendment 05
E2007-G000-338
FINAL:  v11.0, 19 Nov 2018
Confidential
Page 97 of 97
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2007-G000-338
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Placebo-controlled 
Trial With an Open-Label Extension Phase of Perampanel as 
Adjunctive Treatment in Subjects at Least 2 Years of Age With 
Inadequately 
Controlled 
Seizures 
Associated 
With 
Lennox-Gastaut Syndrome
Investigational Product 
Name:
Perampanel 
IND Number:
112515
EudraCT Number:
2014-002321-35
I have read this protocol and agree to conduct this trial 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 
GCP guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
 
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Final v 2.0 :  16 Aug 2021 
 
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CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2007-G000-338 
Study Protocol 
Title: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial 
With an Open-Label Extension Phase of Perampanel as Adjunctive 
Treatment in Subjects at Least 2 years of Age With Inadequately 
Controlled Seizures Associated With Lennox-Gastaut Syndrome 
Date: 
16 August 2021. 
Version: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final 2.0 
 


 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS 
2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
4 
3 
INTRODUCTION 
6 
3.1 
Study Objectives 
6 
3.1.1 
Primary Objective 
6 
3.1.2 
Secondary Objectives 
6 
3.1.3 
Exploratory Objectives 
7 
3.2 
Overall Study Design and Plan 
7 
4 
DETERMINATION OF SAMPLE SIZE 
8 
5 
STATISTICAL METHODS 
9 
5.1 
Study Endpoints 
9 
5.1.1 
Primary Endpoint 
9 
5.1.2 
Secondary Endpoints 
9 
5.1.3 
Exploratory Endpoints 
10 
5.2 
 
 Study Subjects 
11 
5.2.1 
Definitions of Analysis Sets 
11 
5.2.2 
Subject Disposition 
11 
5.2.3 
Protocol Deviations 
11 
5.2.4 
Demographic and Other Baseline Characteristics 
12 
5.2.5 
Prior and Concomitant Therapy 
12 
5.2.6 
Treatment Compliance 
13 
5.3 
Data Analysis General Considerations 
13 
5.3.1 
Pooling of Centers 
13 
5.3.2 
Adjustments for Covariates 
13 
5.3.3 
Multiple Comparisons/Multiplicity 
13 
5.3.4 
Examination of Subgroups 
14 
5.3.5 
Handling of Missing Data, Drop-outs, and Outliers 
14 
5.3.5.1 
Efficacy 
14 
5.3.5.2 
Safety 
14 
5.3.6 
Other Considerations 
15 
5.4 
Efficacy Analyses 
15 
5.4.1 
Primary Efficacy Analyses 
15 
5.4.2 
Secondary Efficacy Analyses 
16 
5.4.3 
Other Efficacy Analyses 
17 
5.5 
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Analyses 
18 
5.6 
Safety Analyses 
18 
5.6.1 
Extent of Exposure 
18 
5.6.2 
Adverse Events 
19 
5.6.2.1 
Deaths, Other Serious Adverse Events, and Other 
Significant Adverse Events 
19 
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5.6.2.2 
Adverse Events of Special Interest 
20 
5.6.3 
Laboratory Values 
20 
5.6.4 
Vital Signs 
21 
5.6.5 
Electrocardiograms 
22 
5.6.6 
Other Safety Analyses 
22 
5.6.6.1 
Metabolic Syndrome 
Error! Bookmark not defined. 
5.6.6.2 
C-SSRS 
22 
5.6.7 
 
22 
5.6.8 
 
23 
5.6.9 
 
23 
5.6.10 
 
24 
5.7 
Exploratory Analyses 
24 
5.8 
Extension Phase Analyses 
24 
6 
INTERIM ANALYSES 
24 
7 
CHANGES IN THE PLANNED ANALYSES 
24 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
24 
8.1 
EFFICACY DATA HANDLING 
24 
8.1.1 
Pre-randomization/baseline efficacy 
24 
8.1.2 
Treatment Duration for Efficacy Analyses 
25 
8.1.3 
Handling of Replicate Data 
25 
8.2 
SAFETY DATA HANDLING 
25 
8.2.1 
Baseline safety 
25 
8.2.2 
Treatment Duration for Safety Analyses 
25 
8.2.3 
Handling of Replicate Data 
28 
9 
PROGRAMMING SPECIFICATIONS 
28 
10 
STATISTICAL SOFTWARE 
28 
11 
MOCK TABLES, LISTINGS AND GRAPHS 
28 
12 
REFERENCES 
28 
13 
APPENDICES 
29 
13.1 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory 
Results 
29 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Term 
AE 
adverse event 
AED 
antiepileptic drug 
ALT 
alanine amino transferase 
ANCOVA 
analysis of covariance 
AST  
aspartate amino transferase  
ATC 
anatomical therapeutic class 
BMI 
body mass index 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG  
electrocardiogram  
FAS 
full analysis set 
LGS 
Lennox-Gastaut Syndrome 
LN 
lower limit of normal  
LLT 
lower level term 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NGM 
Neuroscience and General Medicine 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
preferred term 
PP  
per protocol  
SAE 
serious adverse event 


 
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SAP 
statistical analysis plan 
SI 
Système International 
SOC  
system organ class  
TEAE 
treatment-emergent adverse event 
TEMAV  
treatment-emergent markedly abnormal values  
TLG 
tables, listings, and graphs 
ULN  
upper limit of normal  
WHO 
World Health Organization 
 


 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for the Core Study of Eisai Protocol E2007-
G000-338. The statistical methods used in the Extension Phase will be described in a separate 
SAP.  
3.1 
STUDY OBJECTIVES 
3.1.1 Primary Objective 
The primary objective of the study is to demonstrate that perampanel given as adjunctive anti-
epileptic treatment is superior compared to placebo in reducing the incidence of drop seizures 
during 18 weeks of treatment in subjects with inadequately controlled seizures associated with 
Lennox-Gastaut Syndrome (LGS) 
3.1.2 Secondary Objectives 
1. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in reducing the incidence of all seizures during 18 weeks of treatment in subjects 
with inadequately controlled seizures associated with LGS 
 
2. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in the 50%, 75%, and 100% responder rates for drop seizures during 12 weeks of 
the Maintenance Period in subjects with inadequately controlled seizures associated with 
LGS 
 
3. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in the 50%, 75%, and 100% responder rates for total seizures during 12 weeks of 
the Maintenance Period in subjects with inadequately controlled seizures associated with 
LGS 
 
4. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in reducing the incidence of non-drop seizures during 18 weeks of treatment in 
subjects with inadequately controlled seizures associated with LGS 
 
5. To evaluate the 50%, 75%, and 100% responder rates in non-drop seizure frequency in the 
Maintenance Period  
 
6. To evaluate physicians’ global evaluation of subjects’ overall changes in symptoms 
 
7. To evaluate the safety of perampanel relative to placebo as adjunctive therapy in subjects 
with inadequately controlled seizures associated with LGS during both the Core Study and 
the Extension Phase 
 
8. To evaluate the pharmacokinetics and the pharmacokinetic/pharmacodynamic (PK/PD) 
relationships of perampanel as adjunctive therapy in subjects with inadequately controlled 
seizures associated with LGS 


 
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3.1.3 Exploratory Objectives 
 
 
3.2 
OVERALL STUDY DESIGN AND PLAN 
This was to be a multicenter, double-blind, randomized, placebo-controlled, parallel-group study 
of perampanel as adjunctive therapy in subjects with inadequately controlled seizures associated 
with LGS. The study was to consist of 3 phases: Prerandomization, Randomization, and Extension. 
The Core Study was to consist of the Prerandomization and Randomization Phases. 
 
The Prerandomization Phase was to consist of a 4- to 8-week Screening/Baseline Period during 
which subjects were to be assessed for overall eligibility to participate in the study, including 
seizure activity; Baseline seizure count was to be assessed using all diary data before 
randomization. 
 Following successful completion of this period, subjects were to be randomized to receive 
perampanel or placebo in a 1:1 ratio. 
 
The Randomization Phase was to consist of 3 periods: Titration (6 weeks), Maintenance (12 
weeks), and Follow-up (4 weeks). As required by some regulatory agencies, the following 
estimates were provided: 
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• The study was to begin approximately Jan 2017 and was to end approximately Jan 2020 
(revised per Amendment 01) 
• The maximum estimate period for each subject on the study was anticipated to be 
approximately 82 weeks.  
 
An overview of the study design is presented in Figure 1 of the protocol. 
 
4 
DETERMINATION OF SAMPLE SIZE 
Randomization of 71 subjects to each treatment arm was to provide a sample with adequate power 
for the primary endpoint and the key secondary endpoints. 
 
Primary endpoint percent change from baseline in drop seizures: 
 
Placebo rates in drop seizures in the rufinamide and clobazam clinical trials were +1.4%, and -
12.1%, respectively. In the active treatment arm, rufinamide had a median decrease of 42.5% in 
drop seizures and clobazam had mean decreases of 41.2%, 49.4%, and 68.3% for the low, medium, 
and high doses, respectively. A standard deviation of ~63% was observed for both 
rufinamide and for the medium dose of clobazam for drop seizures. It is assumed that comparable 
results will be seen in this trial for the placebo and perampanel treatment arms for drop seizures. 
 
A sample size of 71 subjects in each treatment arm in the Full Analysis Set (FAS) will have 94% 
power to detect a treatment difference in median percentage seizure frequency change in drop 
seizures per 28 days of 40% (common SD of 63%) between placebo and perampanel based on a 
Wilcoxon rank-sum test at the 0.05 two-sided significance level. 
 
50% responder rate in drop seizures: 
 
A sample size of 71 subjects per treatment arm will have 97% power to detect a 30% difference in 
responder rate proportions between placebo (assuming a placebo response rate of 20%) and 
perampanel treatment groups at the 0.05 two-sided significance level in drop seizures per 28 days 
using a two-group chi-square test. 
 
Percent change in seizure frequency for total seizures: 
 
Decreases in total seizures for placebo, and low, medium, and high doses in the clobazam trial 
were approximately 9%, 35%, 45%, and 65% respectively; common standard deviations ranged 
from 63% to 83%. It is assumed that comparable results will be seen in this trial for the placebo 
and perampanel treatment arms for total seizures. 
 
A sample size of 71 subjects in each treatment arm in the FAS will have 80% power to detect a 
treatment difference in median percentage seizure frequency change in total -seizures per 28 days 
of 36% (SD=73%) between placebo and perampanel based on a Wilcoxon rank-sum test at the 
0.05 two-sided significance level. 


 
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50% responder rate in total seizures: 
 
A sample size of 71 subjects per treatment arm (142 total) will have more than 80% power to 
detect a 22% difference in responder rate proportions between placebo (assuming a placebo 
response rate of 20%) and perampanel treatment groups at the 0.05 two-sided significance level in 
total-seizures per 28 days using a two-group chi-square test. 
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. 
5.1 
STUDY ENDPOINTS 
5.1.1 Primary Endpoint 
The primary efficacy endpoint will be the median percent change in drop seizure frequency per 
28 days during double-blind treatment (Titration Period and Maintenance Period) relative to the 
Prerandomization Phase in the FAS. 
5.1.2 Secondary Endpoints 
The following key secondary endpoints will be evaluated sequentially using the FAS: 
 
1. Median percent change in total seizure frequency per 28 days during double –blind 
treatment (Titration Period and Maintenance Period) relative to the Prerandomization 
Phase. 
 
2. The 50% responder rate in the Maintenance Period of the double-blind treatment relative 
to the Prerandomization Phase for drop seizures 
 
3. The 50% responder rate in the Maintenance Period of the double-blind treatment relative 
to the Prerandomization Phase for total seizures. 
 
Other secondary endpoints are: 
 
4. Median percent change in non-drop seizure frequency per 28 days during double-blind 
treatment (Titration Period and Maintenance Period) relative to the Prerandomization 
Phase 
 
5. Proportion of subjects with 75%, and 100% responder rates for drop, non -drop, and total 
seizures in the Maintenance Period relative to the Prerandomization Phase 
 
6. Proportion of subjects with 50% responder rate in the Maintenance Period of the double-
blind treatment relative to the Prerandomization Phase for non-drop seizures 
 


 
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7. Physicians’ global evaluation of the subject’s overall changes in symptoms (using a 
7-point Likert scale with 1=very much improved and 7=very much worse) at the end of the 
double-blind treatment 
 
8. Incidence of adverse events (AEs) and serious adverse events (SAEs), changes in clinical 
laboratory values, and vital signs 
 
9. Model-derived average perampanel concentrations at steady state (Cav,ss) during the 
Maintenance Period of the Core Study 
5.1.3 Exploratory Endpoints 
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5.2 
 STUDY SUBJECTS 
5.2.1 Definitions of Analysis Sets 
The Safety Analysis Set (SAS) is the group of subjects who received at least one dose of study 
drug and had at least one post-dose safety assessment. 
 
The Full Analysis Set (FAS) is the group of randomized subjects who received at least one dose 
of study drug and had at least one post-dose seizure measurement. 
 
The Per Protocol Analysis Set (PP)  is the group of subjects who sufficiently complied with the 
protocol. Details of the evaluability criteria are given in Section 5.2.3.  
 
The Pharmacokinetic Analysis Set is the group of subjects who received perampanel and had at 
least one quantifiable perampanel concentration during the Maintenance Period of the Core Study 
and adequately documented dosing history. 
 
The PK/PD analysis set is the group of subjects who received perampanel or placebo who had 
seizure frequency data with documented dosing history. Subjects who received perampanel should 
have at least one quantifiable perampanel concentration as per the PK analysis set. 
 
The Intention to Treat Analysis Set (ITT) is the group of randomized subjects who received at 
least one dose of study drug. 
5.2.2 Subject Disposition 
The number of subjects enrolled and the reasons for screen failure will be summarized. 
Subject disposition tables will include the number (percentage) of subjects who were: 
• Randomized into each treatment group; 
• Completed the study; 
• Discontinued early from the study, summarized by primary reason for discontinuation. 
Subject disposition will be summarized overall and by age group. 
5.2.3 Protocol Deviations 
The following provide definitions of major protocol deviations; however, exclusions from the PP 
Analysis Set will be made on a case-by-case basis using these as a guideline and based on 
reasonable clinical judgment. 
 
• Subject did not meet Inclusion Criterion #4, which was: Subjects must have experienced 
at least 2 drop seizures per week in the 4-week Baseline Period preceding randomization. 
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• At any time during the study, subject stopped or interrupted any approved antiepileptic 
drugs (AED)s he/she was taking upon study entry. 
• Subject received incorrect study drug longer than he/she received randomly assigned study 
drug. 
• Subject had <80% study medication compliance 
• Subject had <80% diary compliance during the Prerandomization and Randomization 
Phases. 
Other criteria may be identified during the course of the study. Identification of subjects with major 
protocol deviations will occur before DBL and treatment unblinding. 
5.2.4 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the SAS will be summarized for each treatment 
group using descriptive statistics. Continuous demographic and baseline variables include age, 
weight, height and body mass index (BMI); categorical variables include sex, age group (2-<12, 
12-<18, 18-<65, ≥65), race and ethnicity. 
MEDICAL HISTORY 
The number (percentage) of subjects reporting a history of any medical condition, as recorded on 
the case report form (CRF), will be summarized for the SAS for each treatment group and overall.  
A subject data listing of medical and surgical history will be provided. 
Epilepsy-specific medical history for the SAS will be summarized for each treatment group and 
by age group using descriptive statistics, including time since diagnosis and seizure type. 
5.2.5 Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code using 
the World Health Organization Drug Dictionary (WHO DD) (Mar 2021).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on the 
FAS by treatment group, Anatomical Therapeutic Chemical (ATC) class (i.e., anatomical class, 
therapeutic class, pharmacologic 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.  All medications will be presented in subject data 
listings. 
The number of baseline AEDs will be summarized by treatment group and by age group and a 
summary of baseline and concomitant AEDs will be produced by treatment group and by age 
group. A baseline AED is an AED taken at the date of randomization. Concomitant AEDs are 
defined as above for concomitant medications. 


 
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5.2.6 Treatment Compliance 
For subjects taking tablets, percent compliance will be calculated for the Randomization Phase 
and by visit for the FAS as follows:  
Compliance = Total number of tablets dispensed – Total number of tablets returned x 100  
Planned total number of tablets to be taken  
For subjects taking oral suspension, percent compliance will be calculated for the randomization 
phase and by visit for the FAS as follows: 
 
Compliance = Total weight in grams dispensed – Total weight in grams returned x 100  
Planned total volume in mL to be taken x suspension density of 1.07 grams per mL 
Where subjects have taken both tablets and oral suspension, overall compliance will be derived by 
averaging the visit compliance across the Randomization Phase.  
Overall compliance with study medication will be summarized using descriptive statistics for each 
treatment group and by age group. Subjects will also be categorized by compliance categories of 
<80%, 80%-120% and >120%.  
 
5.3 
DATA ANALYSIS GENERAL CONSIDERATIONS 
5.3.1 Pooling of Centers  
This is a multi-center, international study conducted in three geographic regions, i.e. United States, 
Europe, and Asia. Data from the centers in the same region and age group will be pooled together 
for analysis purposes. Each of these strata should have at least 6 subjects. If there are strata with 
<6 subjects then age-groups will be combined within the region.  
For analyses by country, if there are countries with <6 subjects then the countries will be sorted 
in descending order by the number of subjects in each geographic region. Starting from the 
smallest, countries will be pooled until the criteria of 6 subjects is fulfilled or there is no country 
of size <6 left to be pooled in that geographic region. If there is no country of size <6 left to be 
pooled but the current country is of size <6 then the current country will be pooled with the next 
country in that geographic region in the order. 
5.3.2 Adjustments for Covariates 
The Prerandomization Phase seizure frequency per 28 days value will be used as a covariate, and 
region and age group will be used as a factor in the efficacy models for the primary analysis. 
Additional covariates may also be explored. 
5.3.3 Multiple Comparisons/Multiplicity 
If the primary endpoint is statistically significant then the 3 key secondary efficacy endpoints will 
be tested in a sequential manner. 
 


 
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Median percent change in total seizure frequency per 28 days during double -blind treatment will 
be tested first. If this test is significant at 0.05 level, then the 50% responder rate in the Maintenance 
Period for drop seizures will be tested. If this is significant then the 50% responder rate in the 
Maintenance Period for total seizures will be tested. All tests will be at a 2 -sided 0.05 significance 
level. 
5.3.4 Examination of Subgroups 
The following endpoints will be summarised by age (2-<12, 12-<18, 18-<65, ≥65): 
Disposition; demography; epilepsy-specific medical history, number of baseline AEDs, baseline 
AEDs, compliance, percent change in drop, non-drop and total seizure frequency, 50%/75% 
response and seizure freedom rates in drop, non-drop and total seizures; clinical global impression 
exposure; treatment-emergent adverse events; change from baseline in laboratory values; 
treatment-emergent markedly abnormal laboratory values;  change from baseline in vital signs;  
and Columbia Suicide Severity Rating Scale (C-SSRS), for subjects 8 years and over. 
5.3.5 Handling of Missing Data, Drop-outs, and Outliers 
5.3.5.1 Efficacy 
For the last observation carried forward (LOCF) analyses, such as “Maintenance-LOCF” analyses 
of percent change and responder rate, if the overall duration of the Maintenance Period is less than 
8 weeks, the diary data up to the last 8 weeks during the Titration and Maintenance Periods 
combined will be used to calculate the seizure frequency per 28 days for Maintenance-LOCF. 
 
For the ITT analysis, subjects with no post-baseline efficacy data will have their baseline 
observation carried forward. 
 
Since data is rank transformed prior to analysis, outliers will have no effect on the primary analysis. 
 
5.3.5.2 Safety 
The algorithm on the assumptions used for imputing the missing dates for AEs is given in the 
programming specifications.  
 
If the day and month are missing, events will be considered treatment-emergent if the year is equal 
to or after the year of the first dose date; if days are missing, events will be considered treatment-
emergent if the year is after the year of the first dose, or if the year is equal to the year of the first 
dose date and the month is equal to or after the month of the first dose date.  
 
For the purpose of summarizing maximum severity, if the severity of an AE is missing for a 
subject, then, if this subject has another AE with the same preferred term that has “severe” severity, 
the maximum severity of the AE will be noted as “severe’; otherwise the maximum severity will 
be noted as missing. Similarly, for the purpose of summarizing closest relationship, if the 
relationship of an AE to study drug is missing, the AE will be noted to be related if there is another 
related AE with the same preferred term, otherwise this relationship will be noted as missing.  
 


 
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For determining treatment emergent markedly abnormal lab values, a missing baseline lab value 
will be assumed to be of grade 0. 
 
The algorithm to impute missing dates for concomitant medications is given in the programming 
specifications. No special handling of missing data is planned for the analysis of any of the other 
safety variables. 
 
Data exceptions or outliers will be determined by inspection of the tables, listings, and graphs in 
consultation with the clinical study team. The effect of outliers on analyses may be assessed by re-
analyzing the data without the outliers. 
 
All the listings will display the original missing values.  
5.3.6 Other Considerations 
Not applicable. 
5.4 
EFFICACY ANALYSES 
5.4.1 Primary Efficacy Analyses 
The primary efficacy endpoint will be the percent change from baseline in drop seizure frequency 
per 28 days during treatment. 
 
A drop seizure is defined as a tonic-atonic or myoclonic with fall. 
 
The null hypothesis and alternative hypothesis are: 
 
H0: perampanel is not superior to placebo in reducing drop seizure frequency 
H1: perampanel is superior to placebo in reducing drop seizure frequency 
 
The percent change from baseline will be analyzed over the Titration and Maintenance Periods 
combined in the FAS. Drop seizure frequency per 28 days (as determined from subject diaries) 
will be calculated as the number of drop seizures divided by the number of days in the interval and 
multiplied by 28. 
 
Analysis will be conducted using rank analysis of covariance (ANCOVA) with treatment, region 
(Asia/Pacific, Europe, North America) and age-group (2-<12 years, >=12 years) as factors, and 
the baseline drop seizure frequency as a covariate (Conover and Inman, 1982).  
In this analysis, all drop seizure frequency data will first be rank-transformed for both baseline and 
endpoint drop seizure frequencies separately. The ANCOVA will then be conducted based on the 
rank-transformed data. Treatment effect will be tested at a 2-sided 5% level.  
 
Due to an expected irregular distribution of drop seizure frequency, median will be the primary 
statistic of interest for the primary endpoint. Hodges-Lehmann estimator (Hodges and Lehmann, 
1963) and 95% confidence interval (CI) for this estimator will be displayed for understanding the 
treatment effect size. 


 
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The following sensitivity analyses will be conducted for the endpoint of percent change in drop 
seizure frequency: 
 
• Analysis on the Maintenance with LOCF to impute for missing data, and Titration period 
in the FAS. In the “Maintenance-LOCF” Analysis for the percent change, if a subject has 
less than 8 weeks of Maintenance Period, the drop seizure frequency during the last 8 weeks 
of the Titration and Maintenance Periods combined (or drop seizure frequency during the 
Titration and Maintenance Periods combined for subjects with less than 8 weeks of 
Titration and Maintenance Periods combined) will be used to impute for this sensitivity 
analysis. 
 
A duration of 8 weeks for the missing data imputation for the percent change is meant to 
provide more stable estimates for the drop seizure frequency. 
 
• Analysis of the percent change using the PP Analysis Set. 
 
• Analysis of the percent change using the ITT Analysis Set. 
 
• Analysis of subjects in the FAS who complete the entire study period i.e. have last 
scheduled double-blind visit completed and is marked by the investigator to have 
completed the study (Completers). 
 
A by visit summary of percentage change will also be produced. 
The following graphical displays will be produced: cumulative distribution function of percent 
change in drop seizure frequency during treatment, plots of median percent change from pre-
randomization in drop seizure frequency by major analysis windows, by week during titration and 
by visit. A bubble plot of the Hodges-Lehmann median difference between perampanel and 
placebo by country and forest plots of percent change in drop seizure frequency by analysis 
windows and sub-groups will also be produced.  
5.4.2 Secondary Efficacy Analyses 
If the primary endpoint is statistically significant then the 3 key secondary efficacy endpoints will 
proceed in a sequential manner. 
 
Median percent change in total seizure frequency per 28 days during double -blind treatment will 
be tested first. If this test is significant at 0.05 level, then the 50% responder rate in the Maintenance 
Period for drop seizures will be tested. If this is significant then the 50% responder rate in the 
Maintenance Period for total seizures will be tested. All tests will be at a 2 -sided 0.05 significance 
level. 
 
The same ANCOVA model employed for the primary efficacy variable will be employed to 
analyze percentage change from baseline in total seizures. 


 
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50% responder rates will be analyzed using the Cochran-Mantel-Haenszel (CMH) test, adjusting 
for region (Asia/Pacific, Europe, North America) and age group (2-<12 years, >=12 years). The 
homogeneity of the odds ratios will be checked across strata. For subjects who discontinue the 
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 double-blind treatment duration if <8 weeks of data are available) will 
be used in lieu of Maintenance Period. 
 
Sensitivity analyses of the key secondary endpoints will be performed in the PP and ITT 
populations. 
  
The primary and key secondary efficacy endpoints will be summarized by age group. 
75% responder rate and seizure-freedom rate in drop and total seizures will be analysed by 
treatment group in the Maintenance-LOCF Period.  
Percent change from baseline in non-drop seizures will be analysed similarly to drop and total 
seizures.  
Summaries of the 50%, 75% and seizure freedom rates in non-drop seizures will also be produced. 
Seizure freedom is defined as being seizure free during the maintenance period and completing 
the core study.  
The other secondary efficacy endpoint of Physicians’ global evaluations over time will be analyzed 
using the CMH test.  
5.4.3 Other Efficacy Analyses 
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5.5 
Pharmacokinetic, Pharmacodynamic, and PHARMACOGENOMIC/PHARMACOGENETIC 
ANALYSES 
Perampanel plasma concentrations were obtained from blood samples drawn at Weeks 7, 13 and 
19/ET visit.  A listing of perampanel plasma concentrations will be produced. Details of the 
analysis methods for population pharmacokinetic/pharmacodynamics (PK/PD) modeling will not 
be described in this statistical analysis plan (SAP) but will be described in a separate analysis plan. 
Pharmacogenomics analyses may be performed and will be reported separately. Details of these 
analyses will be described in a separate analysis plan if appropriate. 
5.6 
SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
treatment group, will be summarized on an “as treated” basis 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, Study Day 1 for all safety analyses is defined as the date 
of the first dose of study drug. 
Summaries of exposure, TEAEs and treatment-emergent markedly abnormal values (TEMAVs) 
will be presented by age group. 
5.6.1 Extent of Exposure 
Duration of Randomization 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 Randomization Phase. The 
results will be summarized by treatment groups using median, mean, standard deviation, 
minimum, maximum, and number of subjects with non- missing data. 
Exposure to the study medication will also be summarized by categories of cumulative weeks. 
 
The mean, modal, median, maximum and last daily dose over the Titration and Maintenance 
Periods for each of the randomized treatment arms will be summarized. The mean daily dose for 
each of the arm will be calculated by taking the average of all the doses taken weighted by the total 
duration of exposure and rounded to 1 decimal place, ie sum of (days on each dose*dose)/total 
dose duration of subjects. For subjects ≥12 years, dose will be summarized in mg. For subjects 
<12 dose will be summarised in mg/kg. 
 
The number of subjects who down-titrated or discontinued at their maximum daily dose will be 
summarized. 
 
Cumulative extent of exposure and summaries of dose will be presented by age group.  
 


 
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5.6.2 Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (Version 24.1 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 TEAE is defined as an AE that emerged during treatment, having been absent at pre-treatment 
(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. 
 
TEAEs will be summarized by treatment group and by age group. 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). Summaries of treatment-related 
TEAEs will be produced. 
 
There will also be summaries of TEAEs by dose at onset and exposure-adjusted event rates. 
5.6.2.1 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
A subject data listing of all AEs leading to death will be provided. 
 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) will 
be summarized by MedDRA SOC and PT for each treatment group, overall and by pooled country. 
A subject data listing of all SAEs will be provided. 
 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug will 
be summarized by MedDRA SOC and PT for each treatment group. A subject data listing of all 
AEs leading to discontinuation from study drug will be provided.  
 


 
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The number (percentage) of subjects with TEAEs leading to dose adjustment will be summarized 
by MedDRA SOC and PT for each treatment group. A subject data listing of all AEs leading to 
dose adjustment will be provided. 
5.6.2.2 Adverse Events of Special Interest 
A listing and summary of subjects with AEs related to suicidality, identified by the depression and 
suicide/self-injury standardized MedDRA query (SMQ) terms, will be provided. TEAEs of special 
interest listed below will be summarized by SOC and PT for each treatment group. 
 
SMQs will be used to identify relevant terms for the following TEAEs. All of these TEAEs will 
be summarized by broad and narrow terms, except those related to abuse potential, 
hostility/aggression and psychosis/psychotic disorder, which will be summarized by both broad 
and narrow terms and by narrow terms. 
 
• TEAEs suggestive of abuse potential: SMQ of drug abuse, dependence and withdrawal 
• TEAEs related to alertness and cognition: SMQ of dementia 
• TEAEs related to hostility/aggression: SMQ of hostility/aggression 
• TEAEs related to psychosis and psychotic disorder: SMQ of psychosis and psychotic 
disorders 
• TEAEs related to status epilepticus/convulsions: SMQ of convulsions 
• TEAEs related to drug related hepatic disorder abnormalities: SMQ of drug-related hepatic 
disorders 
• Cardiac and electrocardiogram (ECG) TEAEs: SMQs of cardiac arrhythmia terms (incl 
bradyarrhythmias and tachyarrythmias, arrhythmia related investigations, signs and 
symptoms, cardiac failure, cardiomyopathy, ischaemic heart diseases, and Torsade de 
pointes/QT prolongation 
• Rash: SMQ of severe cutaneous adverse reactions and hypersensitivity 
 
 
Falls will be summarized for Prerandomization Phase and Follow-up Period, and by actual dose 
of onset for the Titration Period and Maintenance Period. 
 
Exposure-adjusted rates of falls and AEs in the accident/injury SMQ will be presented. 
 
5.6.3 Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
Actual value and change from baseline in all quantitative parameters will be summarized by visit 
and treatment group for each postbaseline visit and to the end of treatment (defined as the last on-
treatment value). Qualitative parameters will be summarized using frequencies at each visit. 
Whenever normal ranges are available, it will be determined whether the lab value is above (H), 
below (L) or within (N) the normal 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 


 
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visit and at the end of treatment.  Similar shift tables will be used to compare the baseline LNH 
classification to the LNH classification for the highest and lowest value during the treatment 
period.  
The number of abnormal records and the number of subjects with two consecutive abnormal 
records will also be summarized. 
 
The incidence of TEMAVs will be summarized over all scheduled and unscheduled visits for the 
parameters with defined notable ranges given in Section 13.1 of this analysis plan. A phosphate 
value will be determined to be a TEMAV if the post baseline National Cancer Institute (NCI) 
common toxicity criteria grade increases from baseline and the post baseline grade is greater than 
or equal to 3. For all other parameters in Section 13.1, a value will be determined to be a TEMAV 
if the post baseline NCI grade increases from baseline and the post baseline grade is greater than 
or equal to 2. The number (percentage) of subjects with TEMAVs will be displayed. Additionally 
the number of subjects with TEMAVs who were normal at baseline and the number of TEMAVs 
will also be summarized. 
 
For alanine amino transferase (ALT), aspartate amino transferase (AST) and alkaline phosphatase, 
the number of subjects with > 3x but ≤ 5x the Upper Limit Normal (ULN) and the number of 
subjects with > 5x the ULN will be summarized by treatment group by visit. For bilirubin, the 
number of subjects with serum concentrations > 2x ULN will be summarized by treatment group 
by visit. These summaries will also be provided for the maximum value in the treatment duration. 
In addition, the number of subjects who meet the criteria for Hy’s Law at the same visit will be 
summarized by visit and during the treatment duration. A subject will be determined to have met 
Hy’s Law if AST or ALT is > 3x ULN, bilirubin > 2x ULN, and alkaline phosphatase ≤ 2x ULN 
at a visit. The number of subjects who meet each of the criteria for Hy’s Law during treatment (but 
not all necessarily at the same visit) will also be summarized. 
 
Potentially clinically significant (abnormal) changes, defined as an increase in NCI grade to 
Grade 2 or higher from baseline when the baseline value is normal will be summarized. 
 
5.6.4 Vital Signs 
Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
respiration rate, temperature, weight, height) and changes from baseline to each post-baseline visit 
and to the last post-baseline visit will be presented by treatment group 
In addition, the criteria described in Table 1 will be used to determine clinically notable results for 
blood pressure and heart rate. The number (percentage) of subjects with clinically notable results 
over all scheduled and unscheduled visits will be summarized by treatment group. 
Table 1: Criteria for Clinically Notablea Vital Signs 
Variable  
Criterion Value  
Change Relative to Baseline  
Systolic BP  
> 180 mmHg  
Increase of ≥ 20 mmHg  
< 90 mmHg  
Decrease of ≥ 20 mmHg  


 
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Diastolic BP  
>105 mmHg  
Increase of ≥ 15 mmHg  
< 50 mmHg  
Decrease of ≥ 15 mmHg  
Heart Rate  
>120 bpm  
Increase of ≥ 15 bpm  
< 50 bpm  
Decrease of ≥ 15 bpm  
Weight  
  
Increase of > 7%  
  
Decrease of > 7%  
a: Clinically notable means that a value must have met both the criterion value and satisfied 
the magnitude of change relative to baseline.  
 
 
5.6.5 Electrocardiograms 
12-lead ECG will be obtained at the Screening Visit only.  Since the data are not planned to be 
included in the database, no ECG summaries will be produced. 
5.6.6 Other Safety Analyses 
5.6.6.1 C-SSRS 
Scoring of the C-SSRS will be performed as suggested by the C-SSRS Columbia website 
http://www.cssrs.columbia.edu/clinical_trials.html. 
 
The following summaries will be presented for the treatment duration (defined as the period from  
the date of first dose up to 28 days after the date of last dose, inclusive). 
• Number (percentage) of subjects with any treatment-emergent report of suicidal behavior, 
suicidal ideation, and suicidality (suicidal behavior and/or ideation) will be displayed. A 
treatment-emergent report of suicidal behavior, suicidal ideation, or suicidality is an answer 
of ‘Yes’ to any question in the respective category during the treatment duration. 
• Shift from baseline to the maximum suicidal ideation severity rating (0=no ideation present 
to 5=active ideation with plan and intent) in the treatment duration will assess worsening 
of suicidal ideation. Any score greater than 0 indicates the presence of suicidal ideation 
while a score of 4 (active suicidal ideation with some intent to act) or 5 (active suicidal 
ideation with specific plan and intent) can be used to indicate serious suicidal ideation. 
 
Descriptive statistics and changes from baseline will be presented by visit for the suicidal ideation 
severity rating (treated as a continuous variable) to assess change in suicidal ideation over time. 
Other Analyses 
5.7 
OTHER ANALYSES 
5.7.1 
 
 
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5.7.2 
 
5.7.3 
 
 
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5.7.4 
 
5.8 
EXPLORATORY ANALYSES 
5.9 
EXTENSION PHASE ANALYSES 
The statistical methods used in the extension phase will be described in a separate SAP. 
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
7 
CHANGES IN THE PLANNED ANALYSES 
There are no changes to the statistical methods in this analysis plan compared to the protocol. Any 
future changes to the analysis will be documented separately and will be addressed in the Clinical 
Study Report. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
EFFICACY DATA HANDLING 
Only “valid days” and “valid seizure counts” will be used in the calculations of seizure frequency 
per 28 days. A “valid day” is defined as the day where seizure counts information is present, that 
is, either a record with an answer of ‘No’ to the question ‘Did the subject experience any seizures?’ 
or a positive number of seizures for at least one of the seizure types collected. “Valid seizure 
counts” are the seizure counts that are read from the valid seizure days. 
 
8.1.1 Pre-randomization/Baseline Efficacy 
All diary data prior to first dose date will be used in the computation of Prerandomization Phase 
seizure frequency per 28 days. All subjects should have approximately 4 weeks of diary data prior 
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to baseline (Visit 2). The baseline value for other efficacy endpoints will be the last non-missing 
measurement occurring prior to the first dose of the study drug. 
8.1.2 Treatment Duration for Efficacy Analyses 
The date of first dose of the study drug is considered Day 1 in the treatment duration. 
 
The first dose date is the study drug start date and the last dose date is study drug end date from 
the study medication CRF page. 
 
The treatment duration for efficacy variables is defined as follows: 
• For diary seizure data: The duration between the day of first double-blind study drug dose 
and the last day of double-blind study drug dose, inclusive. 
• For non-diary efficacy data: The duration between the day of first double-blind study drug 
dose and 7 days after the last double-blind study drug dose, inclusive. 
 
For all efficacy analyses, data reported only during the treatment duration will be analyzed. 
 
8.1.3 Handling of Replicate Data 
 
If there is more than 1 diary entry for a date, then the entry with the highest number of drop seizures 
will be used for that date. 
 
For the CGIC assessment, the last visit, within the treatment duration will be used. 
8.2 
SAFETY DATA HANDLING 
8.2.1 Baseline safety 
The baseline value for all safety endpoints will be the last non-missing measurement occurring 
prior to the first dose of the study medication. 
8.2.2 Treatment Duration for Safety Analyses 
The treatment duration for non-AE safety variables is considered to begin at or after the first dose 
of study drug on Day 1 and ends 14 days after the last dose of double-blind study medication. For 
AEs, the treatment duration is considered to begin on Day 1 and ends 28 days after the last dose 
of double-blind study medication. 
 
The post-treatment duration is considered to begin on the day after the treatment duration for 
safety. Since it is not always possible for all study participants to come in for their clinic visits on 
the exact day specified in the protocol schedule, the visit week of a subject’s visit will be based on 
the actual visit occurring during the treatment duration These visits will be used to create by visit 
summaries for laboratory, and vital signs data. The end of treatment value is the last non-missing 
value in the treatment duration. 
 


 
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Any concomitant medication taken within the 14 days after the last dose data will be listed/ 
summarized as part of the concomitant medication listing/table. 
 
AEs for the subject were collected and reported on CRF starting from the time the subject signed 
informed consent to the last visit in the Treatment Phase following the subject’s last dose. Serious 
AEs were collected for 28 days after the last dose. 
 
For summaries of safety by time points, the time points will be relative to date of first dose.  For 
standardized reporting, study day windows relative to the first dose (Day 1) in the study will be 
applied to determine into which week the data will be mapped.  Scheduled, unscheduled, and early 
withdrawal visits will be mapped to weeks.  Table 2 below gives the mapping of relative day ranges 
to week for vital sign assessments.  Table 3 below gives the mapping of relative day ranges to 
week for laboratory assessments. If a subject did not have a recorded observation falling within a 
given range of days in order to be assigned to a week, the subject’s data for that week will be 
regarded as missing for summarization purposes.  If there are two or more assessments in the same 
window then: 
• if the window is the baseline assessment, then the latest assessment will be used in the 
summary tables; 
• if the window is the follow-up assessment, then the latest assessment will be used in the 
summary tables; 
If the window is not the baseline or the follow-up assessment, then the assessment closest to the 
scheduled assessment will be used in the summary tables.  Note that if two assessments are 
equidistant from the scheduled assessment then the earliest assessment of the two (within the 
allowable window) will be used.  . 


 
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Table 1:  Mapping of Study Day Ranges to Week for Vital Signs and Weight 
 
Windowing Period 
Study Day Range  
(Relative to First Dose) 
Week 
Pretreatment 
Day ≤1a 
0 
Treatment 
2 ≤ Day ≤ 20 
2 
Treatment 
21 ≤ Day ≤ 31 
4 
Treatment 
32 ≤ Day ≤ 66 
7 
Treatment 
67 ≤ Day ≤ 104 
12 
Treatment 
105 ≤ Day ≤ 140 
18 
 
Day Relative to 14 Days After Last Dose 
 
Post-Treatment 
Day ≤ 999c 
4 
a:  All assessments performed on the same date as the date of first dose were to be performed prior to dosing; 
results from these assessments will be regarded as Pretreatment values in the analyses. 
b:  Measurements must have been taken during the treatment duration, ie, within 14 days of the day of last dose, 
to be included in analyses as on-treatment assessments. 
c:   Measurements must have been taken more than 14 days after the day of last dose to be included in analyses 
as Post-treatment assessments. Target day is 28 days after last dose or Post-treatment Week 4. 
 
It should be noted that for the post-treatment duration, the study week window is defined relative 
to the last dose, rather than to the first dose. 
Table 3:  Mapping of Study Day Ranges to Week for Laboratory Assessments 
 
Windowing Period 
Study Day Range  
(Relative to First Dose) 
Week 
Pretreatment 
Day ≤1a 
0 
Treatment 
2≤ Day ≤ 76 
4 
Treatment 
77≤ Day ≤ 140 
18 
 
Day Relative to 14 Days After Last Dose 
 
Post-Treatment 
Day ≤ 999c 
4 
a:  All assessments performed on the same date as the date of first dose were to be performed prior to dosing; 
results from these assessments will be regarded as Pretreatment values in the analyses. 
b:  Measurements must have been taken during the treatment duration, ie, within 14 days of the day of last dose, 
to be included in analyses as on-treatment assessments. 
c:   Measurements must have been taken more than 14 days after the day of last dose to be included in analyses 
as Post-treatment assessments. Target day is 28 days after last dose or Post-treatment Week 4. 
 


 
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8.2.3 Handling of Replicate Data 
A subject having an AE coded to the same preferred term more than once during the study will be 
counted only once in the incidence calculations for that AE. Similarly, if a subject has more than 
one AE in a single body system, the incidence will be counted only once for that body system. If 
a subject has the same AE more than once, the occurrence that is of greatest severity will be used 
in the calculation of the incidence of individual AE by severity. Similarly, the AE considered most 
closely related to study drug will be used in the calculation of incidence of individual AE by 
relationship. 
 
If the subject has taken the same concomitant medication (as coded to preferred WHO-drug term) 
more than once, the subject will be counted only once in the tabulation. 
9 PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS. 
11 MOCK TABLES, LISTINGS AND GRAPHS 
The study table, listing and graph (TLG) shells will be provided in a separate document, which 
will show the content and format of all tables, listings, and graphs in detail. 
12 REFERENCES 
Conover, W. J. and Iman, Ronald L. Analysis of Covariance Using the Rank Transformation. 
Biometrics, Vol. 38, No. 3, Special Issue: Analysis of Covariance (Sep., 1982), pp. 715- 724.  
 
Hodges, J. L., Jr. and Lehmann, E. L. (1963). Estimates of location based on rank tests, The 
Annals of Math. Statistics, 34, 598-611. 


 
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13 APPENDICES 
13.1 Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results  
The following table is of Sponsor’s Grading for Laboratory Values from the version in the 
protocol, Appendix 1. 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
< LLN – 10.0 g/dL 
< LLN – 100 g/L 
< LLN – 6.2 mmol/L 
< 10.0 – 8.0 g/dL 
< 100 – 80 g/L 
< 6.2 – 4.9 mmol/L  
< 8.0 g/dL 
< 80 g/L 
< 4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; 
urgent 
intervention 
indicated 
Leukocytes (total WBC) 
< LLN – 3.0 x 109/L 
< LLN – 3000/mm3  
< 3.0 – 2.0 x 109/L 
< 3000 – 2000/mm3  
< 2.0 – 1.0 x 109/L 
< 2000 – 1000/mm3  
< 1.0 x 109/L 
< 1000/mm3  
Lymphocytes  
• 
2-6 years old 
 
• 
7-12 years old 
 
• 
12 years or older 
 
 
NA 
 
NA 
 
< LLN – 800/mm3  
< LLN – 0.8 x 109/L 
 
 
NA 
 
NA 
 
< 800 – 500/mm3 
< 0.8 – 0.5 x 109/L 
 
 
NA 
 
NA 
 
< 500 – 200/mm3  
< 0.5 – 0.2 x 109/L 
 
 
NA 
 
NA 
 
< 200/mm3 
< 0.2 x 109/L 
Neutrophils  
< LLN – 1.5 x 109/L 
< LLN – 1500/mm3  
< 1.5 – 1.0 x 109/L 
< 1500 – 1000/mm3 
< 1.0 – 0.5 x 109/L 
< 1000 – 500/mm3  
< 0.5 x 109/L 
< 500/mm3  
Platelets 
< LLN – 75.0 x 109/L 
< LLN – 75,000/mm3  
< 75.0 – 50.0 x 109/L 
< 75,000 – 50,000/mm3  
< 50.0 – 25.0 x 109/L 
< 50,000 – 25,000/mm3 
< 25.0 x 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 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
ALT, SGPT (serum glutamic 
pyruvie transaminase) 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
AST, SGOT (serum glutamic 
oxaloacetic transaminase) 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
Bicarbonate, serum-low  
< LLN – 16 mEq/L 
< 16 – 11 mEq/L 
<11 – 8 mEq/L 
< 8 mEq/L  
Bilirubin (hyperbilirubinemia) 
> ULN – 1.5 x ULN  
> 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x ULN  
> 10.0 x 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 x ULN 
> 1.5 – 3.0 x ULN 
> 3.0 – 6.0 x ULN 
> 6.0 x ULN 
GGT (γ-Glutamyl transpeptidase)  
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x 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 


 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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 
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 
NA 
< 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  
NA 
> 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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SIGNATURE PAGE 
Author: 
 
 
Neurology Business Group 
Eisai Product Creation Systems 
Eisai Ltd. 
 
 
[electronic signature in eDMS]  
Signature 
Date:  ______________ 
 
Approval 
Biostatistics: 
 
 
 
Neurology Business Group 
Eisai Product Creation Systems 
Eisai Inc. 
 
[electronic signature in eDMS] 
Signature 
Date: ________________ 
Study Director: 
 
 
Neurology Business Group 
Eisai Product Creation Systems 
Eisai Inc. 
 
[electronic signature in eDMS] 
Signature 
Date: ________________ 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E2007-G000-338 (Extension) 
Study Protocol 
Title: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial 
With an Open-Label Extension Phase of Perampanel as Adjunctive 
Treatment in Subjects at Least 2 years of Age With Inadequately 
Controlled Seizures Associated With Lennox-Gastaut Syndrome 
Date: 
19 August 2021. 
Version: 
Final 1.0 


 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS 
2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
4 
3 
INTRODUCTION 
5 
3.1 
Study Objectives 
5 
3.1.1 
Primary Objective 
5 
3.1.2 
Secondary Objectives 
5 
3.1.3 
Exploratory Objectives 
6 
3.2 
Overall Study Design and Plan 
6 
4 
DETERMINATION OF SAMPLE SIZE 
7 
5 
STATISTICAL METHODS 
7 
5.1 
Study Endpoints 
7 
5.1.1 
Primary Endpoint 
7 
5.1.2 
Secondary Endpoints 
7 
5.1.3 
Exploratory Endpoints 
8 
5.1.4 
Definitions of Analysis Sets 
9 
5.1.5 
Subject Disposition 
9 
5.1.6 
Protocol Deviations 
9 
5.1.7 
Demographic and Other Baseline Characteristics 
9 
5.1.8 
Prior and Concomitant Therapy 
9 
5.1.9 
Treatment Compliance 
10 
5.2 
Data Analysis General Considerations 
10 
5.2.1 
Pooling of Centers 
10 
5.2.2 
Adjustments for Covariates 
10 
5.2.3 
Multiple Comparisons/Multiplicity 
10 
5.2.4 
Examination of Subgroups 
10 
5.2.5 
Handling of Missing Data, Drop-outs, and Outliers 
10 
5.2.6 
Other Considerations 
11 
5.3 
Efficacy Analyses 
11 
5.3.1 
Pre-Perampanel Baseline Analysis 
11 
5.4 
Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic/Pharmacogenetic Analyses 
12 
5.5 
Safety Analyses 
12 
5.5.1 
Extent of Exposure 
12 
5.5.2 
Adverse Events 
12 
5.5.2.1 
Deaths, Other Serious Adverse Events, and Other 
Significant Adverse Events 
13 
5.5.3 
Laboratory Values 
14 
5.5.4 
Vital Signs 
14 
5.5.5 
Electrocardiograms 
14 
5.5.6 
Other Safety Analyses 
14 
5.5.6.1 
C-SSRS 
14 
5.6 
Other Analyses 
14 


 
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5.6.1 
 
14 
5.7 
Exploratory Analyses 
14 
6 
INTERIM ANALYSES 
14 
7 
CHANGES IN THE PLANNED ANALYSES 
14 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
15 
8.1 
EFFICACY DATA HANDLING 
15 
8.1.1 
Baseline Seizure Frequency 
15 
8.1.2 
Treatment Duration for Efficacy Analyses. 
15 
8.1.3 
Seizure Frequency Formulae 
15 
8.2 
SAFETY DATA HANDLING 
15 
8.2.1 
Baseline safety 
15 
8.2.2 
Treatment Duration for Safety Analyses 
15 
8.2.3 
Handling of Replicate Data 
16 
9 
PROGRAMMING SPECIFICATIONS 
16 
10 
STATISTICAL SOFTWARE 
16 
11 
MOCK TABLES, LISTINGS AND GRAPHS 
16 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Term 
AE 
adverse event 
AED 
antiepileptic drug 
BMI 
body mass index 
CRF 
case report form 
FAS 
full analysis set 
LGS 
Lennox-Gastaut Syndrome 
LLT 
lower level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
preferred term 
PP  
per protocol  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SI 
Système International 
SOC  
system organ class  
TEAE 
treatment-emergent adverse event 
TLG 
tables, listings, and graphs 
 


 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for the Extension Study of Eisai Protocol 
E2007-G000-338.  
3.1 
STUDY OBJECTIVES 
3.1.1 Primary Objective 
The primary objective of the study is to demonstrate that perampanel given as adjunctive anti-
epileptic treatment is superior compared to placebo in reducing the incidence of drop seizures 
during 18 weeks of treatment in subjects with inadequately controlled seizures associated with 
Lennox-Gastaut Syndrome (LGS) 
3.1.2 Secondary Objectives 
1. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in reducing the incidence of all seizures during 18 weeks of treatment in subjects 
with inadequately controlled seizures associated with LGS 
 
2. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in the 50%, 75%, and 100% responder rates for drop seizures during 12 weeks of 
the Maintenance Period in subjects with inadequately controlled seizures associated with 
LGS 
 
3. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in the 50%, 75%, and 100% responder rates for total seizures during 12 weeks of 
the Maintenance Period in subjects with inadequately controlled seizures associated with 
LGS 
 
4. To demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to 
placebo in reducing the incidence of non-drop seizures during 18 weeks of treatment in 
subjects with inadequately controlled seizures associated with LGS 
 
5. To evaluate the 50%, 75%, and 100% responder rates in non-drop seizure frequency in the 
Maintenance Period  
 
6. To evaluate physicians’ global evaluation of subjects’ overall changes in symptoms 
 
7. To evaluate the safety of perampanel relative to placebo as adjunctive therapy in subjects 
with inadequately controlled seizures associated with LGS during both the Core Study and 
the Extension Phase 
 
8. To evaluate the pharmacokinetics and the pharmacokinetic/pharmacodynamic (PK/PD) 
relationships of perampanel as adjunctive therapy in subjects with inadequately controlled 
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3.1.3 Exploratory Objectives 
 
 
3.2 
OVERALL STUDY DESIGN AND PLAN 
 
Extension A consisted of 3 periods: 6-week Conversion, 46-week Maintenance, and 4-week 
Follow-up (except for subjects who planned to enter into Extension B). Extension A was to last 
approximately 52 weeks overall, or until such time that perampanel was made commercially 
available or accessible to subjects via an EAP if activated in the country in which they reside, 
whichever happened sooner.  
During the Conversion Period, subjects who received perampanel during the Core Study were to 
continue receiving perampanel in a blinded manner at the same dose last received during the Core 
Maintenance Period. Subjects who received placebo during the Core Study were to begin treatment 
with perampanel in a blinded manner, following the same dosing regimen and titration schedule 
as that in the Core Study, starting at 2 mg/day and would then be up-titrated to the optimal dose 
per the investigator’s discretion, not to exceed a maximum dose of 8 mg/day. 
After the double-blind Conversion Period, subjects could be titrated up to 12 mg/day (except in 
Japan, where the maximum allowed dose remained at 8 mg/day), at 2-week intervals per the 
investigator’s discretion. Addition, deletion, and dose changes to the concomitant AEDs were 
allowed during Extension Maintenance Period.  
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The dosing schedule for Extension A is summarized in Table 7 of the protocol. 
 
An overview of the study design is presented in Figure 1 of the protocol. 
 
 
4 
DETERMINATION OF SAMPLE SIZE 
 
There was no a priori determination of sample size for the extension phase of the study. The 
number of subjects was determined by the number who completed the Core Study and who chose 
to enrol into Extension A.  
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. 
In general, the scope of endpoints and analyses will include the entirety of perampanel exposure 
(Core and Extension A).  
5.1 
STUDY ENDPOINTS 
5.1.1 Primary Endpoint 
The primary efficacy endpoint will be the median percent change in drop seizure frequency per 
28 days during double-blind treatment (Titration Period and Maintenance Period) relative to the 
Prerandomization Phase in the Full Analysis Set (FAS). 
5.1.2 Secondary Endpoints 
The following key secondary endpoints will be evaluated sequentially using the FAS: 
 
1. Median percent change in total seizure frequency per 28 days during double –blind 
treatment (Titration Period and Maintenance Period) relative to the Prerandomization 
Phase. 
 
2. The 50% responder rate in the Maintenance Period of the double-blind treatment relative 
to the Prerandomization Phase for drop seizures 
 
3. The 50% responder rate in the Maintenance Period of the double-blind treatment relative 
to the Prerandomization Phase for total seizures. 
 
Other secondary endpoints are: 
 
4. Median percent change in non-drop seizure frequency per 28 days during double-blind 
treatment (Titration Period and Maintenance Period) relative to the Prerandomization 
Phase 


 
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5. Proportion of subjects with 75%, and 100% responder rates for drop, non -drop, and total 
seizures in the Maintenance Period relative to the Prerandomization Phase 
 
6. Proportion of subjects with 50% responder rate in the Maintenance Period of the 
doubleblind treatment relative to the Prerandomization Phase for non-drop seizures 
 
7. Physicians’ global evaluation of the subject’s overall changes in symptoms (using a 
7-point Likert scale with 1=very much improved and 7=very much worse) at the end of the 
double-blind treatment 
 
8. Incidence of AEs and SAEs, changes in clinical laboratory values, and vital signs 
 
9. Model-derived average perampanel concentrations at steady state (Cav,ss) during the 
Maintenance Period of the Core Study 
5.1.3 Exploratory Endpoints 
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5.1.4 Definitions of Analysis Sets 
The Safety Analysis Set (Extension) is the group of subjects who entered into the Extension and 
received at least one dose of perampanel and had at least one post-perampanel safety assessment. 
 
The Full Analysis Set (Extension) is the group of subjects who entered into the Extension and 
received at least one dose of perampanel and had at least one post-perampanel seizure 
measurement. 
 
5.1.5 Subject Disposition 
The disposition of all subjects with respect to Extension A and B will be summarized for all 
enrolled subjects. Subject disposition summaries will present the number (percentage [%]) of 
subjects who had discontinued or completed, and the primary reason for discontinuation.   
5.1.6 Protocol Deviations 
Not applicable.  
5.1.7 Demographic and Other Baseline Characteristics 
 Demographic and other baseline characteristics for the Safety Analysis Set (Extension) will be 
summarized.   
Continuous demographic and baseline variables include age, weight, height and body mass index 
(BMI); categorical variables include sex, age group (2-<12, 12-<18, 18-<65, ≥65), race and 
ethnicity. 
Age is recorded at date of informed consent.  
MEDICAL HISTORY 
Epilepsy-specific medical history, including time since diagnosis and seizure type will be 
summarized for the Safety Analysis Set (Extension) using descriptive statistics. 
5.1.8 Prior and Concomitant Therapy 
The number of baseline AEDs will be summarized and a summary of baseline AEDs will be 
produced. A baseline AED is an AED taken at the date of randomization to the Core Study.  
Other Prior and Concomitant Therapy will be listed.  
 
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5.1.9 Treatment Compliance 
Investigator assessment of compliance, as recorded on the e-CRF at each visit, will be listed. 
 
5.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
5.2.1 Pooling of Centers  
There will be no pooling of centers.  
5.2.2 Adjustments for Covariates 
No models will be fitted to the data hence there will be no adjustments for covariates. 
5.2.3 Multiple Comparisons/Multiplicity 
As no P-values will be reported, there will be no multiplicity issues.  
5.2.4 Examination of Subgroups 
All summaries will be presented by the following age groups and overall: 2-<12years, 12-<18 
years, 18-<65 and 65 years and above.  
5.2.5 Handling of Missing Data, Drop-outs, and Outliers 
A conservative principle will be used for an AE with missing date(s) to determine if it is treatment-
emergent, that is, if there are missing or partially missing AE start and/or stop dates, and it cannot 
be determined definitively whether an AE started during the perampanel treatment duration, it will 
be assumed that the AE was treatment-emergent.   
 
If the day and month are missing, events will be considered treatment-emergent if the year is equal 
to or after the year of the first dose date; if days are missing, events will be considered treatment-
emergent if the year is after the year of the first dose, or if the year is equal to the year of the first 
dose date and the month is equal to or after the month of the first dose date.  A similar principle 
will be used for a medication with missing date(s).  If there are missing or partially missing 
medication start and/or stop dates, and it cannot be determined definitely whether a medication 
was taken concomitantly with perampanel, it will be assumed that the medication is concomitant.  
A detailed algorithm to impute missing dates is given in the programming specifications.  
 
For the purpose of summarizing maximum severity, if the severity of an adverse event (AE) is 
missing for a subject, then, if this subject has another AE with the same preferred term that has 
“severe” severity, the maximum severity of the AE will be noted as “severe’; otherwise the 
maximum severity will be noted as missing.  Similarly, for the purpose of summarizing closest 
relationship, if the relationship of an AE to study drug is missing, the AE will be noted to be 
probably related if there is another probably related AE with the same preferred term, otherwise 
this relationship will be noted as missing.  
 
No special handling of missing data is planned for the analysis of any of the other safety variables. 
 
All the listings will display the original missing values.  


 
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5.2.6 Other Considerations 
A subject who has an AE coded to the same preferred term more than once during perampanel 
treatment will be counted only once in calculations for that AE.  Similarly, if a subject has more 
than one AE in a system organ class (SOC), the incidence will be counted only once for that SOC.  
If a subject has the same AE more than once, the occurrence that is of greatest severity will be 
used in the calculation of the incidence of individual AE by severity.  Similarly, the AE considered 
most closely related to open-label treatment will be used in the calculation of incidence of 
individual AE by relationship.  
If no seizure diary data is observed during a period, then the seizure frequency per 28 days for that 
period will be set to missing.  Missing diary data should not be interpreted as equivalent to a non-
missing record of zero.  
5.3 
EFFICACY ANALYSES 
Seizure frequency for a given seizure type (or overall) for any given interval will be based on the 
number of seizures of that particular type (or overall) recorded over the given interval based only 
on “days with a valid seizure count,” and rescaled to a 28-day window, calculated as the number 
of seizures over the time interval, multiplied by 28, and divided by the number of “days with a 
valid seizure count” in the interval.  A “valid day” is defined as the day where seizure counts 
information is present, that is, either a record with an answer of ‘No’ to the question ‘Did the 
subject experience any seizures?’ or a positive number of seizures for at least one of the seizure 
types collected. “Valid seizure counts” are the seizure counts that are read from the valid seizure 
days. 
 
The baseline for a given seizure type (or total) is defined as the seizure frequency per 28 days of 
the given type (or total) based on all valid seizure diary data dated before the first dose date of 
perampanel. Although driven by first dose date and not time periods, this means that for subjects 
randomized to perampanel in the Core Study, baseline will be based on all valid seizure diary data 
occurring during the Core Study baseline period whereas baseline for subject randomized to 
placebo in the Core Study will be based on all valid seizure diary data from the Core Study prior 
to the first dose in the Extension Phase.  
 
The perampanel treatment duration for efficacy analyses consists of (a) the Randomization Phase 
of the Core Study plus the Extension Phase A for subjects randomized to the perampanel treatment 
arm during the Core Study, or (b) the Extension Phase A for subjects randomized to placebo 
treatment during the Core Study.  
 
5.3.1 Pre-Perampanel Baseline Analysis 
The following analyses will be conducted for drop, non-drop and total seizures using the Full 
Analysis Set (Extension): 
• Median percentage change in seizure frequency per 28 days from baseline over the entire 
perampanel treatment duration. 


 
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• Proportion of subjects with ≥50%,  ≥75%, and 100% response for the perampanel treatment 
duration. 
Efficacy endpoints will be summarised in 13-week intervals and overall.  
For summaries by 13-week intervals a subject needs at least 1 day of seizure frequency data in 
a 13-week interval to be included in the summary for the overall perampanel treatment 
duration. To be counted as seizure-free, they would need to have completed the time interval.  
 
5.4 
Pharmacokinetic, Pharmacodynamic, and PHARMACOGENOMIC/PHARMACOGENETIC 
ANALYSES 
Not applicable. 
5.5 
SAFETY ANALYSES 
All safety analyses will be performed on the  Safety Analysis Set (Extension).  Treatment-emergent 
adverse events will be summarized. The incidence of on treatment suicidality as measured by the 
C-SSRS will be summarized.   Clinical laboratory parameters and  vital signs data will be listed. 
Study Day 1 for all safety analyses is defined as the date of the first dose of perampanel. 
5.5.1 Extent of Exposure 
Total perampanel exposure will be calculated as the number of days between the date the subject 
received the first dose of perampanel (from Core Study or Extension Phase ) and the date the 
subject received the last dose of study drug in Extension Phase (A or B).  
 
The mean, modal, median, maximum and last daily dose over the conversion, extension 
maintenance (A+B), overall extension and overall perampanel treatment duration will be 
summarized..  The mean daily dose will be calculated by taking the average of all the doses taken 
weighted by the total duration of exposure and rounded to 1 decimal place.  
 
5.5.2 Adverse Events 
Adverse events will be addressed with respect to the Safety Analysis Set (Extension).  
 
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) will also be captured in the database. 
 
A TEAE is defined as an AE that emerged during treatment, having been absent at pre-treatment 
(Baseline) or 
 
●Re-emerged during treatment, having been present at pre-treatment (Baseline) but 
stopped before treatment, or 


 
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●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. 
 
For subjects randomized to the perampanel treatment group in the Core Study, the first dose date 
of perampanel is from the Core Study.  For subjects randomized to placebo in the Core study, the 
first dose date of perampanel is from the Extension Phase  
 
TEAEs will be summarized.  The incidence of TEAEs will be reported as the number (percentage) 
of subjects with TEAEs by PT and decreasing frequency.  A subject will be counted only once 
within a PT, even if the subject experienced more than one TEAE within a specific PT. 
Treatment-related TEAEs will also be summarized.  
 
5.5.2.1  Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
 
A listing of deaths will be produced.  
 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) will 
be listed and summarized by MedDRA PT and decreasing frequency.  
 
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug will 
be listed and summarized by MedDRA PT and decreasing frequency  
 
Standardized MedDRA Query (SMQ) will be used to identify relevant terms for the following 
TEAEs. All of these TEAEs will be summarized by narrow terms. 
 
• TEAEs suggestive of abuse potential: SMQ of drug abuse, dependence and withdrawal 
• TEAEs related to alertness and cognition: SMQ of dementia 
• TEAEs related to hostility/aggression: SMQ of hostility/aggression 
• TEAEs related to psychosis and psychotic disorder: SMQ of psychosis and psychotic disorders 
• TEAEs related to status epilepticus/convulsions: SMQ of convulsions 
• TEAEs related to drug related hepatic disorder abnormalities: SMQ of dryg-related hepatic 
disorders 
• Cardiac and electrocardiogram (ECG) TEAEs: SMQs of cardiac arrhythmia terms (including 
bradyarrhythmias and tachyarrhytmias, arrhythmia related investigations, signs and symptoms, 
cardiac failure, cardiomyopathy, ischaemic heart diseases, and Torsade de pointes/QT 
prolongation 
• Rash: SMQ of severe cutaneous adverse reactions and hypersensitivity 


 
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5.5.3 Laboratory Values 
Laboratory results will be listed.  
 
5.5.4 Vital Signs 
Vital signs data will be listed.  
 
5.5.5 Electrocardiograms 
ECG was not obtained during the extension. 
 
5.5.6 Other Safety Analyses 
5.5.6.1 C-SSRS 
 
The following summary will be presented for the treatment duration (defined as the period from  
the date of first dose up to 28 days after the date of last dose, inclusive) . 
Number (percentage) of subjects with any treatment-emergent report of suicidal behavior, suicidal 
ideation, and suicidality (suicidal behavior and/or ideation) will be displayed.  A treatment-
emergent report of suicidal behavior, suicidal ideation, or suicidality is an answer of ‘Yes’ to any 
question in the respective category during the treatment duration. 
 
5.6 
OTHER ANALYSES 
Not applicable. 
 
5.6.1 
 
  
 
5.7 
EXPLORATORY ANALYSES 
There will be no exploratory analysis.  
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
7 
CHANGES IN THE PLANNED ANALYSES 
Limited data summaries are being produced due to the early termination of the study.  Any future 
changes to the analysis will be documented separately and will be addressed in the Clinical Study 
Report. 
CCI
CCI


 
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8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
EFFICACY DATA HANDLING 
8.1.1 Baseline Seizure Frequency 
For the summaries of overall perampanel treatment duration, all diary data before the first 
perampanel dose date will be used in the computation of the baseline seizure frequency per 28 
days.  For subjects assigned to perampanel treatment during the Core Study, baseline will be 
computed from the Prerandomization Phase of the Core study.  For subjects assigned to placebo 
treatment during the Core Study, baseline would be computed from data during the Core Study 
plus the Prerandomization Phase of the Core Study.  
8.1.2 Treatment Duration for Efficacy Analyses. 
 
The treatment duration for diary seizure data are defined as follows: 
• The date of first perampanel dose during the Core Study to the last perampanel dose during 
the Extension Phase A for subjects assigned to perampanel treatment during the Core 
Study. 
 
• The date of first to last perampanel dose during Extension Phase A for subjects assigned to 
placebo treatment during the Core Study. 
 
 
8.1.3 Seizure Frequency Formulae 
 
The following formula will be used to estimate the “seizure frequency per 28 days” period for each 
subject, where “Y” is the number of days with valid diary data for that period: 
Seizure frequency = Number of seizures of type(s) of interest (captured over Y days) x 28/Y days. 
8.2 
SAFETY DATA HANDLING 
8.2.1 Baseline safety 
The baseline value for all safety endpoints will be the last non-missing measurement occurring 
prior to the first dose of perampanel. 
 
8.2.2 Treatment Duration for Safety Analyses 
 
For AEs, the perampanel treatment duration is considered to begin: 
• at the first dose of perampanel in the Core Study and ends 28 days after the last dose of 
perampanel in Extension Phase A for subjects assigned to perampanel treatment during 
the Core Study 
• at the date of first perampanel dose to 28 days after the last dose of perampanel in 
Extension Phase A for subjects assigned to placebo treatment during the Core Study.  


 
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The Post-treatment duration will begin on the day after the permapanel treatment duration during 
Extension Phase A.  
 
AEs for the subject were collected and reported on the CRF starting from the time subject signed 
informed consent to the last visit in the Treatment Phase following subject’s last dose.  Serious 
AEs were collected for 28 days after the last dose. 
 
 
8.2.3 Handling of Replicate Data 
A subject having an AE coded to the same preferred term more than once during the study will be 
counted only once in the incidence calculations for that AE.  Similarly, if a subject has more than 
one AE in a single body system, the incidence will be counted only once for that body system.  If 
a subject has the same AE more than once, the occurrence that is of greatest severity will be used 
in the calculation of the incidence of individual AE by severity.  Similarly, the AE considered most 
closely related to study drug will be used in the calculation of incidence of individual AE by 
relationship. 
 
9 PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS. 
11 MOCK TABLES, LISTINGS AND GRAPHS 
The study table, listing and graph (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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SIGNATURE PAGE 
Author: 
 
 
Neurology Business Group 
Eisai Product Creation Systems 
Eisai Europe Ltd. 
 
 
[electronic signature in eDMS]  
Signature 
Date:  ______________ 
 
Approval 
Biostatistics: 
 
 
 
Neurology Business Group 
Eisai Product Creation Systems 
Eisai Inc. 
 
 
[electronic signature in eDMS] 
Signature 
Date: ________________ 
Study Director: 
 
 
Neurology Business Group 
Eisai Product Creation Systems 
Eisai Inc. 
 
[electronic signature in eDMS] 
Signature 
Date: ________________ 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD