Clinical trial NCT03288129
Conditions: Partial Onset Seizures Secondarily Generalized Seizures Primary Generalized Tonic-Clonic Seizures
Keywords: monotherapy adjunctive therapy open-label multicenter
Sponsor: Eisai Inc.
Start date: 2017-08-23; Completion date: 2021-04-27
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will assess the retention rate of perampanel when given as monotherapy or first adjunctive therapy in participants with partial-onset seizures or primary generalized tonic clonic seizures. The study consists of 4 periods: a Screening Period (to start no earlier than 6 weeks before the first dose of study drug), a Titration Period (up to 13 weeks), a Maintenance Period (39 weeks), and a Follow-Up Period (4 weeks).

Detailed description:

Arms: arm 1: Perampanel will be administered orally once daily (QD) at bedtime. At the beginning of the Titration Period, oral perampanel will start at a dose of 2 milligrams (mg) QD. Doses of perampanel will then be up titrated in increments of 2 mg at no less than 2-week intervals according to the investigator's judgment. At the 4 mg dose, the investigator will confirm whether further dose escalation is needed based on participant response and tolerability. The investigator may adjust dosing further or leave the participant at 4 mg. The maximum dose is 12 mg. During the 39-week Maintenance Period, participants will continue to receive the perampanel dose level that was administered at the end of the Titration Period.
Interventions: intervention 1: Perampanel
Intervention descriptions: intervention 1: film-coated tablets

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol
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REVISION HISTORY
Revisions to Version v1.0
New version/date:  Version 2.0/12 Apr 2019 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Clarified, in the text, the number and 
location of study sites, and the number 
of subjects. 
Document quality
Synopsis (Section 2) –

Sites

Number of Subjects

Sample Size Rationale
Section 6
Section 9.3
Section 9.7.2
Clarified, in the text, the Screening 
Period seizure requirements. 
Document quality
Synopsis (Section 2) –

Study Design

Efficacy Assessments
Section 9.1.1
Section 9.3.1
Section 9.5.1.2
Clarified, in the text, the length of 
Titration Period. 
Document quality
Synopsis (Section 2) –

Study Design

Duration of Treatment
Section 9.1
Section 9.1.2
Section 9.3.3.1
Updated minimum age for study 
inclusion. 
To reflect approved 
product prescribing 
information. 
Synopsis (Section 2) –

Number of Subjects 

Inclusion Criteria
Section 7.1
Section 9.1.1
Section 9.3.1
Section 9.4.4
Clarified, in the text, the requirements 
to support epilepsy diagnosis and 
analysis of efficacy endpoints.
Document quality
Synopsis (Section 2) –

Inclusion Criteria

Assessments

Safety Analyses
Section 9.3.1
Section 9.5.1.1.2
Updated exclusion criteria regarding 
concomitant therapies and procedures.
Subject safety
Synopsis (Section 2) –

Exclusion Criteria

Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.7


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Revisions to Version v1.0
New version/date:  Version 2.0/12 Apr 2019 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Updated subject treatment during the 
Follow-Up Period. 
To allow option for 
subject to switch to 
treatment with 
commercial perampanel 
after Maintenance 
Period completion.
Synopsis (Section 2) –

Study Design
Section 9.1.3
Figure 1
Section 9.1.4
Table 4
Clarified, in the text, process for 
tracking subject dosing. 
Document quality
Synopsis (Section 2) –

Study Design
Section 9.1.2
Section 9.4.1
Clarified, in the text, restricted 
concomitant therapies, and use before 
Visit 1, and clarification of previous 
AED medication.
Document quality
Synopsis (Section 2) –

Concomitant 
Drug/Therapy
Section 9.4.7
Clarified, in the text, safety 
assessments based on subject age.
Document quality
Synopsis (Section 2) –

Assessments
Section 9.5.1.6.5
Section 9.5.1.6.9
Section 9.7.1.8.3
Table 4
Added fasting laboratory assessments 
at screening and last treatment visit.
Regulatory authority 
compliance
Table 3
Table 4
Updated Medical Monitor and Study 
Director information.
Personnel change
Protocol Signature Page
Grammatical, typographical, and 
formatting changes were also made.
Document quality 
Throughout the Document


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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2007-G000-410
Study Protocol 
Title:
Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of 
Perampanel as Monotherapy or First Adjunctive Therapy in Subjects 
With Partial Onset Seizures With or Without Secondarily Generalized 
Seizures or With Primary Generalized Tonic-Clonic Seizures
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
United States
Investigational 
Product Name:
E2007/Fycompa® (Perampanel)
Indication:
Monotherapy or adjunctive therapy for partial-onset seizures with or 
without secondarily generalized seizures and primary generalized 
tonic-clonic seizures in ≥12-year-old epilepsy patients 
Phase:
4
IND Number:
068368
EudraCT number 2017-001180-20
Approval Date:
V1.0
23 Mar 2017 (original protocol)
V2.0
12 Apr 2019 (Amendment 01)
GCP Statement:
This study is to be performed in full compliance with International 
Council 
on 
Harmonisation 
of 
Technical 
Requirements 
for 
Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local GCP and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.  E2007
Name of Active Ingredient:  Perampanel
Study Protocol Title
Multicenter, Open-Label, Study to Evaluate the Efficacy and Safety of Perampanel as Monotherapy 
or First Adjunctive Therapy in Subjects With Partial Onset Seizures With or Without Secondarily 
Generalized Seizures or With Primary Generalized Tonic-Clonic Seizures
Investigators
To be determined
Sites
The study will be conducted at up to approximately 25 investigational sites in the US.  (revised per 
Amendment 01)
Study Period and Phase of Development
Approximately 24 months
Phase 4
Objectives
Primary Objective
To assess the retention rate of perampanel when given as monotherapy or 1st adjunctive therapy in 
subjects with partial-onset seizures (POS) or primary generalized tonic-clonic seizures (PGTCS)
Secondary Objectives

To evaluate the efficacy of perampanel when given as monotherapy or 1st adjunctive therapy in 
subjects with POS or PGTCS as measured by seizure freedom

To assess the proportion of subjects with POS or PGTCS that are able to convert from 
1st adjunctive therapy to perampanel monotherapy

To assess the safety of perampanel as initial monotherapy or 1st adjunctive therapy in subjects 
with POS or PGTCS

To assess dosing and titration of perampanel when administered as initial monotherapy or 1st
adjunctive therapy in subjects with POS or PGTCS
Exploratory Objectives

To evaluate the efficacy of perampanel in subjects with POS or PGTCS as measured by 
responder rates (50% and 75%, in subjects who have sufficient baseline seizure frequency data 
available)

To evaluate the efficacy of perampanel in subjects with POS or PGTCS as measured by median 
percent reduction in seizure frequency (in subjects who have sufficient baseline seizure frequency 
data available)

To assess cognition, including the impact of depression, in subjects with POS or PGTCS
administered perampanel as monotherapy or as 1st adjunctive therapy

To assess subjective sleep quality in subjects with POS or PGTCS administered perampanel as 
monotherapy or as 1st adjunctive therapy

To assess quality of life in subjects with POS or PGTCS administered perampanel as 
monotherapy or as 1st adjunctive therapy
Study Design
This is a multi-center, open-label, Phase 4 study.  Subjects who meet all of the inclusion and none of 


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the exclusion criteria will receive perampanel.  Baseline seizure counts (frequency) data will be 
collected by subjects or guardian/legally authorized representative, retrospectively (for history prior 
to screening) and prospectively as needed (during baseline).  The study consists of 4 periods:  a 
Screening Period (to start no earlier than 6 weeks before the 1st dose of study drug), a Titration 
Period (up to 13 weeks), a Maintenance Period (39 weeks), and a Follow-Up Period (4 weeks).  
(revised per Amendment 01)
Study subjects will include the following:

Subjects who have been diagnosed with POS or PGTCS but have not previously received 
treatment with an antiepileptic drug (AED) or are currently receiving monotherapy treatment (no 
history of AED polytherapy) and wish to switch to another monotherapy treatment; or

Subjects who are currently receiving treatment with a single AED administered at a stable dose 
for at least 8 weeks before Visit 2 (Week 0) and need additional AED treatment; subjects should 
not have previously received adjunctive AED therapy.
Screening Period
During the Screening Period, informed consent/pediatric assent will be obtained and screening 
assessments will be conducted.  The Screening Visit (Visit 1) will take place no earlier than 6 weeks 
before the 1st dose of study drug.  Seizure data from up to 12 weeks preceding the 1st dose should be 
collected by the investigator retrospectively and prospectively.  Subjects will be eligible for study 
enrollment after they have experienced either the 2 required unprovoked (or reflex) seizures or the 
1 unprovoked (or reflex) seizure with EEG evidence of seizures, and they will not need to complete 
the full 12-week diary to enter the Titration Period.  (revised per Amendment 01)
Titration Period
The Titration Period will begin with Visit 2, which may overlap with the Screening Visit (Visit 1), 
and will last for up to 13 weeks.  (revised per Amendment 01) Subjects will receive perampanel 
tablets once daily (QD) before bedtime.  The initial dose of perampanel 2 mg/day may be up-titrated 
in increments of 2 mg according to the investigator’s judgment, based on individual clinical response 
and tolerability, as shown in the following dosing schedule:
Dosing Titration Schedule
Category
Weeka
Perampanel Dose (mg/day)
Required
1
2
2
2
3
4
4
4
Telephone Visit
Optional Escalationb
5
6
6
6
Follow-Up Telephone Callc
7
8
8
8
Follow-Up Telephone Callc
9
10
10
10
Follow-Up Telephone Callc
11
12
12
12
13
12


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a:  Subjects on a concomitant enzyme-inducing antiepileptic drug may be up-titrated 
at 1-week intervals if needed.
b:  Subjects should be titrated to 4 mg.  Additional dose escalation is optional 
depending on subject response and tolerability, following assessment by Telephone 
Visit or follow-up calls.
c:  If needed; investigator should follow-up with subject via telephone call prior to 
further dose escalation.
Treatment will initially be titrated up to perampanel 4 mg based on clinical response and tolerability.  
Thereafter, titration will be based on the investigator’s judgment; subjects may have further dose 
increases in increments of 2 mg, per evaluation by the investigator (Telephone Visit 3) prior to 
further dose escalation.  The maximum dose is 12 mg.  At least 2 weeks must elapse between dose 
increases, with the exception of subjects who are taking any concomitant drug that shortens the 
half-life of perampanel (eg, phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine), in which 
case the treatment may be up-titrated at 1-week intervals if needed.  Sites must enter the perampanel 
dosing information into the Interactive Response Technology (IRT) system on Weeks 2, 4, 6, 8, 10, 
and 12 to track subject dosing.  Adjustments of the concomitant AED dose level during the Titration 
Period are not permitted.  (revised per Amendment 01)
The perampanel dose can be down-titrated based on tolerability, at the discretion of the investigator.  
Subjects who cannot tolerate the 4 mg dose by the end of the Titration Period will be discontinued 
from the study.
Maintenance Period
Subjects will continue to receive the perampanel dose level that was administered at the end of the 
Titration Period, when they enter the 39-week Maintenance Period.  Subjects will come to the study 
site for Visit 4 (Week 13), Visit 5 (Week 26), Visit 6 (Week 39), Visit 7 (Week 52), and at the 
Follow-Up Visit (Visit 8).  All subjects who discontinue the study are to complete the study’s early 
discontinuation procedures indicated in the Schedule of Procedures/Assessments.
(revised per 
Amendment 01)
According to the investigator’s clinical judgment, subjects who experience adverse events (AEs) may
have their perampanel dose reduced.  Conversely, if seizures are not adequately controlled, subjects 
may have their dose increased up to a maximum of perampanel 12 mg.  During the Maintenance 
Period, subjects whose perampanel dose has been reduced may have the dose increased again, at the 
discretion of the investigator, as soon as tolerability improves. Subjects who cannot tolerate a dose 
of 4 mg will discontinue perampanel treatment and be withdrawn from the study. Adjustment of the 
concomitant AED dose level during the Maintenance Period is permitted; any dose adjustments will 
be recorded.  Subjects who receive perampanel as a 1st adjunctive therapy may also be converted to 
perampanel monotherapy at the discretion of the investigator.
Number of Subjects
Approximately 125 male or female subjects ≥4 years of age who have a diagnosis of epilepsy with 
POS, with or without secondarily generalized seizures (SGS) or PGTCS, will be enrolled in this 
study.  (revised per Amendment 01)
Inclusion Criteria
1.
Subjects will be male or female and no younger than 4 years of age and be able to swallow
perampanel tablets.  (revised per Amendment 01)
2. Subjects must have a diagnosis of epilepsy with POS (with or without SGS) or with PGTCS.  
Either of the following must have occurred to support an epilepsy diagnosis:  (revised per 
Amendment 01)
a.
At least 2 unprovoked (or reflex) seizures occurring greater than 24 hours apart


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b.
1 unprovoked (or reflex) seizure with EEG evidence of seizures
3.
Subjects who receive perampanel as a 1st adjunctive therapy must currently have been treated 
with stable doses of monotherapy with an AED for 8 weeks prior to Visit 2 (Week 0), have not 
previously received adjunctive AED treatment, and must, in the investigator’s judgement, be in 
need of initial adjunctive therapy after failure to control seizures with AED monotherapy, at the 
optimal dose and duration.  (revised per Amendment 01)
4.
Subjects who receive perampanel as monotherapy, who were newly diagnosed (treatment naïve) 
following the defined diagnosis of epilepsy.  (revised per Amendment 01)
5.
Subjects who are currently receiving monotherapy treatment may receive perampanel as 
monotherapy if, in the investigator’s judgment, the subject may benefit from a change in 
monotherapy treatment.  Subjects must not have previously received adjunctive AED treatment.
6.
If antidepressants or antianxiety drugs are used, subjects must be on a stable dose regimen of
these drugs during the 8 weeks before Visit 2 (Week 0).
Exclusion Criteria
1.
Subjects should not have previously received or currently be receiving perampanel.
2.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin [hCG] 
test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG or hCG); a separate 
baseline assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the 1st dose of study drug.
3.
Females of childbearing potential who:
•
Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following:
-
Total abstinence (if it is their preferred and usual lifestyle)
-
An intrauterine device or intrauterine hormone-releasing system 
-
An oral contraceptive (with additional barrier method if using contraceptive containing 
levogesterol); subject must be on a stable dose of the same oral contraceptive product 
for at least 28 days before dosing and throughout the study and for 28 days after study 
drug discontinuation
-
Have a vasectomized partner with confirmed azoospermia
•
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation
For sites outside of the EU, it is permissible that if a highly effective method of contraception is 
not appropriate or acceptable to the subject, then the subject must agree to use a medically 
acceptable method of contraception, ie, double-barrier methods of contraception such as 
condom plus diaphragm or cervical/vault cap with spermicide.
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).
4.
Presence of or previous history of Lennox-Gastaut syndrome
5.
Presence of non-motor simple partial seizures only


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6.
A history of status epilepticus within 1 year before Screening Visit (Visit 1)
7.
Subjects on antipsychotics or who have psychotic disorder(s) or unstable recurrent affective 
disorder(s) with a history of attempted suicide within 1 year before Screening Visit (Visit 1)
8.
Presence of a progressive central nervous system (CNS) disease, including degenerative CNS 
diseases and progressive tumors
9.
Concomitant use of barbiturates (except for seizure control indication and premedication for 
EEG) and benzodiazepines (except for seizure control indication) within 8 weeks prior to Visit 2
(Week 0)
10. Use of intermittent rescue benzodiazepines (ie, 1-2 doses over a 24-hour period is considered a 
1-time rescue) 2 or more times in the 8 week period prior to Visit 2 (Week 0)
11. Severe renal insufficiency (defined by estimated glomerular filtration rate of <30 mL/min) or 
subjects who receive hemodialysis
12. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease, 
hepatic disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
study conduct
NOTE:  Stable elevation of liver enzymes, alanine aminotransferase
and aspartate 
aminotransferase due to concomitant medication(s), will be allowed if they are less than 3 times
the upper limits of normal.  
13. Hypersensitivity to perampanel or any excipients
14. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption 
15. Subjects who are participating in other interventional clinical trial
16. Subject who are judged to have inadequate cognitive ability for participation in the study 
(intelligence quotient [IQ] <80 or investigator judgment)
17. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months of 
screening, as indicated by answering “Yes” to questions 4 and 5 on the Suicidal Ideation section 
of the Columbia-Suicide Severity Rating Scale (C-SSRS)
18. Any lifetime suicidal behavior based on the C-SSRS
19. Concomitant use of any form of cannabidiol (CBD)  (revised per Amendment 01)
20. Planned brain surgery during study participation  (revised per Amendment 01)
Study Treatment
Test drug: E2007 (perampanel) oral tablet(s) (2, 4, 6, 8, 10, and/or 12 mg), QD before bedtime
Comparator Drug (if applicable): Not applicable
Duration of Treatment
Titration Period: up to 13 weeks  (revised per Amendment 01)
Maintenance Period: 39 weeks
Concomitant Drug/Therapy
•
Concomitant AEDs for subjects who receive perampanel as a 1st adjunctive therapy
o
Only 1 AED can be used.  
o
A concomitant AED must be used at a stable dose administered between 8 weeks prior to 
Visit 2 (Week 0) and the end of Titration Period.  The dose and administration of the AED 


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may be modified during the Maintenance Period based on the investigator’s judgment.
•
Concomitant medication
The following concomitant drugs are prohibited throughout the study period (up to the 
Follow-Up Period or early discontinuation visit):  (revised per Amendment 01)
o
Cytochrome P450(CYP)3A4-inducing drugs and food below as follows (from 30 days 
before Visit 1):  Rifampicin, troglitazone, barbiturates except for use as AED, modafinil, 
efavirenz, nevirapine, glucocorticoid except for topical use, pioglitazone, rifabutin, and food 
containing St. John’s Wort (Hypericum perforatum).  (revised per Amendment 01)
o
Antipsychotics
o
Other investigational drugs (revised per Amendment 01)
o
CBD products  (revised per Amendment 01)
Restricted concomitant drugs:
o
Any changes in the dosing regimen of antidepressant or antianxiety drugs during the study 
must be recorded.
o
Barbiturates (except for seizure control indication and premedication for EEG) and 
benzodiazepines (except for seizure control indication) within 8 weeks prior to Visit 2 
(Week 0)
•
Concomitant therapy  (revised per Amendment 01)
Prohibited concomitant therapy 
The following therapies must not be concurrently implemented during the study:
o
Investigational device 
Restricted concomitant therapy:
o
Vagus nerve stimulation is allowed, but stimulator parameters cannot be changed for 8 
weeks prior to Visit 2 (Week 0) or thereafter during the study.
o
A ketogenic diet will be allowed as long as the subject has been on this diet for 8 weeks 
prior to Visit 2 (Week 0). Additionally, a ketogenic diet cannot be newly added or 
discontinued during the study.
Clarification of previous AED medication:
o
Subjects may switch monotherapies provided the time to complete the conversion is less 
than 30 days.
o
Subjects on short-term monotherapy (<2 weeks) may be eligible for the study provided they 
stop the initial therapy at the time of perampanel dosing.
Assessments
Efficacy Assessments
Exposure data will be utilized to assess the primary endpoint.  Baseline seizure count (frequency) 
data will be collected retrospectively and prospectively from the subject or their guardian/legally 
authorized representative for up to 12 weeks before Visit 2 (Week 0).  Subjects will be eligible for 
study enrollment after they have experienced the 2 unprovoked (or reflex) seizures occurring greater 
than 24 hours apart, or 1 unprovoked (or reflex) seizure with EEG evidence of seizures, and will not 
need to complete the full 12 week diary to enter the Titration Period. (revised per Amendment 01)  
The incidence of seizures during treatment will be assessed by prospective reference to seizure 
diaries or other information collected retrospectively. Diaries will be reviewed at each study visit, 
as listed in the Schedule of Procedures/Assessments.  Seizure frequency from prospective diary 
entries or principal investigator verification will be used to assess efficacy endpoints as appropriate.  


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(revised per Amendment 01)
Pharmacokinetic Assessments
Not applicable.
Pharmacodynamic Assessments
Not applicable.
Pharmacogenomic Assessments
Whole blood samples for preparation of genomic DNA may be obtained at baseline from subjects 
for additional exploratory analyses.
Safety Assessments
Safety will be assessed by monitoring and recording of all of AEs and serious adverse events 
(SAEs), discontinuation from treatment, prior and concomitant medication usage, periodic 
measurement of weight, and assessments of cognitive functioning and monitoring of suicidal 
thoughts or depressive symptoms.  The C-SSRS will be administered at specified intervals.
Cognition will be assessed in patients 6 years of age and older using the EpiTrack® assessment tool.  
The EpiTrack (second edition with recently extended and revised norms) is a screening tool 
dedicated to the tracking of adverse cognitive effects of antiepileptic medication (Lutz and 
Helmstaedter, 2005).  Studies have demonstrated the usefulness of the EpiTrack with regard to 
cognitive monitoring of the impact of pharmacological treatments (Lutz and Helmstaedter, 2005; 
Helmstaedter and Witt, 2008; Helmstaedter and Witt, 2010; Helmstaedter and Witt, 2013; Witt, et 
al., 2014).  The test includes 6 subtests:  response inhibition, visuo-motor speed, mental flexibility, 
visual motor planning, verbal fluency, and working memory.  Based on the subtest results, an 
age-corrected total score is calculated.  Higher scores reflect better performance with a maximum 
score of 49 points.  The interval for mild impairment is 29 to 31 points, and the cutoff for significant 
impairment is 28 or fewer points.  Practice corrected reliable change indices indicate a significant 
change with a gain of more than 3 points and a loss of more than 2 points.  The EpiTrack Junior will 
be administered for subjects ages ≥6 to 16 years old.  (revised per Amendment 01)
The Beck Depression Inventory-II (BDI-II) is a 21-question multiple-choice self-report inventory 
and is widely used for measuring the severity of depression.  The depression score will be used to 
aid in interpretation of the cognition score.  The BDI-II will be administered in patients 16 years of 
age and older who are administered the EpiTrack.
The Pittsburgh Sleep Quality Index (PSQI) is a retrospective sleep quality instrument with 19 items 
(Buysse, et al., 1989).  It measures subjects’ perspectives on sleep parameters (length of sleep, sleep 
disturbances), sleep quality, and impact on daily functioning.  The PSQI will be administered to 
patients 12 years of age and older.
The Quality of Life in Epilepsy Inventory-31 (QOLIE-31) is a survey of health-related quality of 
life for adults (18 years or older) with epilepsy.
An assessment of suicidality will be performed using the C-SSRS, which is a series of questions 
about suicidal thoughts and behaviors.  The C-SSRS will be administered to patients 6 years of age 
and older.  Subjects under 6 years of age will be clinically monitored for suicidality. (revised per 
Amendment 01)
Bioanalytical Methods
Not applicable.
Statistical Methods
All summaries of efficacy will be produced by seizure type (POS and PGTCS).  Summaries of 
safety data will be produced by seizure type (POS and PGTCS) and overall.


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Study Endpoints
Primary Endpoint:
•
Retention rate, defined as the proportion of subjects remaining on perampanel at the specified 
time points:  3, 6, 9, and 12 months after initiation of treatment.
Secondary Endpoints
•
Proportion of subjects who achieve seizure-free status for POS, SGS, and PGTCS during the 
Maintenance Period. 
•
Proportion of subjects who achieve 3-month seizure-free status for POS, SGS, and PGTCS.
•
Proportion of subjects who achieve 6-month seizure-free status for POS, SGS, and PGTCS.
•
Proportion of subjects who receive perampanel as a 1st adjunctive therapy who are able to 
convert to perampanel monotherapy
•
Safety and tolerability of perampanel administered as monotherapy or 1st adjunctive therapy in 
adolescents and adults
•
Maximum and last dose during the titration period and the maintenance period
Exploratory Endpoints: 
•
50% responder rate in total POS, SGS, and PGTCS; 50% responders are defined as subjects who 
have at least a 50% reduction in seizure frequency relative to baseline (in subjects with 
sufficient baseline seizure frequency data)
•
75% responder rate in total POS, SGS, and PGTCS; 75% responders are defined as subjects who 
have at least a 75% reduction in seizure frequency relative to baseline (in subjects with 
sufficient baseline seizure frequency data)
•
Median percent change in total POS, SGS, and PGTCS frequency in the Titration and 
Maintenance Periods relative to baseline (in subjects with sufficient baseline seizure frequency 
data) 
•
Proportion of subjects with no/mild/clear cognitive impairment relative to baseline using the 
EpiTrack total score
•
Change in subjective sleep quality at the end of the Maintenance Period relative to baseline 
using the PSQI
•
Change in quality of life at the end of the Maintenance Period relative to baseline using the 
QOLIE-31
Analysis Sets
The Safety Analysis Set (SAS) is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose safety assessment.
The Full Analysis Set (FAS) is the group of subjects who received at least 1 dose of study drug and 
had at least 1 postdose seizure measurement.
Efficacy Analyses
The SAS will be used to summarize retention rate and all safety data. The FAS will be used to 
summarize seizure data.
The retention rate, defined as the proportion of patients remaining on perampanel treatment at 3, 6, 
9, and 12 months after initiation of treatment, will be summarized. The number and percentage of 
subjects remaining on treatment at each time point and 95% CIs will be summarized.
Analyses of exploratory efficacy endpoints will be performed in the subset of the FAS with 
sufficient baseline seizure frequency.  All seizure-related summaries will be produced by seizure 


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type (POS, SGS, and PGTCS).
This is a study without a control arm.  Therefore, formal hypothetical inferences are not necessary, 
and only descriptive statistics will be performed, as shown below.
For percent change in seizure frequency endpoints:
•
Mean, standard deviation, median (95% CIs), minimum, and maximum will be provided.
For responder rate endpoints:
•
Number of responders
•
Responder rate and its 95% CI
The details for the analyses will be described in the statistical analysis plan.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacokinetic Analyses
Not applicable.
Pharmacodynamic Analyses
Not applicable.
Pharmacogenomic Analyses
Variation in exposure of perampanel, baseline levels, and changes in clinical measurements (eg, 
efficacy or other safety parameters such as labs), or occurrence of AEs may be evaluated by testing 
for association of genetic variants with these measurements or traits.  Details of any 
pharmacogenomic analyses will be described and reported separately.
Safety Analyses
For AEs, drug-related AEs, SAEs and AEs leading to discontinuation, the frequency and percent 
will be provided.  All AEs will be categorized by system organ class (SOC) and preferred term (PT) 
assigned to the event using Medical Dictionary for Regulatory Activities (MedDRA) terms.  
Suicidality will be assessed using the C-SSRS and summaries will include the incidence of suicidal 
behavior and suicidal ideation.  Cognitive function in subjects 6 years of age and older will be 
evaluated using EpiTrack; the EpiTrack Junior will be administered for subjects ages ≥6 to 16 years 
old.  (revised per Amendment 01).
Summaries of the proportion of subjects with no/mild/clear 
cognitive impairment and shifts between these categories from baseline to end of treatment will be 
produced.  The BDI-II will be used to assess depression.
Vital signs and body weight will be summarized.
A laboratory value that is considered abnormal and clinically significant may meet the criteria to 
qualify as an AE.  In these instances, the AE corresponding to the laboratory abnormality will be 
recorded on the Adverse Event electronic Case Report Form (eCRF).
Other Analyses
Duration of treatment and summaries of maximum and last dose will be produced.
Interim Analyses
Interim analyses will be conducted at various intervals, depending on the number of accrued 
subjects.
Sample Size Rationale 
The efficacy of perampanel as monotherapy and 1st adjunctive therapy for POS and PGTCS is to be 
evaluated.  The primary endpoint is retention rate.  The study is to enroll approximately 
125 subjects.  This sample size is considered adequate for an open-label Phase 4 study where there 


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is no statistical hypothesis to be tested.  (revised per Amendment 01)


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3
TABLE OF CONTENTS
REVISION HISTORY...............................................................................................................1
1
TITLE PAGE.....................................................................................................................3
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................4
3
TABLE OF CONTENTS.................................................................................................14
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
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..........................................................20
7
INTRODUCTION ...........................................................................................................20
7.1
Planned Indication .................................................................................................20
7.2
Study Rationale......................................................................................................20
8
STUDY OBJECTIVES....................................................................................................21
8.1
Primary Objective:.................................................................................................21
8.2
Secondary Objectives: ...........................................................................................21
8.3
Exploratory Objectives: .........................................................................................21
9
INVESTIGATIONAL PLAN..........................................................................................21
9.1
Overall Study Design and Plan..............................................................................21
9.1.1
Screening Period (Week -6 ~ Week 0) ........................................................22
9.1.2
Titration Period............................................................................................23
9.1.3
Maintenance Period .....................................................................................24
9.1.4
Follow-Up Period (4 weeks)........................................................................25
9.2
Discussion of Study Design...................................................................................26
9.2.1
Rationale for Subject Population .................................................................26
9.2.2
Rationale for Efficacy Endpoints.................................................................26
9.2.3
Rationale for Prohibited/Restricted Concomitant Drug/Therapy ................26
9.3
Selection of Study Population................................................................................26
9.3.1
Inclusion Criteria .........................................................................................26
9.3.2
Exclusion Criteria ........................................................................................27
9.3.3
Removal of Subjects from Therapy or Assessment.....................................29
9.3.3.1
Scheduled Termination......................................................................29
9.3.3.2
Withdrawals.......................................................................................29
9.4
Treatment ...............................................................................................................29
9.4.1
Treatment Administered ..............................................................................29
9.4.2
Identity of Investigational Product...............................................................30


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9.4.2.1
Chemical Name, Structural Formula of E2007..................................30
9.4.2.2
Comparator Drug ...............................................................................31
9.4.2.3
Labeling for Study Drug....................................................................31
9.4.2.4
Storage Conditions.............................................................................31
9.4.3
Method of Assigning Subjects to Treatment Group ....................................31
9.4.4
Selection of Doses in the Study...................................................................31
9.4.5
Selection and Timing of Dose for Each Subject..........................................31
9.4.6
Blinding........................................................................................................31
9.4.7
Prior and Concomitant Drug/Therapy .........................................................31
9.4.8
Treatment Compliance.................................................................................32
9.4.9
Drug Supplies and Accountability...............................................................33
9.5
Study Assessments.................................................................................................34
9.5.1
Assessments.................................................................................................34
9.5.1.1
Demographic/Baseline Assessments .................................................34
9.5.1.2
Efficacy Assessments.........................................................................35
9.5.1.3
Pharmacokinetic Assessments ...........................................................36
9.5.1.4
Pharmacodynamic Assessments ........................................................36
9.5.1.5
Pharmacogenomic Assessments ........................................................36
9.5.1.6
Safety Assessments............................................................................36
9.5.1.7
Description of Procedures/Assessments Schedule.............................41
9.5.2
Schedule of Procedures/Assessments ..........................................................42
9.5.3
Appropriateness of Measurements...............................................................45
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated With Special Situations .............................................................45
9.5.4.1
Reporting of Serious Adverse Events................................................45
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................46
9.5.4.3
Reporting of Events Associated With Special Situations..................46
9.5.4.4
Expedited Reporting ..........................................................................47
9.5.4.5
Breaking the Blind.............................................................................47
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................47
9.5.5
Completion/Discontinuation of Subjects.....................................................47
9.5.6
Abuse or Diversion of Study Drug ..............................................................48
9.6
Data Quality Assurance .........................................................................................48
9.6.1
Data Collection ............................................................................................48
9.6.2
Clinical Data Management ..........................................................................48
9.7
Statistical Methods.................................................................................................48
9.7.1
Statistical and Analytical Plans....................................................................49
9.7.1.1
Study Endpoints.................................................................................49
9.7.1.2
Definitions of Analysis Sets...............................................................50
9.7.1.3
Subject Disposition............................................................................50


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9.7.1.4
Demographic/Baseline Characteristics..............................................50
9.7.1.5
Prior and Concomitant Therapy.........................................................50
9.7.1.6
Efficacy Analyses ..............................................................................50
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................51
9.7.1.8
Safety Analyses..................................................................................51
9.7.2
Determination of Sample Size .....................................................................53
9.7.3
Interim Analysis...........................................................................................53
9.7.4
Other Statistical/Analytical Issues ...............................................................53
10
REFERENCE LIST .........................................................................................................54
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......55
11.1
Changes to the Protocol .........................................................................................55
11.2
Adherence to the Protocol......................................................................................55
11.3
Monitoring Procedures...........................................................................................55
11.4
Recording of Data..................................................................................................56
11.5
Identification of Source Data.................................................................................56
11.6
Retention of Records..............................................................................................56
11.7
Auditing Procedures and Inspection......................................................................57
11.8
Handling of Study Drug.........................................................................................57
11.9
Publication of Results ............................................................................................57
11.10 Disclosure and Confidentiality ..............................................................................58
11.11 Discontinuation of Study .......................................................................................58
11.12 Subject Insurance and Indemnity...........................................................................58
12
APPENDICES .................................................................................................................59
LIST OF IN-TEXT TABLES
Table 1
Dosing Titration Schedule .........................................................................23
Table 2
Formulation/Drug Appearance ..................................................................30
Table 3
Clinical Laboratory Tests...........................................................................39
Table 4
Schedule of Procedures/Assessments in Study E2007-G000-410  
(revised per Amendment 01) .......................................................................................42
LIST OF IN-TEXT FIGURES
Figure 1
Study Design..............................................................................................25


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
BDI-II
Beck Depression Inventory-II
CBD
cannabidiol
CNS
central nervous system
CRA
Clinical Research Associate
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450 
eCRF
electronic Case Report Form
FAS
full analysis set
hCG
human chorionic gonadotropin
ICF
informed consent form
ICH
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IQ
intelligence quotient
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator’s Study File
MedDRA
Medical Dictionary for Regulatory Activities
PGTCS
primary generalized tonic-clonic seizures
PI
principal investigator
POS
partial-onset seizures
PSQI
Pittsburgh Sleep Quality Index
PT
preferred term
QD
once daily
QOLIE-31
Quality of Life in Epilepsy Inventory-31
SAE
serious adverse event
SAS
safety analysis set
SGS
secondarily generalized seizures
SOC
system organ class
TEAE
treatment-emergent adverse event


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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 on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) E6 (GCP), Section 3, and any local regulations.
Any protocol amendment or 
revision to the ICF will be resubmitted to the IRB/IEC for review and approval, except for 
changes involving only logistical or administrative aspects of the study (eg, change in 
Clinical Research 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 (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4). If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations. If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.
The investigators or the sponsor will submit, depending on local regulations, periodic reports 
and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines and local 
IRB/IEC standards of practice. Upon completion of the study, the investigator will provide 
the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC within the period, according 
to requirement of each IRB/IEC.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC within the period, according to requirement of each IRB/IEC, and a detailed written 
explanation of the reasons for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:
•
Principles of the World Medical Association Declaration of Helsinki (2008)
•
ICH E6 Guideline for GCP of the European Agency for the Evaluation of Medicinal 
Products, Committee for Proprietary Medicinal Products, ICH (CPMP/ICH/135/95)


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


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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai Inc. at 
up to approximately 25 investigational sites in the US.  (revised per Amendment 01)
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the Contract Research Organization(s) (CRO[s]) are listed in the 
Investigator Study File or the Regulatory Binder provided to each site.
7
INTRODUCTION
7.1
Planned Indication
Perampanel (E2007; Fycompa®) is a potent, orally active, noncompetitive, and highly 
selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist.  
Perampanel tablets were approved for marketing as an adjunctive therapy for the treatment of 
partial-onset seizures (POS) with or without secondarily generalized seizures (SGS) in 
subjects aged 12 years and older in the EU in July 2012, in the US in October 2012, and in 
other countries subsequently.  Perampanel was also approved for marketing as an adjunctive 
therapy for the treatment of primary generalized tonic-clonic seizures (PGTCS) in subjects 
with epilepsy aged 12 years and older in the EU and the US in June 2015, and in other 
countries subsequently.  Perampanel was approved for treatment of POS with or without SGS
in patients with epilepsy 4 years of age and older in September 2018.
(revised per 
Amendment 01)
7.2
Study Rationale
Currently, there is little information from clinical studies regarding the use of perampanel as 
monotherapy; however, in clinical practice, doctors routinely prescribe antiepileptic drugs 
(AEDs) approved for adjunctive use as monotherapy or withdraw other drugs to 
monotherapy as per clinical response.  In a meeting between Eisai and the European 
Medicines Agency, the usefulness of information about withdrawal of previous AEDs in the 
context of combination therapy with perampanel was acknowledged.  In particular, 
observational studies were recognized as an option to collect real-world clinical data to add 
to the Summary of Product Characteristics for perampanel.  Moreover, according to the 
“Guideline on clinical investigation of medicinal products in the treatment of epileptic 
disorders” (CHMP/EWP/566/98 Rev.2/Corr) from the European Medicines Agency, the 
availability of data regarding clinical use of perampanel as adjunctive therapy or 
monotherapy would be informative for patient management and useful to include in the 
Summary of Product Characteristics. 
Early adjunctive therapy is a frequent modality of use, for which there is limited information
for perampanel, since the adjunctive therapy registration studies use late adjunctive therapy 
in a treatment-resistant patient population.


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8
STUDY OBJECTIVES
8.1
Primary Objective:
•
To assess the retention rate of perampanel when given as monotherapy or 1st adjunctive 
therapy in subjects with POS or PGTCS
8.2
Secondary Objectives:
•
To evaluate the efficacy of perampanel when given as monotherapy or 1st adjunctive 
therapy in subjects with POS or PGTCS as measured by seizure freedom
•
To assess the proportion of subjects with POS or PGTCS that are able to convert from 
1st adjunctive therapy to perampanel monotherapy
•
To assess the safety of perampanel as initial monotherapy or 1st adjunctive therapy in 
subjects with POS or PGTCS
•
To assess dosing and titration of perampanel when administered as initial monotherapy or 
1st adjunctive therapy in subjects with POS or PGTCS
8.3
Exploratory Objectives:
•
To evaluate the efficacy of perampanel in subjects with POS or PGTCS as measured by 
responder rates (50% and 75%, in subjects who have sufficient baseline seizure 
frequency data available)
•
To evaluate the efficacy of perampanel in subjects with POS or PGTCS as measured by 
median percent reduction in seizure frequency (in subjects who have sufficient baseline 
seizure frequency data available)
•
To assess cognition, including the impact of depression, in subjects with POS or PGTCS
administered perampanel as monotherapy or as 1st adjunctive therapy
•
To assess subjective sleep quality in subjects with POS or PGTCS administered 
perampanel as monotherapy or as 1st adjunctive therapy
•
To assess quality of life in subjects with POS or PGTCS administered perampanel as 
monotherapy or as 1st adjunctive therapy
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multi-center, open-label, Phase 4 study. Subjects who meet all of the inclusion and 
none of the exclusion criteria will receive perampanel. Baseline seizure counts (frequency) 
data will be
collected by subjects or guardian/legally authorized representative, 
retrospectively (for history prior to screening) and prospectively as needed (during baseline).  
The study consists of 4 periods: a Screening Period (to start no earlier than 6 weeks before


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the 1st dose of study drug), a Titration Period (up to 13 weeks), a Maintenance Period (39 
weeks), and a Follow-up Period (4 weeks).  The study duration for each subject is expected 
to be approximately 1 year in total.  (revised per Amendment 01)
Study subjects will include the following:

Subjects who have been diagnosed with POS or PGTCS but have not previously received 
treatment with an AED or are currently receiving monotherapy treatment (no history of 
AED polytherapy) and wish to switch to another monotherapy treatment; or

Subjects who are currently receiving treatment with a single AED administered at a 
stable dose for at least 8 weeks before Visit 2 (Week 0) and need additional AED 
treatment; subjects should not have previously received adjunctive AED therapy
9.1.1
Screening Period (Week -6 ~ Week 0)
The Screening Visit (Visit 1) will take place no earlier than 6 weeks before the 1st dose of 
study drug.  Seizure data from up to 12 weeks preceding 1st dose will be collected by the 
investigator, including retrospective data collection as needed.  Subjects will be eligible for 
study enrollment after they have experienced either the 2 required unprovoked (or reflex) 
seizures or the 1 unprovoked (or reflex) seizure with EEG evidence of seizures, and they will 
not need to complete the full 12 week diary to enter the Titration Period.  (revised per 
Amendment 01)  Subjects without the required seizure data will fail screening, but may be 
rescreened 1 time.  During the Screening Period, informed consent will be obtained and 
screening assessments will be conducted.  
Before or at the Screening Visit (Visit 1), informed consent will be obtained after the study 
has been fully explained to each subject and before any baseline procedures or assessments
are conducted. Procedures to be followed when obtaining informed consent are detailed in 
Section 5.3.
Investigators will confirm the inclusion/exclusion criteria and will conduct the planned 
evaluations.
Subjects should be no younger than 4 years of age and able to swallow
perampanel tablets.  They must have been diagnosed with epilepsy, consisting of POS with 
or without SGS or PGTCS.  (revised per Amendment 01)  Additionally, they must need
monotherapy or they must need 1st adjunctive therapy with perampanel after failure to 
control seizures on monotherapy with another AED at the optimal dose and duration for that 
AED. 
Screening results must be recorded on the appropriate electronic Case Report Form (eCRF) 
to indicate whether or not the subject is eligible to participate in the study and to provide 
reasons for screen failure if applicable.  In addition, medical history, prior concomitant 
medications and prior concomitant AED of subjects will be obtained.  Subjects who complete 
Visit 2 (Week 0) and meet all of the inclusion/exclusion criteria (Section 9.3.1 and
Section 9.3.2) will be enrolled and will begin the Titration Period.


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9.1.2
Titration Period
The Titration Period will begin with Visit 2, which may overlap with the Screening Visit 
(Visit 1), and will last for up to 13 weeks.  (revised per Amendment 01)  Subjects will 
receive perampanel tablets once daily (QD) before bedtime.  The initial dose of perampanel 2 
mg/day may be up-titrated in increments of 2 mg according to the investigator’s judgment, 
based on individual clinical response and tolerability, as shown in the following dosing 
schedule (Table 1):
Table 1
Dosing Titration Schedule
Category
Weeka
Perampanel Dose (mg/day)
Required
1
2
2
2
3
4
4
4
Telephone Visit
Optional Escalationb
5
6
6
6
Follow-Up Telephone Callc
7
8
8
8
Follow-Up Telephone Callc
9
10
10
10
Follow-Up Telephone Callc
11
12
12
12
13
12
a:  Subjects on a concomitant enzyme-inducing antiepileptic drug may be 
up-titrated at 1-week intervals if needed.
b:  Subjects should be titrated to 4 mg.  Additional dose escalation is optional 
depending on subject response and tolerability, following assessment by 
Telephone Visit or follow-up calls.
c:  If needed; investigator should follow up with subject via telephone call 
prior to further dose escalation.
Treatment will initially be titrated up to perampanel 4 mg based on clinical response and 
tolerability.  Thereafter, titration will be based on the investigator’s judgment; subjects may 
have further dose increases in increments of 2 mg, per evaluation by the investigator 
(Telephone Visit 3) prior to further dose escalation.  The maximum dose is 12 mg.  At least 
2 weeks must elapse between dose increases, with the exception of subjects who are taking 
any concomitant drug that shortens the half-life of perampanel (eg, phenytoin, 
carbamazepine, oxcarbazepine, eslicarbazepine), in which case the treatment may be 
up-titrated at 1-week intervals if needed.  Sites must enter the perampanel dosing information 


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into the Interactive Response Technology (IRT) system on Weeks 2, 4, 6, 8, 10, and 12 to 
track subject dosing.  Adjustments of the concomitant AED dose level during the Titration 
Period are not permitted.  (revised per Amendment 01)
The perampanel dose can be down-titrated based on tolerability, at the discretion of the 
investigator.  Subjects who cannot tolerate the 4 mg dose by the end of the Titration Period 
will be discontinued from the study.
9.1.3
Maintenance Period
Maintenance Period
Subjects will continue to receive the perampanel dose level that was administered at the end 
of the Titration Period, when they enter the 39-week Maintenance Period.  Subjects will 
come to the study site for Visit 4 (Week 13), Visit 5 (Week 26), Visit 6 (Week 39), Visit 7
(Week 52), and at the Follow-Up Visit (Visit 8).  All subjects who discontinue the study are 
to complete the study’s early discontinuation procedures indicated in the Schedule of 
Procedures/Assessments.  (revised per Amendment 01)
According to the investigator’s clinical judgment, subjects who experience AEs may have 
their perampanel dose reduced.  Conversely, if seizures are not adequately controlled, 
subjects may have their dose increased up to a maximum of perampanel 12 mg.  During the 
Maintenance Period, subjects whose perampanel dose has been reduced may have the dose 
increased again, at the discretion of the investigator, as soon as tolerability improves. 
Subjects who cannot tolerate a dose of 4 mg will discontinue perampanel treatment and be 
withdrawn from the study.
Adjustment of the concomitant AED dose level during the 
Maintenance Period is permitted.  Subjects who receive perampanel as a 1st adjunctive 
therapy may also be converted to perampanel monotherapy at the discretion of the 
investigator.  All adjustments to concomitant AED dose levels must be reported in the eCRF.
The overall study design is depicted in Figure 1.


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Figure 1
Study Design
a:  Follow-up phone calls to Visit 3 will be performed biweekly, as necessary, for dose 
adjustment according to the discretion of the investigator.  Dose adjustments and rationale, 
as well as any adverse events will be recorded in the electronic case report form.
9.1.4
Follow-Up Period (4 weeks)
The Follow-Up Period will begin at the end of the Maintenance Period.  Subjects may 
continue to receive commercial perampanel during the Follow-Up Period.  (revised per 
Amendment 01) At the end of the Follow-Up Period, a Follow-Up Visit will take place.  
Subjects who are withdrawn from the study for any reason will also undergo a Follow-Up 
Visit.
The end of the study will be the date of the last study visit for the last subject. However, if 
there are AEs that are present and not resolved at the last scheduled visit, these AEs should 
be followed to stabilization or resolution.


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9.2
Discussion of Study Design
9.2.1
Rationale for Subject Population
Perampanel has been extensively evaluated in multiple Phase 3 studies, predominantly in a 
refractory patient population.  The Phase 3 study protocols specified that subjects should 
have failed therapy with at least 2 AEDs and currently be administered 1 to 3 concomitant 
AEDs.  The current study aims to obtain data in earlier-onset subject groups who require 
initial AED therapy either with monotherapy or a 1st adjunctive therapy.  These data will 
complement the extensive data that are already available for perampanel and will support its 
use in early-onset patients.
9.2.2
Rationale for Efficacy Endpoints
According to “Guideline on clinical investigation of medicinal products in the treatment of 
epileptic disorders” provided by European Medicines Agency, in an adjunctive study, the 
primary endpoint should dichotomize the data into responders/non-responders, where 
responders are subjects who obtained at least a certain pre-defined percentage reduction of 
seizure frequency (Steinhoff, et al., 2013).
Retention rate is commonly used for studies 
resembling real life, as it represents the result of satisfactory efficacy and safety.
The primary efficacy endpoint is the retention rate of perampanel when given as 
monotherapy or 1st adjunctive therapy in subjects with POS or PGTCS.
9.2.3
Rationale for Prohibited/Restricted Concomitant Drug/Therapy
For the evaluation of perampanel as 1st adjunctive therapy, 1 concomitant AED is permitted, 
if it has been administered at a stable dose for 8 weeks before Visit 2 (Week 0). Details of 
prohibited/restricted concomitant drugs and other therapy are presented in Section 9.4.7.
9.3
Selection of Study Population
Approximately 125 subjects will be entered at up to approximately 25 sites in the US.
(revised per Amendment 01)  Subjects who do not meet all of the inclusion criteria or who 
meet any of the exclusion criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Subjects will be male or female and no younger than 4 years of age and be able to 
swallow perampanel tablets.  (revised per Amendment 01)
2. Subjects must have a diagnosis of epilepsy with POS with or without SGS, or with 
PGTCS.  Either of the following must have occurred to support an epilepsy diagnosis:  
(revised per Amendment 01)
a.
At least 2 unprovoked (or reflex) seizures occurring greater than 24 hours apart


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b. 1 unprovoked (or reflex) seizure with EEG evidence of seizures
3. Subjects who receive perampanel as a 1st adjunctive therapy must currently have been 
treated with stable doses of monotherapy with an AED for 8 weeks prior to Visit 2 
(Week 0), have not previously received adjunctive AED treatment, and must, in the 
investigator’s judgement, be in need of initial adjunctive therapy after failure to control 
seizures with AED monotherapy, at the optimal dose and duration.  (revised per 
Amendment 01)
4. Subjects who receive perampanel as monotherapy, who were newly diagnosed (treatment
naïve), following the defined diagnosis of epilepsy.  (revised per Amendment 01)  
5. Subjects who are currently receiving monotherapy treatment may receive perampanel as 
monotherapy if, in the investigator’s judgment, the subject may benefit from a change in 
monotherapy treatment.  Subjects must not have previously received adjunctive AED 
treatment.
6. If antidepressants or antianxiety drugs are used, subjects must be on a stable dose 
regimen of these drugs during the 8 weeks before Visit 2 (Week 0).
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Subjects should not have previously received or currently be receiving perampanel.
2. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] [or human chorionic gonadotropin 
(hCG)] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or 
hCG]); a separate baseline assessment is required if a negative screening pregnancy test 
was obtained more than 72 hours before the 1st dose of study drug.
3. Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
- Total abstinence (if it is their preferred and usual lifestyle)
- An intrauterine device or intrauterine hormone-releasing system
- An oral contraceptive (with additional barrier method if using contraceptive 
containing levogesterol); subject must be on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and throughout the study 
and for 28 days after study drug discontinuation
- Have a vasectomized partner with confirmed azoospermia
•
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation
For sites outside of the EU, it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, then the subject must agree to 
use a medically acceptable method of contraception, ie, double-barrier methods of 
contraception such as condom plus diaphragm or cervical/vault cap with spermicide.


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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).
4. Presence of or previous history of Lennox-Gastaut syndrome
5. Presence of non-motor simple partial seizures only 
6. A history of status epilepticus within 1 year before Screening Visit (Visit 1)
7. Subjects on antipsychotics or who have psychotic disorder(s) or unstable recurrent 
affective disorder(s) with a history of attempted suicide within 1 year before Screening 
Visit (Visit 1)
8. Presence of a progressive central nervous system (CNS) disease, including degenerative 
CNS diseases and progressive tumors
9. Concomitant use of barbiturates (except for seizure control indication and premedication 
for EEG) and benzodiazepines (except for seizure control indication) within 8 weeks 
prior to Visit 2 (Week 0)
10. Use of intermittent rescue benzodiazepines (ie, 1-2 doses over a 24-hour period is 
considered a 1-time rescue) 2 or more times in the 8 week period prior to Visit 2 (Week 0)
11. Severe renal insufficiency (defined by estimated glomerular filtration rate of <30 mL/min) 
or subjects who receive hemodialysis
12. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease, hepatic disease) that in the opinion of the investigator(s) could affect the 
subject’s safety or study conduct
NOTE:  Stable elevation of liver enzymes, alanine aminotransferase and aspartate 
aminotransferase due to concomitant medication(s), will be allowed if they are less than 
3 times the upper limits of normal.  
13. Hypersensitivity to perampanel or any excipients
14. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
15. Subjects who are participating in other interventional clinical trial
16. Subject who are judged to have inadequate cognitive ability for participation in the study 
(intelligence quotient [IQ] <80 or investigator judgment)
17. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months 
of Screening, as indicated by answering “Yes” to questions 4 and 5 on the Suicidal 
Ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS)
18. Any lifetime suicidal behavior based on the C-SSRS
19. Concomitant use of any form of cannabidiol (CBD)  (revised per Amendment 01)  
20. Planned brain surgery during study participation  (revised per Amendment 01)


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9.3.3
Removal of Subjects from Therapy or Assessment
9.3.3.1
Scheduled Termination
Subjects will be considered to have completed the Titration Period after up to 13 weeks of 
titration treatment and completion of the Visit 4 (Week 13) visit procedures. (revised per 
Amendment 01)  Subjects who have completed the Titration Period will enter the 
Maintenance Period. Subjects will be considered to have completed the Maintenance Period
after 39 weeks of maintenance treatment and completion of the Visit 7 (Week 52) visit 
procedures. Upon completion of the Titration Period, the Maintenance Period, and the 
Follow-Up Period, and after resolution of any AEs that may be present on the last visit, the 
subject will be considered to have completed the study.
9.3.3.2
Withdrawals
Subjects who were administered at least 1 dose of study drug but could not participate in the 
study are classified as ‘withdrawals’. 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.
Reasons for withdrawal are as the following: 

Withdrawal of informed consent

AE(s) requiring discontinuation of study therapy 

Eligibility violation

Lack of efficacy

Administration of prohibited medications

Lost to follow-up

Unable to continue the study in the investigator’s judgment
The investigator will make every reasonable effort to follow up subjects for any AEs. He/she 
will use all possible ways to communicate (phone call, letters, and visit to home) with the 
subject. The reason for withdrawal should be documented on the eCRF. Final assessments 
of withdrawn subjects should be conducted and documented as described in Section 9.6.1.
Withdrawn subjects will not be allowed to re-enter the study. 
9.4
Treatment
9.4.1
Treatment Administered
Perampanel will be administered to subjects during each study period. Tablets at the 
assigned dose strength will be taken orally once daily before bedtime. At the beginning of 
the Titration Period, oral perampanel will start at a dose of 2 mg QD. Doses of perampanel 
will then be up-titrated in increments of 2 mg/day at no less than 2-week intervals according 
to the investigator’s judgment.  At the 4 mg dose (Week 4, telephone call, Visit 3), the 
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and tolerability. The investigator may adjust dosing further or leave the subject at 4 mg.  The 
maximum dose is 12 mg.  Subjects who are taking concomitant AEDs that are known 
cytochrome P450 (CYP) enzyme inducers (eg, phenytoin, carbamazepine, oxcarbazepine, 
eslicarbazepine) which shorten the half-life of perampanel, can undergo up-titration in 2-mg 
increments at intervals of at least 1 week.
The study drug will be dispensed to each subject or guardian/legally authorized 
representative at Visit 2 (Week 0), Visit 4 (Week 13), Visit 5 (Week 26), and Visit 6 
(Week 39).  Sites must enter the perampanel dosing information into the IRT system on 
Weeks 2, 4, 6, 8, 10, and 12 to track subject dosing.  (revised per Amendment 01)
Tablet(s) cannot be split, broken or crushed prior to administration, and should be 
administered whole at bedtime.
9.4.2
Identity of Investigational Product
•
Perampanel will be supplied by the sponsor.
•
Product name/manufacturer: Fycompa/Eisai Inc.
•
Formulation/drug appearance is presented in Table 2.
•
Storage condition:  20°C to 25°C (68°F to 75°F) with excursions permitted at 
15°C to 30°C (59°F to 86°F).
Table 2
Formulation/Drug Appearance
Tablet strength
Description
2 mg
Orange, round, biconvex, film-coated tablets
4 mg
Red, round, biconvex, film-coated tablets
6 mg
Pink, round, biconvex, film-coated tablets
8 mg
Purple, round, biconvex, film-coated tablets
10 mg
Green, round, biconvex, film-coated tablets
12 mg
Blue, round, biconvex, film-coated tablets
9.4.2.1
Chemical Name, Structural Formula of E2007
•
Test drug code:  E2007
•
Generic name:  Perampanel
•
Chemical name: 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile
•
Molecular formula: C23H15N3O
•
Molecular weight: 349.38 (anhydrous)


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9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Test drug will be labeled in accordance with text that is in full regulatory compliance with
each participating country and is translated into the required language(s) for each of those
countries. Perampanel (E2007) is a Schedule III Controlled Drug Substance in the United 
States (US) and will be labeled as such for US sites.
9.4.2.4
Storage Conditions
Perampanel will be stored in accordance with the labeled storage conditions. Temperature 
monitoring is required at the storage location to ensure that the perampanel is maintained 
within an established temperature range, 20°C to 25°C (68°F to 75°F) with excursions 
permitted at 15°C to 30°C (59°F to 86°F).
9.4.3
Method of Assigning Subjects to Treatment Group
This is an open-label study.  An interactive voice response system will be used to register 
subjects into this study.  All subjects who provide signed informed consent to participate in 
this study and satisfy all eligibility requirements (see Section 9.3) will be assigned to receive
perampanel for the Titration Period and Maintenance Period. There is no randomization in 
this study.
9.4.4
Selection of Doses in the Study
Perampanel is approved for the treatment of POS, with or without SGS, in patients with 
epilepsy 4 years of age and older, and as adjunctive therapy of PGTCS, in patients with 
epilepsy 12 years of age and older.  (revised per Amendment 01)  The initial dose of 
perampanel will be 2 mg/day and this dose can be escalated by increments of 2 mg/day no 
more frequently than at weekly intervals, up to 12 mg, a maximum dose, depending on the 
clinical response and tolerability in subjects.
9.4.5
Selection and Timing of Dose for Each Subject
Subjects will begin receiving perampanel 2 mg/day and be up-titrated in increments of 2 mg 
to a maximum dose of 12 mg, depending on the clinical response and tolerability in each 
subject. Subjects will start taking study drug at bedtime at Visit 2 (Week 0).
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Drug/Therapy

Concomitant AED for subjects who receive perampanel as a 1st adjunctive therapy


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o
Only 1 AED can be used.
o
A concomitant AED must be used at the stable dose and administered between 
8 weeks before Visit 2 (Week 0) and the end of the Titration Period.  The dose and 
administration of the AED may be modified during the Maintenance Period based on 
the investigator’s judgment.

Concomitant medication
The following concomitant drugs are prohibited throughout the study period (up to the 
Follow-Up Period or early discontinuation visit):  (revised per Amendment 01)
o
CYP3A4-inducing drugs and food below as follows (from 30 days before Visit 1):  
Rifampicin, troglitazone, barbiturates except for use as AED, modafinil, efavirenz, 
nevirapine, glucocorticoid except for topical use, pioglitazone, rifabutin, and food 
containing St. John’s Wort (Hypericum perforatum). (revised per Amendment 01)
o
Antipsychotics
o
Other investigational drugs.  (revised per Amendment 01). 
o
CBD products  (revised per Amendment 01)
Restricted concomitant drug:
o
Any changes in the dosing regimen of antidepressant or antianxiety drugs during the 
study must be recorded. 
o
Barbiturates (except for seizure control indication and premedication for EEG) and 
benzodiazepines (except for seizure control indication) within 8 weeks prior to Visit 2 
(Week 0)

Concomitant therapy  (revised per Amendment 01)
Prohibited concomitant therapy
The following therapies must not be implemented during the study:
o
Investigational device 
Restricted concomitant therapy:
o
Vagus nerve stimulation is allowed, but stimulator parameters cannot be changed for
8 weeks before Visit 2 (Week 0) or thereafter during the study.
o
A ketogenic diet will be allowed as long as the subject has been on this diet for 
8 weeks prior to Visit 2 (Week 0). Additionally, a ketogenic diet cannot be newly 
added or discontinued during the study.
Clarification of previous AED medication:
o
Subjects may switch monotherapies provided the time to complete the conversion is 
less than 30 days.
o
Subjects on short-term monotherapy (<2 weeks) may be eligible for the study 
provided they stop the initial therapy at the time of perampanel dosing.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study. CRAs will 
review treatment compliance during site visits and at the completion of the study.


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The importance of compliance with the treatment regimen will be emphasized at each visit.
The subject must be reminded to return all unused medication from the previous treatment 
period and report the number of tablet(s) lost to the investigator if tablet(s) are lost. The 
investigator or designated study site personnel should count the number of tablets returned by 
the subject and investigate the number of tablet(s) lost from the subject to establish the 
number of tablets used, and compare this to the number of tablets expected to be used for the 
period. A record of this reconciliation must be maintained using the accountability forms, 
and any issues of non-compliance discussed with the subject.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
An investigator-signed and dated FDA Form FDA 1572, where applicable
•
Financial disclosure form(s) for the PI and all subinvestigators listed on Form FDA 1572, 
where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the regulatory authority approval for the country in which the study is being 
conducted, and the Import License
•
For US sites only:
A copy of the controlled Substance Registration Certificate 
(DEA-Form 223), which must be current (ie, not expired) and have the appropriate 
controlled substance schedule listed for the study drug. Study drug will only be shipped 
to the exact address found on the DEA-Form 223 registration. 
The investigator and the designated pharmacist will be responsible for the accountability of 
all study drugs (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.


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Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol. Study drug will not be dispensed to any individual who is not 
enrolled in the study, or to the guardian/legally authorized representative of an adolescent 
who is not enrolled in the study.
The site must maintain an accurate and timely record of the following: receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site. 
This includes, but may not be limited to: 
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, and (d) documentation of returns to the sponsor. All 
forms will be provided by the sponsor. Any comparable forms that the site wishes to use 
must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg, 
FDA, Medicines and Healthcare products Regulatory Agency). As applicable, all unused 
study drugs and empty and partially empty containers from used study drugs are to be 
returned to the investigator or the designated pharmacist by the subject and, together with 
unused study drugs that were shipped to the site but not dispensed to subjects, are to be 
returned to the sponsor’s designated central or local depot(s) during the study or at the 
conclusion of the study, unless provision is made by the sponsor for destruction of study 
drugs and containers at the site. Destruction at the site will only occur under circumstances 
where regulation or supply type prohibits the return of study drugs to the central or local 
depot(s). Approval for destruction to occur at the site must be provided by the sponsor in 
advance. Upon completion of drug accountability and reconciliation procedures by the site’s 
personnel and documentation procedures by the sponsor’s personnel, study drugs that are to 
be returned to the sponsor’s designated central or local depot(s) must be boxed, sealed, and 
shipped back to the central or local depot(s) following all local regulatory requirements. In 
some regions, study drugs may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives. Where study drugs are approved for destruction at 
the site, destruction will occur following the site’s standard procedures and certificates of 
destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demographic/Baseline Assessments
9.5.1.1.1
DEMOGRAPHY
Subject demography information will be collected at Screening Visit (Visit 1). Demography 
information includes date of birth (or age), sex.


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9.5.1.1.2
DIAGNOSIS
The subject must have been diagnosed with epilepsy with POS (with or without SGS) or with
PGTCS. To support an epilepsy diagnosis, either of the following must have occurred: at 
least 2 unprovoked (or reflex) seizures occurring greater than 24 hours apart, or 
1 unprovoked (or reflex) seizure with EEG evidence of seizures.  (revised per Amendment 
01)  In addition, subjects should be receiving treatment with a single AED, and need 
additional AED treatment or have not previously received treatment with an AED or are 
currently receiving monotherapy treatment (no history of AED polytherapy) and wish to 
switch to another monotherapy treatment.
9.5.1.1.3
SEIZURE TYPE AND FREQUENCY
Seizure type and frequency/interval from the 12 weeks preceding the 1st perampanel dose 
(Visit 2) will be collected by the investigator, including retrospective data collection as 
needed.
9.5.1.1.4
MEDICAL HISTORY 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit. All pertinent medical and surgical history within 5 years before the Screening Visit
must be noted on the appropriate eCRF.
Vital signs including blood pressure, body temperature, respiratory rate and pulse rate will be 
performed as designated in Section 9.5.1.6.4. Documentation of vital signs will be included 
in the source documentation at the site. Weight should be recorded at each visit, and height 
should be recorded at baseline.  For subjects <18 years of age, height should also be recorded 
at the last Follow-Up Visit.
Prior and concomitant medications including drug name, dosage, administration route, within 
24 weeks (and as long as available, for AEDs) before the Screening Visit will be recorded.
9.5.1.1.5
CONCOMITANT ANTIEPILEPTIC DRUGS
AED treatment including drug name, dosage, and administration route, will be obtained 
throughout the study.
9.5.1.2
Efficacy Assessments
Exposure data will be utilized to assess the primary endpoint.  Secondary efficacy variables 
will be based on seizure frequency. Seizure frequency data will be collected in subject 
diaries by subjects or guardian/legally authorized representative during the study including 
the Titration Period and the Maintenance Period.  Baseline seizure frequency data for up to 
12 weeks before Visit 2 (Week 0) will be collected by subjects or guardian/legally authorized 
representative, retrospectively (for history prior to screening) and prospectively (during 
baseline).  Subjects will be eligible for study enrollment after they have experienced the 
2 unprovoked (or reflex) seizures occurring greater than 24 hours apart, or 1 unprovoked (or 


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reflex) seizure with EEG evidence of seizures, and will not need to complete the full 12-week 
diary to enter the Titration Period.  (revised per Amendment 01)  Seizure frequency data in 
subject diaries will be reviewed with the investigator(s) at Visit 2, 4, 5, 6, and 7. Seizure 
frequency from diary entries or principal investigator verification will be used to assess 
efficacy endpoints as appropriate.  (revised per Amendment 01)
9.5.1.3
Pharmacokinetic Assessments
Not applicable.
9.5.1.4
Pharmacodynamic Assessments
Not applicable.
9.5.1.5
Pharmacogenomic Assessments
Whole blood samples for preparation of genomic DNA may be obtained at baseline from 
subjects for additional exploratory analyses.
9.5.1.6
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs); discontinuation from treatment, prior and concomitant medication usage, 
periodic measurement of weight, and assessments of cognitive functioning and monitoring of 
suicidal thoughts or depressive symptoms.  The C-SSRS will be administered at specified 
intervals.
9.5.1.6.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product. 
An AE does not necessarily have a causal 
relationship with the medicinal product. For this study, the study drug is perampanel.
The criteria for identifying AEs 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:  A sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease
•
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, electrocardiography 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 at
pretreatment (ie, at baseline)


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An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding of 
study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the eCRF. 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. Subjects who fail screening primarily due 
to AE(s) must have the AE(s) leading to screen failure reported on the Screening Disposition 
eCRF. 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 eCRF. 
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE.  
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.
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 eCRF. The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.6.2 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


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•
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 eCRF 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.
9.5.1.6.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL 
SITUATIONS
A SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs. Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 


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In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error. These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria. All AEs associated with special situations are to be reported on the eCRF 
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
9.5.1.6.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 3. Subjects should be in a seated or supine position during blood 
collection.
As depicted in the Schedule of Procedures/Assessments (Table 4), blood for 
clinical laboratory tests and urine for urinalysis will be collected at Screening.  Clinical 
laboratory evaluations may be performed at other visits, per the investigator’s discretion, if 
required for assessment of an AE.
Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, total cholesterol, glucose (fasting), lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid, 
lipid profile (fasting).  
Urinalysis
glucose, ketones, occult blood, pH, protein, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.


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A laboratory value that is considered abnormal and clinically significant may meet the 
criteria to qualify as an AE as described in this protocol (see Section 9.5.1.6.1) and the eCRF 
Completion Guidelines. 
In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the Adverse Event eCRF.
9.5.1.6.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (eg, systolic and diastolic blood pressure [mmHg], pulse [beats per 
minute], respiratory rate [per minute], body temperature [in centigrade]), weight (kg) and 
height (cm)
will be obtained at the visits designated in the Schedule of 
Procedures/Assessments (Table 4) by a validated method. Blood pressure and pulse will be 
measured after the subject has been sitting for at least 5 minutes.  All blood pressure
measurements should be performed on the same arm, preferably by the same person.
9.5.1.6.5
EPITRACK
Cognition will be assessed in subjects 6 years of age and older at Visit 2 (Week 0) and at 
3 and 12 month visits (Visits 4 and 7, respectively) using the EpiTrack® assessment tool.
The EpiTrack (second edition with recently extended and revised norms) is a screening tool 
dedicated to the tracking of adverse cognitive effects of antiepileptic medication (Lutz and 
Helmstaedter, 2005). Studies have demonstrated the usefulness of the EpiTrack with regard 
to cognitive monitoring of the impact of pharmacological treatments (Lutz and 
Helmstaedter, 2005; Helmstaedter and Witt, 2008;
Helmstaedter and Witt, 2010;
Helmstaedter and Witt, 2013; Witt, et al., 2014).  The test includes 6 subtests: response 
inhibition, visuo-motor speed, mental flexibility, visual motor planning, verbal fluency, and 
working memory. Based on the subtest results, an age-corrected total score is calculated. 
Higher scores reflect better performance with a maximum score of 49 points.  The interval 
for mild impairment is 29 to 31 points, and the cutoff for significant impairment is 28 points
or less.  Practice corrected reliable change indices indicate a significant change with a gain of 
more than 3 points and a loss of more than 2 points.  
The EpiTrack Junior will be administered for subjects ages ≥6 to 16 years old.  (revised per 
Amendment 01)
At the investigator’s discretion, a subject may be excluded from the cognition assessments 
based on their assessment of the subject and the subject’s capability to complete the 
assessment at baseline.  If the cognition assessments are not done for a subject, the 
justification should be recorded in the eCRF.  
9.5.1.6.6
BECK DEPRESSION INVENTORY-II
The Beck Depression Inventory-II (BDI-II) is a 21-question multiple-choice self-report 
inventory and is widely used for measuring the severity of depression.  The depression score 
will be used to aid in interpretation of the cognition score.  The BDI-II will be administered 
in patients 16 years of age and older who are administered the EpiTrack.


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At the investigator’s discretion, a subject may be excluded from the cognition assessments 
based on their assessment of the subject and the subject’s capability to complete the 
assessment at baseline.  If the cognition assessments are not done for a subject, the 
justification should be recorded in the eCRF.  
9.5.1.6.7
PITTSBURGH SLEEP QUALITY INDEX
The Pittsburgh Sleep Quality Index (PSQI) is a retrospective sleep quality instrument with 
19 items (Buysse et al., 1989).  It measures subjects’ perspectives on sleep parameters 
(length of sleep, sleep disturbances), sleep quality, and impact on daily functioning.  The 
PSQI will be administered to patients 12 years of age and older.
9.5.1.6.8
QUALITY OF LIFE IN EPILEPSY INVENTORY-31
The Quality of Life in Epilepsy Inventory-31 is a survey of health-related quality of life for 
adults (18 years or older) with epilepsy. 
9.5.1.6.9
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
An assessment of suicidality will be performed using the C-SSRS at the visits designated in 
the Schedule of Procedures/Assessments (Table 4).  The C-SSRS will be administered to 
patients 6 years of age and older.  Subjects under 6 years of age will be clinically monitored 
for suicidality.  (revised per Amendment 01)
9.5.1.6.10
PREGNANCY TEST
A urine or serum-hCG pregnancy test will be performed during the Screening Period 
(Visit 1) and/or at Visit 2 (Week 0), Visit 6 (Week 39) and Follow-Up Visit for 
premenopausal women and postmenopausal women who have been amenorrheic for less than 
12 months.
9.5.1.7
Description of Procedures/Assessments Schedule
The study procedures and assessments are shown in Table 4.


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9.5.2
Schedule of Procedures/Assessments 
Table 4
Schedule of Procedures/Assessments in Study E2007-G000-410  (revised per Amendment 01)
Period
Screeninga
Titrationb
(Wk 0 to Wk 12)
Maintenanceb
Early 
Discontinuation
Follow-
Upb,c
Unscheduledd
Study Week(s)
Wk -6 to 
Wk 0
Wk 0
Wk 2e
Wk 4
Biweeklyf,g
Wk 13
Wk 26
Wk 39
Wk 52
Wk 56
Study Day
1
15
29
92
183
274
365
Visit Number
1
2
3
4
5
6
7
8
Procedure/
Assessment
Informed 
consent/assenth
X
Inclusion/ 
exclusion criteria
X
X
Demographic data
X
Seizure type and 
frequency
X
X
Medical historyi
X
Documentation of 
perampanel dose
X
X
X
X
X
X
X
X
Concomitant 
medications
Xj
X
X
X
X
X
X
X
Xd
Concomitant AED
Xj
X
X
X
X
X
X
X
Xd
Vital signs
X
X
X
X
X
X
X
X
Xd
Cognition 
assessment 
(EpiTrack)k
X
X
X
X


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Table 4
Schedule of Procedures/Assessments in Study E2007-G000-410  (revised per Amendment 01)
Period
Screeninga
Titrationb
(Wk 0 to Wk 12)
Maintenanceb
Early 
Discontinuation
Follow-
Upb,c
Unscheduledd
Study Week(s)
Wk -6 to 
Wk 0
Wk 0
Wk 2e
Wk 4
Biweeklyf,g
Wk 13
Wk 26
Wk 39
Wk 52
Wk 56
Study Day
1
15
29
92
183
274
365
Visit Number
1
2
3
4
5
6
7
8
Procedure/
Assessment
Depression 
assessment 
(BDI-II)
X
X
X
X
QOLIE-31
X
X
X
PSQI
X
X
X
C-SSRSl
X
X
X
X
X
X
X
Clinical laboratory 
evaluationsm
X
X
Blood sample for 
pharmacogenomics
X
Pregnancy test
X
Xn
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Dispense study 
drug
X
X
X
X
Return study drug
X
X
X
X
X
Study drug 
compliance
X
X
X
X
X
Dispense subject 
diary
Xo
X
X
X
X


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Table 4
Schedule of Procedures/Assessments in Study E2007-G000-410  (revised per Amendment 01)
Period
Screeninga
Titrationb
(Wk 0 to Wk 12)
Maintenanceb
Early 
Discontinuation
Follow-
Upb,c
Unscheduledd
Study Week(s)
Wk -6 to 
Wk 0
Wk 0
Wk 2e
Wk 4
Biweeklyf,g
Wk 13
Wk 26
Wk 39
Wk 52
Wk 56
Study Day
1
15
29
92
183
274
365
Visit Number
1
2
3
4
5
6
7
8
Procedure/
Assessment
Return and review 
subject diary
X
X
X
X
X
X
AED = antiepileptic drug, BDI-II = Beck Depression Inventory II, eCRF = electronic Case Report Form, C-SSRS = Columbia-Suicide Severity Rating Scale, PSQI = Pittsburgh 
Sleep Quality Index, QOLIE-31 = Quality of Life in Epilepsy Inventory-31, Wk = week.
a:  Up to 12 weeks of baseline seizure frequency to be determined at screening; any screening assessments may repeated during the Screening Period, at the discretion of the 
investigator.
b:  Visit to be done within ±7 days of the schedule.  Subjects may continue to receive commercial perampanel during the Follow-Up Period.  (revised per Amendment 01)
c:  To be completed by subjects who are withdrawn from the study for any reason after Visit 2 (Week 0) and before Visit 6 (Week 39). (revised per Amendment 01)
d:  At the unscheduled visit, only the assessments that the investigator(s) judged necessary based on the subject’s condition will be performed
e:  At the end of Week 2, the perampanel dose increases from 2 to 4 mg; this is not a visit.
f:  Telephone Visit; all dose adjustments and rationale for the adjustments, as well as adverse events will be recorded on the eCRF.
g:  Follow-up telephone calls to Visit 3 may occur biweekly, or at a frequency of the investigator’s discretion.  All dose adjustments and rationale for adjustments, as well as 
adverse events will be recorded in the eCRF.
h:  Informed consent/assent may be obtained prior to study start; it must be obtained prior to any study related procedures.
i:  All pertinent medical and surgical history within 5 years before Visit 1 (Week 0).
j:  Prior and concomitant medication(s) within 24 weeks (and as long as available for AED[s]) before Visit 2 (Week 0).
k:  Subjects 6 years and older.  EpiTrack Junior will be administered for subjects aged ≥6 to 16 years old. (revised per Amendment 01)
l:  The C-SSRS will be administered to patients 6 years of age and older.  Subjects under 6 years of age will be clinically monitored for suicidality.  (revised per Amendment 01)
m: Any laboratory value that is considered abnormal and clinically significant will be reported as an adverse event.  Clinical laboratory evaluations may be performed at other 
visits if required for assessment of an adverse event. Blood for laboratory evaluations must be collected in fasting state.  (revised per Amendment 01)
n:  Required only if a negative screening pregnancy test was obtained more than 72 hours before the 1st dose of study drug.
o:  Subjects may also provide retrospective seizure frequency history if available.


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9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of initial 
adjunctive treatment for POS with or without SGS.
The safety assessments to be performed in this study, including assessment of AEs and 
SAEs, discontinuation from treatment, prior and concomitant medication usage, periodic 
measurement of weight, and assessments of cognitive functioning and monitoring of suicidal 
thoughts or depressive symptoms, 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 (in 
US) no later than 1 business day or (in EU) no later than 24 hours from the time at 
which the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the last visit. All SAEs 
must be followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE judged 
by the investigator to be related to the study treatment or any protocol-required procedure 
should be reported to the sponsor regardless of the length of time that has passed since study 
completion.
The detailed contact information for reporting of SAEs is provided in the ISF.
For urgent safety issues call:  Designated CRO (C&R Research) contact number.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the ISF.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report. This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt. If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.


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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 
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 ISF. The Pregnancy 
Report Form must be used for reporting. All pregnancies must be followed to outcome. The 
outcome of the pregnancy must be reported as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated With Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
AEs associated with study drug overdose, misuse, abuse, and medication error refer to AEs 
associated with uses of the study drug outside of that specified by the protocol. Overdose,
misuse, abuse, and medication error are defined as follows:
Overdose:  Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose.
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 eCRF and also reported using the procedures detailed in Reporting of 


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Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event eCRF.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames). For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
AEs will be reported by the sponsor or a third party acting on behalf of the sponsor to 
regulatory authorities in compliance with local and regional law and established guidance. 
The format of these reports will be dictated by the local and regional requirements.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC. 
All 
suspected unexpected serious adverse reactions will be reported, as required, to the 
competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason. All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 4).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject. A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, progression 
of disease, withdrawal of consent, pregnancy, study terminated by sponsor, or other.
In 
addition to the primary reason, the subject may indicate 1 or more secondary reason(s) for 
discontinuation. Study disposition information will be collected on the Subject Disposition 
eCRF.


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A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drug.  AEs associated with abuse or diversion will be appropriately reported as AEs and 
monitored per Section 9.5.4.  Abuse is always to be captured as an AE.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations and 
guidelines. Site audits will be made periodically by the sponsor’s or the CRO’s qualified 
compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study. 
9.6.1
Data Collection
Data required by the protocol will be collected on the eCRFs and entered into a validated 
data management system that is compliant with all regulatory requirements. As defined by 
ICH guidelines, the eCRF 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 eCRF must follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the eCRF.
The investigator or designee must sign the completed 
eCRF to attest to its accuracy, authenticity, and completeness.
Completed, original eCRFs 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 eCRF and external data, will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released. Statistical analyses will be performed 
using SAS software or other validated statistical software as required. 
Details of the 
statistical analyses will be included in a separate statistical analysis plan, which will be 
finalized before database lock.


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9.7.1
Statistical and Analytical Plans
All summaries of seizure-related efficacy endpoints will be produced by seizure type (POS, 
SGS, and PGTCS).  Summaries of retention rate and safety data will be produced by seizure 
type (POS and PGTCS) and overall.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is retention rate, defined as the proportion of subjects remaining on 
perampanel at the specified time points:  3, 6, 9, and 12 months after initiation of treatment.
9.7.1.1.2
SECONDARY ENDPOINTS
•
Proportion of subjects who achieve seizure free status for POS, SGS, and PGTCS during 
the Maintenance Period. 
•
Proportion of subjects who achieve 3-month seizure-free status for POS, SGS, and 
PGTCS.
•
Proportion of subjects who achieve 6-month seizure-free status for POS, SGS, and 
PGTCS.
•
Proportion of subjects who receive perampanel as a 1st adjunctive therapy who are able 
to convert to perampanel monotherapy
•
Safety and tolerability of perampanel administered as monotherapy or 1st adjunctive 
therapy in adolescents and adults
9.7.1.1.3
EXPLORATORY ENDPOINTS
•
50% responder rate in total POS, SGS, and PGTCS; 50% responders are defined as 
subjects who have at least a 50% reduction in seizure frequency relative to baseline (in 
subjects with sufficient baseline seizure frequency data)
•
75% responder rate in total POS, SGS, and PGTCS; 75% responders are defined as 
subjects who have at least a 75% reduction in seizure frequency relative to baseline (in 
subjects with sufficient baseline seizure frequency data)
•
Median percent change in total POS, SGS, and PGTCS frequency in the Titration and 
Maintenance Periods relative to baseline (in subjects with sufficient baseline seizure 
frequency data) 
•
Proportion of subjects with no/mild/clear cognitive impairment relative to baseline using 
the EpiTrack total score
•
Change in subjective sleep quality at the end of the Maintenance Period relative to 
baseline using the PSQI 


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•
Change in quality of life at the end of the Maintenance Period relative to baseline using 
the QOLIE-31
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set (SAS) is the group of subjects who received at least 1 dose of study 
drug and had at least 1 postdose safety assessment.
The Full Analysis Set (FAS) is the group of subjects who received at least 1 dose of study 
drug and had at least 1 postdose seizure measurement.
9.7.1.3
Subject Disposition
The disposition of all subjects will be summarized. Subject disposition tables will include 
the number (percent) of subjects who will be:
•
Included in each analysis population
•
Discontinued from the study early, summarized by reason for discontinuation
•
Screened and the number (percent) who fail screening will also be summarized
9.7.1.4
Demographic/Baseline Characteristics
Demographic and other baseline characteristics (eg, age, sex) for the SAS will be 
summarized using descriptive statistics. Continuous variables will be summarized using
mean, SD, median, minimum, maximum and categorical variables will be summarized using
number and percentages of subjects.
9.7.1.5
Prior and Concomitant Therapy
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the SAS by Anatomical Therapeutic Chemical class. Prior medication is 
defined as any medication that stopped before the 1st dose of study drug. Concomitant 
medication is defined as any medication that (1) started before the 1st dose of study drug and 
was continuing at the time of the 1st dose of study drug, or (2) started on or after the date of 
the study drug until the last dose of study drug. 
9.7.1.6
Efficacy Analyses
This is a study without a control arm.  Therefore, formal hypothetical inferences are not 
necessary, and only descriptive statistics will be performed, as shown below:
For percent change in seizure frequency endpoints:
•
Mean, standard deviation, median (95% CIs), minimum, and maximum will be provided.
For responder rate endpoints:


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•
Number of responders
•
Responder rate and its 95% CI
The details for the analyses will be described in the statistical analysis plan.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The SAS will be used to summarize retention rate.  The retention rate, defined as the 
proportion of patients remaining on perampanel treatment at 3, 6, 9, and 12 months after 
initiation of treatment, will be summarized.
The number and percentage of subjects remaining on treatment at each time point and 
95% CIs will be summarized. 
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The FAS will be used to summarize seizure data.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
Analyses of exploratory efficacy endpoints will be performed in the subset of the FAS with 
sufficient baseline seizure frequency.  All summaries will be produced by seizure type (POS, 
SGS, and PGTCS).
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Not applicable.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Not applicable.
9.7.1.7.3
PHARMACOGENOMIC ANALYSES
Variation in exposure of perampanel, baseline levels and changes in clinical measurements 
(eg, efficacy or other safety parameters such as labs), or occurrence of AEs may be evaluated 
by testing for association of genetic variants with these measurements or traits.  Details of 
any pharmacogenomic analyses will be described and reported separately.
9.7.1.8
Safety Analyses
The SAS will be used to summarize all safety variables. Safety data will be summarized 
using descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [percentage] for categorical variables). 
Safety summaries will 


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include treatment-emergent adverse events (TEAEs) including SAEs and TEAEs resulting in 
discontinuation of perampanel.
9.7.1.8.1
EXTENT OF EXPOSURE
The extent of exposure to the study drug during the Titration and the Maintenance Period 
will be summarized descriptively. 
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities
(MedDRA). AEs will be coded to the MedDRA (most recent version) lower level term
closest to the verbatim term. The linked MedDRA preferred term (PT) and primary system 
organ class (SOC) are also captured in the database.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT. A subject will be counted only once within an SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT. 
The number
(percentage) of subjects with TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of patients with TEAEs leading to death will be summarized by
MedDRA, SOC, and PT. A patient data listing of all TEAEs leading to death will be
provided.
The number (percentage) of patients with treatment-emergent SAEs and AEs leading to
discontinuation will be summarized by MedDRA, SOC, and PT. A patient data listing of all
SAEs will be provided.
9.7.1.8.3
COGNITION, DEPRESSION, AND SUICIDALITY
Cognitive function in subjects 6 years of age and older will be evaluated using EpiTrack. It 
will be administered at Visits 2, 4, and 7 (Weeks 0, 13, and 52, respectively).  Summaries of 
the proportion of subjects with no/mild/clear cognitive impairment and shifts between these 
categories from baseline to end of treatment will be produced. The BDI-II will be used to 
assess depression.  Suicidality will be assessed using the C-SSRS and summaries will include 
the incidence of suicidal behavior and suicidal ideation.  The C-SSRS will be administered to 
patients 6 years of age and older.  Subjects under 6 years of age will be clinically monitored 
for suicidality.  (revised per Amendment 01)


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9.7.1.8.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital signs and body weight will be summarized.  Descriptive statistics for vital signs 
parameters, weight and changes from baseline will be presented by visit.
9.7.2
Determination of Sample Size
The efficacy of perampanel as monotherapy and 1st adjunctive therapy for POS and PGTCS
is to be evaluated. The primary endpoint is retention rate.  There is no statistical hypothesis 
to be tested in this study.
The study is to enroll approximately 125 subjects.  (revised per Amendment 01)
9.7.3
Interim Analysis
Interim analyses will be conducted at various intervals, depending on the number of accrued 
subjects.
9.7.4
Other Statistical/Analytical Issues
Not applicable.


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10 REFERENCE LIST
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ.  The Pittsburgh Sleep Quality 
Index (PSQI):  A new instrument for psychiatric research and practice.  Psychiatry Res.  
1989;28(2):193-213.
Helmstaedter C, Witt JA.  The effects of levetiracetam on cognition:  A non-interventional 
surveillance study.  Epilepsy Behav.  2008;13(4):642-9.
Helmstaedter C, Witt JA. Cognitive outcome of antiepileptic treatment with levetiracetam 
versus carbamazepine monotherapy: A non-interventional surveillance trial. Epilepsy Behav. 
2010;18:74–80.
Helmstaedter C, Witt JA. The longer-term cognitive effects of adjunctive antiepileptic 
treatment with lacosamide in comparison with lamotrigine and topiramate in a naturalistic 
outpatient setting. Epilepsy Behav.  2013;26:182–7.
Lutz MT, Helmstaedter C.  EpiTrack:  Tracking cognitive side effects of medication on 
attention and executive functions in patients with epilepsy.  Epilepsy Behav. 2005;7:708-14.
Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, et al. Efﬁcacy 
and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled 
analysis of three phase III studies. Epilepsia. 2013;54(8):1481–9.
Witt JA, 
Werhahn 
KJ, 
Kramer 
G, 
Ruckes 
C, 
Trinka 
E, 
Helmstaedter 
C.  
Cognitive-behavioral screening in elderly patients with new-onset epilepsy before treatment.  
Acta Neurol Scand.  2014;130:172–7.


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The eCRFs 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 an interactive voice response system, 
x-rays, and other imaging reports (eg, sonograms, computed tomography scans, magnetic 
resonance images, radioactive images, electrocardiographs, rhythm strips, EEG, 
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
•
eCRF components (eg, questionnaires) that are completed directly by subjects and serve 
as their own source
11.4
Recording of Data
An eCRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the eCRF must reflect the corresponding source document, except 
when a section of the eCRF itself is used as the source document.  Any correction to entries 
made on the eCRF 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 eCRF.  The investigator will report the eCRFs to the sponsor 
and retain a copy of the eCRFs.
11.5
Identification of Source Data
All data to be recorded on the eCRF must reflect the corresponding source documents. 
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 
protocol, copies of eCRFs, 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 


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marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of the period of retaining the study records.
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 
standard operating procedures to evaluate compliance with the principles of ICH GCP and all 
applicable local regulations.  If a government regulatory authority requests an inspection 
during the study or after its completion, the investigator must inform the sponsor 
immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  The investigator (or a designated pharmacist) 
must maintain an accurate record of the shipment and dispensing of the study drug in a drug 
accountability ledger, a copy of which must be given to the sponsor at the end of the study.  
An accurate record of the date and amount of study drug dispensed to each subject must be 
available for inspection at any time.  The CRA will visit the site and review these documents 
along with all other study conduct documents at appropriate intervals once study drug has 
been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or, when approval is given by the sponsor, will destroy supplies and 
containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor's proprietary information existing either at the date of the commencement of the 
study or generated during the study.


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The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.


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12 APPENDICES
Not applicable.


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2007-G000-410
Study Protocol Title:
Multicenter, Open-Label Study to Evaluate the Efficacy and 
Safety of Perampanel as Monotherapy or First Adjunctive 
Therapy in Subjects with Partial Onset Seizures With or 
Without Secondarily Generalized Seizures or With Primary 
Generalized Tonic-Clonic Seizures
Investigational Product 
Name:
E2007/Fycompa® (Perampanel)
SIGNATURES
Authors:
Neurology Business Group
Eisai Inc.
Date
Neurology Business Group
Eisai Ltd.
Date
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2007-G000-410
Study Protocol Title:
Multicenter, Open-Label Study to Evaluate the Efficacy and 
Safety of Perampanel as Monotherapy or First Adjunctive 
Therapy in Subjects With Partial Onset Seizures With or 
Without Secondarily Generalized Seizures or With Primary 
Generalized Tonic-Clonic 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 ICH and all applicable local GCP guidelines, including
the Declaration of Helsinki.  
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2007-G000-410
Study Protocol 
Title:
Multicenter, Open-Label Study to Evaluate the Efficacy and Safety 
of Perampanel as Monotherapy or First Adjunctive Therapy in 
Subjects With Partial Onset Seizures With or Without Secondarily 
Generalized Seizures or With Primary Generalized Tonic-Clonic 
Seizures
Date:
May 17, 2021
Version:
Final Version 1.0


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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...............................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................4
3
INTRODUCTION.........................................................................................................5
3.1
Study Objectives..................................................................................................5
3.1.1
Primary Objective ......................................................................................5
3.1.2
Secondary Objectives .................................................................................5
3.1.3
Exploratory Objectives...............................................................................5
3.2
Overall Study Design and Plan.............................................................................6
4
DETERMINATION OF SAMPLE SIZE.......................................................................7
5
STATISTICAL METHODS..........................................................................................7
5.1
Study Endpoints...................................................................................................8
5.1.1
Primary Endpoint .......................................................................................8
5.1.2
Secondary Endpoints..................................................................................8
5.1.3
Exploratory Endpoints................................................................................8
5.2
Study Subjects .....................................................................................................9
5.2.1
Definitions of Analysis Sets........................................................................9
5.2.2
Subject Disposition.....................................................................................9
5.2.3
Protocol Deviations ....................................................................................9
5.2.4
Demographic and Other Baseline Characteristics........................................9
5.2.5
Prior and Concomitant Therapy................................................................10
5.2.6
Treatment Compliance .............................................................................10
5.3
Data Analysis General Considerations................................................................10
5.3.1
Pooling of Centers....................................................................................10
5.3.2
Adjustments for Covariates ......................................................................10
5.3.3
Multiple Comparisons/Multiplicity...........................................................10
5.3.4
Examination of Subgroups........................................................................10
5.3.5
Handling of Missing Data, Dropouts, and Outliers....................................11
5.3.5.1
Efficacy ..........................................................................................11
5.3.5.2
Safety .............................................................................................11
5.3.6
Other Considerations................................................................................11
5.4
Efficacy Analyses ..............................................................................................11
5.4.1
Primary Efficacy Analyses .......................................................................12
5.4.2
Secondary Efficacy Analyses ...................................................................12
5.4.3
Exploratory Efficacy Analyses .................................................................12
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................13


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5.6
Safety Analyses..................................................................................................13
5.6.1
Extent of Exposure...................................................................................13
5.6.2
Adverse Events.........................................................................................13
5.6.3
Vital Signs................................................................................................14
5.6.4
Other Safety Analyses ..............................................................................15
5.7
Other Analyses...................................................................................................17
6
INTERIM ANALYSES...............................................................................................17
7
CHANGES IN THE PLANNED ANALYSES ............................................................17
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................17
8.1
EFFICACY DATA HANDLING.......................................................................17
8.1.1
Baseline efficacy ......................................................................................17
8.1.2
Treatment Duration for Efficacy Analyses................................................17
8.2
SAFETY DATA HANDLING...........................................................................18
8.2.1
Baseline safety .........................................................................................18
8.2.2
Treatment Duration for Safety Analyses ...................................................18
8.2.3
Handling of Replicate Data.......................................................................19
8.2.4
Handling of prior/concomitant medication................................................19
9
PROGRAMMING SPECIFICATIONS .......................................................................20
10
STATISTICAL SOFTWARE......................................................................................20
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................20
12
REFERENCES............................................................................................................20
13
APPENDICES.............................................................................................................21
13.1
EpiTrack Age-Corrected Total Score and Performance Category .......................21
SIGNATURE PAGE...........................................................................................................23


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ATC
anatomical therapeutic class
BDI-II
Beck depression inventory-II
BP
blood pressure 
CI
confidence interval 
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
DMC
Data Monitoring Committee
EOT
end of treatment
FAS
Full Analysis Set
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
PGTCS
primary generalized tonic-clonic Seizures
POS
partial-onset seizures
PSQI
Pittsburgh Sleep Quality Index
PT
preferred term
QOLIE-31
Quality of Life in Epilepsy Inventory-31
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Safety Analysis Set
SD
Standard deviation
SGS
Secondarily Generalized Seizures
SOC
system organ class
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
WHO DD
World Health Organization drug dictionary


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3
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for the Eisai Protocol 
E2007-G000-410.
3.1
Study Objectives
3.1.1
Primary Objective
To assess the retention rate of perampanel when given as monotherapy or 1st adjunctive 
therapy in subjects with partial-onset seizures (POS) or primary generalized tonic-clonic 
seizures (PGTCS).
3.1.2
Secondary Objectives

To evaluate the efficacy of perampanel when given as monotherapy or 1st adjunctive 
therapy in subjects with POS or PGTCS as measured by seizure freedom

To assess the proportion of subjects with POS or PGTCS that are able to convert from 
1st adjunctive therapy to perampanel monotherapy

To assess the safety of perampanel as initial monotherapy or 1st adjunctive therapy in 
subjects with POS or PGTCS

To assess dosing and titration of perampanel when administered as initial monotherapy 
or 1st adjunctive therapy in subjects with POS or PGTCS
3.1.3
Exploratory Objectives

To evaluate the efficacy of perampanel in subjects with POS or PGTCS as measured 
by responder rates (50% and 75%, in subjects who have sufficient baseline seizure 
frequency data available)

To evaluate the efficacy of perampanel in subjects with POS or PGTCS as measured 
by median percent reduction in seizure frequency (in subjects who have sufficient 
baseline seizure frequency data available)

To assess cognition, including the impact of depression, in subjects with POS or 
PGTCS administered perampanel as monotherapy or as 1st adjunctive therapy.

To assess subjective sleep quality in subjects with POS or PGTCS administered 
perampanel as monotherapy or as 1st adjunctive therapy

To assess quality of life in subjects with POS or PGTCS administered perampanel as 
monotherapy or as 1st adjunctive therapy


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3.2
Overall Study Design and Plan
This is a multi-center, open-label, Phase 4 study.  Subjects who met all of the inclusion and 
none of the exclusion criteria will receive perampanel. Baseline seizure counts (frequency) 
data will be collected by subjects or guardian/legally authorized representative, retrospectively 
(for history prior to screening) and prospectively as needed (during baseline).  The study 
consists of 4 periods:  a Screening Period (to start no earlier than 6 weeks before the 1st dose 
of study drug), a Titration Period (13 weeks), a Maintenance Period (39 weeks), and a 
Follow-up Period (4 weeks).  The study duration for each subject is expected to be 
approximately 1 year in total.
Study subjects includes the following:

Subjects who have been diagnosed with POS or PGTCS but have not previously 
received treatment with an antiepileptic drug (AED) or are receiving monotherapy 
treatment (no history of AED polytherapy) and wish to switch to another monotherapy 
treatment; or

Subjects who are receiving treatment with a single AED administered at a stable dose 
for at least 8 weeks before Visit 2 (Week 0) and needs additional AED treatment; 
subjects should not have previously received adjunctive AED therapy.
An overview of the study design is presented below.


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4
DETERMINATION OF SAMPLE SIZE
The efficacy of perampanel as monotherapy and 1st adjunctive therapy for POS and PGTCS
is to be evaluated.  The primary endpoint is retention rate.  The study is planned to enroll 
approximately 125 subjects.  This sample size is considered adequate for an open-label Phase 4 
study where there is no statistical hypothesis to be tested.
5
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum, and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects.
All summaries of seizure-related efficacy endpoints will be produced by seizure type (POS, 
secondarily generalized seizures [SGS], and PGTCS) and overall.  Summaries of retention rate 
and safety data will be produced by seizure type (POS, SGS, and PGTCS) and overall.


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5.1
Study Endpoints
5.1.1
Primary Endpoint
The primary endpoint is retention rate, defined as the proportion of subjects remaining on 
perampanel at the specified time points:  3, 6, 9, and 12 months after initiation of treatment.
5.1.2
Secondary Endpoints

Proportion of subjects who achieve seizure free status for POS, SGS, and PGTCS
during the Maintenance Period. 

Proportion of subjects who achieve 3-month seizure-free status for POS, SGS, and 
PGTCS.

Proportion of subjects who achieve 6-month seizure-free status for POS, SGS, and 
PGTCS.

Proportion of subjects who receive perampanel as a 1st adjunctive therapy who are able 
to convert to perampanel monotherapy

Safety and tolerability of perampanel administered as monotherapy or 1st adjunctive 
therapy in adolescents and adults

Maximum and last dose during the titration period and the maintenance period
5.1.3
Exploratory Endpoints

50% responder rate in total POS, SGS, and PGTCS; 50% responders are defined as 
subjects who have at least a 50% reduction in seizure frequency relative to baseline (in 
subjects with sufficient baseline seizure frequency data.

75% responder rate in total POS, SGS, and PGTCS; 75% responders are defined as 
subjects who have at least a 75% reduction in seizure frequency relative to baseline (in 
subjects with sufficient baseline seizure frequency data)

Median percent change in total POS, SGS, and PGTCS frequency in the Titration and 
Maintenance Periods relative to baseline (in subjects with sufficient baseline seizure 
frequency data) 

Proportion of subjects with no/mild/clear cognitive impairment relative to baseline 
using the EpiTrack total score

Change in subjective sleep quality at the end of the Maintenance Period relative to 
baseline using the PSQI 

Change in quality of life at the end of the Maintenance Period relative to baseline using 
the QOLIE-31

Proportion of subjects with Depression relative to baseline using BDI-II scores.


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5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Safety Analysis Set (SAS) is the group of subjects who received at least 1 dose of study 
drug and had at least 1 postdose safety assessment.
The Full Analysis Set (FAS) is the group of subjects who received at least 1 dose of study drug 
and had at least 1 postdose seizure measurement.
5.2.2
Subject Disposition
The disposition of all subjects will be summarized. Subject disposition tables will include the 
number (percent) of subjects who will be:
•
Included in each analysis population
•
Discontinued from the study early, summarized by reason for discontinuation
•
Screened and the number (percent) who fail screening will also be summarized
5.2.3
Protocol Deviations
Subjects with major protocol deviations will be listed.  These may include:

Recruitment of a subject who did not satisfy the inclusion/exclusion criteria

Subjects who took excluded medication

Overdose of Investigational Products of 120% or above between 2 consecutive visits
or Study Medication compliance <80% between two consecutive visits.

Continuation of treatment with Study Medication after a treatment related withdrawal 
event 

Unauthorized dose adjustment during Titration Period and Maintenance Period.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics (e.g., age, sex) for the SAS will be summarized 
using descriptive statistics.  Continuous variables will be summarized using mean, SD, median, 
minimum, maximum, and categorical variables will be summarized using number and 
percentages of subjects.
The number (percentage) of subjects in the SAS reporting a history of any medical condition, 
as recorded on the CRF, will be summarized.  A subject data listing of medical and surgical 
history will be provided.
Epilepsy-specific medical history for the SAS will be summarized using descriptive statistics, 
including time since diagnosis, suspected localization of the epileptogenic region, and seizure 
type.


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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). The latest version before 
database lock will be used for analysis. The number (percentage) of subjects who took prior 
and concomitant medications will be summarized on the Safety Analysis Set by Anatomical 
Therapeutic Chemical (ATC) class and WHO DD preferred term (PT). Prior medications are
defined as any medications that stopped before the 1st dose of study drug. Concomitant 
medications are defined as medications that (1) started before the 1st dose of study drug and 
were continuing at the time of the 1st dose of study drug, or (2) started on or after the date of 
the 1st dose of study drug up until 28 days after the subject’s last dose. All medications will be 
presented in subject data listings.
5.2.6
Treatment Compliance
Compliance with study medication during the Titration Period and Maintenance Period will be 
summarized using descriptive statistics. Overall percent compliance will be calculated as 
follows:
Compliance = (Study Med issued in grams – Study Med Returned in grams) x100
(Number of Days x Prescribed Daily Dose in grams) 
Overall study medication compliance will also be summarized using the categories <80%, 80%
to 100%, 100%-120%, and >120%.
5.3
Data Analysis General Considerations
5.3.1
Pooling of Centers 
Subjects from all centers will be pooled for all analyses.
5.3.2
Adjustments for Covariates
Not applicable.
5.3.3
Multiple Comparisons/Multiplicity
Not applicable.
5.3.4
Examination of Subgroups
All summaries of seizure-related efficacy endpoints will be produced by seizure type (POS, 
SGS, and PGTCS) and overall.  Summaries of retention rate and safety data will be produced 
by seizure type (POS, SGS, and PGTCS) and overall. All summaries of retention rate and 
seizure-related efficacy endpoints will also be produced by sex and age group (<12, 12-<=18, 
18–<=65, >65). 


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5.3.5
Handling of Missing Data, Dropouts, and Outliers
5.3.5.1
Efficacy
Analysis of percent change and responder rate for the seizure frequency per 28 days during the 
Maintenance Period will use a last observation carried forward (LOCF) type of imputation for 
handling missing data. For the last observation carried forward (LOCF) analyses, if the overall 
duration of the Maintenance Period is less than 8 weeks, the diary data up to the last 8 weeks 
during the Titration and Maintenance Periods combined will be used to calculate the seizure 
frequency per 28 days.
5.3.5.2
Safety
The algorithm on the assumptions used for imputing the missing dates for AEs is given in the 
programming specifications. 
If the day and month are missing, events will be considered treatment-emergent if the year is 
equal to or after the year of the first dose date; if days are missing, events will be considered 
treatment-emergent if the year is after the year of the first dose, or if the year is equal to the 
year of the first dose date and the month is equal to or after the month of the first dose date. 
For the purpose of summarizing maximum severity, if the severity of an adverse event (AE) is 
missing for a subject, then, if this subject has another AE with the same preferred term that has 
“severe” severity, the maximum severity of the AE will be noted as “severe’; otherwise the 
maximum severity will be noted as missing. Similarly, for the purpose of summarizing closest 
relationship, if the relationship of an AE to study drug is missing, the AE will be noted to be 
related if there is another related AE with the same preferred term, otherwise this relationship 
will be noted as missing. 
The algorithm to impute missing dates for concomitant medications is given in the 
programming specifications. No special handling of missing data is planned for the analysis of 
any other safety variables.
Data exceptions or outliers will be determined by inspection of the tables, listings, and graphs
in consultation with the clinical study team. The effect of outliers on analyses may be assessed 
by re-analyzing the data without the outliers.
All the listings will display the original missing values.
5.3.6
Other Considerations
Not applicable.
5.4
Efficacy Analyses
This is a study without a control arm.  Therefore, only descriptive statistics will be performed. 
The SAS will be used to summarize retention rate and the FAS will be used to summarize 


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seizure data.
5.4.1
Primary Efficacy Analyses
The retention rate, defined as the proportion of subjects remaining on perampanel treatment at 
3, 6, 9, and 12 months after initiation of treatment, will be summarized.  The number and 
percentage of subjects remaining on treatment at each time point will be summarized using 
SAS.  Corresponding 95% CIs may also be presented if allowed by the data. 
5.4.2
Secondary Efficacy Analyses
The FAS will be used to summarize seizure freedom data and conversion data of perampanel
as a 1st adjunctive therapy converted to perampanel monotherapy. The number and percentage 
of subjects who achieved seizure-free status or who converted to perampanel monotherapy will 
be summarized. 95% CIs may also be calculated if allowed by the data.
The seizure-free status at 3-month in Maintenance Period, at 6-month in Maintenance Period, 
and during the entire Maintenance Period will only be counted for subjects who complete the 
respective period. A subject who dropped out early relative to the respective period would be 
counted as ‘No’ for seizure-free status in that period.  
A subject is considered converted to perampanel monotherapy during Maintenance Period if 
the subject had a scheduled visit in Maintenance Period and was not taking any concomitant
AED at any time during the scheduled visit. A subject who dropped out early before the 
conversion would be counted as ‘No’ for conversion status.
5.4.3
Exploratory Efficacy Analyses
Analyses of exploratory efficacy endpoints will be performed in the subset of the FAS with 
sufficient baseline seizure frequency i.e. at least 1 seizure during the baseline.  All summaries 
will be produced by seizure type (POS, SGS, and PGTCS).
For percent change in seizure frequency endpoints at each treatment Period [pre-treatment, 
treatment, (titration plus maintenance), maintenance and maintenance-LOCF], and for each 
seizure type:
•
Mean, standard deviation, median, minimum, and maximum will be provided.
For responder rate endpoints at each time point (3, 6, 9, and 12 months in maintenance period,
maintenance and maintenance-LOCF), and for each seizure type:
•
Number and percentage of responders will be provided
95% confidence intervals for the percentage change and responder rate may also be calculated 
if allowed by the data.


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5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
Not Applicable
5.6
Safety Analyses
The SAS will be used to summarize all safety variables.  Safety data will be summarized using 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum, maximum for 
continuous variables; and n [percentage] for categorical variables).
Safety variables include treatment-emergent adverse events (TEAEs), vital signs, EpiTrack, 
BDI-II, PSQI, QOLIE-31, and C-SSRS scores. Study Day 1 for all safety analyses is defined 
as the date of the first dose of study drug.
5.6.1
Extent of Exposure
The extent of exposure to the study drug during the Titration Period and the Maintenance 
Period will be summarized descriptively. The duration of treatment (Titration Period and 
Maintenance Period) will be calculated as the number of days between the date the subject 
receives their first treatment dose and the date the subject receives the last dose of treatment. 
These values will be used to summarize the extent of exposure to study drug.
The mean daily dose, maximum dose, last dose, and modal dose (mg) for each subject over the 
Titration period and Maintenance period will be summarized. The mean daily dose will be 
calculated by taking the average of all the doses taken during the time period weighted by the 
number of days on each dose, rounded to 1 decimal place (i.e., sum of [days on each 
dose*dose]/during the time period).
5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities
(MedDRA). AEs will be coded to the MedDRA (most recent version) lower level term closest 
to the verbatim term.  The linked MedDRA preferred term (PT) and primary system organ 
class (SOC) are also captured in the database.
A treatment-emergent AE (TEAE) is defined as an AE that emerged during treatment, having 
been absent at pretreatment (Baseline) or 
●
Reemerged during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 
●
Worsened in severity during treatment relative to the pretreatment state, when the AE 
was continuous.


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Only those AEs that are treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized using the Safety Analysis Set. The incidence of TEAEs will 
be reported as the number (percentage) of subjects with TEAEs by SOC and PT. A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1 
TEAE within a specific SOC and PT. The number (percentage) of subjects with TEAEs will 
also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC, and PT.  A patient data listing of all TEAEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC, and PT.  A patient 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.
5.6.3
Vital Signs
Descriptive statistics for vital signs parameters (i.e., systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.
The number (percentage) of subjects with clinically notable results over all scheduled and 
unscheduled visits will be summarized using Table 1 below:
Table 1: Criteria for Clinically Notablea Vital Signs
Variable 
Criterion Value 
Change Relative to Baseline 
Systolic BP 
> 180 mmHg 
Increase of ≥ 20 mmHg 
< 90 mmHg 
Decrease of ≥ 20 mmHg 
Diastolic BP 
>105 mmHg 
Increase of ≥ 15 mmHg 
< 50 mmHg 
Decrease of ≥ 15 mmHg 
Heart Rate 
>120 bpm 
Increase of ≥ 15 bpm 
< 50 bpm 
Decrease of ≥ 15 bpm 
Weight 
Increase of > 7% 
Decrease of > 7% 
a: Clinically notable means that a value must have met both the criterion value and satisfied 
the magnitude of change relative to baseline.


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The number of subjects with abnormal results for blood pressure and heart rate will be 
summarized using the criteria in Table 2 below.
Table 2: Criteria for Abnormal Vital Signs
Variable 
Change Relative to Baseline 
Systolic BP 
Increase of ≥ 20 mmHg 
Decrease of ≥ 20 mmHg 
Increase of ≥ 40 mmHg 
Decrease of ≥ 40 mmHg 
Diastolic BP 
Increase of ≥ 10 mmHg 
Decrease of ≥ 10 mmHg 
Increase of ≥ 20 mmHg 
Decrease of ≥ 20 mmHg 
Pulse 
Increase of ≥ 15 bpm 
Decrease of ≥ 15 bpm 
Increase of ≥ 30 bpm 
Decrease of ≥ 30 bpm 
5.6.4
Other Safety Analyses
EpiTrack
Cognition will be assessed in subjects 6 years of age and older at Visit 2 (Week 0) and at 3 and 
12-month visits (Visits 4 and 7, respectively) using the EpiTrack® assessment tools (Epitrack 
for subjects aged 16 years and older and EpiTrack Junior for subjects aged 6 to 16 years at 
Visit 2 [Week 0]?). The EpiTrack includes 6 subtests:  response inhibition, visuo-motor speed, 
mental flexibility, visual motor planning, verbal fluency, and working memory.  Based on the 
subtest results, an age-corrected total score is calculated. “Higher total scores indicate more 
severe depressive symptoms. The calculation details and performance categories are provided 
in Section 13.1. Practice corrected reliable change indices indicate a significant change with a 
gain of more than 3 points and a loss of more than 2 points. 
Descriptive statistics for age-corrected total score and changes from baseline will be presented 
by visit. Summaries of the proportion of subjects with no/mild/clear cognitive impairment and 
shifts between these categories from baseline to end of treatment will be produced.
Beck Depression Inventory-II (BDI-II)
The Beck Depression Inventory-II (BDI-II) is a 21-question multiple-choice self-report 
inventory and is widely used for measuring the severity of depression. The BDI-II will be 
administered in subjects 16 years of age and older who are administered the EpiTrack.


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There is a four-point scale for each item ranging from 0 to 3. Each of the 21 items 
corresponding to a symptom of depression is summed to give a single total score for the BDI-
II from 0 to 63. Higher total scores indicate more severe depressive symptoms. Descriptive 
statistics for BDI-II total score and changes from baseline will be presented by visit.
Pittsburgh Sleep Quality Index (PSQI)
Based on 19 items, the PSQI measures several different aspects of sleep, offering seven 
component scores and one composite score. The component scores consist of subjective sleep 
quality, sleep latency (i.e., how long it takes to fall asleep), sleep duration, habitual sleep 
efficiency (i.e., the percentage of time in bed that one is asleep), sleep disturbances, use of 
sleeping medication, and daytime dysfunction.
Each item is weighted on a 0–3 interval scale. The global PSQI score is then calculated by 
totaling the seven component scores, providing an overall score ranging from 0 to 21, where 
lower scores denote a healthier sleep quality. The scoring details of global PSQI score are 
provided by PSQI website: http://www.psychiatry.pitt.edu/node/8240. Descriptive statistics 
for individual component and global PSQI scores and changes from baseline will be presented 
by visit.
Quality of Life in Epilepsy Inventory-31 (QOLIE-31) 
The QOLIE-31 contains 7 multi-item scales that tap the following health concepts: emotional 
well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, 
medication effects, and overall quality of life. A QOLIE-31 overall score is obtained using a 
weighted average of the multi-item scale scores. Scoring details of the QOLIE-31 overall score 
will be
performed as instructed by RAND QOLIE-31 scoring manual website:
https://www.rand.org/content/dam/rand/www/external/health/surveys_tools/qolie/qolie31_sc
oring.pdf. The QOLIE-31 also includes a single item that assesses overall health. QOLIE-31 
raw scores are scaled from 0-100 with higher scores reflecting better quality of life.  
The overall score is calculated by summing the scale scores after weighting with empirically 
derived weights provided in the manual. Descriptive statistics for QOLIE-31 subscale and 
overall score and changes from baseline will be presented by visit.
Columbia Suicide Severity Rating Scale (C-SSRS)
Suicidality will be assessed using the C-SSRS and summaries will include the incidence of 
suicidal behavior and suicidal ideation for subjects 6 years of age and older. Scoring of the 
C-SSRS will be performed as suggested by the C-SSRS Columbia website:
http://www.cssrs.columbia.edu.
The following summaries will be presented for the treatment duration (Titration Period and 
Maintenance Period).

Number (percentage) of subjects with any treatment-emergent report of suicidal 
behavior, suicidal ideation, and suicidality (suicidal behavior and/or ideation) will be 
displayed. A treatment-emergent report of suicidal behavior, suicidal ideation, or 


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suicidality is an answer of ‘Yes’ to any question in the respective category during the 
treatment duration.

Shift from baseline to the maximum suicidal ideation severity rating (0=no ideation 
present to 5=active ideation with plan and intent) in the treatment duration will assess 
worsening of suicidal ideation. Any score greater than 0 indicates the presence of 
suicidal ideation while a score of 4 (active suicidal ideation with some intent to act) or 
5 (active suicidal ideation with specific plan and intent) can be used to indicate serious 
suicidal ideation.
Descriptive statistics and changes from baseline will be presented by visit for the suicidal 
ideation intensity score and the suicidal ideation severity rating (treated as a continuous 
variable) to assess change in suicidal ideation over time. The suicidal ideation intensity score 
ranges from 0 to 25 and is the sum of the 5 intensity items.
5.7
Other Analyses
Not applicable.
6
INTERIM ANALYSES
Interim analyses may be conducted at various intervals, depending on the number of accrued 
subjects.
7
CHANGES IN THE PLANNED ANALYSES
Due to recruitment challenges, enrollment was terminated before reaching the planned sample 
size. Thus, there will not be enough sample size to calculate the 95% CIs.  Analysis of BDI-
II scale is added as an exploratory analysis. 
There are no other changes to the analysis in this statistical analysis plan compared to the 
protocol. Any future changes to the analysis will be documented separately and will be 
addressed in the Clinical Study Report.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
8.1
EFFICACY DATA HANDLING
8.1.1 Baseline efficacy
All diary data prior to first dose date plus 6-week prior historical data at the time of enrollment 
will be used in the computation of baseline seizure frequency per 28 days. All subjects should 
have at least 6 weeks of diary data prior to baseline (Visit 2). 
8.1.2 Treatment Duration for Efficacy Analyses
The date of first dose of the study drug is considered day 1 in the treatment duration. The first 
dose date is the study drug start date and the last dose date is study drug end date from the 


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study medication CRF page. The end of treatment (EOT) value is the last non-missing value while 
on-treatment.
The treatment duration for efficacy variables is defined as follows:

For diary seizure data: The duration between the date of first dose and the last date of
study drug in treatment duration (Titration Period and Maintenance Period), inclusive.

For non-diary efficacy data: The duration between the date of first dose and 7 days after 
the last visit of schedule in treatment, inclusive.

Data reported only during the treatment duration will be analysed. 
8.2
SAFETY DATA HANDLING
8.2.1 Baseline safety
The baseline value for all safety endpoints will be the last non-missing measurement occurring 
prior to the first dose of the study drug.
8.2.2 Treatment Duration for Safety Analyses
For AEs, the treatment duration is considered to begin on Day 1 and ends 28 days after the last 
dose of treatment.
For summaries of safety by time points, the time points will be relative to date of first dose.  
For standardized reporting, study day windows relative to the first dose (Day 1) in the study
will be applied to determine into which study week the data will be mapped.  Scheduled, 
unscheduled, and early withdrawal visits will be mapped into study weeks. Table 1 below 
gives the mapping of relative day ranges to week for non-AE safety variables. If a subject did 
not have a recorded observation falling within a given range of days in order to be assigned to 
a study week, the subject’s data for that week will be regarded as missing for summarization 
purposes.  If there are two or more assessments in the same window then:

if the window is the baseline assessment, then the latest assessment will be used in the 
summary tables.

if the window is not the baseline assessment, then the assessment closest to the 
scheduled assessment will be used in the summary tables.  
Note that if two assessments are equidistant from the scheduled assessment then the last
assessment of the two (within the allowable window) will be used.


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Table 1:  Mapping of Study Day Ranges to Week
Period 
Study Week
Study Day Range 
(Relative to First Dose 
of Study Drug)
Target Day
Screnning
Baseline
Day 1a
1
Titration
Week 13
  2 ≤ Day ≤ 138
92
Maintenance
Week 26
139 ≤ Day ≤ 229
183
Maintenance
Week 39
230 ≤ Day ≤ 320
274
Maintenance
Week 52
321 ≤ Day ≤ 999b
365
a:  All assessments at Visit 2 were to be performed prior to first dose of study drug; results 
from these assessments will be regarded as Pretreatment values in the analyses.
b:  The last non-missing value measured in the treatment duration will be handled as the data 
of EOT of the Study. The Follow-up visit will not be included in this analysis visit.
8.2.3 Handling of Replicate Data
A subject having an AE coded to the same preferred term more than once during the study will 
be counted only once in the incidence calculations for that AE. Similarly, if a subject has more 
than one AE in a single body system, the incidence will be counted only once for that body 
system. If a subject has the same AE more than once, the occurrence that is of greatest severity 
will be used in the calculation of the incidence of individual AE by severity. Similarly, the AE 
considered most closely related to study drug will be used in the calculation of incidence of
individual AE by relationship.
For the vital signs, EpiTrack, BDI-II, PSQI, QOLIE-31, and C-SSRS datasets, the 
measurement noted as the scheduled visit measurement will be used in the analysis. If more 
than one assessment is present at a scheduled visit, then the nearest assessment for evaluation 
visit(day) will be used in the summaries of the actual values and changes from baseline. In the 
event of two assessments being equally close to the scheduled visit day, the last assessment 
will be used.
8.2.4
Handling of prior/concomitant medication
If the subject has taken the same concomitant medication (as coded to preferred WHO-drug 
term) more than once, the subject will be counted only once in the tabulation.


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9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications will be provided in separate 
documents.
10 STATISTICAL SOFTWARE
All statistical analyses will be performed using SAS v 9.3 or later.
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
12 REFERENCES
1. Pittsburgh Sleep Quality Index (PSQI). University of Pittsburgh. PSQI scoring available 
from: http://www.psychiatry.pitt.edu/node/8240
2. Quality of Life in Epilepsy Inventory-31 (QOLIE-31). RAND QOLIE-31 scoring manual 
available from: 
https://www.rand.org/content/dam/rand/www/external/health/surveys_tools/qolie/qolie31_sc
oring.pdf.
3. Columbia-Suicide Severity Rating Scale (C-SSRS). Columbia University. Available from: 
http://www.cssrs.columbia.edu/scales_cssrs.html


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13 APPENDICES
13.1 EpiTrack Age-Corrected Total Score and Performance Category
Dependent on age group points must be added to total score for correction. The result is the
age-corrected total EpiTrack score.
EpiTrack Junior
Table 1: Age Correction
6 years
+14 points
7 years
+7 points
8 years
+4 points
9 years
+2 points
10 years
No age Correction
11-14 years
-2 points
15-18 years
- 4 points
Based on the age-corrected total score the Epitrack performance categories are defined as 
follows:
Table 2: EpiTrack Performance Categories 
Good 
36 ≤ score points
Average 
31 to 35 score points
Mildly impaired 
29 to 30 score points
Significantly impaired 
≤ 28 score points


Statistical Analysis Plan
E2007-G000-410
Eisai
Final : May 17, 2021
Confidential
Page 22 of 23
EpiTrack (Regular)
Table 1: Age Correction
16 to 20 years
+1 point 
21 to 35 years 
No correction
36 to 45 years
+1 point 
46 to 50 years
+3 points 
51 to 65 years
+4 points 
66 to 70 years
+6 points 
> 70 years
+7 points
Based on the age-corrected total score the Epitrack performance categories are defined as 
follows:
Table 2: EpiTrack Performance Categories 
Excellent 
39 ≤ score points
Average 
32 to 38 score points
Mildly impaired 
29 to 31 score points
Significantly impaired 
≤ 28 score points


Statistical Analysis Plan
E2007-G000-410
Eisai
Final : May 17, 2021
Confidential
Page 23 of 23
SIGNATURE PAGE
Author(s):  
[electronic signature in eDMS]
Neuroscience Business Group, Eisai Inc.
Date
Approval:
[electronic signature in eDMS]
Neuroscience Business Group, Eisai Inc.
Date
[electronic signature in eDMS]
Neuroscience Business Group, Eisai Inc.
Date
PPD
PPD
PPD