Clinical trial NCT03201900
Conditions: Partial Onset Seizures
Keywords: perampanel
Sponsor: Eisai Co., Ltd.
Start date: 2017-06-28; Completion date: 2020-07-27
Enrollment: 91 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is conducted to evaluate the seizure-free rate of the 26-week Maintenance Period in untreated participants with partial onset seizures (POS).

Detailed description:

Arms: arm 1: The Treatment Phase consists of the 4 milligrams (mg) Treatment Phase (the Titration Period \[6 weeks\] and the Maintenance Period \[26 weeks\]) and the 8 mg Treatment Phase (the Titration Period \[4 weeks\] and the Maintenance Period \[26 weeks\]) if participants require a higher dose. In the 4 mg Titration Period (6 weeks), participants will initiate 2 mg perampanel once daily (QD) for 2 weeks and then will be up-titrated to 4 mg QD and will continue this dose for 4 weeks. If participants have no safety issues at the end of the Titration Period, they will start the 4 mg Maintenance Period for 26 weeks. Participants will only need the higher dose if they are having seizures. In the 8 mg Titration Period (4 weeks), participants will be administered 6 mg perampanel QD for 2 weeks and then will be up-titrated to 8 mg QD and will continue this dose for 2 weeks. If participants have no safety issues at the end of the Titration Period, they will start the 8 mg Maintenance Period for 26 weeks.
Interventions: intervention 1: E2007
Intervention descriptions: intervention 1: Oral tablet

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol
E2007-J000-342
Eisai
Final:  v7.0, 31 Oct 2019
Confidential
Page i of iv
Revision History 
Revisions to Version v6.0
New version/date:  Version 7.0/31 Oct 2019 
Change
Rationale
Affected Protocol Section(s)
Extended the study period
To continue the study until
perampanel monotherapy 
is available in Korea.
Synopsis – Study Period and 
Phase of Development
Revisions to Version v5.0
New version/date:  Version 6.0/22 Feb 2019 
Change
Rationale
Affected Protocol Section(s)
Added “End of Study visit” and 
related 
description 
including 
procedure, 
measurement 
and 
schedule 
Clarification
Synopsis – Study Design
Section 9.1
Section 9.1.3 Extension phase
Section 9.1.4 Follow-up phase
Section 9.5.2 – Table 5
Revisions to Version v4.0
New version/date:  Version 5.0/05 Jul 2018 
Change
Rationale
Affected Protocol Section(s)
Added “Analysis at primary 
endpoint achievement”
To conduct analysis if the 
primary endpoint is 
achieved. 
Section 9.7.1.6.4
Revisions to Version v3.0
New version/date:  Version 4.0/21 Feb 2018 
Change
Rationale
Affected Protocol Section(s)
Added “Study drug compliance” 
and “Return unused medication” at 
Visit 2a
To correct an error/missing 
items in table 4
Section 9.5.2 – Table 4
Revised footnote “e”, such that at 
Visit 4a, if a subject is down-
titrated to 6 mg due to 
intolerability after up-titrated to 8 
mg, the subject will enter the 
Maintenance Period with 6 mg.  
Removed extra words “and remain 
seizure free ” due to a mistake in 
writing
To correct an error, to keep 
a consistency
Section 9.5.2 – Table 4


Clinical Study Protocol
E2007-J000-342
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Final:  v7.0, 31 Oct 2019
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Revisions to Version v3.0
New version/date:  Version 4.0/21 Feb 2018 
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, and 
formatting changes were also 
made.
Document quality. 
Throughout the document
Revisions to Version v2.0
New version/date:  Version 3.0/04 Dec 2017 
Change
Rationale
Affected Protocol Section(s)
Correct the name of ICH
To correct typographic
error
Title page – GCP statement
Investigator signature page
Added the exclusion criteria #24, 
for subject who is diagnosed with 
dementia
To clarify that dementia 
patients are “not eligible” 
in this study.
Synopsis – Exclusion Criteria 
Section 9.3.2 
Added antidementia drugs in 
prohibited concomitant therapy
To clarify that concomitant 
use of antidementia drug is 
prohibited.
Synopsis – Prohibited 
concomitant drugs 
Section 9.4.7.1.1
Expanded the prohibited 
concomitant therapy to 
neuromodulation therapy 
(including vagal nerve stimulation 
[VNS] and transcranial magnetic 
stimulation)
To clarify that concomitant 
neuromodulation therapy
without limiting VNS is 
prohibited.
Synopsis – Prohibited 
concomitant therapy 
Section 9.4.7.1.2
Removed “eg.”  from the text of 
Urine Drug Test
To correct typographic 
error
Section 9.5.1.2.3
Revisions to Version v1.0
New version/date:  Version 2.0/05 Jul 2017
Change
Rationale
Affected Protocol Section(s)
Correct the name of ICH
To correct typographic
error
Title page – GCP statement
List of abbreviations and 
definitions of terms
Section 5.1
Section 5.2
Investigator signature page
Revised the text for subject 
discontinuation at extension phase, 
such that if subjects need to take 
To clarify the description 
of the subject 
Section 9.1.3


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Final:  v7.0, 31 Oct 2019
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Revisions to Version v1.0
New version/date:  Version 2.0/05 Jul 2017
Change
Rationale
Affected Protocol Section(s)
other antiepileptic drugs (AEDs) or 
withdraw perampanel because of 
insufficient efficacy or tolerability 
issue of perampanel by the 
investigator’s judgement, they will 
discontinue the study
discontinuation at 
extension phase 
Revised the exclusion criteria #9, 
such that evidence of clinically 
significant active hepatic disease
To correct miss description 
on the exclusion criteria #9 
assuming add-on therapy 
with concomitant enzyme-
inducer drug(s).
Section 9.3.2
Revised the exclusion criteria #15, 
such that subjects who have used 
intermittent rescue medication on 2 
or more occasions within 4 weeks 
before the pretreatment phase
To clarify the exclusion 
criteria for previous use of 
intermitted rescue 
medication (not limited to 
benzodiazepines)
Section 9.3.2
Added the text “and return unused 
medication” in footnote “c” for
when a taper is provided after 
discontinuation in  follow-up phase
To correct an error/missing 
items in table 3
Section 9.5.2 – Table 3
Added the text “in case of the local 
laboratory analysis, the 
measurement of bicarbonate and 
magnesium are not mandatory at 
visit 1, and after that should be 
conducted as scheduled” in 
footnote “i”
To correct an error/missing 
items in table 3
Section 9.5.2 – Table 3
Added the footnote “p” that if a 
taper is decided based on the 
judgment of the investigator, 
dispensing the study drug should 
be needed at early discontinuation 
visit
To correct an error/missing 
items in table 3
Section 9.5.2 – Table 3
Added early transition visit with
required procedures/assessments 
To correct an error/missing 
items in table 4
Section 9.5.2 – Table 4
Added the footnote “k” that the 
visit for transition from the 8 mg 
treatment phase to the extension 
phase before completion of the 8 
mg treatment phase at early 
transition visit
To correct an error/missing 
items in table 4
Section 9.5.2 – Table 4


Clinical Study Protocol
E2007-J000-342
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Final:  v7.0, 31 Oct 2019
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Page iv of iv
Revisions to Version v1.0
New version/date:  Version 2.0/05 Jul 2017
Change
Rationale
Affected Protocol Section(s)
Added the footnote “j” that if a 
taper is decided based on the 
judgment of the investigator, 
dispensing the study drug should 
be needed at early discontinuation 
visit
To correct an error/missing 
items in table 4
Section 9.5.2 – Table 4
Added  the text “return unused 
medication” in footnote “c” for 
when a taper is provided after 
discontinuation in follow-up phase
To correct an error/missing 
items in table 4
Section 9.5.2 – Table 4
Added the footnote “a” on follow-
up phase to indicate that visit to be 
done within ±7 days of the 
schedule 
To correct an error/missing 
items in table 5
Section 9.5.2 – Table 5
Added the footnote “g” that if a 
taper is decided based on the 
judgment of the investigator, 
dispensing the study drug should 
be needed, for early 
discontinuation visit
To correct an error/missing 
items in table 5
Section 9.5.2 – Table 5
Added the text “Return unused 
medication is needed.” in the foot 
note “b”
To correct an error/missing 
items in table 5
Section 9.5.2 – Table 5
Added “Dispense subject diary” at
early discontinuation visit
To correct an error/missing 
items in table 5
Section 9.5.2 – Table 5
Revised the text for adverse events, 
such that a treatment-emergent 
adverse event (TEAE) is defined as 
an AE that emerges during time 
from the first dose of study drug to 
the last visit or 28 days after the 
subject’s last dose, whichever 
comes later.  
To correct typographic 
error
Section 9.7.1.8.2 – Adverse 
events
Removed extra text, such that 
descriptive statistics for ECG 
parameters and changes from 
baseline will be presented by visit
To correct an error/missing 
items in table 5
Section 9.7.1.8.5 –
Electrocardiograms


Clinical Study Protocol
E2007-J000-342
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2007-J000-342
Study Protocol 
Title:
A multicenter, uncontrolled, open-label study and extension study for 
verification of efficacy and safety for perampanel monotherapy in 
untreated patients with partial onset seizures (including secondarily 
generalized seizures)
Sponsor:
Eisai Co., Ltd. 
4-6-10 Koishikawa, 
Bunkyo-Ku, 
Tokyo 112 8088
JP
Investigational 
Product Name:
E2007/Fycompa® (perampanel)
Indication:
Partial onset seizures
Phase:
3
Approval Date:
V1.0
V2.0
V3.0
V4.0
V5.0
V6.0
V7.0
03 Apr 2017 (original protocol)
05 Jul 2017 (revised protocol)
04 Dec 2017 (revised protocol)
21 Feb 2018 (revised protocol)
05 Jul 2018 (revised protocol)
22 Feb 2019 (revised protocol)
31 Oct 2019 (revised protocol)
GCP Statement:
This study is to be performed in full compliance with International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) and all applicable local Good Clinical Practice (GCP) 
and regulations.  All required study documentation will be archived as 
required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or performing 
this study.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2007
Name of Active Ingredient:  Perampanel
Study Protocol Title
A multicenter, uncontrolled, open-label study and extension study for verification of efficacy and 
safety for perampanel monotherapy in untreated patients with partial onset seizures (including 
secondarily generalized seizures)
Sites
Japan and South Korea
Study Period and Phase of Development
Study Period: April 2017 to November 2020
Phase: Phase 3
Objectives
Primary Objective:

To evaluate the seizure-free rate of the 26-week Maintenance Period in untreated patients with 
partial onset seizures (POS) 
Secondary Objectives:

To evaluate the seizure-free rate of the 52-week treatment in untreated patients with POS

To confirm time to first seizure onset and time to withdrawal from the study from the first date of 
the Maintenance Period in untreated patients with POS

To evaluate the safety and tolerability of perampanel monotherapy in untreated patients with POS
Exploratory Objectives:

To investigate the seizure free-rate of the 26-week Maintenance Period by seizure type in 
untreated patients with POS

To investigate the percent change in seizure frequency from baseline during the Maintenance
Period and Extension Phase in untreated patients

To investigate the pharmacokinetics of perampanel as monotherapy

To evaluate the impact of perampanel over time (End of Treatment – Baseline) on overall health-
related quality of life as measured by the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L)
Study Design
This study will consist of 3 phases: Pretreatment Phase, Treatment Phase (Titration Period, 
Maintenance Period) and Extension Phase.
[Pretreatment Phase]
During the Pretreatment Phase (maximally 4 weeks), patients will be screened and be assessed for 
their eligibility to participate in the study.
[Treatment Phase]


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The Treatment Phase consists of the Titration Period and the Maintenance Period of 4 mg, and the 
Titration Period and the Maintenance Period of 8 mg, if subjects require higher dose.
[4 mg Titration and Maintenance Period]
In the 4 mg Titration Period (6 weeks), subjects will initiate 2 mg QD of perampanel for 2 weeks and 
then will be up-titrated to 4 mg QD and will continue for 4 weeks. If subjects have no safety issues at 
the end of the Titration Period, they will start the 4 mg Maintenance Period for 26 weeks.
If subjects experience seizures during the 4 mg Maintenance Period, the investigator will end the 
4 mg Maintenance Period and judge the transition to the 8 mg Titration Period based on the subject’s 
tolerability and safety.  If subjects could not continue 4 mg dosing due to intolerable adverse event 
during the 4 mg Maintenance Period, they will discontinue the study.
During the 2 weeks of Weeks 3 and 4 in the 4 mg Titration Period, if subjects are suspected to have 
tolerability issues for 4 mg dosing due to occurrence of adverse events, 2 mg QD can be administered
in accordance with the investigators’ discretion.  In that case, subjects will visit the investigational 
site via unscheduled visit within 4 weeks after starting study treatment and will be up-titrated to 4 mg 
QD (for subjects who has continued 4 mg QD, occurrence of AEs will be confirmed via telephone).  
All subjects will continue 4 mg QD during the 2 weeks of Weeks 5 and 6.  If subjects could not 
continue 4 mg QD due to intolerable adverse event, they will discontinue the study.  
[8 mg Titration and Maintenance Period]
In the 8 mg Titration Period (4 weeks), subjects will be administered 6 mg QD of perampanel for 
2 weeks and then will be up-titrated to 8 mg QD and will continue for 2 weeks.  If subjects have no 
safety issues at the end of the Titration Period, they will start the 8 mg Maintenance Period for 
26 weeks.  
If subjects don’t tolerate 8 mg administration of perampanel, they will be able to down-titrate to 6 mg 
in accordance with the investigators’ discretion. After the down-titration, subjects could continue the 
study with 6 mg QD.
If subjects experience the occurrence of seizures or could not continue 8 mg (or 6 mg) dosing due to
intolerable adverse event during the 8 mg Maintenance Period, they will end the Treatment Phase.
[Extension Phase]
When subjects complete the Treatment Phase and agree to continue receiving the perampanel 
monotherapy, they could enter the Extension Phase. Subjects who complete the 26-week 
Maintenance Period will continue the last dose of the Maintenance Period. Subjects who end the 
Treatment Phase due to insufficient efficacy or safety issue before the completion of the 26-week 
Maintenance Period will adjust their appropriate dose (within 4 – 8 mg of perampanel) and continue 
the Extension Phase. Subjects will be allowed to adjust within 2 – 8 mg of perampanel with 
investigators’ consideration for their condition of the seizures and/or tolerability. During whole study 
period, the maximum dose of perampanel is 8 mg QD.  The dose will be increased at intervals of 1
week or more in increments of 2 mg. 
If subjects need to take other antiepileptic drugs (AEDs) or withdraw perampanel because of 
insufficient efficacy or tolerability issue of perampanel by the investigator’s judgement, they will 
discontinue the study.
Once perampanel monotherapy is approved in each country, an End of Study Visit should be 
conducted promptly, and the subject would have to switch to the commercial product. If a subject 
does not switch to the commercial product promptly, an End of Study Visit and a Follow-up Visit 
should be conducted for the subject.


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Subjects who will finish or discontinue the study will conduct the follow-up visit 4 weeks after 
withdrawal of perampanel. Follow-up Visit is not required for subjects who will be switching to the 
commercial product and attend an End of Study Visit.
The study design is shown below.
Number of Subjects
Eighty subjects with POS who are untreated with any AED(s)
Inclusion Criteria
1.
Be considered reliable and willing to be available for the study period and are able to record 
seizures and report adverse events (AEs) himself/herself or have a caregiver who can record 
seizures and report AEs for them 
2.
Male or female aged between 12 and 74 years old
3.
Subjects who are newly diagnosed or recurrent epilepsy and have experienced at least 2 
unprovoked seizures separated by a minimum of 24 hours in the 1 year prior to the Pretreatment
Phase, of which, at least 1 unprovoked seizure (but below 20 seizures) occurred in the 12 weeks
prior to the Pretreatment Phase.  For subjects with recurrent epilepsy, they must have relapsed at 
least 2 years after the end of the last AED treatment. 
4.
Subjects who have excluded the progressive CNS abnormality occurring seizures by CT or MRI 
conducted within 1 year before the Pretreatment Phase
5. Subjects who have had a diagnosis of epilepsy with partial seizures with or without secondarily 
generalized seizures according to the International League Against Epilepsy (ILAE) 
Classification of Epileptic Seizures (1981). Diagnosis should have been established by clinical 
history and an electroencephalogram (EEG) that is consistent with localization-related epilepsy; 
normal interictal EEGs will be allowed provided that the subject meets the other diagnosis 
criterion (ie, clinical history).
Exclusion Criteria
Note:  In this protocol, 1 month refers to 28 days (4 weeks).  
1.
Subjects who present only simple partial seizures without motor signs
2 mg QD
4 mg QD
6 mg QD
8 mg QD*
Day 1 
Week6
Week2 
Week32
Day 1 
Week 4
Week 2 
Week 30
Primary 
endpoint
Primary 
endpoint
Extension Phase or 
Study  discontinuation
26 weeks
26 weeks
4 mg Titration Period
4 mg Maintenance Period
8 mg Titration Period
8 mg Maintenance Period
Seizure occur
Pretreatment 
Phase
Day -28
* If 8 mg is not tolerable, subjects will be down-titrated to 6 mg and continue the Maintenance Period
Seizure occur
Extension 
Phase
Extension 
Phase


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2.
Subjects who have seizure clusters where individual seizures cannot be counted
3.
Subjects who present or have a history of Lennox-Gastaut syndrome
4.
Subjects who have a history of status epilepticus within 1 year prior to Day 1 of the Treatment
Phase
5.
Subjects who have a history of psychogenic non-epileptic seizures within 5 years prior to Day 1 
of the Treatment Phase
6.
Subjects who have a history of suicidal ideation/attempt within 5 years prior to Day 1 of 
Treatment Phase
7.
Subjects who present clinically problematic psychological or neurological disorder(s)
8.
Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) 
that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the 
study assessments  
9.
Evidence of clinically significant active hepatic disease.
10. A prolonged QTcF interval (>450 ms [2 or 3 times]) as demonstrated by a repeated (3 times) 
electrocardiogram (ECG)
11. Subjects who have a history of receiving any AEDs (except for AEDs used as rescue treatment), 
antipsychotics or anti-anxiety drugs within 12 weeks prior to the Pretreatment Phase
12. Subjects who have not used a stable dose of antidepressant in the 12 weeks prior to the 
Pretreatment Phase, if they treat
13. Subjects who have a history of any type of surgery for brain or central nervous system within 
1 year prior to the Pretreatment Phase
14. Subjects who have a history of receiving any AED (including AED used as rescue treatment) for 
more than 2 weeks in total within 2 years prior to the Pretreatment Phase
15. Subjects who have used intermittent rescue medication on 2 or more occasions within 4 weeks
before the Pretreatment Phase (1 to 2 doses over a 24-hour period considered one-time rescue)
16. Subjects who have a history of receiving any AED polytherapy
17. Subjects who experienced treatment with perampanel
18. Subjects who have had non-constant ketogenic diet within 4 weeks before the Pretreatment Phase
19. Subjects who have a history of drug or alcohol dependency or abuse within the last 2 years before 
the Pretreatment Phase
20. Subjects who 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
21. Females who are breastfeeding or pregnant in the Pretreatment Phase (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] test)  
22. Females of childbearing potential who: 

Within 28 days before the start of the Pretreatment Phase, 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
a contraceptive implant


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o
an oral contraceptive (with additional barrier method) (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.
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.
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, bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before 
dosing).
23. Subjects who have participated in a study involving administration of an investigational drug or
device within 4 weeks before Visit 1, or within approximately 5 half-lives of the previous 
investigational compound, whichever is longer. 
24. Subject who is diagnosed with dementia
Study Treatment
Test drug
Perampanel is orally administered once a day before bedtime.
Comparator drug
Not applicable.
Duration of Treatment
Pretreatment Phase: maximally 4 weeks
Treatment Phase: maximally 62 weeks (4 mg Titration Period: 6 weeks, 4 mg Maintenance Period: 
26 weeks, 8 mg Titration Period: 4 weeks, 8 mg Maintenance Period: 26 weeks)
Extension Phase: 3 or less months from the date of approval of perampanel monotherapy in each 
country
Concomitant Drug/Therapy
1.
Concomitant Medication
(1) Prohibited Concomitant Drug
Throughout the study period, concomitant use of the following drugs is prohibited (till the visit at the 
time of early discontinuation for discontinued subjects).

Other AEDs (if emergency care is needed, eg, status epilepticus, uncontrolled seizures, or 
clusters, occasional use (prn) of other AEDs including diazepam, phenytoin will be permitted as
rescue treatment)

The following drugs or food known to induce CYP3A (not limited to these drugs or food). If one 
of these drugs was being used at enrollment, washout of the drug will start at this time point.  The 
duration of washout of the drug must be at least 2 weeks.  


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[carbamazepine, enzalutamide, mitotane, phenytoin, phenobarbital, amobarbital, secobarbital, 
rifabutin, rifampicin, food containing St. John’s Wort (hypericum perforatum), bosentan, 
efavirenz, etravirine, modafinil, armodafinil, rufinamide, nevirapine, oxcarbazepine, and 
glucocorticoid (except for topical use)]

Antipsychotics

Antianxiety drugs

Benzodiazepine hypnotic

Other investigational agents

Antidementia drugs
(2) Restricted Concomitant Drug
The dosing regimen of the following drugs must not be altered, newly introduced, or discontinued 
throughout the study. Only for discontinued subjects, this does not apply after the visit at early 
discontinuation.

Antidepressants
2.
Concomitant Therapy
(1) Prohibited Concomitant Therapy
The following therapies must not concurrently be implemented during the study.

Brain surgery

Medical device under clinical trial

Neuromodulation therapy (including vagal nerve stimulation [VNS] and transcranial magnetic 
stimulation) 
(2) Restricted Concomitant Therapy
The following therapy must not be changed or discontinued during the study. Only for discontinued 
subjects, this does not apply after the visit at early discontinuation.

Ketogenic diet
Assessments
1.
Efficacy Endpoint
(1) Primary Endpoint

The seizure free rate in the 26-week Maintenance Period for subjects with POS
(2) Secondary Endpoints

The seizure free rate in the 52-week treatment (ie, 26-week Maintenance Period plus 26-week 
Extension Phase) for subjects with POS

Time to first seizure onset and time to withdrawal from the study from the first date of the 
Maintenance Period 
(3) Exploratory Endpoints

The seizure free rate in the 26-week Maintenance Period for subjects with POS by types of partial 
seizure


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
The percent change in seizure frequency of POS per 28 days in the Maintenance Period and 
Extension Phase relative to the Pretreatment Phase

Change in EQ-5D-5L measurements in the 26-week Maintenance Period and at Week 26 of the 
Extension Phase relative to the Pretreatment Phase
2.
Safety Assessment

Adverse events (AEs), prior and concomitant medications, clinical laboratory evaluations 
(biochemistry, hematology, urinalysis), vital signs, weight, and 12-Lead electrocardiogram 
(ECG)
3.
Pharmacokinetic Assessment

Plasma concentrations of perampanel
Bioanalytical Methods
The plasma perampanel concentration will be quantified by a validated analytical method.
Statistical Methods
1.
Analysis Sets
(1) Safety Analysis Set
The Safety Analysis Set is the group of subjects who sign informed consent, receive at least 1 dose of 
study drug and have at least 1 postdose safety assessment.
(2) Intent-to-Treat (ITT) Analysis Set
The ITT Analysis Set is the group of subjects who sign informed consent, receive at least 1 dose of
study drug and have at least 1 postdose primary efficacy measurement.
(3) Modified Intent-to-Treat (mITT) Analysis Set
The mITT Analysis Set is the subset of the ITT Analysis Set who enter the 4 mg Maintenance Period 
and have at least 1 postdose primary efficacy measurement in the 26-week Maintenance Period.
2.
Efficacy Analyses
Primary Efficacy Analysis
The number (percentage) of subjects with POS who achieved seizure-free during the 26-week 
Maintenance Period of 4 mg and the corresponding 95% confidence interval (CI) will be calculated 
on the mITT Analysis Set.  The primary interest of this study will be to confirm that the 95% lower 
CI is above the pre-specified threshold (ie, 40%).  If subjects experience no seizures during the 4 mg 
Maintenance Period, those will be regarded as seizure-free in this analysis.  Otherwise, subjects will 
be regarded as non-seizure-free.
Secondary Efficacy Analyses
The number (percentage) of subjects with POS who achieved seizure-free during the 26-week 
Maintenance Period regardless of perampanel dose and the corresponding 95% CI will be calculated 
on the mITT Analysis Set.  To examine if the 95% lower CI exceeds the threshold (ie, 40%) is the 
key secondary efficacy analysis.
The number (percentage) of subjects in the mITT population with POS who achieved seizure-free 
during the 52-week treatment (ie, 26-week Maintenance Period and 26-week Extension Phase) and 
the corresponding 95% confidence interval (CI) will be calculated.
Median time to first seizure onset will be estimated by Kaplan-Meier method. Time to first seizure 
onset will be defined as the time from the first date of Maintenance Period to the date of first seizure 


Clinical Study Protocol
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onset during the Maintenance Period. Subjects who withdraw from the study before first seizure 
onset will be censored at the time of study discontinuation.
Median time to withdraw from the study will be estimated by Kaplan-Meier method. Time to 
withdraw from the study will be defined as the time from the first date of Maintenance Period to the 
date of discontinuation from the study. Subjects who are ongoing at the data cutoff will be censored 
at the time of data cutoff.
Exploratory Efficacy Analyses
The number (percentage) of subjects with POS who achieved seizure-free during the 26-week 
Maintenance Period and the corresponding 95% confidence interval (CI) will be calculated by types 
of partial seizure.
The percent change in seizure frequency of POS per 28 days in the Maintenance Period and 
Extension Phase relative to the Pretreatment Phase will be summarized.
The change in EQ-5D-5L measurements from baseline to each postbaseline visit will be summarized.
3.
Safety Analyses
All safety analyses will be performed based on the Safety Analysis Set.
The AE verbatim descriptions (investigator terms from the CRF) will be coded to system organ class 
(SOC) and preferred terms (PT) using the Medical Dictionary for Regulatory Activities (MedDRA).  
The number (percentage) of subjects with treatment-emergent adverse events (TEAEs) and serious 
adverse events (SAEs) will be summarized by MedDRA SOC and PT. The incidence of TEAEs will 
be summarized by severity (mild, moderate, or severe).  The TEAEs will be summarized for the 
Treatment Phase and the entire study period (ie, the Treatment Phase or the Extension Phase).  The 
changes from baseline will be summarized by visit using descriptive statistics for continuous 
variables (eg, laboratory values, vital sign, weight, and ECG parameter). Categorical variables will 
be summarized as number (percentage) of subjects by visit.
4.
Pharmacokinetic Analysis
The Safety Analysis Set will be used for pharmacokinetic analysis.  Summary statistics of plasma 
perampanel concentrations will be obtained by visit.
Interim Analyses
No interim analysis is planned for this study.
Sample Size Rationale
In this study, perampanel will be determined to be efficacious if, in untreated subjects with POS 
(including secondary generalized seizures), the lower limit of the 95% confidence interval for the 
seizure-free rate in the 26-week Maintenance Period is above the pre-specified threshold (40%).
Based on the results from research papers of AEDs for mono-therapy (Chadwick, et al., 1999, 
Arroyo, et al., 2005, Mikkelsen, et al., 1981, Heller, et al., 1995, and Kaneko, et al., 2015), the 
expected seizure free rate for other AEDs would be assumed 50.0%.  According to Glauser, et al.
(2013), the relative difference >20% versus the adequate comparator’s efficacy point estimate could 
be considered non-inferior margin if its 95% lower confidence limit was above this lower acceptable 
cutoff (Glauser, et. al., 2013).
Under the assumption that the expected seizure free rate of perampanel in the 26-week Maintenance 
Period would be 60%, sample size of 72 will provide greater than 90% power that the lower limit of 
the 95% confidence interval for the seizure free rate in the 26-week Maintenance Period is above 
40%. Taking into consideration the drop-out rate in the Titration Period (approximately 10%), 
80 subjects need to be as the ITT Analysis Set.  


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If the number of subjects who achieve seizure-free is above the following criteria, this study can 
declare to confirm the efficacy of perampanel.  
Seizure free rate and 95% Confidence Interval
Target Number of mITT
Minimum Number of Subjects Who 
Achieve 26-week Seizure-free to 
Exceed the Pre-specified Threshold
Seizure-free Rate
(95% CI) (%)a
71
38
53.5 (41.3, 65.5)
72
38
52.8 (40.7, 64.7)
73
38
52.1 (40.0, 63.9)
74
39
52.7 (40.7, 64.4)
75
39
52.0 (40.2, 63.7)
76
40
52.6 (40.8, 64.2)
77
40
51.9 (40.3, 63.5)
78
41
52.6 (40.9, 64.0)
79
41
51.9 (40.4, 63.3)
80
42
52.5 (41.0, 63.8)
81
42
51.9 (40.5, 63.1)
CI = confidence interval, mITT = modified intent-to-treat.  
a:  95%CI is based on Clopper-Pearson method.


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................11
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................16
5
ETHICS.......................................................................................................................18
5.1
Institutional Review Boards/Independent Ethics Committees.............................18
5.2
Ethical Conduct of the Study..............................................................................18
5.3
Subject Information and Informed Consent ........................................................19
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................19
7
INTRODUCTION.......................................................................................................21
7.1
Indication...........................................................................................................21
7.1.1
Current Therapeutic Options.....................................................................21
7.1.2
E2007/perampanel....................................................................................21
7.2
Study Rationale..................................................................................................22
8
STUDY OBJECTIVES................................................................................................24
8.1
Primary Objective ..............................................................................................24
8.2
Secondary Objectives.........................................................................................24
8.3
Exploratory Objectives.......................................................................................24
9
INVESTIGATIONAL PLAN ......................................................................................25
9.1
Overall Study Design and Plan...........................................................................25
9.1.1
Pretreatment Phase ...................................................................................26
9.1.2
Treatment Phase .......................................................................................26
9.1.2.1
4 mg Titration and Maintenance Period
26
9.1.2.2
8 mg Titration and Maintenance Period
27
9.1.3
Extension Phase........................................................................................27
9.1.4
Follow-up Phase.......................................................................................28
9.2
Discussion of Study Design, Including Choice of Control Groups......................28
9.3
Selection of Study Population ............................................................................28
9.3.1
Inclusion Criteria......................................................................................28
9.3.2
Exclusion Criteria.....................................................................................29
9.3.3
Removal of Subjects From Therapy or Assessment ..................................31
9.4
Treatment...........................................................................................................31
9.4.1
Treatment Administered ...........................................................................31
9.4.2
Identity of Investigational Product............................................................32
9.4.2.1
Chemical Name, Structural Formula of E2007
33
9.4.2.2
Comparator Drug
33
9.4.2.3
Labeling for Study Drug
33


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9.4.2.4
Storage Conditions
33
9.4.3
Method of Assigning Subjects to Treatment Groups .................................34
9.4.4
Selection of Doses in the Study ................................................................34
9.4.5
Selection and Timing of Dose for Each Subject ........................................34
9.4.6
Blinding ...................................................................................................34
9.4.7
Prior and Concomitant Therapy................................................................34
9.4.7.1
Prohibited Concomitant Therapies and Drugs
35
9.4.7.1.1
Prohibited Concomitant Drug.....................................................35
9.4.7.1.2
Prohibited Concomitant Therapy................................................35
9.4.7.2
Restricted Concomitant Drugs and Therapies
35
9.4.7.2.1
Restricted Concomitant Drug .....................................................35
9.4.7.2.2
Restricted Concomitant Therapy.................................................36
9.4.8
Treatment Compliance..............................................................................36
9.4.9
Drug Supplies and Accountability ............................................................36
9.5
Study Assessments.............................................................................................37
9.5.1
Assessments .............................................................................................37
9.5.1.1
Demography
37
9.5.1.2
Baseline Assessments
37
9.5.1.2.1
Medical History and Physical Examinations...............................37
9.5.1.2.2
Epilepsy Medical History...........................................................37
9.5.1.2.3
Urine Drug Test .........................................................................37
9.5.1.3
Efficacy Assessments
37
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments
38
9.5.1.4.1
Pharmacokinetic Assessments ....................................................38
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...............................................................................38
9.5.1.5
Safety Assessments
38
9.5.1.5.1
Adverse Events ..........................................................................38
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations ...................................................................................40
9.5.1.5.3
Laboratory Measurements ..........................................................41
9.5.1.5.4
Vital Signs and Weight Measurements .......................................42
9.5.1.5.5
Physical Examinations................................................................42
9.5.1.5.6
Electrocardiograms.....................................................................43
9.5.1.5.7
Other Safety Assessments...........................................................43
9.5.1.6
Other Assessments
43
9.5.2
Schedule of Procedures/Assessments........................................................43
9.5.3
Appropriateness of Measurements............................................................49


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9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations............................................................49
9.5.4.1
Reporting of Serious Adverse Events
49
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding
49
9.5.4.3
Reporting of Events Associated with Special Situations
50
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ..........................50
9.5.4.3.2
Reporting of Study-Specific Events............................................51
9.5.4.4
Expedited Reporting
51
9.5.4.5
Breaking the Blind
51
9.5.4.6
Regulatory Reporting of Adverse Events
51
9.5.5
Completion/Discontinuation of Subjects...................................................51
9.5.6
Abuse or Diversion of Study Drug............................................................51
9.5.7
Confirmation of Medical Care by Another Physician................................52
9.6
Data Quality Assurance......................................................................................52
9.6.1
Data Collection.........................................................................................52
9.6.2
Clinical Data Management .......................................................................52
9.7
Statistical Methods.............................................................................................52
9.7.1
Statistical and Analytical Plans.................................................................53
9.7.1.1
Study Endpoints
53
9.7.1.1.1
Primary Endpoint .......................................................................53
9.7.1.1.2
Secondary Endpoints..................................................................53
9.7.1.1.3
Exploratory Endpoints................................................................53
9.7.1.2
Definitions of Analysis Sets
54
9.7.1.3
Subject Disposition
54
9.7.1.4
Demographic and Other Baseline Characteristics
54
9.7.1.5
Prior and Concomitant Therapy
54
9.7.1.6
Efficacy Analyses
55
9.7.1.6.1
Primary Efficacy Analysis..........................................................55
9.7.1.6.2
Secondary Efficacy Analyses .....................................................55
9.7.1.6.3
Exploratory Efficacy Analyses ...................................................55
9.7.1.6.4
Analysis at primary endpoint achievement..................................56
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses
56
9.7.1.7.1
Pharmacokinetic Analyses..........................................................56
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.....................................................................................56
9.7.1.8
Safety Analyses
56
9.7.1.8.1
Extent of Exposure.....................................................................56
9.7.1.8.2
Adverse Events ..........................................................................56


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9.7.1.8.3
Laboratory Values......................................................................57
9.7.1.8.4
Vital Signs .................................................................................58
9.7.1.8.5
Electrocardiograms.....................................................................58
9.7.1.8.6
Other Safety Analyses ................................................................58
9.7.1.9
Other Analyses
58
9.7.2
Determination of Sample Size ..................................................................58
9.7.3
Interim Analysis .......................................................................................59
9.7.4
Other Statistical/Analytical Issues.............................................................59
9.7.5
Procedure for Revising the Statistical Analysis Plan .................................59
10
REFERENCE LIST.....................................................................................................60
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......62
11.1
Changes to the Protocol......................................................................................62
11.2
Adherence to the Protocol ..................................................................................62
11.3
Monitoring Procedures.......................................................................................62
11.4
Recording of Data..............................................................................................63
11.5
Identification of Source Data..............................................................................63
11.6
Retention of Records..........................................................................................64
11.7
Auditing Procedures and Inspection ...................................................................64
11.8
Handling of Study Drug .....................................................................................64
11.9
Publication of Results ........................................................................................64
11.10 Disclosure and Confidentiality ...........................................................................65
11.11 Discontinuation of Study....................................................................................65
11.12 Subject Insurance and Indemnity........................................................................65
12
APPENDICES.............................................................................................................66
LIST OF IN-TEXT TABLES
Table 1
Treatment Administered (Treatment Phase) ..............................................32
Table 2
Clinical Laboratory Tests..........................................................................42
Table 3
Schedule of Procedures/Assessments (Pretreatment Phase to 4 mg 
Treatment Phase) in Study E2007-J000-342 .............................................44
Table 4
Schedule of Procedures/Assessments (8 mg Treatment Phase) in Study 
E2007-J000-342 .......................................................................................46
Table 5
Schedule of Procedures/Assessments (Extension Phase) in Study 
E2007-J000-342 .......................................................................................48
Table 6
Seizure free rate and 95% Confidence Interval..........................................59


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LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E2007-J000-342..................................................26
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values..................................................67


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
β-hCG
beta-human chorionic gonadotropin
BMI
Body mass index
BUN
blood urea nitrogen
CoA
certificate(s) of analysis
CI
confidence interval
CNS
central nervous system
CPK
creatine phosphokinase
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P450
EAID
enzyme inducing antiepileptic drug
ECG
electrocardiogram
EEG
electroencephalogram
EIAED
enzyme inducing antiepileptic drug
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels
EU
European Union
GABA
gamma-aminobutylic acid
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
ILAE
International League Against Epilepsy


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Abbreviation
Term
IRB
institutional review board
ITT
intent-to-treat
IUPAC
International Union of Pure and Applied Chemistry
IUS
intrauterine hormone-releasing system
LC-MS/MS
liquid chromatography with tandem mass spectrometry
LLT
lowest level term
LNH
low/normal/high
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MRI
magnetic resonance imaging
POS
partial onset seizure
PT
preferred term
QD
once daily
QT
time from the beginning of the QRS complex to the end of the T wave
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SOC
system organ class
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
ULN
upper limit of normal
VNS
vagal nerve stimulation
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 Council for
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 [CRA], change 
of telephone number).  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 (or if regionally required, the head of the medical institution) 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 (or if regionally required, the head of the medical institution) 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 (or if regionally required, the investigator, the head of the 
medical institution, and the relevant IRB via the head of the medical institution) 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.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOPs) 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

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Pharmaceuticals for Human Use

Other applicable regulatory authorities’ requirements or directives


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5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian/legally authorized representative the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved, any 
potential discomfort, potential alternative procedure(s) or course(s) of treatment available to 
the subject, and the extent of maintaining confidentiality of the subject’s records.  Each 
subject must be informed that participation in the study is voluntary, that he/she may 
withdraw from the study at any time, and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF (eg, Pretreatment Phase) before any study-specific procedures are performed.  
No subject can enter the study before his/her informed consent has been obtained.
If an underage subject is able to understand the study participation, the investigator should 
explain the nature of the study etc. to the subject with informed assent document prepared 
separately from the informed consent document and obtain a signature.  If a subject is unable 
to sign the ICF, the investigator should confirm that the subject has orally consented to the 
subject’s participation in the study and record it on the consent form.  
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 documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 45 investigational sites in Japan and South Korea.


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The name and telephone and fax numbers of the sponsor’s responsible medical officer and 
other contact personnel at the sponsor are listed in the Investigator Study File provided to 
each site.


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7
INTRODUCTION
7.1
Indication
Epilepsy is a common, serious neurological disorder with an overall prevalence of 0.5% to 
1%. Epilepsy is characterized by the spontaneous recurrence of seizures and requires long 
term, often life-long, pharmacological management. There are 2 major types of seizures: 
generalized and partial (focal) seizures. The most frequent type is partial seizures.  Subjects 
suffering from partial seizures often have poor seizure control.  Uncontrolled seizures lead to 
a wide variety of medical consequences (eg, severe trauma due to seizures, sudden death, 
depression, intermittent psychotic disorders).  In addition, uncontrolled seizures lead to 
significant lifestyle limitations and social handicaps (eg, loss of driving privileges,
difficulties getting and maintaining a job).  
The goal of epilepsy treatment is to achieve a long term seizure-free status without adverse 
effects (Walker, et al., 1996).  In the patients with untreated epilepsy, 47% became seizure-
free with the first AED, 13% seizure free with the second AED, and only 4% are seizure free 
with the third AED or multiple AEDs (Kwan, et al., 2000).  Monotherapy has been promoted 
as the ideal in epilepsy treatment because of reduced adverse effects, better compliance, 
lower cost and avoids drug interactions.  
Recent epidemiological studies in the Europe and the United States have consistently shown 
that, the incidence of the epilepsies in children is decreasing, on the other hand the incidence 
in elderly is increasing.  Partial onset seizures (POS) are the most common type of seizures in 
elderly-onset.  Stroke is the leading cause of POS accounting for up to 30 to 40% of newly 
diagnosed seizures among the elderly.  By the reason that elderly epilepsy patients are more 
likely to develop seizure recurrence than are younger adults, treatment should be started after 
a single unprovoked seizure.  
7.1.1
Current Therapeutic Options
Current treatment guidelines recommend monotherapy for initial management approach in 
epilepsy.  In the updated guideline of International League Against Epilepsy (ILAE) 
(Glauser, et al., 2013), carbamazepine, phenytoin, levetiracetam, and zonisamide are 
recommended as initial monotherapy for adults with partial onset seizures with level A 
efficacy/effectiveness evidence.  In the guideline for Epilepsy Treatment by Japanese Society 
of Neurology (2014), carbamazepine is considered as first-line treatment, and phenytoin, 
zonisamide, and valproic acid are is considered as second-line treatment.
7.1.2
E2007/perampanel
E2007 (perampanel; Fycompa®) is a first-in-class noncompetitive and highly selective α-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist
discovered and developed by Eisai.  
Perampanel tablets were approved for marketing as an adjunctive therapy for the treatment of 
partial-onset seizures with or without secondarily generalized seizures in patients aged 


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12 years and older in the European Union (EU) and the United States in 2012, and in more 
than 50 countries subsequently.  Perampanel was also approved for marketing as an 
adjunctive therapy for the treatment of primary generalized tonic clonic seizures in patients 
with epilepsy aged 12 years and older in the EU and the United States in Jun 2015.  In 
addition, perampanel was approved in Japan indicated as an adjunctive therapy for partial-
onset seizures or tonic-clonic seizures in patients with epilepsy showing inadequate response 
to other antiepileptic drugs (AEDs).
Depending on mechanism of action, existing AEDs are divided into two groups, one of 
which decrease neuronal excitation, and the other of which enhance inhibition.  Major target 
sites for AEDs are blockage of voltage-operated sodium channels or calcium channels, 
regulation of neuronal transmitter release, inhibition of glutamatergic neural transmission, 
and facilitation gamma-aminobutryic acid (GABA)ergic neurotransmission.  Current major 
AEDs has speculated to have a selective or mixed action on these targets.  Perampanel is 
only available drug showing selective inhibition on AMPA receptor.  Therefore, not only
adjunctive therapy for refractory epilepsy, perampanel is expected to become novel 
monotherapy for untreated epilepsy.
7.2
Study Rationale
In general, the clinical development for the novel AED is to confirm the efficacy of the 
adjunctive therapy in adult patients with refractory epilepsy at first, and after that to confirm 
the efficacy of monotherapy.  To date, a large number of monotherapy studies for AEDs 
were conducted after acquiring their clinical evidence for the adjunctive therapy and the 
efficacy of monotherapy has been confirmed as well as adjunctive therapy.  In accordance 
with these historical knowledge, International League Against Epilepsy (ILAE) has 
recommended that AEDs should be approved for the treatment of specific seizure types, or 
the treatment of seizures associated with a specific epilepsy syndrome, without regard to use 
as sole or adjunctive therapy (Mintzer, et al., 2015). 
Perampanel has been conducted the clinical trials for the adjunctive therapy in patients with 
partial onset seizures and primary generalized tonic-clonic seizures and has been confirmed 
the effectiveness. And also, single-administration of perampanel shows broad effect to 
various non-clinical seizure model in mice. Based on above evidence, perampanel can be 
also expected to obtain the sufficient efficacy for use as monotherapy.
From these background, this Phase 3 study to confirm the efficacy and safety of perampanel 
for use as monotherapy was planned.
In this study, target population is untreated epilepsy patients with partial onset seizures
(POS).
This population is commonly targeted in the clinical study for monotherapy. In the Phase 3 
study of lamotrigine monotherapy, not only the untreated newly patients but also the 
recurrent patients were targeted (Yamamoto, et al., 2014).  In this study, patients who had 


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once achieved end of treatment before 2 years or more but are recurrent thereafter are 
allowed to enroll. 
The primary objective of this study is to evaluate the seizure-free rate of the 26-week 
Maintenance Period in untreated patients with POS.  The primary endpoint is commonly used 
in studies evaluating the effect of AED monotherapy.  According to the guideline of Europe 
(EMA, 2010), it should be evaluated for more than six months (exclude titration period) 
when the presence of completion disappearance of seizures (seizure-free) is evaluated.  
It is difficult to conduct a placebo controlled study for the AED monotherapy because it has 
ethical concerns.  In this study, the seizure free rate in the 26-week Maintenance Period will 
be compared with the estimate calculated by other AED monotherapy studies.  
Safety data of this study will be compared with the data of adjunctive treatment study of 
perampanel in patients with POS aged 12 years and older (Study E2007-J000-335 [hereafter 
referred to as Study 335]).  Based on the comparison, safety signals for perampanel 
monotherapy will be evaluated.  
See Section 9.4.4 for selection of doses in the Study.


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8
STUDY OBJECTIVES
8.1
Primary Objective

To evaluate the seizure-free rate of the 26-week Maintenance Period in untreated patients 
with partial onset seizures (POS) 
8.2
Secondary Objectives

To evaluate the seizure-free rate of the 52-week treatment in untreated patients with POS

To confirm time to first seizure onset and time to withdrawal from the study from the first 
date of the Maintenance Period in untreated patients with POS

To evaluate the safety and tolerability of perampanel monotherapy in untreated patients 
with POS
8.3
Exploratory Objectives

To investigate the seizure free-rate of the 26-week Maintenance Period by seizure type in 
untreated patients with POS

To investigate the percent change in seizure frequency from baseline during the 
Maintenance Period and Extension Phase in untreated patients.

To investigate the pharmacokinetics of perampanel as monotherapy

To evaluate the impact of perampanel over time (End of Treatment – Baseline) on overall 
health-related quality of life as measured by the EuroQol 5 Dimensions 5 Levels (EQ-5D-
5L)


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
Study Design
This study is a multicenter, uncontrolled, open-label, single-arm study in untreated patients 
with partial onset seizures (including secondarily generalized seizures).  This study consists
of a Pretreatment Phase, a Treatment Phase (a Titration Period, a Maintenance Period), an 
Extension Phase, and a Follow-up Phase.
Pretreatment Phase
During the Pretreatment Phase (maximally 4 weeks), patients will be screened and be 
assessed for their eligibility to participate in the study.  
Treatment Phase
The Treatment Phase consists of the 4 mg Treatment Phase (the Titration Period [6 weeks]
and the Maintenance Period [26 weeks]) and the 8 mg Treatment Phase (the Titration Period 
[4 weeks] and the Maintenance Period [26 weeks]) if subjects require higher dose.
Extension Phase
When subjects complete the Treatment Phase and agree to continue receiving the perampanel 
monotherapy, they could enter the Extension Phase. Subjects will continue to receive 
perampanel until 3 or less months from the date of approval of perampanel monotherapy in 
each country unless subjects experience tolerability issues such as occurrence of adverse 
events or need to take other antiepileptic drugs (AEDs) because of insufficient efficacy of 
perampanel.  Once perampanel monotherapy is approved in each country, an End of Study 
Visit should be conducted promptly, and the subject would have to switch to the commercial 
product. If a subject does not switch to the commercial product promptly, an End of Study 
Visit and a Follow-up Visit should be conducted for the subject.
Follow-up Phase
Subjects who will finish or discontinue the study will conduct the follow-up visit 4 weeks 
after withdrawal of perampanel.  Follow-up Visit is not required for subjects who will be 
switching to the commercial product and attend an End of Study Visit.
The study design is shown in Figure 1.


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Figure 1
Study Design for Study E2007-J000-342
9.1.1
Pretreatment Phase
During the Pretreatment Phase (maximally 4 weeks), patients will be screened and be 
assessed for their eligibility to participate in the study.  Screening will occur between Day –
28 and Day 1 (Day 1 is the date of first dose of perampanel 2 mg).  The purpose of the 
screening at Visit 1 is to obtain informed consent and to establish protocol eligibility.  
Informed consent will be obtained after the study has been fully explained to each subject 
and before the conduct of any screening procedures or assessments.  Procedures to be 
followed when obtaining informed consent are detailed in Section 5.3.  
Subjects must have a diagnosis of epilepsy with partial seizures with or without secondary 
generalized seizures according to International League Against Epilepsy (ILAE)
Classification of Epileptic Seizures (1981).
Subjects who complete the screening and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Treatment Phase.
9.1.2
Treatment Phase
The Treatment Phase consists of the 4 mg Treatment Phase (the Titration Period [6 weeks]
and the Maintenance Period [26 weeks]) and the 8 mg Treatment Phase (the Titration Period 
[4 weeks] and the Maintenance Period [26 weeks]) if subjects require higher dose.
9.1.2.1
4 mg Titration and Maintenance Period
In the 4 mg Titration Period (6 weeks), subjects will initiate 2 mg QD of perampanel for 
2 weeks and then will be up-titrated to 4 mg QD and will continue for 4 weeks.  If subjects 
have no safety issues at the end of the Titration Period, they will start the 4 mg Maintenance 
Period for 26 weeks.  
2 mg QD
4 mg QD
6 mg QD
8 mg QD*
Day 1 
Week6
Week2 
Week32
Day 1 
Week 4
Week 2 
Week 30
Primary 
endpoint
Primary 
endpoint
Extension Phase or 
Study  discontinuation
26 weeks
26 weeks
4 mg Titration Period
4 mg Maintenance Period
8 mg Titration Period
8 mg Maintenance Period
Seizure occur
Pretreatment 
Phase
Day -28
* If 8 mg is not tolerable, subjects will be down-titrated to 6 mg and continue the Maintenance Period
Seizure occur
Extension 
Phase
Extension 
Phase


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If subjects experience seizures during the 4 mg Maintenance Period, the investigator will end 
the 4 mg Maintenance Period and judge the transition to the 8 mg Titration Period based on 
the subject’s tolerability and safety.  If subjects could not continue 4 mg dosing due to 
intolerable adverse event during the 4 mg Maintenance Period, they will discontinue the 
study. 
During the 2 weeks of Weeks 3 and 4 in the 4 mg Titration Period, if subjects are suspected 
to have tolerability issues for 4 mg dosing due to occurrence of adverse events, 2 mg QD can 
be administered in accordance with the investigators’ discretion.  In that case, subjects will 
visit the investigational site via unscheduled visit within 4 weeks after starting study 
treatment and will be up-titrated to 4 mg QD (for subjects who has continued 4 mg QD, 
occurrence of AEs will be confirmed via telephone).  All subjects will continue 4 mg QD 
during the 2 weeks of Weeks 5 and 6.  If subjects could not continue 4 mg QD due to 
intolerable adverse event, they will discontinue the study.  
9.1.2.2
8 mg Titration and Maintenance Period
In the 8 mg Titration Period (4 weeks), subjects will be administered 6 mg QD of perampanel 
for 2 weeks and then will be up-titrated to 8 mg QD and will continue for 2 weeks.  If 
subjects have no safety issues at the end of the Titration Period, they will start the 8 mg 
Maintenance Period for 26 weeks.  
If subjects don’t tolerate 8 mg administration of perampanel, they will be able to down-titrate 
to 6 mg in accordance with the investigators’ discretion. After the down-titration, subjects 
could continue the study with 6 mg QD.
If subjects experience the occurrence of seizures or could not continue 8 mg (or 6 mg) dosing 
due to intolerable adverse event during the 8 mg Maintenance Period, they will end the 
Treatment Phase.
9.1.3
Extension Phase
When subjects complete the Treatment Phase and agree to continue receiving the perampanel 
monotherapy, they could enter the Extension Phase. Subjects who complete the 26-week 
Maintenance Period will continue the last dose of the Maintenance Period. Subjects who end 
the Treatment Phase due to insufficient efficacy or safety issue before the completion of the 
26-week Maintenance Period will adjust their appropriate dose (within 4 – 8 mg of 
perampanel) and continue the Extension Phase. Subjects will be allowed to adjust within 2 –
8 mg of perampanel with investigators’ consideration for their condition of the seizures 
and/or tolerability. During whole study period, the maximum dose of perampanel is 8 mg 
QD.  The dose will be increased at intervals of 1 week or more in increments of 2 mg.  
If subjects need to take other antiepileptic drugs (AEDs) or withdraw perampanel because of 
insufficient efficacy or tolerability issue of perampanel by the investigator’s judgement, they 
will discontinue the study.


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Once perampanel monotherapy is approved in each country, an End of Study Visit should be 
conducted promptly, and the subject would have to switch to the commercial product. If a 
subject does not switch to the commercial product promptly, an End of Study Visit and a 
Follow-up Visit should be conducted for the subject.
9.1.4
Follow-up Phase
Subjects who will finish or discontinue the study will conduct the follow-up visit 4 weeks 
after withdrawal of perampanel.  When a taper is provided after discontinuation, it should be 
performed 4 weeks after the last dose at the tapered dose.  Follow-up Visit is not required for 
subjects who will be switching to the commercial product and attend an End of Study Visit.
9.2
Discussion of Study Design, Including Choice of Control Groups
This study is a multicenter, open-label study to evaluate the efficacy, safety and tolerability, 
and pharmacokinetics of perampanel.  
During initial treatment, the dose of monotherapy should be gradually increased to a 
therapeutic range based on the subject’s safety and tolerability (Matsuura, 2009).  The 
interval of titration for each dose was 1 week in the studies of adjunctive therapy, while it is 
changed to 2 weeks in this study.  The point to be considered in medication is the following 
report (Matsuura, 2009):  “When unfavorable side effects such as sleepiness occur in a 
subject, transient reduction to the dose before titration and re-up-titration to planned dose can 
make the planned dose administered to the subject.”  Based on the above report, dose 
reduction from 4 mg to 2 mg is allowed during the 4 mg Titration Period.  
The 26-week Maintenance Period is the duration to evaluate the seizure-free rate as primary 
objective (see Section 7.2).  In addition, the Extension Phase is established to confirm the
subsequent seizure-free period for subjects who completed the Maintenance Period; and the 
subsequent clinical course of non-seizure-free subjects who do not have trouble in daily life, 
have sufficient therapeutic effect, and desire to continue the study.  If subjects need to take 
other AEDs because of insufficient efficacy of perampanel, they will discontinue the study.  
9.3
Selection of Study Population
Approximately 80 subjects will be enrolled at approximately 45 sites in Japan and South 
Korea.  Subjects who do not meet all of the inclusion criteria or who meet any of the 
exclusion criteria will not be eligible to receive study drug.  Note that, in this protocol, 
1 month refers to 28 days (4 weeks).  
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Be considered reliable and willing to be available for the study period and are able to 
record seizures and report adverse events (AEs) himself/herself or have a caregiver who 
can record seizures and report AEs for them 


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2. Male or female aged between 12 and 74 years old
3. Subjects who are newly diagnosed or recurrent epilepsy and have experienced at least 2 
unprovoked seizures separated by a minimum of 24 hours in the 1 year prior to the 
Pretreatment Phase, of which, at least 1 unprovoked seizure (but below 20 seizures) 
occurred in the 12 weeks prior to the Pretreatment Phase.  For subjects with recurrent 
epilepsy, they must have relapsed at least 2 years after the end of the last AED treatment. 
4. Subjects who have excluded the progressive CNS abnormality occurring seizures by CT 
or MRI conducted within 1 year before the Pretreatment Phase
5. Subjects who have had a diagnosis of epilepsy with partial seizures with or without 
secondarily generalized seizures according to the International League Against Epilepsy 
(ILAE) Classification of Epileptic Seizures (1981). Diagnosis should have been 
established by clinical history and an electroencephalogram (EEG) that is consistent with 
localization-related epilepsy; normal interictal EEGs will be allowed provided that the 
subject meets the other diagnosis criterion (ie, clinical history).
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Subjects who present only simple partial seizures without motor signs
2. Subjects who have seizure clusters where individual seizures cannot be counted
3. Subjects who present or have a history of Lennox-Gastaut syndrome
4. Subjects who have a history of status epilepticus within 1 year prior to Day 1 of the 
Treatment Phase
5. Subjects who have a history of psychogenic non-epileptic seizures within 5 years prior to
Day 1 of the Treatment Phase
6. Subjects who have a history of suicidal ideation/attempt within 5 years prior to Day 1 of 
Treatment Phase
7. Subjects who present clinically problematic psychological or neurological disorder(s)
8. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments  
9. Evidence of clinically significant active hepatic disease.
10. A prolonged QTcF interval (>450 ms [2 or 3 times]) as demonstrated by a repeated 
(3 times) electrocardiogram (ECG)
11. Subjects who have a history of receiving any AEDs (except for AEDs used as rescue 
treatment), antipsychotics or anti-anxiety drugs within 12 weeks prior to the Pretreatment 
Phase
12. Subjects who have not used a stable dose of antidepressant in the 12 weeks prior to the 
Pretreatment Phase, if they treat
13. Subjects who have a history of any type of surgery for brain or central nervous system 
within 1 year prior to the Pretreatment Phase


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14. Subjects who have a history of receiving any AED (including AED used as rescue 
treatment) for more than 2 weeks in total within 2 years prior to the Pretreatment Phase
15. Subjects who have used intermittent rescue medicine on 2 or more occasions within 
4 weeks before the Pretreatment Phase (1 to 2 doses over a 24-hour period considered 
one-time rescue)
16. Subjects who have a history of receiving any AED polytherapy
17. Subjects who experienced treatment with perampanel
18. Subjects who have had non-constant ketogenic diet within 4 weeks before the 
Pretreatment Phase
19. Subjects who have a history of drug or alcohol dependency or abuse within the last 
2 years before the Pretreatment Phase
20. Subjects who 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
21. Females who are breastfeeding or pregnant in the Pretreatment Phase (as documented by 
a positive beta-human chorionic gonadotropin [β-hCG] test)  
22. Females of childbearing potential who: 

Within 28 days before the start of the Pretreatment Phase, 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
a contraceptive implant
o
an oral contraceptive (with additional barrier method) (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.
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.
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, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing).
23. Subjects who have participated in a study involving administration of an investigational 
drug or device within 4 weeks before Visit 1, or within approximately 5 half-lives of the 
previous investigational compound, whichever is longer.


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24. Subject who is diagnosed with dementia
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
A subject who discontinues study treatment should be followed for subsequent protocol-
specified visits and procedures.  The primary reason for discontinuation contributing to the 
subject’s discontinuation from study drug(s) should be collected.  If subjects need to take 
other AEDs because of insufficient efficacy of perampanel, they will discontinue the study.  
The first date when other AEDs are administered will be defined as the final date of 
perampanel monotherapy, and the subsequent date when the perampanel is completely 
withdrawn will be defined as the discontinuation date of the study.
9.4
Treatment
9.4.1
Treatment Administered
Treatment Phase
The following treatment will be administered to subjects in the Treatment Phase (Table 1).  
Perampanel is orally administered once a day before bedtime.  
[4 mg Treatment Phase]
In the 4 mg Titration Period (6 weeks), subjects will initiate 2 mg QD of perampanel for 
2 weeks and then will be up-titrated to 4 mg QD and will continue for 4 weeks.  If subjects 
have no safety issues at the end of the Titration Period, they will start the 4 mg Maintenance 
Period for 26 weeks.
If subjects experience seizures during the 4 mg Maintenance Period, the investigator will end 
the 4 mg Maintenance Period and judge the transition to the 8 mg Titration Period based on 
the subject’s tolerability and safety.  If subjects could not continue 4 mg dosing due to 
intolerable adverse event during the 4 mg Maintenance Period, they will discontinue the 
study. 
During the 2 weeks of Weeks 3 and 4 in the 4 mg Titration Period, if subjects are suspected 
to have tolerability issues for 4 mg dosing due to occurrence of adverse events, 2 mg QD can 
be administered in accordance with the investigators’ discretion.  In that case, subjects will 
visit the investigational site via unscheduled visit within 4 weeks after starting study 
treatment and will be up-titrated to 4 mg QD (for subjects who has continued 4 mg QD, 
occurrence of AEs will be confirmed via telephone).  All subjects will continue 4 mg QD 
during the 2 weeks of Weeks 5 and 6.  If subjects could not continue 4 mg QD due to 
intolerable adverse event, they will discontinue the study.  


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[8 mg Treatment Phase]
In the 8 mg Titration Period (4 weeks), subjects will be administered 6 mg QD of perampanel 
for 2 weeks and then will be up titrated to 8 mg QD and will continue for 2 weeks.  If 
subjects have no safety issues at the end of the Titration Period, they will start the 8 mg 
Maintenance Period for 26 weeks.  
If subjects don’t tolerate 8 mg administration of perampanel, they will be able to down-titrate 
to 6 mg in accordance with the investigators’ discretion. After the down-titration, subjects 
could continue the study with 6 mg QD.
If subjects experience the occurrence of seizures or could not continue 8 mg (or 6 mg) dosing 
due to intolerable adverse event during the 8 mg Maintenance Period, they will end the 
Treatment Phase.
A taper will be allowed at the investigator’s discretion upon early discontinuation of the 
study.  
Table 1
Treatment Administered (Treatment Phase)
Treatment Phase
Week
Day
Dose
Frequency and Number 
Dispensed
4 mg Titration Period
Weeks 1 – 2
Days 1 – 14
2 mg
QD, 1 × 2 mg tablet before bedtime
Weeks 3 – 6
Days 15 – 42
4 mg
QD, 2 × 2 mg tablet before bedtime
4 mg Maintenance Period
Weeks 7 – 32
Days 43 – 224
4 mg
QD, 2 × 2 mg tablet before bedtime
8 mg Titration Period
Weeks 1 – 2
Days 1 – 14
6 mg
QD, 3 × 2 mg tablet before bedtime
Weeks 3 – 4
Days 15 – 28
8 mg
QD, 4 × 2 mg tablet before bedtime
8 mg Maintenance Period
Weeks 5 – 30
Days 29 – 210
8 mga
QD, 4 × 2 mg tablet before bedtime
QD = once daily.  
Extension Phase
Subjects who complete the 26-week Maintenance Period will continue the last dose of the 
Maintenance Period. Subjects who end the Treatment Phase due to insufficient efficacy or 
safety issue before the completion of the 26-week Maintenance Period will adjust their 
appropriate dose (within 4 – 8 mg of perampanel) and continue the Extension Phase.  
Subjects will be allowed to adjust within 2 – 8 mg of perampanel with investigators’ 
consideration for their condition of the seizures and/or tolerability.  During whole study 
period, the maximum dose of perampanel is 8 mg QD.  The dose will be increased at 
intervals of 1 week or more in increments of 2 mg.  
9.4.2
Identity of Investigational Product
Perampanel 2-mg tablets will be provided as orange, 6.6 mm diameter, biconvex film –
coated tablets for oral administration. The front side of the tablets will be debossed with


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“E274.” Each tablet will contain 2 mg of perampanel.  The certificate(s) of analysis (CoA) 
will provide manufacturer information.
9.4.2.1
Chemical Name, Structural Formula of E2007

Test drug code:  E2007

Generic name:  perampanel

Chemical name (IUPAC):  2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) 
benzonitrile hydrate (4:3)

Molecular formula:  C23H15N3O • 3/4H2O

Molecular weight:  362.90 (3/4 hydrate), 349.38 (anhydrous)

Structural formula:  
N
N
O
CN
3/4H2O
9.4.2.2
Comparator Drug
Not applicable.  
9.4.2.3
Labeling for Study Drug
Study drug will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and is translated into the required language(s) for each of those 
countries.
9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  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 (or if regionally 
required, the pharmacist or its 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.


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9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will be 
assigned to receive perampanel.  There is no randomization in this study.
9.4.4
Selection of Doses in the Study
In this study, if subjects experience seizures during the 4 mg Maintenance Period, they will 
be titrated to 8 mg.  In Japan, perampanel 4 mg has not been approved as the clinical dosage 
for adjunctive therapy of POS based on the result of Study 335.  However, in many other 
countries including South Korea, perampanel 4 mg is approved as the clinical dosage of 
adjunctive therapy for POS based on the result of Study E2007-G000-306 (hereafter referred 
to as Study 306), which was conducted before Study 335 and demonstrated the efficacy by 
4 mg.  In addition, the efficacy of 4 mg for subjects who did not take enzyme inducing 
antiepileptic drugs (EIAEDs) was comparable in Study 335 and Study 306; and adjunctive 
treatment with perampanel 4 mg for the subjects taking EIAEDs was considered effective in 
improving seizure control.  Therefore, perampanel 4 mg as monotherapy has potential to 
demonstrate the efficacy for POS; and the objective of this study is set to confirmation of the 
efficacy for perampanel 4 mg.  If subjects experience seizures during the 4 mg treatment, the 
efficacy for perampanel monotherapy will be evaluated with 8 mg dose.  
In order to minimize the sample size, the 2 step design, not the two separate arms (4 mg and 
8 mg arm) was chosen.  In this study, all subjects will be up-titrated to 4 mg firstly.  After 
that, only the subjects who experience seizures during the 4 mg Maintenance Period (26 
weeks) will be up-titrated to 8 mg.  
9.4.5
Selection and Timing of Dose for Each Subject
Perampanel is orally administered once a day before bedtime.  
9.4.6
Blinding
The study will not be blinded.  
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent) will be recorded.  For all 
drugs, the name, route of administration, dose (only for drugs to treat primary disease), 
treatment start dates, treatment end dates, and reason for use will be recorded on the CRF.  
Concomitant drugs such as premedications, diagnostic agents, solutions, or fluid transfusions 
provided for surgery, medical examinations, or administrations will be excepted.  For 
concomitant therapy, the name, treatment start dates (or timing of starting treatment), 
treatment end dates, and reason for use will be recorded on the CRF.  The adverse event or 
medical condition for which the concomitant medication or therapy was administered will be 
recorded.  


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Antidepressant administered within 12 weeks prior to the Pretreatment Phase, available 
subject’s lifetime all AED histories (including AED used as rescue treatment), and rescue 
benzodiazepines within 4 weeks before the Pretreatment Phase will be recorded on the CRF.  
9.4.7.1
Prohibited Concomitant Therapies and Drugs
9.4.7.1.1
PROHIBITED CONCOMITANT DRUG
Throughout the study period, concomitant use of the following drugs is prohibited (till the 
visit at the time of early discontinuation for discontinued subjects).

Other AEDs (if emergency care is needed, eg, status epilepticus, uncontrolled seizures, or 
clusters, occasional use (prn) of other AEDs including diazepam, phenytoin will be 
permitted as rescue treatment)

The following drugs or food known to induce CYP3A (not limited to these drugs or 
food). If one of these drugs was being used at enrollment, washout of the drug will start 
at this time point.  The duration of washout of the drug must be at least 2 weeks.  
[carbamazepine, enzalutamide, mitotane, phenytoin, phenobarbital, amobarbital, 
secobarbital, rifabutin, rifampicin, food containing St. John’s Wort (hypericum 
perforatum), bosentan, efavirenz, etravirine, modafinil, armodafinil, rufinamide, 
nevirapine, oxcarbazepine, and glucocorticoid (except for topical use)]

Antipsychotics

Antianxiety drugs

Benzodiazepine hypnotic

Other investigational agents

Antidemetia drugs
9.4.7.1.2
PROHIBITED CONCOMITANT THERAPY
The following therapies must not concurrently be implemented during the study.

Brain surgery

Medical device under clinical trial

Neuromodulation therapy (including vagal nerve stimulation [VNS] and Transcranial 
magnetic stimulation)
9.4.7.2
Restricted Concomitant Drugs and Therapies
9.4.7.2.1
RESTRICTED CONCOMITANT DRUG
The dosing regimen of the following drugs must not be altered, newly introduced, or 
discontinued throughout the study. Only for discontinued subjects, this does not apply after 
the visit at early discontinuation.


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
Antidepressants
9.4.7.2.2
RESTRICTED CONCOMITANT THERAPY
The following therapy must not be changed or discontinued during the study. Only for 
discontinued subjects, this does not apply after the visit at early discontinuation.

Ketogenic diet
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study.
9.4.9
Drug Supplies and Accountability
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to Good Clinical Practice (GCP) guidelines as well as local or regional 
requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, (d) documentation of returns to the sponsor, and (e) 
certificates of destruction for any destruction of study drugs 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 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.  As 
applicable, all unused study drugs and empty and partially empty containers from used study 
drugs are to be returned to the investigator (or if regionally required, the head of the medical 
institution or the designated pharmacist) by the subject and, together with unused study drugs 
that were shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 


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prohibits the return of study drugs to the central or local depot(s).  Approval for destruction 
to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at Visit 1.  Demography information 
includes date of birth, sex, race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at Visit 1.  All 
CNS related medical and surgical history within 2 years and current medical conditions must 
be noted in the Medical History and Current Medical Conditions CRF.  
9.5.1.2.2
EPILEPSY MEDICAL HISTORY
In addition to standard medical history, epilepsy history (date of diagnosis, etiology, epileptic 
syndrome, suspected localization of the epileptogenic region, seizure type, end date of last 
medication for previous epilepsy if subjects are recurrent epilepsy) will be documented for 
each subject at Visit 1.  The available subject’s lifetime all AED histories will be recorded on 
the CRF.  Seizure count and type occurring within 12 weeks before study entry will be 
recorded based on the interview with each subject at Visit 1.
9.5.1.2.3
URINE DRUG TEST
A urine sample will be collected at Visit 1.  This sample will be tested for common drugs of 
use/abuse: PCP (phencyclidine), benzodiazepines, cocaine, amphetamines, cannabinoids, 
opioids (as a group), barbiturates, and tricyclic antidepressant.
9.5.1.3
Efficacy Assessments
Efficacy will be assessed by seizure counts and types as recorded on the diary.  


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Diaries will be dispensed to all subjects and returned from all subjects at each visit as 
described in Table 3.  The diary is to be completed by the subject or the caregiver. All 
seizure counts and types will be recorded.  At each visit the subject or the caregiver will be 
instructed by the site personnel as to how to complete the diary and reminded that they must 
return the diary at their next scheduled clinic visit and at the Early Discontinuation and 
Follow-up Visits (if applicable). To ensure correct seizure classification, the medically 
qualified investigator should review the diary with the subject or the caregiver at all visits. 
Subjects or caregivers must be counseled if diary compliance is not satisfactory.  
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected as specified in Table 3 and Table 4.  See the Laboratory 
Manual for a description of collection, handling, and shipping procedures for 
pharmacokinetic samples.  Pharmacokinetic sampling date and time for plasma 
concentrations of perampanel, treatment compliance (with or without) and dose of last 3 
doses of perampanel, and date and time of last dose of perampanel before pharmacokinetic 
sampling will be recorded on the CRF.  
Plasma perampanel concentrations will be determined by a validated method using liquid 
chromatography with tandem mass spectrometry (LC-MS/MS).  
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Not applicable.  
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs); regular monitoring of hematology, blood chemistry, and urine values; 
periodic measurement of vital signs, weight, and 12-Lead electrocardiogram (ECG); and 
performance of physical examinations as detailed in Table 3, Table 4, and Table 5.  
9.5.1.5.1
ADVERSE EVENTS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drug(s) 
is(are) perampanel.
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 


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symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit.  SAEs will be collected 
for 28 days after the last dose.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.  
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity


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The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the 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 


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SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
Events associated with special situations include pregnancy or exposure to study drug 
through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or 
medication error.  These events associated with special situations are to be captured using the 
SAE procedures but are to be considered as SAEs only if they meet one of the above criteria
(see Sections 9.5.4.2 and 9.5.4.3).  All AEs associated with special situations are to be 
reported on the CRF whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 2.  The Schedule of Procedures/Assessments (Table 3, Table 4, and 
Table 5) shows the visits and time points at which blood for clinical laboratory tests and 
urine for urinalysis will be collected in the study.  


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Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
RBC count, hemoglobin, hematocrit, platelets, and WBC count 
with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Chemistry
Electrolytes
Bicarbonate, chloride, potassium, sodium, calcium, magnesium
Liver function tests
Alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, gamma glutamyl transpeptidase, total bilirubin
Renal function tests
Blood urea nitrogen, creatinine
Other
Glucose, albumin, total cholesterol, triglycerides, phosphorus, 
lactate dehydrogenase, total protein, uric acid, creatine 
phosphokinase
Urinalysis
pH, protein, glucose, ketones, occult blood, specific gravity
RBC = red blood cell, WBC = white blood cell.
Clinical laboratory tests during the study will be performed by a central laboratory.  All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection (in principle) unless otherwise instructed.  In case of a safety concern or 
dispensing study drugs on the start day of the Pretreatment Phase, blood samples will be split 
(or 2 samples drawn) to allow a local laboratory analysis in addition to the central laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [mmHg], pulse [beats per 
minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 3, 
Table 4, and Table 5) by a validated method.  Blood pressure and pulse will be measured 
after the subject has been resting for 5 minutes.  All blood pressure measurements should be 
performed on the same arm, preferably by the same person.  Height (cm) will be measured 
only at Visit 1.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed at the visits as designated in the Schedule of 
Procedures/Assessments (Table 3, Table 4, and Table 5).  Documentation of the physical 
examination will be included in the source documentation at the site.  Only changes from 
screening physical examination findings that meet the definition of an AE will be recorded 
on the Adverse Events CRF.


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9.5.1.5.6
ELECTROCARDIOGRAMS
Twelve-lead ECGs will be obtained at the visits as designated in the Schedule of 
Procedures/Assessments (Table 3, Table 4, and Table 5).  Subjects must be in the recumbent 
position for a period of 5 minutes prior to the ECG.  
At Visit 1 and Visit 2 (Day 1), 3 consecutive ECGs separated by 5-10 minutes will be 
performed in all subjects.  At Visit 3 and thereafter, if the QTcF is measured as >450 ms, 
additional 2 (total of 3) consecutive ECGs separated by 5-10 minutes will be performed to 
confirm the abnormality.  
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the Adverse Events CRF.
9.5.1.5.7
OTHER SAFETY ASSESSMENTS
Pregnancy Test
A serum β-hCG pregnancy test will be performed for all female subjects at Visit 1.  On 
Visit 2 (Day 1) and thereafter, a urine β-hCG pregnancy test will be performed for women of 
childbearing potential (ie, premenopausal women or postmenopausal women who have been 
amenorrheic for less than 12 months).  
If Visit 1 and Visit 2 are the same day and a result of serum pregnancy test can be assessed 
by the local laboratory during the day, urine pregnancy test at Visit 2 is not required.  
9.5.1.6
Other Assessments
EuroQol 5 Dimensions 5 Levels
Quality of life will be assessed using the EQ-5D-5L questionnaires at the visits as designated 
in the Schedule of Procedures/Assessments (Table 3, Table 4, and Table 5).  
Questionnaires should be self-read and self-completed unless the subject has a physical 
disability that prevents him or her from doing so. In these cases, a caregiver or study
coordinator should read and/or record the subject’s answers.  
9.5.2
Schedule of Procedures/Assessments
Table 3, Table 4, and Table 5 present the schedule of procedures/assessments for the study.
Subjects will continue to receive perampanel until 3 or less months from the date of approval 
of perampanel monotherapy in each country or the sponsor discontinues the study.


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Table 3
Schedule of Procedures/Assessments (Pretreatment Phase to 4 mg Treatment Phase) in Study E2007-
J000-342
Phase
Pretreatment 
Phasea
4 mg Treatment Phase
Follow-up 
Phaseb, c
Period
4 mg Titration Perioda
4 mg Maintenance Periodb
Study Week(s) (from Day 1 of 
Titration Period)
Week –4
–
Week 2
Week 4
Week 6
Week 10
Week 14
Week 20
Week 26
Week 32
4 weeks after the 
last dose
Study Day(s) (from Day 1 of 
Titration Period)
Day –28 to 1
Day 1m
Day 15
Day 29
Day 43
Day 71
Day 99
Day 141
Day 183
Day 225
–
Visit
1
2
3
Phonen
4
5
6
7
8
9
–
Unscheduled 
visito
Early 
discontinuation 
visitp
Procedure/Assessment
Informed consent/assentd
X
Inclusion/exclusion criteria
X
X
Physical examinations
X
X
X
X
X
X
X
X
X
X
X
X
Medical history
X
Concomitant medications
Xe
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug compliance
X
X
X
X
X
X
X
X
Dispense subject diary
X
X
X
X
X
X
X
X
X
X
Return and review subject diary
X
X
X
X
X
X
X
X
X
X
Discontinuation/continuation/titration 
judgmentg
X
X
X
X
X
X
X
X
Vital signs and weighth
X
X
X
X
X
X
X
X
Clinical laboratory evaluationsi
X
X
X
X
X
X
X
X
Study drug plasma concentration
X
X
X
Xj
Urine drug screen
X
Urine pregnancy testk
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testk
X
12-Lead ECGl
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X
Return unused medication
X
X
X
X
X
X
X
X
AE = adverse event, β-hCG = beta-human chorionic gonadotropin, ECG = electrocardiogram, EQ-5D-5L = EuroQol 5 Dimensions 5 Levels.
a:
Visit to be done within ±3 days of the schedule. Each visit to be specified based on the date of Visit 2.
b:
Visit to be done within ±7 days of the schedule. Each visit to be specified based on the date of Visit 2.
c:
To be completed by subjects who are withdrawn from the study after Visit 2 and before Visit 9 (for any reason). When a taper is provided after discontinuation, it should be performed 4 weeks after 


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the last dose at the tapered dose and return unused medication.
d:
Informed consent/assent must be obtained prior to any study related procedure.
e:
Prior and concomitant medication(s)
f:
Adverse events will be collected from the time the subject signs the informed consent/assent form through the last visit. Serious adverse events will be collected for 28 days after the subject’s last 
dose.
g:
After Visit 4, if a subject experiences seizures, the investigator will end the 4 mg Maintenance Period and judge the transition to the 8 mg Titration Period based on the subject’s tolerability and safety. 
h:
Height is to be measured only at Visit 1.
i:
At Visit 1, confirm the results of  the local laboratory analysis, if necessary. In case of the local laboratory analysis, the measurement of bicarbonate and magnesium are not mandatory at Visit 1, and 
after that should be conducted as scheduled
j:
Collect blood samples if subjects are withdrawn from the study before Visit 7.  
k:
All female subjects will undergo the serum β-hCG pregnancy test at Visit 1. After Visit 2, only potentially pregnant female subjects will undergo the urine β-hCG pregnancy test.
l:
At Visits 1 and 2, all subjects will undergo 3 consecutive ECGs at 5- to 10-minute intervals. After Visit 3, only subjects whose QTcF is measured as >450 ms at any Visit will undergo additional 2 
consecutive ECGs at 5- to 10-minute intervals (a total of 3 ECGs) to confirm the abnormality.
m:
If Visit 1 and Visit 2 are the same day, only duplicate procedures/assessments will be performed once.  If Visit 1 and Visit 2 are the same day and a result of serum pregnancy test can be assessed by 
the local laboratory during the day, urine pregnancy test at Visit 2 is not required.  
n: 
For subjects who continue 4 mg QD, occurrence of AEs will be confirmed via telephone.  Subjects who continue 2 mg QD or who are reduced from 4 mg QD to 2 mg QD during the 2 weeks of 
Weeks 3 and 4 will visit the investigational site via unscheduled visit within 4 weeks after starting study treatment and will be up-titrated to 4 mg QD.  
o: 
At an unscheduled Visit, only the procedures/assessments that the investigators etc. has judged as necessary according to the subject’s conditions will be performed.
p:
If a taper is decided based on the judgment of the investigator, dispensing the study drug should be needed.


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Table 4
Schedule of Procedures/Assessments (8 mg Treatment Phase) in Study E2007-J000-342
Phase
8 mg Treatment Phase
Follow-up 
Phaseb,c
Period
8 mg Titration Period a
8 mg Maintenance Period b
Study Week(s) (from Day 1 of 8 mg 
Titration Period)
–
Week 2
Week 4
Week 8
Week 12
Week 18
Week 24
Week 30
4 weeks after the 
last dose
Study Day(s) (from Day 1 of 8 mg 
Titration Period)
Day 1
Day 15
Day 29
Day 57
Day 85
Day 127
Day 169
Day 211
–
Visit
2a
3a
4a
5a
6a
7a
8a
9a
–
Early transition 
visitk
Unschedule
d visit i
Early discontinuation 
visitj
Procedure/Assessment
Physical examinations
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsd
X
X
X
X
X
X
X
X
X
X
X
X
Study drug compliance
X
X
X
X
X
X
X
X
X
X
Dispense subject diary
X
X
X
X
X
X
X
X
X
X
Return and review subject diary
X
X
X
X
X
X
X
X
X
X
X
Discontinuation/continuation/titration 
judgment e
X
X
X
X
X
X
X
X
Vital signs ad weight
X
X
X
X
X
X
X
X
Clinical laboratory evaluations
X
X
X
X
X
X
X
X
Study drug plasma concentration
X
X
X
Xg
Xg
Urine pregnancy testf
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG h
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X
X
Return unused medication
X
X
X
X
X
X
X
X
X
X
β-hCG = beta-human chorionic gonadotropin, ECG = electrocardiogram, EQ-5D-5L = EuroQol 5 Dimensions 5 Levels.
a:
Visit to be done within ±3 days of the schedule. Each visit to be specified based on the date of Visit 2a.
b:
Visit to be done within ±7 days of the schedule. Each visit to be specified based on the date of Visit 2a.
c:
To be completed by subjects who are withdrawn from the study after Visit 2a and before Visit 9a (for any reason). When a taper is provided after discontinuation, it should be performed 4 weeks 
after the last dose at the tapered dose and return unused medication.
d:
Adverse events will be collected from the time the subject signs the informed consent/assent form through the last visit. Serious adverse events will be collected for 28 days after the subject’s last 
dose.
e:
At Visit 4a, if a subject is down-titrated to 6 mg due to intolerability after up-titrated to 8 mg, the subject will enter the Maintenance Period with 6 mg.  After Visit 4a, if a subject experiences seizures
or could not continue dosing due to intolerable adverse event, the investigator will end the 8 mg Maintenance Period. 
f:
Only potentially pregnant female subjects will undergo the urine β-hCG pregnancy test.
g:
Collect blood samples if subjects are withdrawn from the study before Visit 7a.
h:
Only subjects whose QTcF is measured as >450 ms at any Visit will undergo additional 2 consecutive ECGs at 5- to 10-minute intervals (a total of 3 ECGs) to confirm the abnormality.
i:
At an unscheduled Visit, only the procedures/assessments that the investigators etc. has judged as necessary according to the subject’s conditions will be performed.  


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j:
If a taper is decided based on the judgment of the investigator, dispensing the study drug should be needed.
k:
The visit for transition from the 8 mg Treatment Phase to the Extension Phase before completion of the 8 mg Treatment Phase


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Table 5
Schedule of Procedures/Assessments (Extension Phase) in Study E2007-J000-342
Phase
Extension Phasea
Follow-up Phasea
Study Week(s) (from start date of 
Extension Phase)
Week 6
Week 12
Week 18
Week 26
Every 12 
weeks 
thereafter
4 weeks after the 
last dose b, i
Study Day(s) (start date of 
Extension Phase)
Day 43
Day 85
Day 127
Day 183
–
–
Visit
10
11
12
13
14~
–
Unscheduled 
visit f
Early discontinuation 
visit g
End of study 
visit h
Procedure/Assessment
Physical examinations
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
Adverse eventsc
X
X
X
X
X
X
X
X
X
Study drug compliance
X
X
X
X
X
X
X
Dispense subject diary
X
X
X
X
X
X
X
Return and review subject diary
X
X
X
X
X
X
X
X
Vital signs ad weight
X
X
X
X
X
X
X
Clinical laboratory evaluations
X
X
X
X
X
X
X
Urine pregnancy testd
X
X
X
X
X
X
X
X
X
12-Lead ECG e
X
X
X
X
X
X
EQ-5D-5L
X
X
X
Dispense study drug
X
X
X
X
X
Return unused medication
X
X
X
X
X
X
X
β-hCG = beta-human chorionic gonadotropin, ECG = electrocardiogram, EQ-5D-5L = EuroQol 5 Dimensions 5 Levels.
a:
Visit to be done within ±7 days of the schedule. Each visit to be specified based on the start date of the Extension Phase
b:
Conduct 4 weeks after complete withdrawal of perampanel, if perampanel is tapered. Return unused medication is needed. 
c:
Adverse events will be collected from the time the subject signs the informed consent/assent form through the last visit. Serious adverse events will be collected for 28 days after the subject’s last 
dose.
d:
Only potentially pregnant female subjects will undergo the urine β-hCG pregnancy test.
e:
Only subjects whose QTcF is measured as >450 ms at any Visit will undergo additional 2 consecutive ECGs at 5- to 10-minute intervals (a total of 3 ECGs) to confirm the abnormality.
f:
At an unscheduled Visit, only the procedures/assessments that the investigators etc. has judged as necessary according to the subject’s conditions will be performed.
g:
If a taper is decided based on the judgment of the investigator, dispensing the study drug should be needed.
h:
Once perampanel monotherapy is approved in each country, an End of Study Visit should be conducted promptly, and the subject would have to switch to the commercial product.
i: 
Follow-up Visit is not required for subjects who will be switching to the commercial product and attend an End of study visit.


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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies evaluating the 
effect of AEDs.  
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, vital signs, weight, 12-lead ECG, and assessment of AEs, are 
standard evaluations to ensure subject safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 1 business day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected for 28 days
after the subject’s last dose.  All SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment or any protocol-required procedure should be reported to the sponsor regardless of 
the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject 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 


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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.  
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 


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is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Not applicable.  
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 3 and Table 4).  
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons.  Study disposition information will be collected on the Subject Disposition CRF.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the CRF.


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Adverse events associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Sections 9.5.1.5.1 and 9.5.1.5.2.  Abuse is always to be captured as an AE.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator must sign the completed CRF to attest to 
its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released.  Statistical analyses will be performed 
using SAS software or other validated statistical software as required.  


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9.7.1
Statistical and Analytical Plans
The statistical analyses of the study data are described in this section.  Further details of the 
analytical plan will be provided in a separate statistical analysis plan (SAP), which will be
finalized before database lock.  
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is defined as follows.  

The seizure free rate in the 26-week Maintenance Period for subjects with POS
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period of 4 mg and regardless of perampanel dose will be calculated.  For 
subjects who increase the perampanel dose from 4 mg to 8 mg, the seizure-free rate of the 
26-week Maintenance Period of 8 mg will be evaluated to calculate the number (percentage) 
of subjects who achieved seizure-free regardless of perampanel dose.
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints are defined as follows.  

The seizure free rate in the 52-week treatment (ie, 26-week Maintenance Period plus 26-
week Extension Phase) for subjects with POS

Time to first seizure onset and time to withdrawal from the study from the first date of 
the Maintenance Period 

The safety and tolerability of perampanel
9.7.1.1.3
EXPLORATORY ENDPOINTS
The exploratory endpoints are defined as follows.  

The seizure free rate in the 26-week Maintenance Period for subjects with POS by types 
of partial seizure

The percent change in seizure frequency of POS per 28 days in the Maintenance Period 
and Extension Phase relative to the Pretreatment Phase

The pharmacokinetics of perampanel as monotherapy

The effect of perampanel on subjects’ quality of life with EQ-5D-5L measurements


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9.7.1.2
Definitions of Analysis Sets
Safety Analysis Set
The Safety Analysis Set is the group of subjects who sign informed consent, receive at least 
1 dose of study drug and have at least 1 postdose safety assessment.
Intent-to-Treat (ITT) Analysis Set
The ITT Analysis Set is the group of subjects who sign informed consent, receive at least 
1 dose of study drug and have at least 1 postdose primary efficacy measurement.
Modified Intent-to-Treat (mITT) Analysis Set
The mITT Analysis Set is the subset of the ITT Analysis Set who enter the 4 mg 
Maintenance Period and have at least 1 postdose primary efficacy measurement in the 26-
week Maintenance Period.
9.7.1.3
Subject Disposition
The number (percentage) of subjects screened for study entry and screen failures, and the 
primary reason for screen failures will be summarized.  The number (percentage) of treated 
subjects will be summarized as well as subjects who discontinued from the study treatment 
and reasons for discontinuation from study treatment.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized using descriptive statistics.  Continuous demographic and baseline variables 
include age, height, weight, and body mass index (BMI); categorical variables include sex, 
age group (<65 years, ≥65 years).  This summary table will be generated on the ITT Analysis 
Set if the Safety Analysis Set and the ITT Analysis Set are not identical.  This summary table 
will also be generated on the mITT Analysis Set.  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by Anatomical Therapeutic Chemical (ATC) class (ie, anatomical 
class, therapeutic class, pharmacologic class, chemical class), and WHO DD preferred term.  
This summary table will be generated on the ITT Analysis Set if the Safety Analysis Set and 
the ITT Analysis Set are not identical.  
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) 


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started on or after the date of the first dose of study drug up to the completion or 
discontinuation of the subject after the subject’s last dose.  All medications will be presented 
in subject data listings.  
9.7.1.6
Efficacy Analyses
All efficacy analyses will be performed based on the mITT Analysis Set unless otherwise 
noted.  
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period of 4 mg and the corresponding 95% confidence interval (CI) will 
be calculated on the mITT Analysis Set.  The primary interest of this study will be to confirm 
that the 95% lower CI is above the pre-specified threshold (ie, 40%).  If subjects experience 
no seizures during the 4 mg Maintenance Period, those will be regarded as seizure-free in this 
analysis.  Otherwise, subjects will be regarded as non-seizure-free.  
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period regardless of perampanel dose and the corresponding 95% CI will 
be calculated on the mITT Analysis Set.  To examine if the 95% lower CI exceeds the 
threshold (ie, 40%) is the key secondary efficacy analysis.
The number (percentage) of subjects in the mITT population with POS who achieved 
seizure-free during the 52-week treatment (ie, 26-week Maintenance Period and 26-week 
Extension Phase) and the corresponding 95% confidence interval (CI) will be calculated.
Median time to first seizure onset will be estimated by Kaplan-Meier method. Time to first 
seizure onset will be defined as the time from the first date of Maintenance Period to the date 
of first seizure onset during the Maintenance Period. Subjects who withdraw from the study 
before first seizure onset will be censored at the time of study discontinuation.
Median time to withdraw from the study will be estimated by Kaplan-Meier method. Time 
to withdraw from the study will be defined as the time from the first date of Maintenance 
Period to the date of discontinuation from the study. Subjects who are ongoing at the data 
cutoff will be censored at the time of data cutoff.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period and the corresponding 95% confidence interval (CI) will be 
calculated by types of partial seizure.
The percent change in seizure frequency of POS per 28 days in the Maintenance Period and 
Extension Phase relative to the Pretreatment Phase will be summarized.


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The change in EQ-5D-5L measurements from baseline to each postbaseline visit will be 
summarized.  
9.7.1.6.4
ANALYSIS AT PRIMARY ENDPOINT ACHIEVEMENT
If the primary endpoint is successfully achieved, statistical analysis of the Treatment Phase 
will be performed when all subjects end the 4 mg Maintenance Period. 
At that time, the subjects who are continuing the 8 mg Treatment Phase will be regarded as 
non-seizure free, and their data until the latest visit will be analyzed. In addition, subsequent 
data after that will be regarded as data of the Extension Phase.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for pharmacokinetic analysis.  Summary statistics of 
plasma perampanel concentrations will be obtained by visit.  
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Not applicable.  
9.7.1.8
Safety Analyses
All safety analyses will be performed based on the Safety Analysis Set. Safety data will be 
summarized using descriptive statistics (eg, 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, 
weight, and 12-lead ECG results.  Study Day 1 for all safety analyses will be defined as the 
date of the first dose of study drug.  
9.7.1.8.1
EXTENT OF EXPOSURE
Extent of exposure to the study drug (eg, mean daily dose, maximum dose, last dose, 
duration of exposure) will be summarized using descriptive statistics.  The exposure to the 
study drug will be classified by an appropriate category, and the number (percentage) of 
subjects will be summarized for the category, if necessary.  
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 19.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database.  


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A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during time 
from the first dose of study drug to the last visit or 28 days after the subject’s last dose, 
whichever comes later, having been absent at pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized.  The incidence of TEAEs will be reported as the number 
(percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted only once 
within an SOC and PT, even if the subject experienced more than 1 TEAE within a specific 
SOC and PT.  The number (percentage) of subjects with TEAEs will also be summarized by 
maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).  
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.  A subject data listing of all SAEs will be 
provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT. A subject data listing of all AEs leading to 
discontinuation from study drug will be provided.
The TEAEs will be summarized for the Treatment Phase and the entire study period (ie, the 
Treatment Phase or the Extension Phase).  
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters, the actual value and the change from baseline to each 
postbaseline visit will be summarized by visit using descriptive statistics.  Qualitative 
parameters will be summarized using frequencies (number and percentage of subjects), and 
changes from baseline to each postbaseline visit will be reported using shift tables.  
Percentages will be based on the number of subjects with both nonmissing baseline and 
relevant postbaseline results.


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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 shift tables that compare the baseline LNH classification to the LNH classification at each 
postbaseline visit.  
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used 
to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  The definition of 
TEMAV will be detailed in the SAP.  When displaying the incidence of TEMAVs, each 
subject may be counted once in the laboratory parameter high and in the laboratory parameter 
low categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic blood pressure, 
pulse, respiratory rate, temperature) and weight; and changes from baseline will be presented 
by visit and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) by visit.
9.7.1.8.6
OTHER SAFETY ANALYSES
Not applicable.  
9.7.1.9
Other Analyses
Not applicable.  
9.7.2
Determination of Sample Size
In this study, perampanel will be determined to be efficacious if, in untreated subjects with 
POS (including secondary generalized seizures), the lower limit of the 95% confidence 
interval for the seizure-free rate in the 26-week Maintenance Period is above the pre-
specified threshold (40%).
Based on the results from research papers of AEDs for mono-therapy (Chadwick, et al., 
1999, Arroyo, et al., 2005, Mikkelsen, et al., 1981, Heller, et al., 1995, and Kaneko, et al., 
2015), the expected seizure free rate for other AEDs would be assumed 50.0%.  According to 
Glauser, et al. (2013), the relative difference >20% versus the adequate comparator’s efficacy 
point estimate could be considered non-inferior margin if its 95% lower confidence limit was 
above this lower acceptable cutoff (Glauser, et. al., 2013).


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Under the assumption that the expected seizure free rate of perampanel in the 26-week 
Maintenance Period would be 60%, sample size of 72 will provide greater than 90% power 
that the lower limit of the 95% confidence interval for the seizure free rate in the 26-week 
Maintenance Period is above 40%. Taking into consideration the drop-out rate in the 
Titration Period (approximately 10%), 80 subjects need to be as the ITT Analysis Set.  
If the number of subjects who achieve seizure-free is above the following criteria, this study 
can declare to confirm the efficacy of perampanel.
Table 6
Seizure free rate and 95% Confidence Interval
Target Number of mITT
Minimum Number of Subjects Who 
Achieve 26-week Seizure-free to 
Exceed the Pre-specified Threshold
Seizure-free Rate
(95% CI) (%)a
71
38
53.5 (41.3, 65.5)
72
38
52.8 (40.7, 64.7)
73
38
52.1 (40.0, 63.9)
74
39
52.7 (40.7, 64.4)
75
39
52.0 (40.2, 63.7)
76
40
52.6 (40.8, 64.2)
77
40
51.9 (40.3, 63.5)
78
41
52.6 (40.9, 64.0)
79
41
51.9 (40.4, 63.3)
80
42
52.5 (41.0, 63.8)
81
42
51.9 (40.5, 63.1)
CI = confidence interval, mITT = modified intent-to-treat.  
a:  95%CI is based on Clopper-Pearson method.
9.7.3
Interim Analysis
No interim analysis is planned for this study.  
9.7.4
Other Statistical/Analytical Issues
Not applicable.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.  


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10 REFERENCE LIST
Arroyo S, Dodson WE, Privitera MD, Glauser TA, Naritoku DK, Dlugos DJ, et al. 
Randomized dose-controlled study of topiramate as first-line therapy in epilepsy. Acta 
Neurol Scand. 2005;112:214–22.
Chadwick D, Vigabatrin European Monotherapy Study Group. Safety and efficacy of 
vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised 
double-blind study. Lancet. 1999;354:13–9.
Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, et al. 
Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial 
monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54:551–63.
Guideline for epilepsy treatment 2010 Supplement (2014). Japanese Society of Neurology, 
2014.  
Guideline on clinical investigation of medicinal products in the treatment of epileptic 
disorders. EMA, 2010.
Heller AJ, Chesterman P, Elwes RD, Crawford P, Chadwick D, Johnson AL, et al. 
Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult 
epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry. 
1995;58:44–50.
Kaneko S, Chan R, Nakatsu T, Yoshida K. A Phase III, multicenter, randomized, open-label 
study of levetiracetam monotherapy in Japanese patients with partial onset seizures. 
J.Jpn.Epil.Soc. 2015;32:519-32.
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Eng J Med. 
2000;342(5):314–9.
Matsuura M, editor. Clinical question of epilepsy examination 194. Shindan to Chiryo Sha,
Inc., 2009.
Mikkelsen B, Berggreen P, Joensen P, Kristensen O, Køhler O, Mikkelsen BO. Clonazepam 
(Rivotril®) and Carbamazepine (Tegretol®) in Psychomotor Epilepsy: A Randomized 
Multicenter Trial. Epilepsia. 1981;22:415–20.
Mintzer S, French JA, Perucca E, Cramer JA, Messenheimer JA, Blum DE, et al. Is a 
separate monotherapy indication warranted for antiepileptic drugs?. The Lancet Neurology. 
2015;14(12):1229–40.
Walker MC, Sander JW. The impact of new antiepileptic drugs on the prognosis of epilepsy 
Seizure freedom should be the ultimate goal. Neurology. 1996;46(4):912–4.


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Yamamoto T, Hong SB, Shimizu M, Sato K, Numachi Y. Lamotrigine monotherapy in 
newly diagnosed epilepsy or recurrent epilepsy: A multi-center, open-label study. Epilepsy & 
Seizure. 2014;7: 5–65.


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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 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.  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/contract research organization’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 (or if regionally required, the head of the medical 
institution) will allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to 
assure compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production


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
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, 
rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of how 
these images are stored, including microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs

CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each consented 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.  For 
the following item(s), the data recorded directly on the CRF are to be considered source data:

Study drug compliance (eg, the reason for any change of dosage)

Indication for prior/concomitant medication (drug/therapy)

Discontinuation information (eg, in the case of lost to follow-up due to the subject 
choice)

Sampling date and time for the drug concentration; date and time of dosing of study drug

Sampling date for the clinical laboratory tests

Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome)


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11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, ICFs, and IRB/IEC correspondence).  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, the investigator contact 
the sponsor, allowing the sponsor the option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  A government regulatory authority may request an inspection during the study 
or after its completion.
11.8
Handling of Study Drug
All study drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study (upon request).  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 
(upon request) to the sponsor.
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 


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pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
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 – 3.0×109/L
<LLN – 3000/mm3
<3.0 – 2.0×109/L
<3000 – 2000/mm3
<2.0 – 1.0×109/L
<2000 – 1000/mm3
<1.0×109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8×109/L
<800 – 500/mm3
<0.8 – 0.5×109/L
<500 – 200/mm3
<0.5 – 0.2×109/L
<200/mm3
<0.2×109/L
Neutrophils 
<LLN – 1.5×109/L
<LLN – 1500/mm3
<1.5 – 1.0×109/L
<1500 – 1000/mm3
<1.0 – 0.5×109/L
<1000 – 500/mm3
<0.5×109/L
<500/mm3
Platelets
<LLN – 75.0×109/L
<LLN – 75,000/mm3
<75.0 – 50.0×109/L
<75,000 – 50,000/mm3
<50.0 – 25.0×109/L
<50,000 – 25,000/mm3
<25.0×109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
ALP
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN
ALT
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN
AST
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN
Bicarbonate, serum-low
<LLN – 16 mmol/L
11 – 15 mmol/L
8 – 10 mmol/L
<8 mmol/L
Bilirubin (hyperbilirubinemia)
>ULN – 1.5×ULN 
>1.5 – 3.0×ULN
>3.0 – 10.0×ULN 
>10.0×ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5×ULN
>1.5 – 3.0×ULN
>3.0 – 6.0×ULN
>6.0×ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0×ULN
>3.0 – 5.0×ULN
>5.0 – 20.0×ULN
>20.0×ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALP = alkaline phosphatase, 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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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2007-J000-342
Study Protocol Title:
A multicenter, uncontrolled, open-label study and extension 
study for verification of efficacy and safety for perampanel 
monotherapy in untreated patients with partial onset seizures 
(including secondarily generalized seizures)
Investigational Product 
Name:
E2007/Fycompa® (perampanel)
SIGNATURES
Authors:
 Eisai Co., Ltd.
Date
 Eisai Co., Ltd.
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2007-J000-342
Study Protocol Title:
A multicenter, uncontrolled, open-label study and extension 
study for verification of efficacy and safety for perampanel 
monotherapy in untreated patients with partial onset seizures 
(including secondarily generalized seizures)
Investigational Product
Name:
E2007/Fycompa® (perampanel)
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
16.1.9 
Documentation of Statistical Methods 
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Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
Study 
Protocol 
Number: 
E2007-J000-342 
Study 
Protocol 
Title: 
A multicenter, uncontrolled, open-label study and extension study for 
verification of efficacy and safety for perampanel monotherapy in 
untreated patients with partial onset seizures (including secondarily 
generalized seizures) 
Date: 
15 Apr 2019 
Version: 
4.0 
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PPD
PPD
PPD
PPD


Statistical Analysis Plan 
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Page 3 of 29 
 
1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ....................................................................................... 3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................ 5 
3 
INTRODUCTION ................................................................................................. 7 
3.1 
Study Objectives .......................................................................................... 7 
3.1.1 
Primary Objective .............................................................................. 7 
3.1.2 
Secondary Objectives ......................................................................... 7 
3.1.3 
Exploratory Objective ........................................................................ 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 ....................................................................... 10 
5.1.3 
Exploratory Endpoints ..................................................................... 10 
5.2 
Study Subjects ............................................................................................ 10 
5.2.1 
Definitions of Analysis Sets ............................................................. 10 
5.2.2 
Subject Disposition .......................................................................... 10 
5.2.3 
Protocol Deviations .......................................................................... 11 
5.2.4 
Demographic and Other Baseline Characteristics ........................... 11 
5.2.5 
Prior and Concomitant Therapy ....................................................... 12 
5.2.6 
Treatment Compliance ..................................................................... 12 
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 ............................................................... 13 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers ......................... 13 
5.3.6 
Other Considerations ....................................................................... 13 
5.4 
Efficacy Analyses ...................................................................................... 13 
5.4.1 
Primary Efficacy Analyses .............................................................. 13 
5.4.2 
Secondary Efficacy Analyses .......................................................... 14 
5.4.3 
Exploratory Efficacy Analyses ........................................................ 14 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ................................................................................... 16 
5.5.1 
Pharmacokinetic Analyses ............................................................... 16 
5.5.1.1 
Plasma Concentration Analysis ............................................. 16 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses ........................................................................................... 17 
5.6 
Safety Analyses .......................................................................................... 17 
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5.6.1 
Extent of Exposure ........................................................................... 17 
5.6.2 
Adverse Events ................................................................................ 18 
5.6.3 
Laboratory Values ............................................................................ 19 
5.6.4 
Vital Signs ........................................................................................ 20 
5.6.5 
Electrocardiograms .......................................................................... 20 
5.6.6 
Other Safety Analyses ...................................................................... 20 
5.7 
Other Analyses ........................................................................................... 20 
6 
INTERIM ANALYSES ....................................................................................... 20 
7 
CHANGES IN THE PLANNED ANALYSES ................................................... 20 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ................... 22 
8.1 
General Data Handling .............................................................................. 22 
8.2 
Efficacy Data Handling .............................................................................. 22 
8.3 
Safety Data Handling ................................................................................. 24 
8.4 
Pharmacokinetic Data Handling ................................................................ 25 
8.4.1 
Lower Limit of Quantification of Perampanel Plasma 
Concentration ................................................................................... 25 
8.4.2 
BLQ Handling for Calculation of PK Parameters ........................... 25 
8.4.3 
BLQ Handling for Developing Concentration-Time Profiles ......... 25 
8.4.4 
Handling of Anomalous Concentration Values ............................... 26 
8.4.5 
General Rules for Presentation of Drug Concentrations and PK 
Parameters ........................................................................................ 26 
9 
PROGRAMMING SPECIFICATIONS .............................................................. 26 
10 STATISTICAL SOFTWARE .............................................................................. 26 
11 MOCK TABLES, LISTINGS, AND GRAPHS .................................................. 26 
12 REFERENCES .................................................................................................... 26 
13 APPENDICES ..................................................................................................... 28 
13.1 
Sponsor’s Grading for Laboratory Values ................................................. 28 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMPA 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
β-hCG 
beta-human chorionic gonadotropin 
BMI 
Body mass index 
BUN 
blood urea nitrogen 
CoA 
certificate(s) of analysis 
CI 
confidence interval 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CYP 
cytochrome P450 
EAID 
enzyme inducing antiepileptic drug 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
EIAED 
enzyme inducing antiepileptic drug 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels 
EU 
European Union 
GABA 
gamma-aminobutylic acid 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
ILAE 
International League Against Epilepsy 
IRB 
institutional review board 
ITT 
intent-to-treat 
IUPAC 
International Union of Pure and Applied Chemistry 
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Abbreviation 
Term 
IUS 
intrauterine hormone-releasing system 
LC-MS/MS 
liquid chromatography with tandem mass spectrometry 
LLT 
lowest level term 
LNH 
low/normal/high 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
POS 
partial onset seizure 
PT 
preferred term 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory values 
ULN 
upper limit of normal 
VNS 
vagal nerve stimulation 
WHO DD 
World Health Organization Drug Dictionary 
 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and 
statistical methods in detail that will be used to analyze and report results Eisai Protocol 
E2007-J000-342. 
If the primary endpoint is successfully achieved, statistical analysis of the Treatment Phase 
will be performed when all subjects end the 4 mg Maintenance Period. At that time, the 
subjects who are continuing the 8 mg Treatment Phase will be regarded as non-seizure free, 
and their data until the latest visit will be analyzed.  In addition, subsequent data after that 
will be regarded as data of the Extension Phase. 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
To evaluate the seizure-free rate of the 26-week Maintenance Period in untreated patients 
with partial onset seizures (POS) 
3.1.2 
Secondary Objectives 
・ To evaluate the seizure-free rate of the 52-week treatment in untreated patients with 
POS 
・ To confirm time to first seizure onset and time to withdrawal from the study from the 
first date of the Maintenance Period in untreated patients with POS 
・ To evaluate the safety and tolerability of perampanel monotherapy in untreated patients 
with POS 
3.1.3 
Exploratory Objective 
・ To investigate the seizure free-rate of the 26-week Maintenance Period by seizure type 
in untreated patients with POS 
・ To investigate the percent change in seizure frequency from baseline during the 
Maintenance Period and Extension Phase in untreated patients.  
・ To investigate the pharmacokinetics of perampanel as monotherapy 
・ To evaluate the impact of perampanel over time (End of Treatment – Baseline) on 
overall health-related quality of life as measured by the EuroQol 5 Dimensions 5 
Levels (EQ-5D-5L) 
3.2 
Overall Study Design and Plan 
This study is a multicenter, uncontrolled, open-label, single-arm study in untreated patients 
with partial onset seizures (including secondarily generalized seizures). This study consists 
of a Pretreatment Phase, a Treatment Phase (a Titration Period, a Maintenance Period), an 
Extension Phase, and a Follow-up Phase. 
Pretreatment Phase 
During the Pretreatment Phase (maximally 4 weeks), patients will be screened and be 
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assessed for their eligibility to participate in the study. 
Treatment Phase 
The Treatment Phase consists of the 4 mg Treatment Phase (the Titration Period [6 weeks] 
and the Maintenance Period [26 weeks]) and the 8 mg Treatment Phase (the Titration Period 
[4 weeks] and the Maintenance Period [26 weeks]) if subjects require higher dose.  
Extension Phase 
When subjects complete the Treatment Phase and agree to continue receiving the 
perampanel monotherapy, they could enter the Extension Phase. Subjects will continue to 
receive perampanel until 3 or less months from the date of approval of perampanel 
monotherapy in each country unless subjects experience tolerability issues such as 
occurrence of adverse events or need to take other antiepileptic drugs (AEDs) because of 
insufficient efficacy of perampanel. 
Follow-up Phase 
Subjects who will finish or discontinue the study will conduct the follow-up visit 4 weeks 
after withdrawal of perampanel. 
The study design is shown in Figure 1. 
 
Figure 1 Study Design 
  
4 
DETERMINATION OF SAMPLE SIZE 
In this study, perampanel will be determined to be efficacious if, in untreated subjects with 
POS (including secondary generalized seizures), the lower limit of the 95% confidence 
interval for the seizure-free rate in the 26-week Maintenance Period is above the pre-
specified threshold (40%). 
Based on the results from research papers of AEDs for mono-therapy (Chadwick, et al., 
1999, Arroyo, et al., 2005, Mikkelsen, et al., 1981, Heller, et al., 1995, and Kaneko, et al., 
2015), the expected seizure free rate for other AEDs would be assumed 50.0%.  According 
to Glauser, et al. (2013), the relative difference >20% versus the adequate comparator’s 
2 mg QD
4 mg QD
6 mg QD
8 mg QD*
Day 1 
Week6
Week2 
Week32
Day 1 
Week 4
Week 2 
Week 30
Primary 
endpoint
Primary 
endpoint
Extension Phase or 
Study  discontinuation
26 weeks
26 weeks
4 mg Titration Period
4 mg Maintenance Period
8 mg Titration Period
8 mg Maintenance Period
Seizure occur
Pretreatment 
Phase
Day -28
* If 8 mg is not tolerable, subjects will be down-titrated to 6 mg and continue the Maintenance Period
Seizure occur
Extension 
Phase
Extension 
Phase
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efficacy point estimate could be considered non-inferior margin if its 95% lower confidence 
limit was above this lower acceptable cutoff (Glauser, et. al., 2013). 
Under the assumption that the expected seizure free rate of perampanel in the 26-week 
Maintenance Period would be 60%, sample size of 72 will provide greater than 90% power 
that the lower limit of the 95% confidence interval for the seizure free rate in the 26-week 
Maintenance Period is above 40%.  Taking into consideration the drop-out rate in the 
Titration Period (approximately 10%), 80 subjects need to be as the ITT Analysis Set.   
If the number of subjects who achieve seizure-free is above the following criteria, this study 
can declare to confirm the efficacy of perampanel. 
Table 1 
Seizure free rate and 95% Confidence Interval 
Target Number of mITT 
Minimum Number of Subjects Who 
Achieve 
26-week 
Seizure-free 
to 
Exceed the Pre-specified Threshold 
Seizure-free Rate 
(95% CI) (%)a 
71 
38 
53.5 (41.3, 65.5) 
72 
38 
52.8 (40.7, 64.7) 
73 
38 
52.1 (40.0, 63.9) 
74 
39 
52.7 (40.7, 64.4) 
75 
39 
52.0 (40.2, 63.7) 
76 
40 
52.6 (40.8, 64.2) 
77 
40 
51.9 (40.3, 63.5) 
78 
41 
52.6 (40.9, 64.0) 
79 
41 
51.9 (40.4, 63.3) 
80 
42 
52.5 (41.0, 63.8) 
81 
42 
51.9 (40.5, 63.1) 
CI = confidence interval, mITT = modified intent-to-treat.   
a:  95%CI is based on Clopper-Pearson method. 
 
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 endpoint is defined as follows. 
The seizure free rate in the 26-week Maintenance Period for subjects with POS  
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period of 4 mg and regardless of perampanel dose will be calculated. 
For subjects who increase the perampanel dose from 4 mg to 8 mg, the seizure-free rate of 
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the 26-week Maintenance Period of 8 mg will be evaluated to calculate the number 
(percentage) of subjects who achieved seizure-free regardless of perampanel dose. 
5.1.2 
Secondary Endpoints 
The secondary endpoints are defined as follows. 
・ The seizure free rate in the 52-week treatment (ie, 26-week Maintenance Period plus 
26-week Extension Phase) for subjects with POS 
・ Time to first seizure onset and time to withdrawal from the study from the first date of 
the Maintenance Period 
・ The safety and tolerability of perampanel 
5.1.3 
Exploratory Endpoints 
The exploratory endpoints are defined as follows. 
・ The seizure free rate in the 26-week Maintenance Period for subjects with POS by 
types of partial seizure 
・ The percent change in seizure frequency of POS per 12 weeks in the Maintenance 
Period and Extension Phase relative to the Pretreatment Phase 
・ The pharmacokinetics of perampanel as monotherapy 
・ The effect of perampanel on subjects’ quality of life with EQ-5D-5L measurements 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
Safety Analysis Set 
The Safety Analysis Set is the group of subjects who sign informed consent, receive at least 
1 dose of study drug and have at least 1 postdose safety assessment. 
Intent-to-Treat (ITT) Analysis Set 
The ITT Analysis Set is the group of subjects who sign informed consent, receive at least 
1 dose of study drug and have at least 1 postdose primary efficacy measurement. 
Modified Intent-to-Treat (mITT) Analysis Set 
The mITT Analysis Set is the subset of the ITT Analysis Set who enter the 4 mg 
Maintenance Period and have at least 1 postdose primary efficacy measurement in the 26-
week Maintenance Period. 
The number of subjects enrolled, the number (percentage) of subjects included in each 
analysis set will be presented.  Subject data listings will be provided. 
5.2.2 
Subject Disposition 
For the summary table of screening subjects, the number (percentage) of subjects who were 
enrolled (ie, subjects who signed informed consent), entered the Treatment Phase after 
screening, failed screening, and the primary reason for screen failures will be presented.  
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For the summary of the subject disposition, the following items will be presented; 
• 
the number (percentage) of subjects who were treated/not treated 
• 
the number (percentage) of subjects who completed/discontinued the 4 mg 
Treatment Phase and the primary reason and other reason for the discontinuation 
• 
the number (percentage) of subjects who entered/completed/ongoing/discontinued 
the 8 mg Treatment Phase and the primary reason and other reason for the 
discontinuation 
• 
the number (percentage) of subjects who completed/ongoing/discontinued the 
Treatment Phase and the primary reason and other reason for the discontinuation 
• 
the number (percentage) of subjects who entered/not entered the Extension Phase 
• 
the number (percentage) of subjects who completed/ongoing/discontinued the 
Extension Phase and the primary reason and other reason for the discontinuation 
(the percentage will be based on the total subjects who entered the Extension 
Phase) 
Subject data listings will be provided. 
5.2.3 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and documented before the database lock.  
5.2.4 
Demographic and Other Baseline Characteristics 
This summary table will be generated on the ITT Analysis Set and Safety Analysis Set. 
(This will be summarized as “ITT / Safety Analysis Set” if the ITT Analysis Set and the 
Safety Analysis Set are the same.) This summary table will also be generated on the mITT 
Analysis Set. And this summary table will be performed by country (Japan/ Korea).    
Continuous demographic and baseline variables include 
・ Age 
・ Height 
・ Weight 
・ BMI 
Categorical demographic and baseline variables include 
・ Age group (< 18 years, 18 - < 65 years, 65years ≤) 
・ Sex 
・ Race 
・ Ethnicity 
・ Country 
Epilepsy specific history and characteristics at study entry will also be summarized by: 
・ History of seizures (newly diagnosed epilepsy, recurrent epilepsy) 
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・ Time since latest diagnosis of epilepsy (months) 
・ Etiology 
・ Epileptic syndrome 
・ Suspected localization of the epileptogenic region 
・ Seizure type 
 Subject data listings for demographic and other baseline characteristics will be provided. 
MEDICAL HISTORY 
A subject data listing of medical history and current medical condition will be provided. 
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) drug codes.   
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 the completion or 
discontinuation of the subject after the subject’s last dose.  Post-treatment medications will 
be defined as medications taken on or after the date of study discontinuation. 
This summary table will be generated on the ITT Analysis Set and Safety Analysis Set. 
(This will be summarized as “ITT / Safety Analysis Set” if the ITT Analysis Set and the 
Safety Analysis Set are the same.) 
The number (percentage) of subjects who took prior anti-epileptic medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) class, and WHO DD preferred 
term. This analysis will also be performed by both history of seizures (newly diagnosed 
epilepsy/recurrent epilepsy) and rescue (yes/no). 
The number (percentage) of subjects who took prior (except fot anti-epileptic medications) 
and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) class, and WHO DD preferred term. 
The concomitant medications will be summarized for the Treatment Phase and the entire 
study period (ie, the Treatment Phase or the Extension Phase). 
All medications will be presented in subject data listings. 
5.2.6 
Treatment Compliance 
Treatment compliance calculated as follows will be summarized using descriptive statistics 
for the 26-week Maintenance Period of 4 mg and the 26-week Maintenance Period of the 
last evaluated dose (ie, 4 or 8mg) on the mITT Analysis Set. 
 Total days of study drug prescribed - Days of incompliance    x 100 
  
 
 
 
Total days of study drug prescribed 
The number (percentage) of subjects in the categories <80%, >= 80% to <= 100%, >100% 
to <= 120%, and > 120% will also be summarized. 
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5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
No adjustment for covariates will be performed. 
5.3.3 
Multiple Comparisons/Multiplicity 
No statistical comparison is planned in this study. 
5.3.4 
Examination of Subgroups 
Primary efficacy analysis, the key secondary efficacy analysis and analysis of TEAEs by 
SOC and PT will be performed by the following subgroups: history of seizures (Newly 
diagnosed epilepsy/Recurrent epilepsy), age group (<18, ≥18 to <65, ≥65), country 
(Japan/Korea) and sex (Male/Female). 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
The details of handling of missing data will be described in section  8. 
5.3.6 
Other Considerations 
Not applicable. 
5.4 
Efficacy Analyses 
All efficacy analyses will be summarized with available data in the clinical database at the 
data cutoff.  The efficacy analysis will be performed based on the mITT Analysis Set, 
unless otherwise indicated.   
5.4.1 
Primary Efficacy Analyses 
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period of 4 mg and the exact corresponding 95% confidence interval 
(CI) will be calculated on the mITT Analysis Set.  The primary interest of this study will 
be to confirm that the exact 95% lower CI is above the pre-specified threshold (ie, 40%).  
If subjects experience no seizures during the 4 mg Maintenance Period, those will be 
regarded as seizure-free in this analysis.  Otherwise, subjects will be regarded as non-
seizure-free. 
The definition of seizure-free status will be detailed in the section 8.  
SENSITIVITY ANALYSIS 
Sensitivity analyses for the primary efficacy analysis will be performed on the ITT Analysis 
Set.  
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5.4.2 
Secondary Efficacy Analyses 
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period regardless of perampanel dose and the exact corresponding 95% 
CI will be calculated.  To examine if the 95% lower CI exceeds the threshold (ie, 40%) is 
the key secondary efficacy analysis. The 26-week Maintenance Period mentioned here is 
the Maintenance Period of the last evaluated dose (ie, 4 or 8mg). 
The number (percentage) of subjects with POS who achieved seizure-free during the 52-
week treatment of 4 mg (ie, 26-week Maintenance Period of 4 mg and 26-week Extension 
Phase) and the corresponding 95% CI will be calculated. 
The number (percentage) of subjects with POS who achieved seizure-free during the 52-
week treatment (ie, 26-week Maintenance Period and 26-week Extension Phase) and the 
corresponding 95% CI will be calculated.  The 26-week Maintenance Period mentioned 
here is the Maintenance Period of the last evaluated dose. 
Median, Q1 and Q3 time to first seizure onset will be estimated by Kaplan-Meier method.  
The cumulative probability of the event (ie, seizure occurrence) at every 26 weeks will also 
be calculated.  Corresponding 2-sided 95% CIs will also be presented.  Kaplan-Meier 
estimates of the time to event will be plotted over time.  The Follow-up Phase will not be 
included in this analysis. The above analysis will be summarized for the entire study period 
of 4 mg and the entire study period of the last evaluated dose, respectively. 
Time to first seizure onset will be defined as the period from the first dose of study drug in 
the Maintenance Period of the last evaluated dose to the first seizure onset.  The censoring 
rule for the analysis of time to first seizure onset will be provide in the section 8. 
Median, Q1 and Q3 time to withdraw from the study will be estimated by Kaplan-Meier 
method.  The cumulative probability of the event (ie, withdraw from the study) at every 26 
weeks will also be calculated.  Corresponding 2-sided 95% CIs will also be presented.  
Kaplan-Meier estimates of the time to event will be plotted over time.  The Follow-up Phase 
will not be the period to be analyzed. The above analysis will be summarized for the entire 
study period of 4 mg and the entire study period of the last evaluated dose, respectively. 
Time to withdraw from the study will be defined as the period from the first dose of study 
drug in the Maintenance Period of the last evaluated dose to the date of study withdrawal.  
The censoring rule for the analysis of time to first seizure onset will be provide in the 
section 8. 
5.4.3 
Exploratory Efficacy Analyses 
The number (percentage) of subjects with POS who achieved seizure-free during the entire 
study period and the corresponding 95% confidence interval (CI) will be calculated.  The 
above analysis will also be summarized for the period between the Maintenance Period of 
the last evaluated dose and the date of data cutoff or the date of study discontinuation, 
whichever comes first. 
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period of 4 mg and the 26-week Maintenance Period of the last 
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evaluated dose, and each corresponding 95% confidence interval (CI) will be calculated by 
types of partial seizure (ie, complex partial seizures, complex partial with secondarily 
generalized seizure, total of the 2 type). 
The number (percentage) of subjects with POS who achieved seizure-free during the 52-
week treatment of 4 mg (ie, 26-week Maintenance Period of 4 mg and 26-week Extension 
Phase) and the corresponding 95% CI will be calculated in subjects who had been scheduled 
to complete 52-week treatment and mITT analysis set. The above analysis will be 
performed by country, and will also be performed for subjects who completed 26-week 
maintenance period of 4 mg and did not enter extension phase excluded. 
The number (percentage) of subjects with POS who achieved seizure-free during the 52-
week treatment (ie, 26-week Maintenance Period and 26-week Extension Phase) and the 
corresponding 95% CI will be calculated in subjects who had been scheduled to complete 
52-Week treatment and mITT analysis set. The 26-week Maintenance Period mentioned 
here is the Maintenance Period of the last evaluated dose. The above analysis will be 
performed by country, and will also be performed for subjects who completed 26-week 
maintenance period of 4 mg and did not enter extension phase excluded. 
Median, Q1 and Q3 time to first seizure onset will be estimated by Kaplan-Meier method 
by country. The cumulative probability of the event (ie, seizure occurrence) at every 26 
weeks will be calculated by country. Corresponding 2-sided 95% CIs will also be presented 
by country. The Follow-up Phase will not be included in this analysis. The above analysis 
will be summarized for the entire study period of 4 mg and the entire study period of the 
last evaluated dose, respectively. 
Median, Q1 and Q3 time to withdraw from the study will be estimated by Kaplan-Meier 
method by country.  The cumulative probability of the event (ie, withdraw from the study) 
at every 26 weeks will also be calculated by country. Corresponding 2-sided 95% CIs will 
also be presented by country. The Follow-up Phase will not be the period to be analyzed. 
The above analysis will be summarized for the entire study period of 4 mg and the entire 
study period of the last evaluated dose, respectively. 
The number (percentage) of subjects with POS who achieved seizure-free during the 26-
week Maintenance Period of 4 mg and the 26-week Maintenance Period of the last 
evaluated dose, and each corresponding 95% CI will be calculated by Medical History of 
Simple Partial Seizure Type. 
 
The percent change in seizure frequency of POS per 12 weeks in the Maintenance Period 
of the last evaluated dose and Extension Phase relative to the baseline will be summarized, 
respectively.  The derivation of seizure frequency will be defined in the section 8. 
The change in EQ-5D-5L measurements from baseline to each postbaseline (ie, the 
Treatment Phase and the Extension Phase) visit, end of treatment phase (the 26-week 
Maintenance Period of the last evaluated dose) and end of treatment (the entire study of the 
last evaluated dose) will be summarized. 
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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual perampanel plasma concentration 
listings and summaries of perampanel plasma concentrations. Plasma perampanel 
concentration data at Early transition visit or Early discontinuation visit will not be included 
in tables and figures for pharmacokinetic analysis. The plasma perampanel concentration 
data will be excluded from the plasma concentration analysis if the treatment compliance 
during site visits at Visit 4, 5, 7, 4a, 5a, or 7a where PK blood sampling will be conducted 
is inadequate for PK evaluation including following cases but not limited to: 
- 
The dose amount is not constant during the last 3 doses of perampanel before PK 
blood sampling at Visit 4, 5, 7, 4a, 5a, or 7a. 
- 
The perampanel is not administered on consecutive 3 days just before PK blood 
sampling at Visit 4, 5, 7, 4a, 5a, or 7a. 
- 
Treatment compliance rate during site visits before PK blood sampling at Visit 4, 
5, 7, 4a, 5a, or 7a is <80%. 
  
5.5.1.1 
Plasma Concentration Analysis 
<Concentration> 
Plasma concentrations for perampanel will be summarized using summary statistics (n, 
mean, SD, median, min and max) at the 4 mg Treatment Phase and at the 8 mg Treatment 
Phase, respectively, by actual dose of the Treatment Phase for all subjects. 
Plasma concentrations for perampanel will be summarized using summary statistics (n, 
mean, SD, median, min and max) at the 4 mg Treatment Phase and at the 8 mg Treatment 
Phase, respectively, by actual dose of the Treatment Phase for patients who have at least 
one plasma perampanel concentration data at the 8 mg Treatment Phase (Titration Period 
and Maintenance Period). 
Plasma concentrations of perampanel will be listed for each subject by actual sampling time. 
The relationship between plasma concentrations of perampanel at steady state and seizure 
free status will be analyzed graphically. 
- 
Individual plasma concentrations of perampanel will be displayed by seizure-free 
status of the 26-week Maintenance Period at week 6 of the Titration Period of 4 
mg (Visit 4) and at week 4 of the Titration Period of 8 mg (Visit 4a). 
- 
Last plasma concentrations of perampanel of 4 mg Treatment Phase and 8 mg 
Treatment Phase will be displayed individually in subjects who have at least 1  each 
plasma perampanel concentration data of both the Treatment Phase of 4 mg and 8 
mg. 
 
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5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable 
5.6 
Safety Analyses 
All safety analysis will be performed based on the Safety Analysis Set.  Safety data will be 
summarized using descriptive statistics (e.g., n, mean, standard deviation, median, 
minimum, maximum for continuous variables; number [percentage] for categorical 
variables). The analysis window for summarizing the safety parameters by visit will be 
defined in the section 8.3.  The follow-up Phase will not be included in the by visit 
summary tables, unless otherwise indicates.  
5.6.1 
Extent of Exposure 
The parameters for extent of exposure defined as follows will be summarized for the period 
of the entire study (treatment phase or the extension phase).  Here “dose” is not actual dose 
but planned dose. Duration of exposure, last dose and mean daily dose will also be 
performed for the period of treatment phase. 
1. Duration of exposure (weeks)  
 From the date of first study drug dosing to the date of last study drug dosing 
including the Follow-up Phase 
2. Maximum dose 
 From the date of first study drug dosing to the date of last study drug dosing not 
including the Follow-up Phase 
3. Last dose 
 From the date of first study drug dosing to the date of last study drug dosing not 
including the Follow-up Phase 
4. Mean daily dose 
 From the date of first study drug dosing to the date of last study drug dosing not 
including the Follow-up Phase 
5. Number of subject-weeks 
 Summation over all subject’s exposure durations 
 
 
Duration of exposure to the study drug for the period of the entire study will be classified 
by categories of cumulative weeks (ie, > 6 weeks, > 14 weeks, > 26weeks, > 38 weeks, > 
52 weeks, > 64 weeks, > 76 weeks, 12-week interval thereafter).   The number (percentage) 
of subjects in each category will also be summarized. 
Subject data listings will be provided. 
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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 version 19.0 or later).  Adverse events will be coded to the MedDRA lower level 
term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database. 
A treatment-emergent adverse event (TEAE), defined in “8.3 Safety Data Handling”, will 
be included in summary tables.  All AEs, treatment emergent or otherwise, will be 
presented in subject data listings. 
A subject will be counted only once within a SOC and PT, even if the subject experienced 
more than 1 TEAE within a specific SOC and PT.  
An overview table, including the incidence of and the number of subjects with TEAEs, 
Treatment-related TEAEs, severe adverse event, serious adverse events (SAEs), deaths, 
and TEAEs that led to treatment discontinuation, dose reduction and interruption will be 
provided. 
All analysis of TEAEs by SOC and PT will also be performed for the Treatment Phase and 
the entire study period (ie, the Treatment Phase or the Extension Phase). The incidence of 
below events will be reported as the number (percentage) of subjects with TEAEs by 
MedDRA SOC and PT.  
・ TEAEs 
・ TEAEs by maximum severity 
・ Serious TEAEs 
・ Non-serious TEAEs 
・ Treatment-related TEAEs 
・ Treatment-related TEAEs by maximum severity 
・ Treatment-related serious TEAEs 
・ Treatment-related non-serious TEAEs 
・ TEAEs leading to discontinuation  
・ TEAEs leading to dose reduction   
・ TEAEs leading to interruption 
In addition, The analysis of TEAEs by SOC and PT will also be performed by dose. The 
analysis by period will be summarized every 3 months, but a subject will be counted only 
the first once within a PT throughout the entire period, even if the subject also experienced 
TEAE in other later period. The analysis by dose will be summarized using final dose for 
the Treatment Phase and dose at or prior to AE onset dose for the entire study period.  
Subject data listings of all deaths, SAEs, AEs leading to death, treatment discontinuation, 
dose reduction and interruption will be provided. All AE regardless of treatment-emergent 
or not will be included in the subject data listings. 
AEs of special Interest 
The following categories of TEAEs of special interest will be summarized by PT. 
TEAEs related to suicidality 
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TEAEs suggestive of abuse potential 
TEAEs related to alertness and cognition 
TEAEs related to psychosis / psychotic disorders 
TEAEs related to hostility/aggression 
TEAEs related to status epilepticus/convulsions 
TEAEs related to drug-related hepatic disorder abnormalities 
Cardiac and ECG TEAEs 
 
A Standardized MedDRA Query (SMQ) will be used to identify relevant terms for each 
category of TEAEs of special interest.   
 
Name of AEI 
SMQ to be used 
Range 
TEAEs related to suicidality 
SMQ for depression and 
suicide/self-injury 
Narrow 
TEAEs suggestive of abuse potential 
SMQ for drug abuse, 
dependence and withdrawal 
Narrow and Broad 
Narrow 
TEAEs related to alertness and 
cognition 
SMQ for dementia 
Narrow and Broad 
TEAEs related to 
psychosis/psychotic disorders 
SMQ for psychosis and 
psychotic disorders 
Narrow and Broad 
Narrow 
TEAEs related to hostility/aggression 
SMQ for hostility/aggression 
Narrow and Broad 
Narrow 
TEAEs related to status 
epilepticus/convulsions 
SMQ for convulsions 
Narrow and Broad 
TEAEs related to drug-related 
hepatic disorder abnormalities 
SMQ for drug-related hepatic 
disorders-comprehensive search 
Narrow and Broad 
Cardiac and ECG TEAEs 
SMQs for cardiac arrhythmia 
terms (including 
bradyarrhythmias and 
tachyarrhythmias), arrhythmia 
related investigations, signs and 
symptoms; cardiac failure; 
cardiomyopathy; ischaemic heart 
disease; and Torsade de 
pointes/QT prolongation 
Narrow and Broad 
 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units.  For all 
quantitative parameters, the actual value and the change from baseline to end of treatment 
will be summarized using summary statistics.  Qualitative parameters will be summarized 
by number and percentage of subjects, and changes from baseline to end of treatment will 
be reported using shift tables.  Percentages will be based on the number of subjects with 
both nonmissing baseline and relevant postbaseline results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according 
to whether the value is below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  The result of LNH classification will be provided in a subject data listing.  
“Sponsor’s Grading for Laboratory Values” will be used to identify subjects with 
Treatment-emergent markedly abnormal laboratory value (TEMAV).   The number 
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(percentage) of subjects with TEMAV (markedly abnormal high/low) will be summarized 
for overall study period including the Follow-up Phase.  The TEMAV will be defined in 
the section 8.3.  TEMAV will also be summarized for the Treatment Phase and the entire 
study period. 
The baseline and end of treatment values for quantitative data will be displayed using Box 
plot. 
Subject data listings will be provided. 
5.6.4 
Vital Signs 
Summary statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
Respiratory rate, and temperature) and weight, and changes from baseline to end of 
treatment will be presented. 
The baseline and end of treatment values will be displayed using Box plot. 
Subject data listings will be provided. 
5.6.5 
Electrocardiograms 
Shift tables will present changes from baseline to end of treatment in ECG interpretation 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant).  
Subject data listings will be provided. 
5.6.6 
Other Safety Analyses 
No other safety analyses are planned for this study.  
5.7 
Other Analyses 
No other analyses are planned for this study. 
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
7 
CHANGES IN THE PLANNED ANALYSES 
A summary of all major additions, changes and deletions in the planned analyses described 
in the protocol will be provided in this section. 
There was a major addition. 
 
Add the descriptuion of statistical analysis and data handling if the primary endpoint 
is successfully achieved according the protocol amendment (section 3). 
There were minor additions, changes and deletions other than the avove. 
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 
Summarization of “The percent change in seizure frequency of POS per 28 days” has 
been changed to per 12 weeks from per 28 days bacause considering baseline collection 
period in the clinical study protocol (section 5.1.3 and 5.4.3). 
 
Summarization of “Treatment Compliance” has been added (section 5.2.6). 
 
Summarization of “The number (percentage) of subjects with POS who achieved 
seizure-free during the 52-week treatment of 4 mg (ie, 26-week Maintenance Period of 
4 mg and 26-week Extension Phase)” has been added (section 5.4.3). 
 
Summarization of “The number (percentage) of subjects with POS who achieved 
seizure-free during the entire study period and the corresponding 95% confidence 
interval (CI)” has been added (section 5.4.3).  
 
Summarization of “TEAEs by SOC and PT by period, and by dose” has been added 
(section 5.6.2). 
 
Summarization of “TEAEs of special interest” has been added (section 5.6.2). 
 
Summarization of “the actual value and the change from baseline to each postbaseline 
visit by visit” has been changed to “the actual value and the change from baseline to 
end of treatment will be summarized” (section 5.4.3). 
 
Summarization of “shift tables that compare the baseline LNH classification to the 
LNH classification at each postbaseline visit” has been deleted (section 5.4.3). 
 
Summarization of “Summary statistics for vital signs parameters and weight, and 
changes from baseline will be presented by visit” has been changed to “Summary 
statistics for vital signs parameters and weight, and changes from baseline to end of 
treatment will be presented” (section 5.6.4). 
 
Summarization of “Shift tables will present changes from baseline in ECG 
interpretation by visit” has been changed to “Shift tables will present changes from 
baseline to end of treatment in ECG interpretation” (section 5.6.5). 
 
The cases when the plasma perampanel concentration data will be excluded from the 
calculation of summary statistics have been added (section 5.5.1). 
 
“The relationship between plasma concentrations of perampanel at steady state and 
seizure free status will be analyzed graphically.” has been added (section 5.5.1.1). 
 
“Plasma perampanel concentration data at Early transition visit or Early 
discontinuation visit will not be included in tables and figures for pharmacokinetic 
analysis.” has been added (section 5.5.1). 
 
“Summarization of plasma concentrations for perampanel at the 4 mg Maintenance 
Period and at the 8 mg Maintenance Period” has been changed to “Summarization of 
plasma concentrations for perampanel at the 4 mg Treatment Phase and at the 8 mg 
Treatment Phase” (section 5.5.1.1). 
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 
Summarization of “seizure-free rate, time to first seizure onset and time to withdraw 
from study during the 52-week maintenance period of 4 mg and the 52-week 
maintenance period of the last evaluated dose by country” has been added (section 
5.4.3). 
 
Summarization of “seizure-free rate during the 26-week maintenance period of 4 mg 
and the 26-week maintenance period of the last evaluated dose by medical history of 
simple partial seizure type” has been added (section 5.4.3). 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
The data will be handled as follows. The sponsor will determine how to handle all data 
prior to data base lock. 
8.1 
General Data Handling 
Definition of Baseline data 
Baseline is defined as the last non-missing value observed on or prior to the first study drug 
dispensing date. 
Definition of Change from Baseline, Percent Change from Baseline 
・Change from baseline = Post-baseline value - Baseline value 
・% Change from baseline = (Change from baseline / Baseline value) * 100 
For any baseline value of 0, the subject’s corresponding percent change from baseline will 
not be included in the summary statistics table. 
Handling of data not within specified periods or within the follow-up period 
Data obtained in the Follow-up Phase except for AE, Duration of Exposure and TEMAV 
will not be included in the summary tables.  These data will be presented in the subject data 
listing. 
Definition of End of Treatment 
End of treatment phase during the 26-week Maintenance Period of the last evaluated dose 
is defined as the closest value observed on or post to the disposition date in the 26-week 
Maintenance Period of the last evaluated dose. If there is no adequate data, the closest value 
observed prior to the disposition date is selected. 
End of treatment during the entire study  (treatment phase or extension phase) is defined as 
the closest value observed on or post to the last disposition date in the entire study. If there 
is no data, the closest value observed prior to the last disposition date is selected. 
8.2 
Efficacy Data Handling 
Definition of Seizure-Free status 
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The definition of seizure-free for perampanel 4 mg will be as follows; 
The subjects who completed the 4 mg Treatment Phase with no seizures will be treated as 
Seizure-Free status.  The subjects who had any seizures will also be treated as Seizure-Free 
status only if the seizure(s) appeared after the Day 183 (ie, the target visit date of the 26th 
week of 4 mg Maintenance Period).  Day 1 is the date of first dose of study drug in the 4 
mg Maintenance Period. Otherwise, subjects will be regarded as non-Seizure-Free for the 
evaluation of perampanel 4 mg. 
The definition of seizure-free for perampanel total (regardless of doses) will be as follows; 
The subjects who completed the Treatment Phase of the last evaluated dose (ie, 4 or 8 mg) 
with no seizures will be treated as Seizure-Free status. The subjects who had any seizures 
will also be treated as Seizure-Free status if the seizure(s) appeared after the Day 183 (ie, 
the target visit date of the 26th week of Maintenance Period for the last evaluated dose).  
Day 1 here is the date of first dose of study drug in the Maintenance Period of the last 
evaluated dose.  If subjects who were titrated up to 8 mg but down-titrated to 6 mg due to 
tolerability issue continued the study and completed the Maintenance Period with no 
seizure, those will also be treated as Seizure-Free status.  Otherwise, subjects will be 
regarded as non-seizure-free. 
Handling of seizure frequency 
・ Baseline  
Baseline seizure frequency will be composed of the record based on the interview at visit 
1 and the dispensed diary.  Baseline seizure frequency will be calculated as the number of 
seizures per 12 weeks (see below).  
Sum of seizures during baseline                                                                  x 84 
the number of days (84 days plus the study days during the Pretreatment Phase)  
Study days during the Pretreatment Phase will be the period between the date of obtaining 
informed consent and the date of first study drug dosing (ie, the date of study drug 
dispensing for visit 2). 
・ Post-Baseline (Maintenance Period and Extension Phase) 
Post-baseline seizure frequency will be composed of the dispensed diary.  Post-baseline 
seizure frequency will be calculated as the number of seizures per 12 weeks (see below). 
The Follow-up Phase will not be included in this analysis. 
Sum of seizures during post-baseline                     x 84 
the number of study days during post-baseline  
Study days during the post-baseline of maintenance period will be the period between the 
date of study drug dispensing for the Maintenance Period of the last evaluated dose and the 
disposition data in maintenance period of the last evaluated dose. Study days during the 
post-baseline of extension phase will be the period between the disposition data in 
maintenance period of the last evaluated dose and the date of data cutoff or the date of study 
discontinuation, whichever comes first. 
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the data on seizure expression that obtained during the Titration Period and the Follow-up 
Phase will be presented only in the subject data listing. 
Handling of missing data 
• 
Seizure frequency 
If subjects have a missing seizure count in any of each seizure type (ie, simple partial with 
motor signs, simple partial without motor signs, complex partial, and complex partial with 
secondarily generalized seizure) for each unique diary record, the overall seizure frequency 
for that record will be handled as missing data.  Similarly, if complex partial and/or 
complex partial with secondarily generalized seizure are missing for each unique diary 
record, then complex partial seizure plus secondary generalized seizure frequency will be 
handled as a missing data. 
• 
EQ-5D-5L 
No imputation will be performed for the missing value. 
Censoring rules for time to event analysis 
1. The censored rule for the analysis of time to first seizure onset will be provided in the 
following table. If subjects met multiple censoring criteria, the censoring date will be 
the earliest date of them. 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
Seizure onset 
Date of the first seizure onset 
Event 
2 
Withdraw from the study 
Date of study withdrawal 
Censored 
3 
Ongoing at the data cutoff (with no seizure) 
Date of data cutoff 
(each subject’s final non-
missing assessment date) 
Censored 
 
2. The censored rule for the analysis of time to study withdrawal will be provided in the 
following table. If subjects met multiple censoring criteria, the censoring date will be 
the earliest date of them. 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
Withdraw from the study 
Date of study withdrawal 
Event 
2 
Ongoing at the data cutoff 
Date of data cutoff 
(each subject’s final non-missing 
assessment date) 
Censored 
8.3 
Safety Data Handling 
Definition of derived variables for extent of exposure 
The derivation rule will be presented in the section 5.6.1. 
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Treatment-emergent adverse event 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during time 
from the first dose of study drug to the last visit or 28 days after the subject’s last dose, 
whichever comes later, having been absent at pretreatment (Baseline) or  
・ Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or  
・ Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
TEMAV (Treatment-Emergent Markedly Abnormal Value) 
A TEMAV is defined as follows:  
・ For a phosphate, if the post baseline grade increases from baseline and the post baseline 
grade is greater than or equal to 3 then a value will be determined to be a TEMAV.  
・ For all other parameters presented in the section 13.1, if the post baseline grade 
increases from baseline and the post baseline grade is greater than or equal to 2 then a 
value will be determined to be a TEMAV. 
If the grade of baseline value is missing, then, if the grade of post-baseline value is Grade 
2 or higher, the laboratory values will be classified into treatment emergent markedly 
abnormal. 
Laboratory values, Vital signs, ECGs 
For the end of treatment, the closest value measured on or post to the last disposition date 
in the Treatment Phase and the entire study period will be imputed using Last Observation 
Carried Forward (LOCF) method. If there is no adequate data, the closest value observed 
prior to the disposition date is selected. 
Handling of below lower quantification values in laboratory results 
In the cases where laboratory result contains below lower quantification (BLQ) value, it 
will be replaced to the lower limit value of quantification (LLOQ) for summary tables. 
8.4 
Pharmacokinetic Data Handling 
8.4.1 
Lower Limit of Quantification of Perampanel Plasma Concentration 
The LLOQ of perampanel plasma concentrations is 0.250 ng/mL. 
8.4.2 
BLQ Handling for Calculation of PK Parameters 
Not applicable 
8.4.3 
BLQ Handling for Developing Concentration-Time Profiles 
Not applicable 
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8.4.4 
Handling of Anomalous Concentration Values 
The handling of anomalous concentration values will follow the guidance in the Eisai 
manual 302-104.00-MNL for non compartmental PK analysis (Version Date: 08 Jun 2016). 
8.4.5 
General Rules for Presentation of Drug Concentrations and PK 
Parameters 
When presenting individual/raw (raw, hereafter) values and summary statistics, the 
following rule will be applied:  for drug concentrations, all summary statistics (mean, 
median, and standard deviation [SD]) will have 3 significant digits.   
Variable 
Unit 
N 
Digit rule 
Raw/ 
Minimum/ 
Maximum 
Mean 
Median 
SD 
 
Geometric  
Mean 
CV 
(%) 
Perampanel 
concentration 
ng/mL 
X 
Significant digits 
3 
3 
3 
- 
- 
 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be conducted by the designee, using validated standard 
programs or double programming.  For analyses needed in data review, single 
programming will be used. 
All statistical analyses will be performed using SAS (version 9.2 or later).  As necessary, 
other validated statistical software will also be used. 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
12 REFERENCES 
・ Arroyo S, Dodson WE, Privitera MD, Glauser TA, Naritoku DK, Dlugos DJ, et al. 
Randomized dose-controlled study of topiramate as first-line therapy in epilepsy. Acta 
Neurol Scand. 2005;112:214–22. 
・ Chadwick D, Vigabatrin European Monotherapy Study Group. Safety and efficacy of 
vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised 
double-blind study. Lancet. 1999;354:13–9. 
・ Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kälviäinen R, et al. 
Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as 
initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54:551–63. 
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・ Heller AJ, Chesterman P, Elwes RD, Crawford P, Chadwick D, Johnson AL, et al. 
Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed 
adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg 
Psychiatry. 1995;58:44–50. 
・ Kaneko S, Chan R, Nakatsu T, Yoshida K. A Phase III, multicenter, randomized, open-
label study of levetiracetam monotherapy in Japanese patients with partial onset 
seizures. J.Jpn.Epil.Soc. 2015;32:519-32. 
・ Mikkelsen B, Berggreen P, Joensen P, Kristensen O, Køhler O, Mikkelsen BO. 
Clonazepam (Rivotril®) and Carbamazepine (Tegretol®) in Psychomotor Epilepsy: A 
Randomized Multicenter Trial. Epilepsia. 1981;22:415–20.
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13 APPENDICES 
13.1 Sponsor’s Grading for Laboratory Values  
The following table of Eisai’s Grading for Laboratory Values is based on 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 
N/A 
Leukocytes (total WBC) 
<LLN – 3.0×109/L 
<LLN – 3000/mm3  
<3.0 – 2.0×109/L 
<3000 – 2000/mm3  
<2.0 – 1.0×109/L 
<2000 – 1000/mm3  
<1.0×109/L 
<1000/mm3  
Lymphocytes  
<LLN – 800/mm3  
<LLN – 0.8×109/L 
<800 – 500/mm3 
<0.8 – 0.5×109/L 
<500 – 200/mm3  
<0.5 – 0.2×109/L 
<200/mm3 
<0.2×109/L 
Neutrophils  
<LLN – 1.5×109/L 
<LLN – 1500/mm3 
<1.5 – 1.0×109/L 
<1500 – 1000/mm3 
<1.0 – 0.5×109/L 
<1000 – 500/mm3  
<0.5×109/L 
<500/mm3  
Platelets 
<LLN – 75.0×109/L 
<LLN – 75,000/mm3  
<75.0 – 50.0×109/L 
<75,000 – 50,000/mm3 
<50.0 – 25.0×109/L 
<50,000 – 25,000/mm3 
<25.0×109/L 
<25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
<LLN – 3 g/dL 
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L 
<2 g/dL 
<20 g/L 
N/A 
ALP 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
ALT 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
AST 
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
11 – 15 mmol/L 
8 – 10 mmol/L 
<8 mmol/L 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5×ULN  
>1.5 – 3.0×ULN 
>3.0 – 10.0×ULN  
>10.0×ULN 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L  
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L  
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L  
>500 mg/dL 
>12.92 mmol/L  
Creatinine 
>ULN – 1.5×ULN 
>1.5 – 3.0×ULN 
>3.0 – 6.0×ULN 
>6.0×ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 3.0×ULN 
>3.0 – 5.0×ULN 
>5.0 – 20.0×ULN 
>20.0×ULN 
Glucose, serum-high (hyperglycemia) 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L  
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L  
>250 – 500 mg/dL; 
>13.9 – 27.8 mmol/L 
>500 mg/dL; 
>27.8 mmol/L  
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 
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 
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Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Potassium, serum-high (hyperkalemia) >ULN – 5.5 mmol/L  
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Potassium, serum-low (hypokalemia)  
<LLN – 3.0 mmol/L 
N/A 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Sodium, serum-high (hypernatremia) 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Sodium, serum-low (hyponatremia) 
<LLN – 130 mmol/L 
N/A 
<130 – 120 mmol/L 
<120 mmol/L 
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  
Uric acid, serum-high (hyperuricemia) 
>ULN – 10 mg/dL  
≤0.59 mmol/L  
N/A 
N/A  
>10 mg/dL 
>0.59 mmol/L  
ALP = alkaline phosphatase, 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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