Clinical trial NCT03686033
Conditions: Photosensitive Epilepsy
Keywords: E2082 Epilepsy Photosensitive Anti-epileptic Seizures Photoparoxysmal response PPR
Sponsor: Eisai Inc.
Start date: 2018-10-31; Completion date: 2019-06-18
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary purpose of the study is to assess pharmacodynamic (PD) activity of E2082 as measured by suppression of epileptic photoparoxysmal response (PPR) in the participant's most sensitive eye condition in participants with photosensitive epilepsy, compared to placebo.

Detailed description:

Arms: arm 1: Participants will receive a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 1 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 2 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between all the treatment periods. arm 2: Participants will receive a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 1 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 2 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods. arm 3: Participants will receive a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 1 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 2 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods. arm 4: Participants will receive a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 1 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 2 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods. arm 5: Participants will receive a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 1 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 2 followed by a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods. arm 6: Participants will receive a single dose of E2082 tablets at 25 mg orally (Treatment C) in Treatment Period 1 followed by a single dose of E2082 tablets at 2.5 mg orally (Treatment B) in Treatment Period 2 followed by a single dose of E2082-matched placebo tablet orally (Treatment A) in Treatment Period 3 followed by a single dose of E2082 tablets at 40 mg orally in Treatment Period 4. A wash-out phase of at least 2 weeks will be maintained between the treatment periods.
Interventions: intervention 1: Placebo intervention 2: E2082
Intervention descriptions: intervention 1: Participants will receive E2082-matched placebo tablets orally. intervention 2: Participants will receive E2082 tablets orally.

Protocol documents:
Prot_000.pdf: 
Clinical Study Report 
E2082-A001-201 
 
16.1.1 
Protocol and Protocol Amendments 
The following versions of the protocol are provided  
• E2082-A001-201 V2.0_12 Apr 2019 
• E2082-A001-201 V1.0_21 Aug 2018 
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REVISION HISTORY
Revisions to Version 1.0 (per Amendment 01)
Amended version/Date: v2.0, 12 Apr 2019
Change
Rationale
Affected 
Protocol 
Sections
Included E2082 10 mg dose to the open-label 
treatment, and the following changes/inclusions are 
made to the study design accordingly: 

For newly enrolled or ongoing subjects in the 
study
who have completed up to the 
Treatment Period 3 at the time of Protocol 
Amendment 01 implementation, the dose to 
be 
administered 
during 
the 
Treatment 
Period 4 will be provided by an independent 
unblinded biostatistician upon review of the 
subject’s PPR data collected during Treatment 
Periods 1 through 3.

Modified the study design to allow subjects 
who completed the study before the protocol 
Amendment 01 to re-enter the study to 
receive E2082 10-mg open-label treatment.

Added additional study visits and new 
schedule of assessments table for subjects in 
Scenario 3

Updated study visits throughout the protocol 
per the changes made to the study design and 
schedule of assessments 
In addition to 25 mg in 
the Original Protocol 
version, 10 mg is being 
added in Protocol 
Amendment 01 in order 
to better characterize 
dose/exposure-response 
relationship and to 
support dose 
recommendation for 
Phase 2 and 3 clinical 
studies in target patient 
population. 
Synopsis - Study design, 
Study treatments, 
Inclusion Criteria, 
Assessments
•
Section 9.1
•
Section 9.1.1.1
•
Section 9.1.2.2
•
Section 9.4.1.2
•
Section 9.4.4
•
Section 9.4.5
•
Section 9.4.6
•
Section 9.4.7.2
•
Section 9.5.1.2.3
•
Section 9.5.1.4.1
•
Section 9.5.1.4.1
•
Section 9.5.1.5.8
•
Section 9.5.2.1
Modified the Inclusion Criterion No. 3:
Modified the text “up to a maximum of 3 concomitant 
antiepileptic drugs (AEDs) are allowed provided that 
doses must have remained stable for at least 4 weeks 
before Screening. In the case where a new AED 
regimen has been initiated for a subject, the dose must 
be stable for at least 8 weeks before Screening.”
to 
“up to a maximum of 3 concomitant AEDs are allowed 
provided that doses must have remained stable for at 
least 4 weeks or 5 half-lives, whichever longer, before 
Screening.  In the case where a new AED regimen has 
been initiated for a subject, the subject must be on the 
new AED for at least 8 weeks and the dose must have 
remained stable for at least 4 weeks or 5 half-lives, 
whichever is longer, before Screening.”
The text in the Prior and Concomitant Therapy section
is updated appropriately in consistent with the Changes 
in Inclusion Criterion No. 3.
Correction for clarity
Synopsis
Inclusion 
Criteria, 
Concomitant 
Drug/Therapy 
•
Section 9.1.2
•
Section 9.3.1
•
Section 9.4.7
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Added the text “consumption of dietary supplements, 
foods, and forms of fruit juice that may affect the 
expression or function of cytochrome P450 (CYP)3A 
within 14 days before study drug administration” to the 
Exclusion Criterion No. 21’ and also updated the 
Prohibited Concomitant Therapies and Drugs section 
accordingly.
Correction for clarity
Synopsis 
Exclusion criteria
Concomitant drug/Therapy
•
Section 9.3.2
•
Section 9.4.7.1
Modified inclusionary age range from “18 to 60 years” 
to “18 to 65 years” (see Inclusion Criterion No. 1).
To increase upper age 
limit allowed in this 
study.
Synopsis 
Inclusion criteria
•
Section 9.3.1
Added a note “Subjects who have completed the study 
per original protocol may re-enter the study provided 
that the subject meet inclusion criteria No. 2 to 7” in 
the inclusion criteria.
Added a note “Subjects in Scenario 3 will not be 
allowed to re-enter the study if they meet any of the 
exclusion criteria listed above” in the exclusion criteria
To improve clarity
Synopsis 
Inclusion criteria
Exclusion criteria
•
Section 9.3.1
•
Section 9.3.2
Specified the timing of study unblinding for planned 
data analyses – (1) first analysis to take place when all 
subjects completed the double-blind, randomized 
crossover treatment period, and (2) second (final) 
analysis to take place at study completion.
To improve clarity
•
Section 9.7
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2082-A001-201
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Crossover, Single-Dose 
Study with An Open-Label Treatment Period Evaluating 
Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy
Sponsor:
Eisai Inc.
100 Tice Boulevard, Woodcliff Lake, New Jersey 07677, US
Investigational 
Product Name:
E2082
Indication:
Not applicable
Phase:
2
Approval Date:
V1.0
21 Aug 2018 (original protocol)
V2.0
12 Apr 2019 (Protocol Amendment 01)
IND Number:
134556
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2082
Name of Active Ingredient:  2-Fluoro-6-[3-fluoro-8-oxo-7-(pyridin-3-yl)-7,8-dihydro-6H-
pyrano[3,2-b:5,4-b′]dipyridin-9-yl]benzonitrile
Study Protocol Title
A Multicenter, Double-Blind, Randomized, Crossover, Single-Dose Study with An Open-Label 
Treatment Period Evaluating Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy
Principal Investigator
Gregory Krauss, MD
Sites
Approximately 6 sites in the US
Study Period and Phase of Development
The total study duration from first subject enrolled to last subject’s last visit/last assessment will be 
approximately 8 to 9 months.
Phase 2
Objectives
Primary Objective

To assess pharmacodynamic (PD) activity of E2082 as measured by suppression of epileptic 
photoparoxysmal response (PPR) in the subject’s most sensitive eye condition in the 
photosensitivity model as a proof of principle of efficacy in subjects with photosensitive
epilepsy, compared to placebo
Secondary Objectives

To assess the PD activity of E2082 as measured by suppression of PPR in each of the 3 eye
conditions (eye closure, eyes closed, and eyes open), compared to placebo

To assess PD activity of E2082 as measured by onset, maximum change, and duration of 
photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes 
open)

To assess proportion of subjects with complete suppression, partial suppression, and no 
response of standardized photosensitivity response (SPR)

To assess other central nervous system (CNS)-related effects of E2082 based on Bond-Lader 
Visual Analogue Scale (BL-VAS) 

To assess the safety and tolerability of E2082 following single oral dose administration

To assess the pharmacokinetics (PK) of E2082 following single oral dose administration
Exploratory Objective

To explore relationships between PK and PD 
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Study Design
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period, crossover study 
with an Open-Label Treatment Period, in adult subjects with photosensitive epilepsy.  This study will 
use the photosensitivity proof of principle model to determine the potential of E2082 to reduce the 
photosensitive range in adult subjects.  
This study will have 2 phases: Pretreatment Phase and Treatment Phase.  The Pretreatment Phase 
will consist of a Screening Period (up to 3 weeks from Visit 1), during which each subject’s study 
eligibility will be determined.  The Treatment Phase will consist of 3 blinded Treatment Periods for a 
randomized crossover design, followed by an Open-label Treatment Period.  During the Randomized 
Crossover Treatment Periods, there will be 3 Treatment Visits (Visit 2 [Treatment Period 1], Visit 3 
[Treatment Period 2], and Visit 4 [Treatment Period 3]) evaluating single-dose administrations of 
either placebo, E2082 2.5 mg, or E2082 25 mg in a blinded manner.  
Scenario 1:  Newly enrolled or ongoing subjects who have completed upto the Treatment Period 3 at 
the time of Protocol Amendment 01 implementation, will undergo 1 treatment visit (Visit 5 
[Treatment Period 4]) during the Open-label treatment period to receive a single-dose administration 
of E2082 40 mg or 10 mg; the dose to be administered will be provided by an independent unblinded 
biostatistician upon review of the subject’s PPR data collected during Treatment Periods 1 through 3.  
(revised per Amendment 01)
Scenario 2:  Subjects who completed the open-label Treatment Period 4 (Visit 5), and have not 
completed the Follow-Up visit [Visit 6]) by the time of Protocol Amendment 01 implementation may 
continue in the study to receive an additional open-label, single oral dose of E2082 10 mg in the 
Treatment Period 5 (Visit 8) without undergoing Follow-up Visit 1 (Visit 6) and Screening 2 
(Visit 7). (revised per Amendment 01)
Scenario 3: Subjects who completed the study (including Follow-Up visit [Visit 6]) before the 
implementation of Protocol Amendment 01 may be allowed to re-enter the study to receive an 
open-label, single-dose administration of E2082 10 mg in the Treatment Period 5 after Screening 2 
(Visit 7).  (revised per Amendment 01)
Treatment visits (ie, Visit 2, Visit 3, Visit 4, and Visit 5) will each be separated by a 2-week 
(±3 days) washout interval for a total of approximately 6 weeks.  Treatment Period 5 (Visit 8) will be 
2 weeks (±3 days) after Treatment Period 4 (Visit 5) for subjects in Scenario 2, and after Screening 2
for subjects in Scenario 3.  (revised per Amendment 01)
All subjects will undergo a Follow-up Period of 2 weeks (±3 days) after the last day of study product 
administration (Visit 5 and/or Visit 8, as applicable).  (revised per Amendment 01).  The anticipated 
study participation duration for each subject is approximately 11 to 15 weeks (revised per 
Amendment 01).  All visits will be conducted on an outpatient basis.
Within 21 days of the Screening Visit (Visit 1), subjects will be asked to return to the study site for 
Visit 2 (Day 1), when the final determination of eligibility will be made.
Subjects meeting all eligibility criteria will enter into the Treatment Phase and be randomly assigned 
to 1 of 6 treatment sequences to receive, in a blinded fashion, a single oral dose of placebo control, 
E2082 2.5 mg, or E2082 25 mg during the Randomized Crossover Treatment Periods.  This is 
followed by the Open-Label Treatment Period, during which each subject will receive a single dose 
of E2082 40 mg and/or 10 mg.  (revised per Amendment 01)
On the day of each Treatment Visit (ie, Visit 2, Visit 3, Visit 4, Visit 5, and, as applicable Visit 8), 
subjects will arrive at the clinic in the morning following an overnight fast of at least 8 hours.  
Baseline intermittent photic stimulation (IPS)-electroencephalogram (EEG) assessments will be 
conducted 30 minutes to 2 hours before study product administration on each treatment day, 
including determination of the lower and upper limit of photosensitivity to IPS threshold frequency 
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for each eye condition.
After completion of the Open-label Treatment Period(s), subjects will enter the Follow-up Period, 
during which they will be required to complete a Follow-up visit (Visit 6 and/or Visit 9, as 
applicable) at 2 weeks ±3 days following the last day of study product administration.  
Subjects who discontinue early from the study for any reason after having been exposed to study drug
will undergo an Early Discontinuation Visit within 2 weeks ±3 days of their last dose of study drug.
Early Discontinuation visit is not required for subjects who discontinued from the study before 
receiving the first study drug administration.  Upon consultation with the sponsor, subjects who 
discontinue from the study early may be replaced. 
The end of study is defined as the last subject completing the Follow-up Visit. 
IPS-EEG specific Subject Withdrawal/Stopping Criteria
At the discretion of the investigator, a subject may be withheld from further IPS-EEG testing during a 
study visit or withdrawn from the study if any of the following 3 circumstances occur:
1.
If a subject experiences:
a) generalized tonic-clonic seizure (GTCS) on any study day, and the subject has not had a 
GTCS in the 6 months before enrollment, that subject will be discontinued from the study.
OR
b) GTCS during photic stimulation, that subject will be discontinued from the study.
2.
If, in the opinion of the investigator, a subject has evidence of proconvulsive activity on the 
EEG (eg, increase in spike-wave activity) following administration of the study drug, that 
subject will be discontinued from the study.
Proconvulsive activity is defined as:
a) generalized spike and wave discharges greater than 5 seconds defined by absence seizures 
or isolated myoclonic jerks do not require stoppage of study drug or subject withdrawal; or 
b) change in the usual pattern of PPR that is typical for the subject such as: decrease in time 
to occurrence of PPRs at the same flash frequency; increase in the duration of the PPR; or, 
clear increase of PPR-related negative sensations (clinical signs) or appearance or increase of 
spontaneous epileptiform activity.
3.
If a subject has widening of the photosensitivity range (becomes more sensitive) by more 
than 3 points on 2 consecutive occasions after dosing compared to Screening, the IPS will be 
terminated and the subject will not be permitted to participate in further IPS-EEG testing on 
the same day.
Number of Subjects
Approximately 9 subjects will be randomized to achieve 6 evaluable subjects.  
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study: 
1.
Male or female 18 to 65 years of age at the time of informed consent. 
2.
A diagnosis and/or history of a PPR on EEG (ie, photosensitivity epilepsy).
3.
If currently being treated with antiepileptic drugs (AEDs), up to a maximum of 
3 concomitant AEDs is allowed provided that doses must have remained stable for at least 
4 weeks or 5 half-lives, whichever is longer, before Screening.  In the case where a new AED 
regimen has been initiated for a subject, the subject must be on the new AED for at least 
8 weeks, and the dose must have remained stable for at least 4 weeks or 5 half-lives, 
whichever is longer, before Screening.  (See Exclusion Criteria No. 17-22 for AEDs that are 
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exclusionary)
4.
Reproducible IPS-induced PPR on EEG of at least 3 points on the SPR scale in at least 1 eye 
condition (eye closure, eyes closed, eyes open) on at least 3 of the EEGs performed at 
Screening.
5.
Body mass index (BMI) between 18 to 35 kg/m2 (inclusive) and a total body weight greater 
than or equal to 45 kg at Screening.
6.
Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour period 
before Screening and during the 24-hour period before each treatment day.
7.
Willing and able to comply with all aspects of the protocol.
Note:  Subjects who have completed the study per original protocol may re-enter the study 
provided that the subject meet inclusion criteria No. 2 to 7.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study: 
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]).  
A separate baseline assessment is required if a negative Screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug. 
2.
Females of childbearing potential who:
a.
Within 30 days before study entry, have had unprotected sexual intercourse and did not 
use a highly effective method of contraception (eg, total abstinence, an intrauterine 
device, a double-barrier method [such as condom plus diaphragm with spermicide], a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) 
b.
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.  If 
currently abstinent, the subject must agree to use a double barrier method as described 
above if she becomes sexually active during the study period or for 28 days after study 
drug discontinuation.  Females who are using hormonal contraceptives must be on a 
stable dose of the same hormonal contraceptive product for at least 4 weeks before 
dosing and must continue to use the same contraceptive during the study and for 28 days 
after study drug discontinuation.
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). 
3.
Male subjects who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days after 
study drug discontinuation).  No sperm donation is allowed during the study period and for 
28 days after study drug discontinuation.
4.
History of nonepileptic seizures (eg, metabolic, structural, or pseudoseizures) while on any 
antiepileptic medication(s).
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5.
History of status epilepticus while on any antiepileptic medication(s) within 2 years before
Screening.
6.
Ongoing or history of GTCS within 6 months before Screening.
7.
Subject who had developed a clinical seizure during previous PPR assessment, or who 
experiences a clinical seizure during the Screening IPS procedure. 
8.
Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening.
9.
Inability to follow restriction on watching television, or use of any device(s) with an 
animated screen (eg, computer, video games, tablets, or smart phone) from the time of arrival 
at the study center until study procedures are completed for that day.
10. Currently active clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) with the exception of epilepsy, which in the opinion of the investigator could affect 
the subject’s safety or interfere with the study assessments.
11. A history of prolonged QT syndrome or risk factors for torsade de pointes (eg, heart failure,
hypokalemia, family history of long QT Syndrome), or the use of concomitant medications 
that prolonged the QT/corrected QT using Fridericia formula (QTcF) interval; or prolonged 
QT/QTcF interval (QTcF >450 msec) demonstrated on ECG at Screening or Baseline (based 
on average of triplicate ECGs).
12. Presence of active CNS infection, demyelinating disease, degenerative neurological disease 
or any CNS disease deemed to be progressive during the course of the study that may 
confound the interpretation of the study results.
13. Current/ongoing clinically significant active liver disease, porphyria, or with a family history 
of severe hepatic dysfunction indicated by abnormal liver function tests (LFTs) greater than 
3 times the upper limit of normal (ULN) (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
14. Any history of gastrointestinal conditions or surgery that may affect PK profiles of E2082 
(eg, hepatectomy, nephrectomy, and digestive organ resection).
15. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
16. Use of perampanel within 6 weeks before Screening.
17. Use of felbamate for less than 2 years or where the dose has not been stable for at least 
8 weeks before Visit 1.  Subject must not have a history of white blood cell (WBC) count 
below equal or less than 2500/μL (2.50 1E+09/L), platelet count below 100,000, LFTs above 
3 times the ULN, or other indication of hepatic or bone marrow dysfunction while receiving 
felbamate.  If subjects received felbamate in the past, it must have been discontinued 8 weeks 
before Visit 1 to be eligible for study participation.
18. Use of vigabatrin within 5 months before Screening.  Subjects who have discontinued 
vigabatrin for at least 5 months before Screening must have documentation showing no 
evidence of vigabatrin-associated clinically significant abnormality in a visual perimetry test 
in order to be eligible for the study.
19. Concomitant use of cannabinoids.
20. Use of benzodiazepines for epilepsy for which the dose has not been stable for greater than 
4 weeks before Screening.  Benzodiazepine use as rescue medication for seizure control is 
allowed; however, intermittent use of benzodiazepines for any other indication (eg, 
anxiety/sleep disorders) is prohibited.
21. Use of concomitant AEDs or other drugs that are known to be potent cytochrome P450 
(CYP)3A enzyme inducers (such as carbamazepine, oxcarbazepine, eslicarbazepine, 
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phenytoin, phenobarbital, and primidone) or CYP3A inhibitors within 4 weeks or 
5 half-lives, whichever is longer, before screening. In addition, consumption of dietary 
supplements, foods, and forms of fruit juice that may affect the expression or function of 
CYP3A within 14 days before study drug administration. (revised per Amendment 01)
22. Vagus nerve stimulation (VNS) implanted within 5 months or changes in parameter within 
4 weeks before Screening.
23. On a ketogenic diet for which the diet is not a stable regimen for at least 4 weeks before
Screening. 
24. History of drug or alcohol dependency or abuse within the 12 months before Screening, or 
those subjects who have a positive drug test or alcohol test at Screening.
25. History of or ongoing multiple drug allergies or severe drug reaction to AED(s), including 
dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
26. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption.
27. Any suicidal ideation with intent with or without a plan within 6 months before Screening or 
during Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the Columbia-Suicide Severity Rating Scale [C-SSRS]).
28. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
29. Any psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
30. Currently enrolled in another clinical study or used any investigational drug or device within 
28 days or 5 half-lives, whichever is longer, preceding informed consent, except the 
investigational study for the evaluation of commercial IPS machine.
Note: Subjects in Scenario 3 will not be allowed to re-enter the study if they meet any of the 
exclusion criteria listed above.
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Study Treatments
Test Drug:  E2082
E2082 will be supplied as 0.5-mg and 5-mg tablets for oral administration.
Comparator Drug:  E2082-matched placebo
Randomized Crossover Treatment Periods
Each subject will receive a single oral dose of E2082 2.5 mg, E2082 25 mg, and matched-placebo in 
a cross-over sequence according to his/her randomization code.
Treatment A (Placebo): 5 x E2082-matched placebo tablets
Treatment B (E2082 2.5 mg): 5 x E2082 0.5-mg tablet
Treatment C (E2082 25 mg): 5 x E2082 5-mg tablets
Open-label Treatment Period
Scenario 1:  Each subject will receive a single oral dose of E2082 40 mg (8 x E2082 5-mg tablets) or 
10 mg (2 x E2082 5-mg tablets).  (revised per Amendment 01)
Scenario 2 and 3:  Each subject will receive a single oral dose of E2082 10 mg (2 x E2082 
5-mg tablets) during Visit 8.  (revised per Amendment 01)
All Study Drug will be administered with approximately 240 mL (8 fluid ounces) of water.  
Additional water may be provided in increments of 50 mL (up to a maximum of 100 mL), if required.  
A light snack can be provided approximately 30 minutes predose (after clinical laboratory blood 
collection) and approximately 2 hours postdose.  Water will be permitted ad libitum except from the 
time of dosing until 1 hour postdose.
Duration of Treatment
Single dose
(ie, the Treatment Phase will consist of 4 or 5 Treatment Periods each with a single dose 
administration) (revised per Amendment 01)
Concomitant Drug/Therapy
Up to 3 concomitant AEDs are allowed during the course of the study, provided that the dosage of 
concomitant AED(s) has remained stable for at least 4 weeks or 5 half-lives, whichever is longer, 
before Screening.  In the case where a new AED regimen has been initiated for a subject, the subject 
must be on the new AED for at least 8 weeks, and the dose must have remained stable for at least 4 
weeks or 5 half-lives, whichever is longer, before screening.  During the study, changes to 
concomitant AEDs (including dosage) are not permitted unless medically necessary and upon 
consultation with the Sponsor. 
Use of the following AEDs during the course of the study is not allowed:

Perampanel

Vigabatrin

Cannabinoids

Benzodiazepines for non-epilepsy indications (eg, anxiety/sleep disorders)

Enzyme-inducing antiepileptic drugs (EIAEDs, eg, carbamazepine, oxcarbazepine, 
eslicarbazepine, phenytoin, phenobarbital, and primidone)
Concomitant use of medications known to be potent CYP3A inducers/inhibitors including, but not 
limited to, rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, modafinil, pioglitazone, and 
rifabutin will not be permitted and are to be discontinued within 4 weeks or 5 half-lives, whichever is 
longer, before Visit 1, and as applicable, Visit 7.  In addition, as E2082 is predominantly metabolized 
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by CYP3A, the consumption of dietary supplements, foods, and forms of fruit juice that may affect 
the expression or function of CYP3A should be avoided 14 days before study drug administration. 
Examples of such dietary supplements, foods, and forms of fruit juice are grapefruit, grapefruit juice, 
grapefruit-containing beverages or other products for consumption.  (revised per Amendment 
01)Vagus nerve stimulation (VNS) is not considered as one of the 3 allowed concomitant AEDs.  
However, VNS implantation during the course of the study is prohibited.  For subjects who have 
VNS implanted before participation in this study, changes to VNS parameters are not allowed unless 
medically necessary.  
Changes to ketogenic diet (eg, median chain triglyceride level) are not allowed during the study.
Assessments
Efficacy Assessments
Not applicable.
Pharmacokinetic Assessments
On each treatment day, blood samples for the determination of plasma concentrations of E2082 will 
be collected from each subject predose (within 2 hours), and at 1 (±10 min), 2 (±10 min),
4 (±15 min), 6 (±15 min), and 8 (±15 min) hours postdose.  
Pharmacodynamic Assessments
IPS-EEG
PD activity of E2082 will be assessed by suppression of PPR following IPS using the Grass PS 33 
photic stimulator with an unpatterned glass lamp and an intensity of 100 cd/m2/flash.  Each IPS-EEG
assessment will be conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open; each 
for a minimum of 2.5 minutes) at ascending and then descending photo stimulation frequencies. The 
lower and upper limit of photosensitivity to IPS threshold frequency will be determined for each eye 
condition.  PPR is expected to be within the range of 2 Hz to 60 Hz, depending on the subject’s 
sensitivity to IPS.  Qualified medical personnel for the management of acute seizures will be present 
during the day of IPS-EEG procedure throughout the study.
During the Screening Visit (Visit 1, and, as applicable Visit 7) (revised per Amendment 01), IPS-
EEG assessment will be performed at 5 time points, over a 4-hour time period (0, 1, 2, 3, and 4 hours; 
within ±15 minutes of the scheduled time point).  Subjects with a reproducible PPR on EEG of at 
least 3 points on the SPR scale in at least 1 eye condition on at least 3 of the EEGs performed at 
Screening will be eligible for the study.  However, the final determination of study eligibility will 
include predose assessments when the subject returns to study site for Visit 2.  On each treatment day
(ie, Visit 2, Visit 3, Visit 4, Visit 5, and as applicable Visit 8) (revised per Amendment 01), IPS-EEG
assessments will be conducted predose (approximately 30 minutes to 2 hours), and at 1, 2, 4, 6, and 
8 hours (within ±15 minutes of each scheduled time point) postdose to characterize the time course of 
E2082 PD activity including the onset, maximum change from baseline, and duration of the reduction 
in PPR response. The predose assessment serves as the baseline on each treatment day.
Other PD assessments
The BL-VAS (Bond A, 1974) for CNS-related effects of E2082 (such as somnolence, sedation, 
dizziness, and body sway) for potential sedative effects of E2082 will be evaluated for each subject 
on each treatment day predose (within 2 hours) and at 1, 2, 4, 6, and 8 hour postdose. 
All PD assessments will be performed within ±15 minutes of the scheduled time point.
Pharmacogenomic and Other Biomarker Assessments
Not applicable.
Safety Assessments
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Safety will be assessed by monitoring and recording all adverse events (AEs).  Additionally, safety 
assessments will consist of physical and neurological examinations, vital signs, 12-lead ECG, clinical 
laboratory test (hematology, blood chemistry, and urinalysis), and (for women of childbearing 
potential only) pregnancy test.  A full neurological examination will be conducted during the 
Screening Visit.  An abbreviated neurological examination will be performed on each treatment day 
(predose and at 4 hours postdose), and during Follow-up/Early Discontinuation visit.
An assessment of suicidality using the C-SSRS will be performed at Screening, during each 
Treatment visit (predose), and at the Follow-up/Early Discontinuation Visit.
Other Assessments
Not applicable.
Bioanalytical Methods
Plasma concentrations of E2082 will be measured using a validated liquid chromatography coupled 
with tandem mass spectrometry (LC-MS/MS) method.
Statistical Methods
Descriptive statistics will be presented including mean and standard deviation of photosensitivity 
range for each subject at Screening and at each time point, for each Treatment visit day by treatment 
group. Graphical displays of the data for each subject will allow exploration of intersubject and 
intrasubject variability.
Details of statistical methods and analyses will be specified in the statistical analysis plan (SAP).
Study Endpoints
Primary Endpoint

Mean change from baseline in the PPR range in each subject’s most sensitive eye condition 
Secondary Endpoints

Mean change from baseline in the PPR range in each of the 3 eye conditions (eye closure, 
eyes closed, and eyes open) 

Onset, maximum change, and duration of response in each of the 3 eye conditions (eye 
closure, eyes closed, and eyes open) 

Frequency and percentage of subjects with complete suppression, partial response, and no 
response of SPR

Changes from baseline in BL-VAS 

Incidence of treatment-emergent adverse events (TEAEs)

Clinically significant changes from baseline in vital signs, serum chemistries, complete blood 
counts, or liver function tests after single doses of E2082, compared to placebo

PK parameters of E2082 (Cmax, time to reach Cmax following drug administration 
[tmax], area under concentration-time curve from time 0 to 8 hours postdose [AUC(0-8h)])
Exploratory Endpoints

Relationship between plasma exposure of E2082 (PK) and PD response (eg, onset, maximum 
change, and duration of photosensitivity response, BL-VAS)
Analysis Sets
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and have at 
least 1 postdose safety assessment.
The PK Analysis Set is the group of randomized subjects who receive at least 1 dose of study drug 
and have sufficient PK data to derive at least 1 PK parameter.
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The PD Analysis Set is the group of randomized subjects who receive at least 1 dose of study drug 
and have sufficient PD data to derive at least 1 PD parameter.
Efficacy Analyses
Not Applicable.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacokinetic Analyses
The Safety Analysis Set will be used for listings of individual E2082 plasma concentrations.  The PK 
analysis set will be used for summaries of plasma E2082 concentrations and for analyses, summaries, 
and listings of PK parameters.  Plasma concentrations will be tabulated by nominal sampling time 
and summarized by treatment dose using summary statistics. 
The following PK parameters will be derived by noncompartmental analysis using plasma 
concentrations of E2082.  These parameters will include, but are not limited to:
Cmax
maximum observed concentration
AUC(0-8h)
area under concentration x time curve from time 0 to 8 hours postdose
tmax
time to reach Cmax following drug administration
The PK of E2082 will be analyzed based on available data from this study.  The PK and PD Analysis 
Sets will be used to evaluate the relationship of PK of E2082 and change in SPR response.  PK-PD 
analyses may include the examination of the relationship of PK of E2082 and SPR (eg, time of onset, 
maximum change, and duration of response; and BL-VAS data) using model-based approaches, data 
permitting.  Details of the PK/PD analyses will be described in a separately prepared analysis plan 
and its report.
Pharmacodynamic Analyses
The PD analysis will be performed on the PD Analysis Set.  
No multiplicity adjustments will be made.  The 5 PPR measured postdose on a study day will be 
averaged and used for the primary endpoint.  The predose PPR data from the respective treatment 
period will be used as the baseline data.  
The primary and secondary endpoints of mean change from baseline of the average PPR in the most 
sensitive and 3 eye conditions will be analyzed using a mixed effects model for the crossover part of 
the study and summarized for each E2082 dose level and placebo regardless of crossover design.  The 
mixed effects model for the crossover part of the study will include treatment (E2082 2.5 mg, 25 mg, 
and placebo), period, and sequence as fixed effects, baseline (predose) measurement as a covariate, 
and subject nested within sequence as a random effect. Where data are normally distributed, least 
squares (LS) means, difference in LS means of each E2082 dose (2.5 mg or 25 mg) compared to 
placebo, and 90% CIs will be presented with no adjustments for multiplicity. 
Additional analysis by graphical exploration for the evaluation of onset, maximum change, and 
duration of photosensitivity response at each dose level will be performed for all 3 eye conditions for 
each treatment.  Similarly, frequency and percentage of subjects with complete suppression, partial 
suppression, and no response at each dose level of E2082 will be summarized descriptively and 
graphically for each treatment.
Sensitivity analyses may be conducted for photosensitivity response, for example, in subjects who 
completed all 3 Treatment Periods 1 through 3 versus those who are included in the PD Analysis Set.
Other exploratory analyses may be conducted as data permit.
All other PD data (ie, BL-VAS) will be listed and summarized by treatment, as appropriate, using 
standard summary statistics.  Descriptive summary statistics (eg, mean, SD, median, minimum, and 
maximum for continuous variables, and the number and percent for categorical variables) of each 
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endpoint and the changes from baseline will be tabulated.
Pharmacogenomic and Other Biomarker Analyses
Not applicable.
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety data that will be evaluated 
include AEs, clinical laboratory results, vital signs, ECGs, and neurological/physical examinations.  
TEAEs will be summarized by presenting for each treatment group, the incidence of AEs.  An 
assessment of suicidal ideation and behavior using the C-SSRS will be performed throughout the 
study.  
Descriptive summary statistics (eg, mean, SD, median, minimum, and maximum for continuous 
variables, and the number and percent for categorical variables) of the laboratory, vital signs, ECG 
parameters, and changes from baseline will be evaluated by treatment group.  The proportion of 
subjects with any treatment-emergent report of suicidal ideation and behavior and intensity of these 
behaviors will be summarized.
Interim Analyses
No formal interim analysis is planned.
Sample Size Rationale
Approximately 9 subjects with photosensitive epilepsy and a stable PPR will be needed to be 
randomized in the study in order to obtain 6 evaluable subjects.  Based on a similar study in subjects 
with photosensitive epilepsy (NCT02564029), an estimated standard deviation of the treatment group 
difference of the SPR in the subject’s most sensitive eye condition is 3.62.  The width of a 90% CI of 
the mean group difference based on this standard deviation assumption and 6 subjects is 2.431.  
Therefore, a sample size of 6 would be sufficient to detect a mean group difference of 3 or larger with 
90% confidence. 
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................3
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................4
3
TABLE OF CONTENTS.................................................................................................15
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................20
5
ETHICS............................................................................................................................22
5.1
Institutional Review Boards/Independent Ethics Committees ..............................22
5.2
Ethical Conduct of the Study.................................................................................22
5.3
Subject Information and Informed Consent...........................................................23
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................23
7
INTRODUCTION ...........................................................................................................24
7.1
Indication ...............................................................................................................24
7.1.1
Mechanism of Action – E2082 ....................................................................24
7.1.2
Clinical Experience With E2082 .................................................................24
7.1.2.1
Pharmacokinetics.................................................................................24
7.1.2.2
Pharmacodynamics ..............................................................................25
7.1.2.3
Safety and Tolerability.........................................................................25
7.2
Study Rationale......................................................................................................25
7.2.1
Photosensitivity Proof-of-Concept Model ...................................................25
8
STUDY OBJECTIVES....................................................................................................26
8.1
Primary Objective..................................................................................................26
8.2
Secondary Objectives.............................................................................................27
8.3
Exploratory Objective............................................................................................27
9
INVESTIGATIONAL PLAN..........................................................................................27
9.1
Overall Study Design and Plan..............................................................................27
9.1.1
Pretreatment Phase.......................................................................................30
9.1.1.1
Screening Period..................................................................................30
9.1.2
Treatment Phase...........................................................................................31
9.1.2.1
Randomized Crossover Treatment Periods (Treatment Periods 1 to 3)31
9.1.2.2
Open-label Treatment Period...............................................................32
9.1.3
Follow-Up Period.........................................................................................32
9.2
Discussion of Study Design, Including Choice of Control Groups.......................33
9.3
Selection of Study Population................................................................................33
9.3.1
Inclusion Criteria .........................................................................................33
9.3.2
Exclusion Criteria ........................................................................................33
9.3.3
Removal of Subjects From Therapy or Assessment....................................36
9.3.3.1
IPS-EEG-Specific Subject Withdrawal/Stopping Criteria...................36
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9.4
Treatments..............................................................................................................37
9.4.1
Treatments Administered.............................................................................37
9.4.1.1
Randomized Crossover Treatment Periods..........................................37
9.4.1.2
Open-label Treatment Period...............................................................37
9.4.2
Identity of Investigational Products.............................................................37
9.4.2.1
Chemical Name, Structural Formula of E2082....................................37
9.4.2.2
Comparator Drug .................................................................................38
9.4.2.3
Labeling for Study Drug......................................................................38
9.4.2.4
Storage Conditions...............................................................................38
9.4.3
Method of Assigning Subjects to Treatment Groups...................................38
9.4.3.1
Randomized Crossover Treatment Periods..........................................38
9.4.3.2
Open-Label Treatment Period..............................................................38
9.4.4
Selection of Doses in the Study...................................................................38
9.4.5
Selection and Timing of Dose for Each Subject..........................................39
9.4.6
Blinding........................................................................................................40
9.4.7
Prior and Concomitant Therapy...................................................................40
9.4.7.1
Prohibited Concomitant Therapies and Drugs.....................................41
9.4.7.2
Restrictions During the Study Period ..................................................41
9.4.8
Treatment Compliance.................................................................................42
9.4.9
Drug Supplies and Accountability...............................................................42
9.5
Study Assessments.................................................................................................43
9.5.1
Assessments.................................................................................................43
9.5.1.1
Demography.........................................................................................43
9.5.1.2
Screening Assessments ........................................................................43
9.5.1.2.1
Medical History and Epilepsy Medical History.............................43
9.5.1.2.2
Height Measurement and BMI computation..................................43
9.5.1.2.3
Urine Drug Test .............................................................................44
9.5.1.2.4
Serology.........................................................................................44
9.5.1.3
Efficacy Assessments...........................................................................44
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments.......................................................................44
9.5.1.4.1
Pharmacokinetic Assessments .......................................................44
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................44
9.5.1.5
Safety Assessments..............................................................................46
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...46
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................48
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9.5.1.5.3
Laboratory Measurements .............................................................49
9.5.1.5.4
Vital Signs and Weight Measurements..........................................50
9.5.1.5.5
Physical Examinations...................................................................51
9.5.1.5.6
Neurological Examinations............................................................51
9.5.1.5.7
Electrocardiograms ........................................................................51
9.5.1.5.8
Other Safety Assessments..............................................................52
9.5.2
Schedule of Procedures/Assessments ..........................................................52
9.5.2.1
Schedule of Procedures/Assessments ..................................................52
9.5.2.2
Description of Procedures/Assessments Schedule...............................60
9.5.3
Appropriateness of Measurements...............................................................60
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
With Special Situations................................................................................60
9.5.4.1
Reporting of Serious Adverse Events..................................................60
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................61
9.5.4.3
Reporting of Events Associated With Special Situations....................61
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................61
9.5.4.4
Expedited Reporting ............................................................................62
9.5.4.5
Breaking the Blind...............................................................................62
9.5.4.6
Regulatory Reporting of Adverse Events ............................................62
9.5.5
Completion/Discontinuation of Subjects.....................................................62
9.5.6
Abuse or Diversion of Study Drug ..............................................................63
9.5.7
Confirmation of Medical Care by Another Physician .................................63
9.6
Data Quality Assurance .........................................................................................63
9.6.1
Data Collection ............................................................................................63
9.6.2
Clinical Data Management ..........................................................................64
9.7
Statistical Methods.................................................................................................64
9.7.1
Statistical and Analytical Plans....................................................................64
9.7.1.1
Study Endpoints...................................................................................64
9.7.1.1.1
Primary Endpoint...........................................................................65
9.7.1.1.2
Secondary Endpoints .....................................................................65
9.7.1.1.3
Exploratory Endpoints ...................................................................65
9.7.1.2
Definitions of Analysis Sets.................................................................65
9.7.1.3
Subject Disposition..............................................................................65
9.7.1.4
Demographic and Other Baseline Characteristics ...............................66
9.7.1.5
Prior and Concomitant Therapy...........................................................66
9.7.1.6
Efficacy Analyses ................................................................................66
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9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses.............................................................................66
9.7.1.7.1
Pharmacokinetic Analyses.............................................................66
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................67
9.7.1.8
Safety Analyses....................................................................................68
9.7.1.8.1
Extent of Exposure.........................................................................68
9.7.1.8.2
Adverse Events ..............................................................................68
9.7.1.8.3
Laboratory Values..........................................................................69
9.7.1.8.4
Vital Signs......................................................................................69
9.7.1.8.5
Electrocardiograms ........................................................................69
9.7.1.8.6
Other Safety Analyses....................................................................70
9.7.2
Determination of Sample Size .....................................................................70
9.7.3
Interim Analysis...........................................................................................70
9.7.4
Other Statistical/Analytical Issues ...............................................................70
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................70
10
REFERENCE LIST .........................................................................................................71
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......72
11.1
Changes to the Protocol .........................................................................................72
11.2
Adherence to the Protocol......................................................................................72
11.3
Monitoring Procedures...........................................................................................72
11.4
Recording of Data..................................................................................................73
11.5
Identification of Source Data.................................................................................73
11.6
Retention of Records..............................................................................................73
11.7
Auditing Procedures and Inspection......................................................................74
11.8
Handling of Study Drug.........................................................................................74
11.9
Publication of Results ............................................................................................74
11.10 Disclosure and Confidentiality ..............................................................................75
11.11 Discontinuation of Study .......................................................................................75
11.12 Subject Insurance and Indemnity...........................................................................75
12
APPENDICES .................................................................................................................76
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LIST OF IN-TEXT TABLES
Table 1
Treatment Sequences .................................................................................31
Table 2
Treatment Description ...............................................................................37
Table 3
Clinical Laboratory Tests...........................................................................50
Table 4
Schedule of Procedures and Assessments in E2082-A001-201 ................53
Table 5
Schedule of Procedures and Assessments in E2082-A001-201 for Subjects 
in Scenario - 3 (Revised per Amendment 01)............................................57
Table 6
Time Windows for Study Assessments on Treatment Days (Revised per 
Amendment 01) .........................................................................................59
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E2082-A001-201- Scenario 1 (Revised per 
Amendment 01) .........................................................................................29
Figure 2
Study Design for Subjects in E2082-A001-201 - Scenario 3 (Revised per 
Amendment 01) .........................................................................................29
Figure 3
Individual plasma concentration-time profiles of E2082 (2.5 mg) 
following single oral dose administration in Study E2082-A001-001 ......39
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................76
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase 
AMPA
α amino 3 hydroxy-5-methyl-4-isoxazolepropionic acid
AST
aspartate aminotransferase
AUC(0-8h)
area under concentration-time curve from time 0 to 8 hours postdose
β-hCG
beta-human chorionic gonadotropin
BL
Bond-Lader
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
EEG
electroencephalogram 
GTCS
generalized tonic-clonic seizure
hCG
human chorionic gonadotropin
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IPS
intermittent photic stimulation
IRB
Institutional Review Board
LFT
liver function test
LNH
low/normal/high
LS
least squares
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetics
POC
proof-of-concept
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Abbreviation
Term
PPR
photoparoxysmal response
PT
preferred term
QTc
corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SAD
single ascending dose
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure
SPR
standardized photosensitivity response
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory value
tmax
time at which the highest drug concentration occurs (time to reach Cmax
following drug administration)
ULN
upper limit of normal
WBC
white blood cell
VAS
Visual Analogue Scale
VNS
vagus nerve stimulation
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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) constituted and functioning in accordance 
with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E6 GCP, Section 3, and any local regulations (Code of Federal Regulations
[CFR], Title 21 CFR Parts 50 and 56).  Any protocol amendment or revision to the ICF will be 
resubmitted to the IRB for review and approval, except for changes involving only logistical or 
administrative aspects of the study (eg, change in clinical research associates [CRAs], change of 
telephone number[s]).  Documentation of IRB 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 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 decides to suspend or 
terminate the study, the investigator will immediately send the notice of study suspension or 
termination by the IRB to the sponsor.
Study progress is to be reported to the IRB annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to the 
IRB, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator or the sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB of any reportable adverse events (AEs) per ICH guidelines and local IRB 
standards of practice.  Upon completion of the study, the investigator will provide the IRB with a 
brief report of the outcome of the study, if required.
The end of study is defined as the last subject completing the Follow-up Visit.  The sponsor 
should also provide the IRB with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB and Competent Authority within 15 calendar days, and a detailed written explanation of the 
reasons for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOP) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required by 
the following:

Principles of the World Medical Association Declaration of Helsinki 

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Pharmaceuticals for Human Use
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
Title 21 of the United States CFR (US 21 CFR) regarding clinical studies, including Part 
50 and Part 56 concerning informed subject consent and IRB regulations and applicable 
sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to each 
subject 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 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, 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, and after 
the subject 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 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-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations.  Each subject must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The original, 
signed ICF for each subject will be verified by the sponsor and kept on file according to local 
procedures at the site.
The subject should be informed in a timely manner if new information becomes available that 
may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 6 investigational sites in the US. 
The name and telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and of the contract research organizations (CROs) will be provided to each site.
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7
INTRODUCTION
7.1
Indication 
The overall development plan of E2082 will be based on the potential role of 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an 
antiepileptogenesis agent in a number of neurological disorders associated with 
glutamate-mediated neuronal overexcitation. 
7.1.1
Mechanism of Action – E2082
E2082 is a selective noncompetitive AMPA type glutamate receptor antagonist.  AMPA 
receptors, located on post-synaptic neurons, are responsible for fast glutamate-mediated 
excitation at synapses. Glutamate is the primary excitatory neurotransmitter in the central 
nervous system (CNS) and is implicated in a number of neurological disorders caused by 
neuronal overexcitation.
E2082 demonstrated potent in vitro inhibitory effect (AMPA receptor functional assay) and in 
vivo antiseizure effect in various animal models of epilepsy (audiogenic seizure, maximal 
electroshock [MES] seizure, and pharmacoresistant 6 Hz psychomotor seizure mouse models).  
Preclinical evidence suggests that E2082 showed a broad window between therapeutic effect and 
AMPA receptor antagonism-related CNS side effects (eg, sedation, ataxia) with a protective 
index (TD50 [rotarod test]/antiseizure ED50) of 3.2- to 20-fold.  Refer to the Investigator’s 
Brochure (IB) for detailed information. 
7.1.2
Clinical Experience With E2082
E2082 is currently under Phase 1 clinical development that comprises the first-in-human, 
double-blind, placebo-controlled, single- and multiple-ascending dose (SAD-MAD) study 
(E2082-J081-001; Study 001) in healthy male subjects in Japan.  The SAD portion of Study 001 
(Part A) evaluated pharmacokinetics (PK), safety and tolerability of E2082 in healthy male adult 
subjects at doses of 0.2, 0.5, 1, 2.5, 5, 10, 15, 25, and 40 mg under fasted condition, as well as at
5 mg under fed condition, and in elderly subjects at 10 mg.  E2082 was administered as oral 
tablets (0.5 or 5-mg dose strengths) in all dose cohorts, except for the 0.2-mg cohort (as oral 
solution).  The SAD portion of Study 001 is completed, in which a total of 60 subjects received a 
single dose of E2082 (0.2 through 40 mg) and 20 subjects received placebo.  The MAD portion 
of Study 001 is ongoing. 
7.1.2.1
Pharmacokinetics
Preliminary PK data suggest that E2082 was rapidly absorbed with median time to maximum 
plasma concentration (tmax) observed approximately 1 to 4 hours following oral administration of 
E2082 tablets over the dose range of 0.5 to 40 mg.  The average half life of E2082 was 
approximately 30 hours.  The mean plasma exposure (peak plasma concentration [Cmax] and area 
under the plasma concentration-time curve from zero time extrapolated to infinite time
[AUC(0-inf)]) increased approximately dose proportionally with increasing dose across the dose 
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range of 0.5 to 40 mg.  Food intake did not appear to affect the rate or extent of E2082 
absorption. Refer to the IB for a full description of PK.
7.1.2.2
Pharmacodynamics
Saccadic eye movements was included in Study 001 for evaluation of potential CNS-related side 
effects of E2082 as an exploratory pharmacodynamic (PD) parameter.   Preliminary results 
suggest a dose/concentration-dependent reduction in peak saccadic velocity following 
single-dose administration of E2082.  Refer to the IB for detailed information. 
7.1.2.3
Safety and Tolerability
Preliminary safety data from Study 001 showed that E2082 was well-tolerated following single 
oral dose administration in healthy subjects. There were no deaths, serious adverse events 
(SAEs), or adverse events leading to discontinuation, and no medically significant findings from 
laboratory tests, ECG, or vital signs.  A total of 16 subjects experienced treatment-emergent 
adverse events (TEAEs); 15/60 (25%) subjects receiving E2082 and 1/20 (5%) in the placebo 
group.  The most common TEAEs reported were dizziness (14/60 [23.3%] subjects) and 
somnolence (6/60 [10.0%] subjects), followed by nausea (2/60 [3.3%] subjects), decreased
appetite (2/60 [3.3%] subjects), back pain (1/60 [1.7%] subjects), and nasopharyngitis (1/20 
[5.0%] subjects).  All TEAEs were deemed related to E2082, except for back pain and 
nasopharyngitis.  All TEAEs reported were mild to moderate in severity, and all resolved without 
any medical interventions. 
Please refer to IB for a full summary of TEAEs, including safety and tolerability information. 
7.2
Study Rationale
7.2.1
Photosensitivity Proof-of-Concept Model
Patients with epilepsy often have intermittent seizures that occur at variable times. Consequently, 
studies evaluating new antiseizure medications require that large numbers of subjects be 
evaluated over several months of treatment to accurately assess treatment effects. In such 
circumstances, it is extremely useful to conduct a “proof-of-concept” (POC) study, which would 
screen potential antiseizure agents for possible efficacy before proceeding to lengthy and 
expensive studies that expose many subjects to a new compound. The photosensitivity POC 
study design has been used successfully to evaluate potential antiseizure effects of new agents in 
early stage development in small groups of subjects with photically-induced generalized 
epileptiform responses on electroencephalogram (EEG), called photoparoxysmal responses 
(PPRs).
Photosensitivity describes the ability to produce epileptiform activities in response to intermittent 
photic stimulation.  This EEG pattern is called PPR.  Some subjects who are photosensitive have 
photosensitive epilepsy, and may have clinical events in response to photic stimulation. This 
response is also characterized as “reflex epilepsy” in the small group of subjects with epilepsy
who have seizures in response to photic stimulation in the absence of adequate treatment.  Many 
other subjects will have PPR demonstrated only as an EEG pattern.  Photosensitivity is typically 
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a genetic trait with a Mendelian autosomal dominant pattern.  When associated with epilepsy, the 
epilepsy type will almost always be classified as generalized idiopathic epilepsy, and the clinical 
seizure semiology will be characterized by absence, generalized tonic-clonic, or myoclonic 
seizures.  Any of these 3 generalized seizure types can be precipitated by photic stimulation.
In the photosensitivity study design model, subjects who have PPR in response to flickering 
diffuse white light are included.  A photosensitivity range for each subject can be determined by 
eliciting the upper and lower limits of sensitivity to intermittent photic stimulation (IPS) in order 
not to evoke seizures for that particular subject.  Subjects are usually sensitive to IPS within 
clearly defined limits of flash frequency (mostly between 10-30 Hz).  The photosensitivity range 
is relatively stable over time for each subject, although it can decrease or be eliminated by the 
use of antiepileptic drugs (AEDs). 
This photosensitivity range, defined as the difference between the highest and lowest flash rates 
that consistently elicit a PPR, can be used as a quantitative measure of photosensitivity and, 
therefore, epileptogenicity.  In photosensitivity studies, a stable baseline is defined as the 
baseline at the Screening and Predose on the day of each Treatment Period.  Usually during a 
photosensitivity study, the baseline is stable throughout the study.  The photosensitivity range is 
measured repeatedly (up to 8 times) over the course of a single day, and the range can be 
measured rapidly (over a 5-minute interval) in an EEG laboratory.  Reduction in the 
photosensitivity range can then be easily quantified after a single dose of an AED. This 
reduction has been used to demonstrate an antiepileptic effect for a number of AEDs currently 
marketed or in development, most notably valproate, levetiracetam, lamotrigine, brivaracetam, 
carisbamate, JZP4 (Jazz Pharmaceuticals), cenobamate (YKP3089, SK Life Sciences), and 
selurampanel (BGG492, Novartis).  This POC model has been successful in identifying multiple 
drugs in early phase drug development that were subsequently effective in large clinical studies 
(Binnie, et al., 1986a; Binnie, et al., 1986b; Binnie, 1988; Kasteleijn-Nolst Trenité, et al., 1996;
Kasteleijn-Nolst Trenité, et al., 2007; Trenité, et al., 2007; French and Krauss, 2014;
Kasteleijn-Nolst Trenité, et al., 2015).  
The intent of this study is to provide a POC signal and evidence of a dose-response relationship, 
and to inform the design and dose selection for Phase 2 of the clinical development program.
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to assess PD activity of E2082 as measured by suppression 
of epileptic PPR in the subject’s most sensitive eye condition in the photosensitivity model as a 
proof of principle of efficacy in subjects with photosensitive epilepsy, compared to placebo.
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8.2
Secondary Objectives
The secondary objectives of the study are: 

To assess the PD activity of E2082 as measured by suppression of PPR in each of the 
3 eye conditions (eye closure, eyes closed, and eyes open), compared to placebo

To assess PD activity of E2082 as measured by onset, maximum change, and duration of 
photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and 
eyes open)

To assess proportion of subjects with complete suppression, partial suppression, and no 
response of standardized photosensitivity response (SPR)

To assess other CNS-related effects of E2082 based on Bond-Lader Visual Analogue
Scale (BL-VAS) 

To assess the safety and tolerability of E2082 following single oral dose administration

To assess the PK of E2082 following single oral dose administration
8.3
Exploratory Objective

To explore relationships between PK and PD 
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period, crossover 
study with an Open-label Treatment Period, in adult subjects with photosensitive epilepsy.  This 
study will use the photosensitivity proof of principle model to determine the potential of E2082 
to reduce the photosensitive range in adult subjects.  
This study will have 2 phases:  Pretreatment Phase and Treatment Phase.  The Pretreatment 
Phase will consist of a Screening Period (up to 3 weeks from Visit 1), during which each 
subject’s study eligibility will be determined.  The Treatment Phase will consist of 3 blinded 
Treatment Periods for a randomized crossover design, followed by an Open-label Treatment 
Period.  During the Randomized Crossover Treatment Periods, there will be 3 Treatment Visits 
(Visit 2 [Treatment Period 1], Visit 3 [Treatment Period 2], and Visit 4 [Treatment Period 3]) 
evaluating single-dose administrations of either placebo, E2082 2.5 mg, or E2082 25 mg in a 
blinded manner.  
Scenario 1:  Newly enrolled or ongoing subjects who have completed upto the Treatment Period 
3 at the time of Protocol Amendment 01 implementation, will undergo 1 treatment visit (Visit 5 
[Treatment Period 4]) during the Open-label treatment period to receive a single-dose 
administration of E2082 40 mg or 10 mg; the dose to be administered will be provided by an 
independent unblinded biostatistician upon review of the subject’s PPR data collected during 
Treatment Periods 1 through 3.  (revised per Amendment 01)
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Scenario 2:  Subjects who completed the open-label Treatment Period 4 (Visit 5), and have not 
completed the Follow-Up visit [Visit 6]) by the time of Protocol Amendment 01 implementation 
may continue in the study to receive an additional open-label, single oral dose of E2082 10 mg in 
the Treatment Period 5 (Visit 8) without undergoing Follow-up Visit 1 (Visit 6) and Screening 2 
(Visit 7).  (revised per Amendment 01)
Scenario 3: Subjects who completed the study (including Follow-Up visit [Visit 6]) before the 
implementation of Protocol Amendment 01 may be allowed to re-enter the study to receive an 
open-label, single-dose administration of E2082 10 mg after Screening 2 (Visit 7).  (revised per 
Amendment 01)
Treatment visits (ie, Visit 2, Visit 3, Visit 4, and Visit 5) will each be separated by a 2-week 
(±3 days) washout interval for a total of approximately 6 weeks.  Treatment Period 5 (Visit 8) 
will be 2 weeks (±3 days) after Treatment Period 4 (Visit 5) for subjects in Scenario 2, and after 
Screening 2 for subjects in Scenario 3.  (revised per Amendment 01).
All subjects will undergo a Follow-up Period of 2 weeks (±3 days) after the last day of study 
product administration (Visit 5 and/or Visit 8, as applicable).  (revised per Amendment 01).  The 
anticipated study participation duration for each subject is approximately 11 to 15 weeks.  All 
visits will be conducted on an outpatient basis.
An overview of the study design is presented in Figure 1.
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Note: FU visit is a single visit at the end of the Follow-up Period.
FU = Follow-up, Pd = Period, R = Randomization, SCR = screening, Trt = Treatment, WO = Washout.
Figure 1
Study Design for Study E2082-A001-201- Scenario 1 (Revised per 
Amendment 01)
FU = Follow-up, SCR = screening, Pd = Period
a:
Study days are with respective to the day of Treatment Period 5 (Visit 8). (revised per 
Amendment 01)
Figure 2
Study Design for Subjects in E2082-A001-201 - Scenario 3 (Revised 
per Amendment 01)
Visit:
Screening 1
SCR-1
-21 to -1
1
57±3
1
15±3
Period:
Phase:
Study Day:
WO Pd 1
(14±3 days)
2
3
4
5
29±3
Pretreatment
Trt Pd 2
(1 day)
WO Pd 2
(14±3 days)
Trt Pd 3
(1 day)
Treatment
Open-label
Treatment
FU Pd
(14±3 days)
6
43±3
Randomized Crossover
Treatment
Follow-Up
1 (FU-1)
Trt Pd 1
(1 day)
WO Pd 3
(14±3 days)
R
Trt Pd 4
(1 day)
Visit:
Screening 2 
(SCR-2)
7
Period:
Phase:
8
9
Pretreatment
Treatment
Open-label
Treatment
Trt Pd 8
(1 day) 
FU Pd
(14±3 days)
Follow-Up 2
(FU-2)
Study Daya:
-21 to -1
1
15±3
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9.1.1
Pretreatment Phase
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks from Visit 1, and as 
applicable, Visit 7) (revised per Amendment 01), during which each subject’s study eligibility 
will be determined.  
9.1.1.1
Screening Period
Screening will occur between Day –21 and Day –1 of Visit 1, and, as applicable, Visit 7 (revised 
per Amendment 01).  The purpose of the Screening Period is to establish protocol eligibility.  
Signed informed consent must be obtained before any study procedures (including screening 
procedures) can be conducted.  Procedures to be followed when obtaining informed consent are 
detailed in Section 5.3.
Subjects must have a diagnosis and/or history of a PPR on EEG (ie, photosensitive epilepsy) for 
which they may receive up to 3 concomitant AEDs (Section 9.4.7).
At the Screening Visit (Visit 1 and, as applicable, Visit 7) (revised per Amendment 01), subjects 
will undergo an IPS-EEG assessment in 3 eye conditions (eye closure, eyes closed, and eyes 
open) at ascending and then descending photo-stimulation frequencies.  At the Screening Visit, 
each frequency will be assessed in 3 eye conditions (eye closure, eyes closed, and eyes open) 
commencing at 2 Hz.  As soon as generalized EEG epileptiform activity appears, the stimulation 
for that particular frequency in that particular eye condition will be instantly terminated.  For the 
other eye conditions, ascending frequencies will be used, until generalized epileptiform activity 
is seen.  This procedure will determine the lower threshold frequencies for each eye condition.  
Similar assessments will then be carried out starting at 60 Hz and descending through the 
standard frequencies.  To avoid occurrence of a seizure, the stimulator will be turned off 
immediately if a generalized response is observed, and the sequence will be stopped at that point 
in that specific eye condition.  In this manner, for each eye condition, the upper threshold 
frequencies are determined.  
During the Screening Visit (Visit 1 and, as applicable, Visit 7) (revised per Amendment 01),
IPS-EEG assessment will be performed at 5 time points, over a 4-hour time period (0, 1, 2, 3, 
and 4 hours; within ±15 minutes of the scheduled time point).  Subjects with a reproducible PPR 
on EEG of at least 3 points on the SPR scale in at least 1 eye condition on at least 3 of the EEGs 
performed at Screening will be eligible for the study.  However, the final determination of study 
eligibility will include predose assessments when the subject returns to study site for Visit 2 and 
as applicable, Visit 8.  The Screening assessments will be conducted, including determination of 
the lower and upper limit of photosensitivity to IPS-EEG threshold frequency for each eye 
condition.  Qualified medical personnel for the management of acute seizures will be present 
during the day of IPS-EEG procedure throughout the study.  
Upon review by the investigator, subjects whose Screening assessments (including Day 1 
[Visit 2] and [Visit 8] predose procedures [revised per Amendment 01]) continue to meet all of 
the inclusion/exclusion criteria will enter the Treatment Phase.
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9.1.2
Treatment Phase
The duration of the Treatment Phase will be 6 weeks and will include 3 blinded Treatment
Periods for a randomized crossover design, followed by an Open-label Treatment Period.  
Up to 3 concomitant AEDs (Section 9.4.7) are allowed during the course of the study, provided 
that the dosage of concomitant AED(s) has remained stable for at least 4 weeks or 5 half-lives, 
whichever is longer, before Screening.  In the case where a new AED regimen has been initiated 
for a subject, the subject must be on the new AED for at least 8 weeks and the dose must have 
remained stable for at least 4 weeks or 5 half-lives, whichever is longer, before screening.  
During the study, changes to concomitant AEDs (including dosage) are not permitted unless 
medically necessary and upon consultation with the Sponsor.  Adherence to a stable AED 
regimen is critical as missed doses or changes during the study may affect the subject’s 
photosensitivity response. 
The Screening Disposition case report form (CRF) page must be completed to indicate whether 
the subject is eligible to participate in the study and to provide reasons for screen failure, if 
applicable.
9.1.2.1
Randomized Crossover Treatment Periods (Treatment Periods 1 to 3)
During the Randomized Crossover Treatment Periods, there will be 3 Treatment Visits (Visit 2
[Treatment Period 1], Visit 3 [Treatment Period 2], and Visit 4 [Treatment Period 3]) evaluating 
single-dose administrations of either placebo, E2082 2.5 mg, or E2082 25 mg.  Subjects will be
randomly assigned to 1 of 6 treatment sequences to receive the 3 treatments, in a blinded manner
in a cross-over sequence according to his/her randomization code (Table 1).
Table 1
Treatment Sequences
Sequence
Treatment Period 1
(Visit 2)
Treatment Period 2
(Visit 3)
Treatment Period 3
(Visit 4)
1: ABC
Placebo
E2082 2.5 mg
E2082 25 mg 
2: BCA
E2082 2.5 mg
E2082 25 mg 
Placebo
3: CAB
E2082 25 mg 
Placebo
E2082 2.5 mg
4: ACB
Placebo
E2082 25 mg 
E2082 2.5 mg
5: BAC
E2082 2.5 mg
Placebo
E2082 25 mg 
6: CBA
E2082 25 mg 
E2082 2.5 mg
Placebo
A = Placebo; B = E2082 2.5 mg; C = E2082 25 mg 
On the day of each Treatment Visit (ie, Visit 2, Visit 3, and Visit 4), subjects will arrive at the 
clinic in the morning following an overnight fast of at least 8 hours.  In order to enable 
discrimination between spontaneous and IPS evoked discharges, the subject will be assessed, at 
the start of each treatment day (ie, Visit 2, Visit 3, and Visit 4), for ≥2.5 minutes with each of the 
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3 eye conditions without any stimulation.  Baseline IPS-EEG assessments will be conducted 
30 minutes to 2 hours before study product administration on each treatment day, including 
determination of the lower and upper limit of photosensitivity to IPS threshold frequency for 
each eye condition.  The predose assessment serves as the baseline on each treatment day.  
Trains of flashes at constant frequency will be delivered for 4 to 6 seconds. Intervals between 
successive flash trains at a given frequency will last for at least 5 seconds.  Determination of the 
photosensitivity ranges will be assessed with separate trains of flashes of 4 to 6 seconds duration 
(or less if generalized epileptic activity occurs).  Flashes will be administered at standard 
frequencies of 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 Hz.  IPS-EEG assessments 
will be repeated at 1, 2, 4, 6, and 8 hours (within ±15 minutes of each scheduled time point) 
following study product administration.  PK, PD (B-L VAS), and vital signs assessments will be 
conducted predose, and at the same postdose time points as IPS-EEG measurements.  Other 
safety assessments will be performed on each treatment visit day either predose only (clinical 
laboratory tests, Columbia-Suicide Severity Rating Scale (C-SSRS), and urine pregnancy test 
[for women of childbearing potential only]), or both predose and at 4 hours postdose (brief 
neurological and 12-lead ECG examinations).
9.1.2.2
Open-label Treatment Period
For subjects in Scenario 1, there will be 1 open-label treatment visit (Visit 5 [Treatment Period 
4]) evaluating single oral dose administration of E2082 40 mg or 10 mg.
For subjects in Scenarios 2 and 3, there will be 2 open-label treatment visits: Treatment Period 4 
to receive a single oral dose E2082 40 mg and Treatment Period 5 to receive E2082 10 mg.  
(revised per Amendment 01).
Subjects will return to the study site after the 2-week [±3 days] washout interval following the 
Randomized Crossover Treatment Period 3 and will receive a single dose of 40 mg or 10 mg 
E2082. The same study procedures for Treatment Periods 1 through 3 (ie, Visit 2, Visit 3, and 
Visit 4) will apply to Treatment Period 4 (ie, Visit 5) as well as Treatment Period 5 (Visit 8)
(revised per Amendment 01), except that study drug administration is not blinded.  Concomitant 
medication restrictions from the Randomized Crossover Treatment Period will apply to the 
Open-label Treatment Period.
9.1.3
Follow-Up Period
After completion of the Open-label Treatment period, subjects will enter the Follow-up Period,
during which they will be required to complete a Follow-up visit (Visit 6) at 2 weeks ±3 days 
following the last day of study product administration. 
For subjects in Scenario 2 and 3, the Follow-up (Visit 9) visit will be 2 weeks ±3 days after 
Treatment Period 5 (Visit 8).  (revised per Amendment 01)
At the end of the Follow-up Period, subjects will be required to complete a Follow-up visit.
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9.2
Discussion of Study Design, Including Choice of Control Groups
Randomization will be used in this study in the Randomized Crossover Treatment Periods to 
avoid bias in the assignment of subjects to treatment, to increase the likelihood that known and 
unknown subject attributes (eg, demographics and baseline characteristics) are balanced across 
treatment groups, and to ensure the validity of statistical comparisons across treatment groups.  
Blinding to treatment will be used to reduce potential bias during data collection and evaluation 
of endpoints.
9.3
Selection of Study Population
Approximately 9 subjects will be randomized to achieve 6 evaluable subjects at approximately 
6 sites in the US.  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. Male or female 18 to 65 years of age at the time of informed consent. 
2. A diagnosis and/or history of a PPR on EEG (ie, photosensitivity epilepsy).
3. If currently being treated with AED(s), up to a maximum of 3 concomitant AEDs is allowed 
provided that doses must have remained stable for at least 4 weeks or 5 half-lives, whichever 
longer, before Screening.  In the case where a new AED regimen has been initiated for a 
subject, the subject must be on the new AED for at least 8 weeks before Screening and the 
dose must have remained stable for at least 4 weeks or 5 half-lives, whichever is longer,
before Screening.  (See Exclusion Criteria No. 17-22 for AEDs that are exclusionary). 
(revised per Amendment 01)
4. Reproducible IPS-induced PPR on EEG of at least 3 points on the SPR scale in at least 1 eye 
condition (eye closure, eyes closed, eyes open) on at least 3 of the EEGs performed at 
Screening.
5. Body mass index (BMI) between 18 to 35 kg/m2 (inclusive) and a total body weight greater 
than or equal to 45 kg at Screening.
6. Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour period 
before Screening and during the 24-hour period before each treatment day.
7. Willing and able to comply with all aspects of the protocol.
Note:  Subjects who have completed the study per original protocol may re-enter the study 
provided that the subject meet inclusion criteria No. 2 to 7. (revised per Amendment 01)
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
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1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]).  
A separate baseline assessment is required if a negative Screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug. 
2. Females of childbearing potential who:
a.
Within 30 days before study entry, have had unprotected sexual intercourse and did not 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, 
a double-barrier method [such as condom plus diaphragm with spermicide], a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) 
b. 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.  If 
currently abstinent, the subject must agree to use a double barrier method as described 
above if she becomes sexually active during the study period or for 28 days after study 
drug discontinuation.  Females who are using hormonal contraceptives must be on a stable 
dose of the same hormonal contraceptive product for at least 4 weeks before dosing and 
must continue to use the same contraceptive during the study and for 28 days after study 
drug discontinuation.
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). 
3. Male subjects who have not had a successful vasectomy (confirmed azoospermia) or they 
and their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days after 
study drug discontinuation).  No sperm donation is allowed during the study period and for 
28 days after study drug discontinuation.
4. History of nonepileptic seizures (eg, metabolic, structural, or pseudoseizures) while on any 
antiepileptic medication(s).
5. History of status epilepticus while on any antiepileptic medication(s) within 2 years before
Screening.
6. Ongoing or history of generalized tonic-clonic seizures (GTCS) within 6 months before
Screening.
7. Subject who had developed a clinical seizure during previous PPR assessment, or who 
experiences a clinical seizure during the Screening IPS procedure. 
8. Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening.
9. Inability to follow restriction on watching television, or use of any device(s) with an 
animated screen (eg, computer, video games, tablets, or smart phone) from the time of arrival 
at the study center until study procedures are completed for that day.
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10. Currently active clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) with the exception of epilepsy, which in the opinion of the investigator could affect 
the subject’s safety or interfere with the study assessments.
11. A history of prolonged QT syndrome or risk factors for torsade de pointes (eg, heart failure, 
hypokalemia, family history of long QT Syndrome), or the use of concomitant medications 
that prolonged the QT/corrected QT using Fridericia formula (QTcF) interval; or prolonged 
QT/QTcF interval (QTcF >450 msec) demonstrated on ECG at Screening or Baseline (based 
on average of triplicate ECGs).
12. Presence of active CNS infection, demyelinating disease, degenerative neurological disease 
or any CNS disease deemed to be progressive during the course of the study that may 
confound the interpretation of the study results.
13. Current/ongoing clinically significant active liver disease, porphyria, or with a family history 
of severe hepatic dysfunction indicated by abnormal liver function tests (LFTs) greater than 
3 times the upper limit of normal (ULN) (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
14. Any history of gastrointestinal conditions or surgery that may affect PK profiles of E2082 
(eg, hepatectomy, nephrectomy, and digestive organ resection).
15. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
16. Use of perampanel within 6 weeks before Screening.
17. Use of felbamate for less than 2 years or where the dose has not been stable for at least 
8 weeks before Visit 1. Subject must not have a history of white blood cell (WBC) count 
below equal or less than 2500/μL (2.50 1E+09/L), platelet count below 100,000, LFTs above 
3 times the ULN, or other indication of hepatic or bone marrow dysfunction while receiving 
felbamate.  If subjects received felbamate in the past, it must have been discontinued 8 weeks 
before Visit 1 to be eligible for study participation.
18. Use of vigabatrin within 5 months before Screening.  Subjects who have discontinued 
vigabatrin for at least 5 months before Screening must have documentation showing no 
evidence of vigabatrin associated clinically significant abnormality in a visual perimetry test 
in order to be eligible for the study.
19. Concomitant use of cannabinoids.
20. Use of benzodiazepines for epilepsy for which the dose has not been stable for greater than 
4 weeks before Screening.  Benzodiazepine use as rescue medication for seizure control is 
allowed; however, intermittent use of benzodiazepines for any other indication (eg, 
anxiety/sleep disorders) is prohibited.
21. Use of concomitant AEDs or other drugs that are known to be potent cytochrome P450 
(CYP)3A enzyme inducers (such as carbamazepine, oxcarbazepine, eslicarbazepine, 
phenytoin, phenobarbital, and primidone) or CYP3A inhibitors within 4 weeks or
5 half-lives, whichever is longer, before screening.  In addition, consumption of dietary 
supplements, foods, and forms of fruit juice that may affect the expression or function of 
CYP3A within 14 days before study drug administration. (revised per Amendment 01)
22. Vagus nerve stimulation (VNS) implanted within 5 months or changes in parameter within 
4 weeks before Screening.
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23. On a ketogenic diet for which the diet is not a stable regimen for at least 4 weeks before
Screening. 
24. History of drug or alcohol dependency or abuse within the 12 months before Screening, or 
those subjects who have a positive drug test or alcohol test at Screening.
25. History of or ongoing multiple drug allergies or severe drug reaction to AED(s), including 
dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions. 
26. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption.
27. Any suicidal ideation with intent with or without a plan within 6 months before Screening or 
during Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the C-SSRS).
28. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
29. Any psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
30. Currently enrolled in another clinical study or used any investigational drug or device within 
28 days or 5 half-lives, whichever is longer, preceding informed consent, except the 
investigational study for the evaluation of commercial IPS machine. 
Note: Subjects in Scenario 3 will not be allowed to re-enter the study if they meet any of the 
exclusion criteria listed above
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or administrative 
reasons.  The subject may stop study drug or withdraw from the study at any time for any reason.
Subjects who discontinue from the study early may be replaced upon consultation with the 
sponsor.
9.3.3.1
IPS-EEG-Specific Subject Withdrawal/Stopping Criteria
The investigator will determine continued subject participation in the IPS assessments.  In 
individual situations, safety assessments will be completed as appropriate, determined by the 
investigator. 
At the discretion of the investigator, a subject may be withheld from further IPS-EEG testing 
during a study visit or withdrawn from the study if any of the following 3 circumstances occur:
1. If a subject experiences:
a) GTCS on any study day, and the subject has not had a GTCS in the 6 months before
enrollment, that subject will be discontinued from the study.
OR
b) GTCS during photic stimulation, that subject will be discontinued from the study.
2. If, in the opinion of the investigator, a subject has evidence of proconvulsive activity on the 
EEG (eg, increase in spike-wave activity), following administration of the study drug, that 
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subject will be discontinued from the study. 
Proconvulsive activity is defined as 
a) generalized spike and wave discharges greater than 5 seconds defined by absence seizures 
or isolated myoclonic jerks do not require stoppage of study drug or subject withdrawal; or 
b) change in the usual pattern of PPR that is typical for the subject such as: decrease in time 
to occurrence of PPRs at the same flash frequency; increase in the duration of the PPR; or, 
clear increase of PPR-related negative sensations (clinical signs) or appearance or increase of 
spontaneous epileptiform activity.
3. If a subject has widening of the photosensitivity range (becomes more sensitive) by more 
than 3 points on 2 consecutive occasions after dosing compared to Screening, the IPS will be 
terminated and the subject will not be permitted to participate in further IPS-EEG testing on 
the same day.
9.4
Treatments
9.4.1
Treatments Administered
9.4.1.1
Randomized Crossover Treatment Periods
The following treatments will be administered as a single oral dose (Table 2).  Each subject will 
receive each treatment in a sequence according to the randomization code (Table 1).   
Table 2
Treatment Description 
Treatment
Study Drug/Dose
Study Drug(s) to be 
Administered
A
Placebo
5 x E2082-matched placebo 
tablets
B
E2082 2.5 mg
5 x E2082 0.5-mg tablets
C
E2082 25 mg 
5 x E2082 5-mg tablets
9.4.1.2
Open-label Treatment Period
Each subject will receive a single oral dose of E2082 40 mg (8 x E2082 5-mg tablets) and/or 10 
mg (2 x E2082 5-mg tablets).  Dose selection (10 or 40 mg) will depend on the individual 
subject’s PPR during the blinded Treatment Periods as described in Section 9.1.  (revised per 
Amendment 01)
9.4.2
Identity of Investigational Products
E2082 film-coated tablets (0.5 mg and 5 mg) and corresponding placebo are yellowish red, 
approximately 5.1 mm in diameter.  Test drug and placebo will be supplied by the sponsor in 
labeled containers.
9.4.2.1
Chemical Name, Structural Formula of E2082

Test drug code:  E2082
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
Generic name:  Not Applicable

Chemical name:  2-Fluoro-6-[3-fluoro-8-oxo-7-(pyridin-3-yl)-7,8-dihydro-6H-
pyrano[3,2-b:5,4-b′]dipyridin-9-yl]benzonitrile

Molecular formula:  C23H12F2N4O2

Molecular weight:  414.37
9.4.2.2
Comparator Drug
Placebo tablet with matching color and appearance to E2082 tablet will be supplied.
9.4.2.3
Labeling for Study Drug
E2082 will be labeled in accordance with text that is in full regulatory compliance.
9.4.2.4
Storage Conditions
E2082 will be stored in accordance with labeled storage conditions.  Temperature monitoring is 
required at the storage location to ensure that E2082 is maintained within 2ºC to 8ºC.  The 
investigator or designee is responsible for ensuring that the temperature is monitored throughout 
the total duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house validated data acquisition system, a 
mechanical recording device, such as a calibrated chart recorder, or by manual means, such that 
minimum and maximum thermometric values over a specific time period can be recorded and 
retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
9.4.3.1
Randomized Crossover Treatment Periods
Subjects will be assigned to all 3 treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent, unblinded, statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
9.4.3.2
Open-Label Treatment Period
Each subject will receive a single oral dose of E2082 40 mg (8 x E2082 5-mg tablets) and/or 10 
mg (2 x E2082 5-mg tablets), as applicable based on blinded review of the subject’s PPR during 
Treatment Periods 1 through 3 as described in Section 9.1.  (revised per Amendment 01)
9.4.4
Selection of Doses in the Study
Single oral doses of 2.5 mg to 40 mg are selected for detection of pharmacodynamics response in 
patients with photosensitivity epilepsy in this study.  (revised per Amendment 01)
The low dose of 2.5 mg was selected based on the exposures observed at ED50 in preclinical 
mouse model (6 Hz psychomotor seizure model).  Based on preliminary SAD PK data from 
Study 001, a single dose of 2.5 mg is expected to achieve plasma concentrations at or above the 
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predicted minimum effective plasma concentration of 80 ng/mL for approximately 8 hours in the 
majority of the subjects (Figure
  The highest dose of E2082 tested in the first-in-human study 
(Study 001) was 40 mg and was found to be well tolerated (revised per Amendment 01).  The 
proposed dose range between 2.5 mg and the highest dose of 40 mg are expected to provide a 
wide range of exposure (approximately 10- to 16-fold) to demonstrate POC and may also support 
exploratory PK/PD response analysis.
In addition to 2.5, 25 and 40 mg, 10 mg is being added in Protocol Amendment 01 in order to 
better characterize dose/exposure-response relationship and to support dose recommendation for 
Phase 2/3 clinical studies in target patient population. (revised per Amendment 01)
Figure 3
Individual plasma concentration-time profiles of E2082 (2.5 mg) 
following single oral dose administration in Study E2082-A001-001
conc = concentration
9.4.5
Selection and Timing of Dose for Each Subject
Following an overnight fast of at least 8 hours, subjects will be administered the study drug 
product with approximately 240 mL (8 fluid ounces) of water on the day of each Treatment Visit
(ie, Visit 2, Visit 3, Visit 4, Visit 5, and, as applicable, Visit 8) (revised per Amendment 01).  A 
light snack can be provided at 30 minutes predose (after clinical laboratory blood collection) and 
at 2 hours postdose.  
Subject ID
3).
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9.4.6
Blinding
Central EEG reading of all EEG records (including Screening and Treatment Periods 1 through 4
and, Treatment Period 5, as applicable) (revised per Amendment 01) will be performed in a 
blinded and independent manner.  Investigator(s) may consult with the central read only during 
the Pretreatment Phase, if needed, for IPS-EEG eligibility determination.  
During the Randomized Crossover Treatment Periods, subjects and all personnel involved with 
the conduct and interpretation of the study, including investigators, site personnel (with the 
exception of the pharmacist preparing and dispensing the study drug), and sponsor/designee 
(with the exception of the independent biostatistician and unblinded CRAs) will be blinded to the 
treatment codes.  Randomization code will be kept strictly confidential, filed securely by an 
appropriate group with the sponsor or CRO and accessible only to authorized persons (eg, Eisai 
Global Safety) until the time of unblinding, per SOP.
The E2082 drug substance and placebo will be provided to an unblinded pharmacist in an open-
label manner.  The unblinded pharmacist will be responsible for preparing and dispensing study 
drug tablets in accordance with subject randomization in a blinded manner.  A master list of all 
treatments and the subject numbers associated with them will be maintained in a sealed envelope 
by the sponsor.  In addition, master code breaker reports or envelopes identifying the treatment 
group of each subject number will be provided to the site and to the sponsor in sealed envelopes.  
These code breaker reports or envelopes are not to be opened unless an emergency occurs and 
knowledge of the subject’s randomization code may affect his/her medical treatment.  If 
possible, before breaking the blind, the investigator should consult with the sponsor to ascertain 
the necessity of breaking the code.  The investigator is to record the date and time of opening the 
code breaker report or envelope and the reason for breaking the code (see also Section 9.5.4.5).  
At the conclusion of the study, where possible, all unused drug supplies at the site, together with 
master code breaker reports or envelopes, are to be returned to the clinical supply vendor for 
final reconciliation and disposition.
Data from any completed cohort may be unblinded for review by the sponsor.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the subject 
during the study within 3 months before the Screening Visit and throughout the course of the 
study (starting at the date of informed consent) will be recorded on the Prior & Concomitant 
Medication CRF or Non-Pharmacological Procedures CRF.  
Up to a maximum of 3 concomitant AEDs (with the exception of those AEDs listed in 
Section 9.4.7.1) are allowed during the course of the study, provided that the dosage of 
concomitant AED(s) has remained stable for at least 4 weeks or 5 half-lives, whichever longer, 
before Screening.  In the case where a new AED regimen has been initiated for a subject, the 
subject must be on the new AED for at least 8 weeks and the dose must have remained stable for 
at least 4 weeks or 5 half-lives, whichever is longer, before screening.  During the study, changes 
to concomitant AEDs (including dosage) are not permitted unless medically necessary and upon 
consultation with the Sponsor.
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Vagus nerve stimulation (VNS) is not considered as one of the 3 allowed concomitant AEDs.  
However, VNS implantation during the course of the study is prohibited.  For subjects who have 
VNS implanted prior to participation in this study, changes to VNS parameters are not allowed 
unless medically necessary.  
Likewise, ketogenic diet is not considered as one of the 3 allowed concomitant AEDs.  However, 
changes to ketogenic diet (eg, median chain triglyceride level) are not allowed during the study.
The investigator will record on the AE CRF any AE for which the concomitant 
medication/therapy was administered.  If the concomitant medication/therapy is being 
administered for a medical condition present at the time of entry into the study, the investigator 
will record the medical condition on the Medical History and Current Medical Condition CRF.
9.4.7.1
Prohibited Concomitant Therapies and Drugs
Use of the following AEDs during the course of the study is not allowed:

Perampanel

Vigabatrin

Cannabinoids

Benzodiazepines for non-epilepsy indications (eg, anxiety/sleep disorders) (Stable doses 
of benzodiazepine or intermittent benzodiazepine use as rescue medication for seizure 
control is allowed)

Enzyme-inducing antiepileptic drugs (EIAEDs, eg, carbamazepine, oxcarbazepine, 
eslicarbazepine, phenytoin, phenobarbital, and primidone)
Concomitant use of medications known to be potent CYP3A inducers/inhibitors including, but 
not limited to, rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, modafinil, 
pioglitazone, and rifabutin will not be permitted and are to be discontinued within 4 weeks or 
5 half-lives, whichever longer before Visit 1, and, as applicable Visit 7.  
9.4.7.2
Restrictions During the Study Period
Study drug will be administered on the day of each Treatment Visit (ie, Visit 2, Visit 3, Visit 4, 
Visit 5, and, as applicable, Visit 8) (revised per Amendment 01) after an overnight fast of at least 
8 hours.  Treatments will be administered orally with approximately 240 mL (8 fluid ounces) of 
water.  Additional water may be provided in increments of 50 mL (up to a maximum of 100 mL), 
if required.  A light snack can be provided at 30 minutes predose (after clinical laboratory blood 
collection) and at 2 hours postdose.
Water will be allowed as desired except from the time of dosing until 1 hour after study drug 
administration.
For study visits where IPS-EEG assessments will be performed, subjects will be required to 
abstain from watching television or using any device with an animated screen (ie, computer, 
video games, tablets, or smart phone) from the time of arrival at the study center until study 
procedures are completed for that day.  Subjects will be required to refrain from strenuous 
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exercise and alcohol consumption during the 24-hour period before Screening and during the 
24-hour period before each treatment day.  Subjects will be instructed to get similar amounts of 
sleep prior to each visit.
9.4.8
Treatment Compliance
Not applicable as study drug will be administered in the study site by study personnel and 
records will be maintained.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB for the institution where the study is to be conducted

A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study

The IRB 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 

A signed and dated clinical studies agreement
The investigator/designee 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.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not enrolled 
in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study drugs, 
dispensing of study drugs to the subject, collection and reconciliation of unused study drugs that 
are either returned by the subjects or shipped to site but not dispensed to subjects, and return of 
reconciled study drugs to the sponsor or (where applicable) destruction of reconciled study drugs 
at the site.  This includes, but may not be limited to:  (a) documentation of receipt of study drugs, 
(b) study drugs dispensing/return reconciliation log, (c) study drugs accountability log, (d) all 
shipping service receipts, (e) documentation of returns to the sponsor, and (f) certificates of 
destruction for any destruction of study drugs that occurs at the site.  All forms will be provided 
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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).  As 
applicable, all unused study drugs and empty and partially empty containers from used study 
drugs are to be returned to the investigator by the subject and, together with unused study drugs 
that were shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s).  Approval for destruction to 
occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may be 
removed from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following the 
site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, and race/ethnicity.
9.5.1.2
Screening Assessments
9.5.1.2.1
MEDICAL HISTORY AND EPILEPSY MEDICAL HISTORY
In addition to standard medical history, surgical, and epilepsy history and current medical 
conditions will be recorded at the Screening Visit.  All medical, surgical, and epilepsy history 
within 10 years must be noted in the Medical History and Current Medical Conditions CRF.
9.5.1.2.2
HEIGHT MEASUREMENT AND BMI COMPUTATION
Height (cm) will be recorded at the Screening Visit and BMI (kg/m2) will be computed from 
height and weight data at Screening.  
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9.5.1.2.3
URINE DRUG TEST
A 30-mL urine sample will be collected at the Screening Visit (Visit 1 and, as applicable Visit 7)
(revised per Amendment 01), as specified in the Schedule of Procedures/Assessments (Table 4 `
Table 5).  This sample will be tested for common drugs of use/abuse:  eg, ethyl alcohol, 
phencyclidine (PCP), benzodiazepines, cocaine, amphetamines, cannabinoids, opioids, 
barbiturates, and tricyclic antidepressant drugs.
9.5.1.2.4
SEROLOGY
A 6 mL sample of blood will be taken for hepatitis B surface antigen and hepatitis C antibodies 
at Screening.
9.5.1.3
Efficacy Assessments
Not applicable.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples for the determination of plasma concentrations of E2082 will be collected from 
each subject.  PK sampling for plasma concentration will be collected predose (within 2 hours) 
and postdose at 1 (±10 min), 2 (±10 min), 4 (±15 min), 6 (±15 min), and 8 (±15 min) hours on 
each treatment day (ie, Visit 2, Visit 3, Visit 4,  Visit 5, and, as applicable, Visit 8) (revised per 
Amendment 01).  Plasma concentrations of E2082 will be measured using a validated liquid 
chromatography coupled with tandem mass spectrometry (LC-MS/MS) method.  Actual PK 
sampling date and time will be recorded at each scheduled and unscheduled sampling time point. 
Actual date and time of study drug administration will also be recorded for each dose 
administration during each Treatment Visit.  See Table 6 for a description of assessment timings 
and window periods.
At time points when vital signs, ECGs, and blood sampling are to be performed at the same time 
point, these procedures will be performed in the following order:  ECGs, vital signs, and then 
blood sampling.  
Information on the PK sample collection, handling, and shipping procedures will be provided to 
the clinical site either as a stand-alone PK laboratory manual or as part of the (central)
Laboratory Manual.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
All PD assessments will be performed within ±15 minutes of the scheduled time point.  See 
Table 6 for a description of assessment timings and window periods.
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IPS-EEG
Throughout the study, the flash frequency will be recorded.  Three eye conditions (eye closure, 
eyes closed, and eyes open) per stimulus for assessment purposes will be recorded. The 
combination of lower and upper frequencies gives a total of 3 photosensitivity ranges, 1 per eye 
condition.  If there is any doubt of the interpretation during any of the assessments (for example 
blinking during the eyes open condition, provoking epileptiform activity) the stimulation in the 
same eye condition will be repeated.  In order to minimize the risk of inducing a seizure, photic 
stimulation will not be carried out between the upper and lower thresholds.  This method has 
been found to be the safest, as it prevents elicitation of seizures by avoiding stimulation of the 
subject at the most sensitive frequencies.  The range for each subject will be recorded in the 
CRF.  The most sensitive eye condition will be noted during every visit; however, assessments in 
all 3 eye conditions will be noted.
During the Screening Visit (Visit 1 and, as applicable, Visit 7) (revised per Amendment 01), IPS-
EEG assessment will be performed at 5 time points, over a 4 hour time period (0, 1, 2, 3, and 4 
hours; within ±15 minutes of the scheduled time point).  Subjects with a reproducible PPR on 
EEG of at least 3 points on the SPR scale in at least 1 eye condition on at least 3 of the EEGs 
performed at Screening will be eligible for the study.  However, the final determination of study 
eligibility will include predose assessments when the subject returns to study site for Visit 2.  
PD activity of E2082 will be assessed by suppression of PPR following IPS under 3 eye 
conditions (eye closure, eyes closed, and eyes open) using the Grass PS 33 photic stimulator with 
an unpatterned glass lamp and an intensity of 100 cd/m2/flash at approximately 30 minutes to 
2 hours predose, and at 1, 2, 4, 6, and 8 hours postdose (within ±15 minutes of each scheduled 
time point), on each treatment day, (ie, Visit 2, Visit 3, Visit 4, Visit 5, and Visit 8) (revised per 
Amendment 01).  The time course (30 minutes to 2 hours predose to 8 hours postdose) will help 
assess the onset, maximum change from baseline, and duration of the reduction in PPR response.  
The predose assessment serves as the baseline on each treatment day.  PPR is expected to be 
within the range of 2 Hz to 60 Hz, depending on the subject’s sensitivity to IPS.
Standard 19-21-channel EEG equipment will be used for recording including video monitoring 
and precise recording of duration and frequency of the flashes (sensor or connection with the 
photostimulator).  The international 10-20 system will be used, with 2 additional channels, 1 for 
eye movements (to detect changes in eye condition more easily) and 1 for flash frequencies.  A 
19-21-channel recording system will be used with a bipolar derivation with emphasis on the 
parieto-temporal-occipital area (maximum and spreading of epileptiform activity).  The display 
montage will include T4-T6-O2-O1-T5-T3 and T4-P4-Pz-P3-T3, apart from 2x4 (8) frontal to 
occipital leads. 
The following settings will be used: 

Amplification:  7-10 microV/mm

High Frequency Filter: 35-70 Hz

Time constant: 0.3-0.6 sec

Display speed: 30 mm/sec
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In order to enable discrimination between spontaneous and IPS evoked discharges, the subject 
will be assessed ,at the start of each treatment day, (ie, Visit 2, Visit 3, Visit 4, Visit 5, and, as 
applicable, Visit 8) (revised per Amendment 01), for ≥2.5 minutes with each of the 3 eye
conditions without any stimulation.  Each IPS-EEG assessment will be conducted in all 3 eye 
conditions (eye closure, eyes closed, and eyes open; each for a minimum of 2.5 minutes) at 
ascending and then descending photo stimulation frequencies. The lower and upper limit of 
photosensitivity to IPS threshold frequency will be determined for each eye condition.  Trains of 
flashes at constant frequency will be delivered for 4 to 6 seconds.  Intervals between successive 
flash trains at a given frequency will last for at least 5 seconds.  Determination of the 
photosensitivity ranges will be assessed with separate trains of flashes of 4 to 6 seconds duration 
(or less if generalized epileptic activity occurs).  Flashes will be administered at standard 
frequencies of 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 Hz.
Bond and Lader Visual Analogue Scale
The Bond and Lader VAS (Bond A, 1974) for CNS–related effects of E2082 (such as 
somnolence, sedation, dizziness, and body sway) will be evaluated for each subject predose 
(within 2 hours) and at 1, 2, 4, 6, and 8 hours postdose on each treatment day (ie, Visit 2, Visit 3, 
Visit 4, Visit 5, and, as applicable, Visit 8).  (revised per Amendment 01)
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; laboratory evaluation for 
hematology, blood chemistry, and urine values; measurement of vital signs and ECGs; 
pregnancy test for women of childbearing potential only; and the performance of neurological 
and physical examinations as detailed in Table 4 and Table 5.
An assessment of suicidality using the C-SSRS will be performed as detailed in Table 4 and 
Table 5.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the medicinal product.  For this study, the study drug is E2082. 
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease 

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
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
Recurrence of an intermittent medical condition (eg, headache) not present at 
pretreatment (Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the last visit (ie, Follow-up/Early Discontinuation Visit).  SAEs must 
be collected for 28 days after the last dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute an 
AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality considered to 
constitute an AE should be reported on the AE CRF. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QT interval corrected by the 
Fridericia formula (QTcF) is greater than 450 msec and there is an increase of more than 
60 msec from baseline.  Any ECG abnormality that the investigator considers as an AE should 
be reported as such.
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects and 
determine if any result constitutes an AE.  Medical and scientific judgment should be exercised 
in deciding whether an isolated suicidality rating scale response should be classified as an AE 
(see Section 9.5.1.5.8 for a description of the C-SSRS). 
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, whichever 
comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
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The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a reasonable 
possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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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Events associated with special situations include pregnancy or exposure to study drug through 
breastfeeding; AEs associated with study drug overdose, misuse, abuse, or medication error.  
These events associated with special situations are to be captured using the SAE procedures but 
are to be considered as SAEs only if they meet one of the above criteria.  All AEs associated 
with special situations are to be reported on the CRF whether or not they meet the criteria for 
SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, blood chemistry, and urinalysis, 
are summarized in Table 3.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 4 and Table 5) shows the visits and 
time points at which blood for clinical laboratory tests and urine for urinalysis will be collected 
in the study. Subjects will fast for at least 8 hours before blood is drawn for clinical laboratory 
assessments.  Clinical laboratory blood collection must be performed before a subject can receive 
the light snack that can be provided at 30 minutes predose.  See Table 6 for a description of 
assessment timings and window periods.
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Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)
Blood Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, 
calcium, 
cholesterol, 
globulin, 
glucose,
lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
All blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the laboratory abnormality will be recorded on the AE CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], heart rate [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 4 and 
Table 5).  Vital signs are to be taken in the supine position after subjects have remained resting 
for at least 5 minutes.  All BP measurements should be performed on the same arm, preferably 
by the same qualified healthcare professional.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital sign 
measurements will be performed before drawing blood samples in order minimize the potential 
effects of blood drawing on recordings obtained during safety assessments.
At time points when vital signs, ECGs, and blood sampling are to be performed at the same time 
point, these procedures will be performed in the following order: ECGs, vital signs, and then 
blood sampling.  Subjects will remain rested in the supine position for 10 minutes before and 
5 minutes after ECG recordings, followed by recording of vital sign measurements.
See Table 6 for a description of assessment timings and window periods.
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9.5.1.5.5
PHYSICAL EXAMINATIONS
Full and abbreviated physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 4 and Table 5).  Documentation of the physical examination will 
be included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions CRF.  Clinically 
significant abnormal findings from the physical examination will be recorded as an AE on the 
AE CRF.
Full Physical Examination
A full physical examination will include evaluations of the head, eyes, ears, nose, throat, neck, 
heart, chest, lungs, abdomen, extremities, skin, and neurological examination.  The subject will
be queried regarding physical status and subjective symptoms as well. A urogenital examination 
will only be required in the presence of clinical symptoms related to this region.
Abbreviated Physical Examination
Health status will be assessed by brief evaluation of the head, eyes, ears, nose, throat, and other 
physical conditions of note.  The subject must be queried regarding changes in physical status 
since the last examination.
9.5.1.5.6
NEUROLOGICAL EXAMINATIONS
Full and abbreviated neurological examinations will be performed as designated in the Schedule 
of Procedures/Assessments (Table 4 and Table 5).  Documentation of the neurological 
examination will be included in the source documentation at the site.  Significant findings at the 
Screening Visit will be recorded on the Medical History and Current Medical Conditions CRF.  
Clinically significant abnormal findings from the neurological examination will be recorded as 
an AE on the AE CRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
ECGs (12-lead) will be obtained as designated in the Schedule of Procedures/Assessments 
(Table 4 and Table 5).  At time points when vital signs, ECGs, and blood sampling are to be 
performed at the same time point, these procedures will be performed in the following order:  
ECGs, vital signs, and then blood sampling.  Subjects will remain rested in the supine position 
for 10 minutes before and 5 minutes after ECG recordings, followed by recording of vital sign
measurements.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the AE CRF.
See Table 6 for a description of assessment timings and window periods.
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9.5.1.5.8
OTHER SAFETY ASSESSMENTS
C-SSRS
An assessment of suicidality using the C-SSRS will be performed at Screening, during each 
Treatment visit (ie, Visit 2, Visit 3, Visit 4, Visit 5, and, as applicable, Visit 8) (revised per 
Amendment 01), and at the Follow-up/Early discontinuation visit, as designated in the Schedule 
of Procedures/Assessments (Table 4 and Table 5).  It is recommended that, for the Treatment 
Visits, C-SSRS be performed predose to ensure there is no increased risk of suicidality since last 
visit.
Pregnancy Test
For women of childbearing potential, a serum β-hCG or hCG test (6 mL blood sample) will be 
performed during Screening Visit (Table 4 and Table 5).  Subsequently, urine pregnancy test will 
be performed prior to dose administration on each treatment visit (ie, Visit 2, Visit 3, Visit 4, and 
Visit 5, and, as applicable, Visit 8) (revised per Amendment 01), and upon return to site during 
Follow-up/Early Discontinuation Visit.  Unscheduled pregnancy test (serum or urine) may be 
performed as medically necessary at the discretion of the investigator.
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 4 presents the schedule of procedures/assessments for the study.
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-upa
(FU-1)/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening 1 (SCR-1)
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
Informed Consent
X
Demography 
X
Randomization
X
Inclusion/exclusion 
criteria
X
X
Medical and surgical 
history
X
Epilepsy medical history
X
Heightc and weight
X
X
X
(X)d
Physical examinatione
X
X
X
(X)d
Neurological 
examinationf
X
X
X
X
X
X
(X)d
Vital signsg,h
X
X
X
X
X
X
(X)d
12-Lead ECGi,h
X
X
X
X
X
X
(X)d
Clinical laboratory testsj,h
X
X
X
X
X
X
(X)d
Serology (HBsAg, HCV 
Ab) 
X
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-upa
(FU-1)/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening 1 (SCR-1)
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
Urine drug testk
X
Serum β-hCG [or hCG]
testl
X
Urine pregnancy testl
X
X
X
X
X
(X)d
PK sampling (plasma)m,h
X
X
X
X
(X)d
IPS-EEG Assessment
Xn
Xo
Xo
Xo
Xo
BL-VASp
X
X
X
X
C-SSRSq
X
X
X
X
X
X
(X)d
Study drug
administration
X
X
X
X
Prior and concomitant 
medication(s)
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
β-hCG = beta-human chorionic gonadotropin (or hCG = human chorionic gonadotropin), BL-VAS = Bond and Lader Visual Analogue Scale, 
C-SSRS = Columbia-Suicide Severity Rating Scale, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, IPS-EEG = intermittent photic 
stimulation electroencephalogram, Pd = Period, PK = pharmacokinetics, QTcF = QT interval corrected by the Fridericia formula, Trt = Treatment, 
VAS = visual analogue scale.
b:
For subjects who completed Open-label Treatment Period. Follow-up visit is to be conducted 2 weeks ±3 days following the last day of
study product administration.
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-upa
(FU-1)/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening 1 (SCR-1)
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
c:
For subjects who discontinued early from the study after having been exposed to study drug, Early Discontinuation Visit is to be 
conducted 2 weeks ±3 days following the last dose administration. Early Discontinuation visit is not required for subjects who 
discontinued from the study before receiving the first study drug administration.
d:
Height will be assessed only during the Screening Visit.
e:
During the unscheduled visits, specific procedure(s) to be performed will be on an as-needed basis at the discretion of the investigator.  
For example, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the investigator.
f:
A full physical examination will be conducted at Screening.  Abbreviated physical examination will be performed during Visit 2 (before
randomization) and Follow-up/Early Discontinuation Visit.  Additional physical examination may be conducted at any other visit(s), as 
medically deemed necessary.  Clinically significant abnormal findings from the physical examinations will be reported as AEs.
g:
A full neurological examination will be conducted at Screening. Abbreviated neurological examination will be performed during each 
treatment visit (predose and at 4 hours [±30 min] postdose) and Follow-up/Early Discontinuation Visit. Clinically significant abnormal 
findings from the neurological examinations will be reported as AEs.
h:
Vital signs (systolic and diastolic blood pressure [BP], heart rate [HR], respiratory rate, and body temperature) will be taken at Screening, 
during each treatment visit, and during Follow-up/Early Discontinuation Visit.  On each treatment day (ie, Visit 2, Visit 3, Visit 4, and 
Visit 5), vital sign measurements will be obtained predose (within 2 hours), and at 1, 2, 4, 6, and 8 hours postdose, with the window for 
collection postdose is (±15 min) at each scheduled timepoint.  Vital signs are to be taken in the supine position after subjects have 
remained resting for at least 5 minutes.  
i:
At time points when vital signs, ECG, and blood sampling are to be performed at the same time point, the following order must be 
followed: ECG, vital signs, and then blood sampling.
j:
ECG assessments will be performed at Screening, during each treatment visit (predose and at 4 hours [±30 min] postdose), and during 
Follow-up/Early Discontinuation Visit.  ECG measurements are to be taken in the supine position after subjects have remained resting for 
at least 5 minutes. If QTcF exceeds 450 msec during any visit, 3 consecutive ECG measurements each separated by 5 – 10 minutes will 
be performed to confirm the abnormality.  Any ECG abnormalities that the investigator deems to be clinically significant will be reported 
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-upa
(FU-1)/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening 1 (SCR-1)
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
as AEs.
k:
Clinical laboratory tests include: hematology, blood chemistry, and urinalysis. Subjects will fast for at least 8 hours before blood is drawn 
for clinical laboratory assessments. Clinical laboratory blood collection must be performed before a subject can receive the light snack 
that can be provided at 30 minutes predose.
l:
Screening for common drugs of use/abuse (eg, ethyl alcohol, phencyclidine (PCP), benzodiazepines, cocaine, amphetamines, 
cannabinoids, opioids, barbiturates, and tricyclic antidepressant drug).
m:
For female subjects of childbearing potential only. 
n:
Blood samples for plasma PK will be obtained predose (within 2 hours) and at 1 (±10 min), 2 (±10 min), 4 (±15 min), 6 (±15 min), and 8
(±15 min) hours postdose on each treatment day (ie, Visit 2, Visit 3, Visit 4, and Visit 5).  
o:
During Screening Visit, IPS-EEG assessment will be performed at 5 time points over a 4-hour interval (0, 1, 2, 3, and 4 hours; within ±15 
minutes of the scheduled time point).
p:
On each treatment day (Visit 2, Visit 3, Visit 4, and Visit 5), IPS-EEG assessment will be performed predose (approximately within 
30 minutes to 2 hours), and at 1, 2, 4, 6, and 8 hours postdose (a window of ±15 minutes is allowed at each postdose timepoint).
q:
BL-VAS will be performed from each subject on each treatment day predose (within 2 hours) and at 1, 2, 4, 6, and 8 hours postdose.  
r:
C-SSRS will be performed at Screening, during each Treatment Visit (recommended to administer C-SSRS predose to ensure there is no 
increased risk of suicidality since last visit), and at the Follow-up/Early Discontinuation Visit.
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Table 5
Schedule of Procedures and Assessments in E2082-A001-201 for 
Subjects in Scenario - 3 (Revised per Amendment 01)
Phase
Pretreatment
Open-Label 
Treatment
Follow-upa (FU-2)
/Early 
Discontinuationb
Unscheduled Visit
Period
Screening 
(SCR-2)
Trt Pd 5
Visit
7
8
9
Study Day
-21 to -1
1
14±3
Procedures/Assessments
Informed Consent
X
Demography 
X
Inclusion/exclusion criteria
X
Medical and surgical history 
(any update)
X
Epilepsy medical history 
(any update)
X
weight
X
X
(X)c
Physical examinationd
X
X
(X)c
Neurological examinatione
X
X
X
(X)c
Vital signsf,g
X
X
X
(X)c
12-Lead ECGh,g
X
X
X
(X)c
Clinical laboratory testsi,g
X
X
X
(X)c
Serology (HBsAg, HCV 
Ab) 
X
Urine drug testj
X
Serum β-hCG [or hCG] testk
X
Urine pregnancy testk
X
X
(X)c
PK sampling (plasma)l,g
X
(X)c
IPS-EEG Assessment
Xm
Xn
BL-VASo
X
C-SSRSp
X
X
X
(X)c
Study drug administration
X
Prior and concomitant 
medication(s)
X
X
X
X
Adverse events
X
X
X
X
Note: Number of days added here with respective to the Treatment Period 5 (Visit 8)
β-hCG = beta-human chorionic gonadotropin (or hCG = human chorionic gonadotropin), BL-VAS = Bond and Lader Visual 
Analogue Scale, C-SSRS = Columbia-Suicide Severity Rating Scale, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C 
virus antibody, IPS-EEG = intermittent photic stimulation electroencephalogram, Pd = Period, PK = pharmacokinetics, 
QTcF = QT interval corrected by the Fridericia formula, Trt = Treatment.
a:
For subjects who completed Open-label Treatment Period 5, Follow-up visit is to be conducted 2 weeks ±3 days 
following the last day of study product administration.
b:
For subjects who discontinued early from the study after having been exposed to study drug, Early 
Discontinuation Visit is to be conducted 2 weeks ±3 days following the last dose administration.  Early 
Discontinuation visit is not required for subjects who discontinued from the study before receiving the first 
study drug administration.
c:
During the unscheduled visits, specific procedure(s) to be performed will be on an as-needed basis at the 
discretion of the investigator.  For example, ECG will only be done if the results from the previous visit were 
deemed to be clinically significant by the investigator.
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d:
A full physical examination will be conducted at Screening.  Abbreviated physical examination will be 
performed during Visit 8 (before randomization) and Follow-up/Early Discontinuation Visit.  Additional 
physical examination may be conducted at any other visit(s), as medically deemed necessary.  Clinically 
significant abnormal findings from the physical examinations will be reported as AEs.
e:
A full neurological examination will be conducted at Screening.  Abbreviated neurological examination will be 
performed during the treatment visit (predose and at 4 hours [±30 min] postdose) and Follow-up/Early 
Discontinuation Visit.  Clinically significant abnormal findings from the neurological examinations will be 
reported as AEs.
f:
Vital signs (systolic and diastolic blood pressure [BP], heart rate [HR], respiratory rate, and body temperature) 
will be taken at Screening, during treatment visit, and during Follow-up/Early Discontinuation Visit.  On 
treatment day (Visit 8), vital sign measurements will be obtained predose (within 2 hours), and at 1, 2, 4, 6, and 
8 hours postdose, with the window for collection postdose is (±15 min) at each scheduled timepoint.  Vital signs 
are to be taken in the supine position after subjects have remained resting for at least 5 minutes.  
g:
At time points when vital signs, ECG, and blood sampling are to be performed at the same time point, the 
following order must be followed: ECG, vital signs, and then blood sampling.
h:
ECG assessments will be performed at Screening, during each treatment visit (predose and at 4 hours [±30 min] 
postdose), and during Follow-up/Early Discontinuation Visit.  ECG measurements are to be taken in the supine 
position after subjects have remained resting for at least 5 minutes.  If QTcF exceeds 450 msec during any visit, 
3 consecutive ECG measurements each separated by 5 – 10 minutes will be performed to confirm the 
abnormality.  Any ECG abnormalities that the investigator deems to be clinically significant will be reported as 
AEs.
i:
Clinical laboratory tests include: hematology, blood chemistry, and urinalysis. Subjects will fast for at least 8 
hours before blood is drawn for clinical laboratory assessments.  Clinical laboratory blood collection must be 
performed before a subject can receive the light snack that can be provided at 30 minutes predose.
j:
Screening for common drugs of use/abuse (eg, ethyl alcohol, phencyclidine (PCP), benzodiazepines, cocaine, 
amphetamines, cannabinoids, opioids, barbiturates, and tricyclic antidepressant drug).
k:
For female subjects of childbearing potential only. 
l:
Blood samples for plasma PK will be obtained predose (within 2 hours) and at 1 (±10 min), 2 (±10 min), 4 (±15 
min), 6 (±15 min), and 8 (±15 min) hours postdose on treatment day (Visit 8).  
m:
During Screening Visit, IPS-EEG assessment will be performed at 5 time points over a 4-hour interval (0, 1, 2, 
3, and 4 hours, within ±15 minutes of the scheduled time point).
n:
On treatment day (Visit 8), IPS-EEG assessment will be performed predose (approximately within 30 minutes 
to 2 hours), and at 1, 2, 4, 6, and 8 hours postdose (a window of ±15 minutes is allowed at each postdose 
timepoint).
o:
BL-VAS will be performed from each subject on each treatment day predose (within 2 hours) and at 1, 2, 4, 6, 
and 8 hours postdose.  
p:
C-SSRS will be performed at Screening, during each Treatment Visit (recommended to administer C-SSRS 
predose to ensure there is no increased risk of suicidality since last visit), and at the Follow-up/Early 
Discontinuation Visit.
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Table 6 presents the blood sampling schedule for pharmacokinetic assessments, in addition for 
window periods for study assessments on Treatment visits (ie, Visit 2, Visit 3, Visit 4, Visit 5, 
and, as applicable Visit 8).  
Table 6
Time Windows for Study Assessments on Treatment Days
(Revised per Amendment 01)
Visit (Window)
Time Relative to the 
Administration
Acceptable Time Window
PK
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Visit 8 (±3 days)
Predose
–2 hours
1, 2 hours
±10 minutes
4, 6, and 8 hours
±15 minutes
Vital Signs
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Visit 8 (±3 days)
Predose
–2 hours
1, 2, 4, 6, and 8 hours
±15 minutes
ECG
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Visit 8 (±3 days)
Predose
–2 hours
4 hours
±30 minutes
Clinical Laboratory Tests
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Visit 8 (±3 days)
Predose
–2 hours to -30 minutes (before light snack)
IPS-EEG Assessment
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Visit 8 (±3 days)
Predose
-2 hours to -30 minutes 
1, 2, 4, 6, and 8 hours
±15 minutes
IPS-EEG = intermittent photic stimulation electroencephalogram, PK = pharmacokinetics
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9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments are shown in Table 4 and Table 5.
9.5.3
Appropriateness of Measurements
Most of the clinical assessments are standard measurements commonly used in Phase 2 studies 
of epilepsy.  The safety assessments to be performed in this study, including monitoring and 
recording all AEs; laboratory evaluation for hematology, blood chemistry, and urine values; 
measurement of vital signs and ECGs; and the performance of neurological and physical 
examinations, are standard evaluations to ensure subject safety.
In addition to the standard safety measurements, CNS-related side effects (eg, somnolence, body 
sway, dizziness and sedation) known to be associated with AMPA receptor antagonism will also 
be assessed using BL-VAS (Bond A, 1974).  As BL-VAS measures effects of E2082 that are 
related to the underlying pharmacological activities of AMPA receptor antagonist, these 
measurements also serve as PD markers in this study.
The IPS-EEG procedure during this study will be performed based upon the protocol of 
Kastelejin et al (Kasteleijn-Nolst Trenité, et al., 1996).  The combination of lower and upper 
frequencies gives a total of 3 photosensitivity ranges, 1 per eye condition (eye closure, eyes 
closed, and eyes open).  In order to minimize the risk of inducing a seizure, photic stimulation 
will not be carried out between the upper and lower thresholds.  However, qualified medical 
personnel for the management of acute seizures will be present during the day of IPS-EEG
procedure throughout the duration of the study.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated With 
Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the last visit (ie, 
Follow-up/Early Discontinuation visit) and for 28 days after the last dose.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE judged by the 
investigator to be related to the study treatment or any protocol-required procedure should be 
reported to the sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
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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 IRB of the occurrence of the SAE in writing, if required by his
institution.  A copy of this communication must be forwarded to the CRO to be filed in the 
sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or within 
28 days of last study treatment, or any exposure to study drug through breastfeeding during study 
treatment or within 28 days of last study treatment, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or email as 
soon as possible but no later than 1 business day from the date the investigator becomes aware of 
the pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File.  The Pregnancy Report 
Form must be used for reporting.  All pregnancies must be followed to outcome.  The outcome 
of the pregnancy must be reported as soon as possible but no later than 1 business day from the 
date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated With Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
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:
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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 
AE CRF and also reported using the procedures detailed in Reporting of Serious Adverse Events 
(Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse is always to be captured as 
an AE.  If the AE associated with an overdose, misuse, abuse, or medication error does not meet 
serious criteria, it must still be reported using the SAE form and in an expedited manner but 
should be noted as nonserious on the SAE form and the AE CRF.
9.5.4.4
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
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code for 
an individual subject.  In all such cases, the AE necessitating the emergency blind break will be 
handled as an SAE in accordance with the procedures indicated above.  Any broken code will be 
clearly justified and documented.  The medical monitor must be notified immediately of the 
blind break.
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.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or administrative 
reasons.  A subject may elect to discontinue the study at any time for any reason.  All subjects 
who discontinue the study early after having been exposed to study drug are to complete the 
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study’s early discontinuation procedures indicated in the Schedule of Procedures/Assessments 
(Table 4 and Table 6).  Early Discontinuation visit is not required for subjects who discontinued 
from the study before receiving the first study drug administration.
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, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate 1 or 
more secondary reason(s) for discontinuation.  Study disposition information will be collected on 
the Subject Disposition CRF.
A subject removed from the study for any reason may be replaced.
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to receive 
medical care by another physician.  At each visit, the investigator will ask the subject whether 
he/she has received medical care by another physician since the last visit or is planning to do so 
in the future.  When the subject is going to receive medical care by another physician, the 
investigator, with the consent of the subject, will inform the other physician that the subject is 
participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 1572 
must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
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Completed, original CRFs are the sole property of Eisai and should not be made available in any 
form to third parties without written permission from Eisai, except for authorized representatives 
of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All data, 
both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released for unblinding.  Statistical analyses will be performed 
using SAS software or other validated statistical software as required.  Data will be unblinded 
once double-blind treatment period has completed.  Two sets of analyses tables will be created: 
one set after the unblinding using all the available data until that point and another set after all 
the subjects have completed the last study visit.
Descriptive statistics will be presented including mean and standard deviation of photosensitivity 
range for each subject at Screening and at each time point, for each Treatment Visit day by 
treatment group.  Graphical displays of the data for each subject will allow exploration of 
intersubject and intrasubject variability.  Details of statistical methods and analyses will be 
included in a separate statistical analysis plan (SAP).  
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
The reduction in PPR response will be evaluated for 8 hours postdose during each Treatment 
Period.  A diminution in response is anticipated with the dose range.  .
The primary endpoint, the mean change from baseline of the average PPR in the most sensitive is 
analyzed using a mixed effects model for crossover part of the study and summarized for each 
E2082 dose level and placebo regardless of crossover design.  Another endpoint will include 
proportions of subjects with complete suppression, partial response, or no response   
Complete suppression is defined as an SPR reduction to 0 over at least 1 time point for all 3 eye 
conditions. Partial response is defined as a reduction in SPR of at least 3 units from baseline for 
at least 3 time points, and no time points with at least 3 units of increase, in the most sensitive 
eye condition; without meeting the complete suppression definition. The definition of no 
response is as follows: Did not meet complete suppression or partial response definitions.
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9.7.1.1.1
PRIMARY ENDPOINT

The primary endpoint of this study is the mean change from baseline in the PPR range in 
each subject’s most sensitive eye condition.
9.7.1.1.2
SECONDARY ENDPOINTS

Mean change from baseline in the PPR range in each of the 3 eye conditions (eye closure, 
eyes closed, and eyes open) 

Onset, maximum change, and duration of response in each of the 3 eye conditions (eye 
closure, eyes closed, and eyes open) 

Frequency and percentage of subjects with complete suppression, partial response, and no 
response of SPR

Changes from baseline in BL-VAS 

Incidence of TEAEs

Clinically significant changes from baseline in vital signs, serum chemistries, complete 
blood counts, or liver function tests after single doses of E2082, compared to placebo

PK parameters of E2082 (Cmax, tmax, area under concentration-time curve from time 0 to 
8 hours postdose [AUC(0-8h)])
9.7.1.1.3
EXPLORATORY ENDPOINTS

Relationship between plasma exposure of E2082 (PK) and PD response (eg, onset, 
maximum change, and duration of photosensitivity response, BL-VAS)
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.
The PK Analysis Set is the group of randomized subjects who receive at least 1 dose of study 
drug and have sufficient PK data to derive at least 1 PK parameter.
The PD Analysis Set is the group of randomized subjects who receive at least 1 dose of study 
drug and have sufficient PD data to derive at least 1 PD parameter.
9.7.1.3
Subject Disposition
The number of subjects screened and the number failing Screening (overall and by reason for 
failure) will be summarized.  Screen failure data will be listed.  The number of subjects 
randomized along with the number of subjects administered each dose of E2082 will also be 
presented.
Subjects who prematurely terminate their participation in the study will be summarized by their 
primary reason for study termination.
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9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be summarized 
by dose group for each part of the study using descriptive statistics.  Continuous demographic 
and baseline variables include age, height, and weight; categorical variables include sex, age 
group, and race.  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary. The number (percentage) of subjects who 
took prior and concomitant medications will be summarized by treatment group, Anatomical 
Therapeutic Chemical (ATC) class, and World Health Organization Drug Dictionary preferred 
term (PT).  Prior medications will be defined as medications that stopped before the dose of 
study drug.  Concomitant medications will be defined as medications that started after the date of 
the dose of study drug up to 28 days after the subject’s dose.  All medications will be presented 
in subject data listings.
9.7.1.6
Efficacy Analyses
Not applicable.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for listings of individual E2082 plasma concentrations.  The 
PK analysis set will be used for summaries of plasma E2082 concentrations and for analyses, 
summaries, and listings of PK parameters.  Plasma concentrations will be tabulated by nominal 
sampling time and summarized by treatment dose using summary statistics.  
The following PK parameters will be derived by noncompartmental analysis using plasma 
concentrations of E2082.  These parameters will include, but are not limited to:

Cmax
maximum observed concentration

AUC(0-8h) area under concentration-time curve from time 0 to 8 hours postdose

tmax
time to reach Cmax following drug administration
The PK of E2082 will be analyzed based on available data from this study.  The PK and PD 
Analysis Sets will be used to evaluate the relationship of PK of E2082 and change in SPR
response.  The PK-PD analyses may include the examination of the relationship of PK of E2082
and SPR (eg, time of onset, maximum change, and duration of response; and BL-VAS data) 
using model-based approaches, data permitting.  Details of the PK/PD analyses will be described 
in a separately prepared analysis plan and its report. 
Analysis variables:
Plasma concentrations of E2082
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Analysis set:
The PK Analysis Set will be used for individual plasma concentration 
listings and summaries of plasma concentrations.
Analysis methods:
The PK of E2082 will be analyzed based on available data from this 
study.  Plasma concentrations will be tabulated by nominal sampling time 
and summarized by treatment dose using summary statistics.  
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The PD analysis will be performed on the PD Analysis Set.  
No multiplicity adjustments will be made. The 5 PPR measured postdose on a study day will be 
averaged and used for the primary endpoint.  The predose PPR data from the respective 
treatment period will be used as the baseline data.  
The primary and secondary endpoints of mean change from baseline of the average PPR in the 
most sensitive and 3 eye conditions will be analyzed using a mixed effects model for the
crossover part of the study and summarized for each E2082 dose level and placebo regardless of 
crossover design.  The mixed effects model for the crossover part of the study will include 
treatment (E2082 2.5 mg, 25 mg, and placebo), period, and sequence as fixed effects, baseline 
(predose) measurement as a covariate, and subject nested within sequence as a random effect. 
Where data are normally distributed, least squares (LS) means, difference in LS means of each 
E2082 dose (2.5 mg or 25 mg) compared to placebo, and 90% CIs will be presented with no 
adjustments for multiplicity. 
Additional analysis by graphical exploration for the evaluation of onset, maximum change, and 
duration of photosensitivity response at each dose level will be performed for all 3 eye 
conditions for each treatment.  Similarly, frequency and percentage of subjects with complete 
suppression, partial suppression, and no response at each dose level of E2082 will be 
summarized descriptively and graphically for each treatment.
Sensitivity analyses may be conducted for photosensitivity response, for example, in subjects 
who completed all 3 Treatment Periods 1 through 3 versus those who are included in the PD 
Analysis Set. Other exploratory analyses may be conducted as data permit.  
All other PD data (ie, BL-VAS data) will be listed and summarized by treatment, as appropriate, 
using standard summary statistics.  Descriptive summary statistics (eg, mean, SD, median, 
minimum, and maximum for continuous variables, and the number and percent for categorical 
variables) of each endpoint and the changes from baseline will be tabulated.
PK-PD analyses may include the examination of the relationship of PK of E2082 and SPR (eg, 
time of onset, maximum change, and duration of response; and BL-VAS data) using 
model-based approaches, data permitting.  Details of the PK/PD analyses will be described in a 
separately prepared analysis plan and its report.
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9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety data that will be 
evaluated include AEs, clinical laboratory results, vital signs, ECGs, and neurological/physical 
examinations.  TEAEs will be summarized by presenting for each treatment group, the incidence 
of AEs.  
An assessment of suicidal ideation and behavior using the C-SSRS will be performed throughout 
the study.  
Descriptive summary statistics (eg, mean, SD, median, minimum, and maximum for continuous 
variables, and the number and percent for categorical variables) of the laboratory, vital signs, and 
ECG parameters, and changes from baseline will be evaluated by treatment group.  The 
proportion of subjects with any treatment-emergent report of suicidal ideation and behavior and 
intensity of these behaviors will be summarized.
9.7.1.8.1
EXTENT OF EXPOSURE
Extent of exposure will be presented by dose level.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA (Version 20.0 or higher) lower level term (LLT) 
closest to the verbatim term.  The linked MedDRA PT and primary system organ class (SOC) are 
also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment 
(Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group, 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]).  A subject data listing of all SAEs, including 
deaths, will be provided.
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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last on-treatment 
value) will be summarized by visit and treatment group using descriptive statistics.  Qualitative 
parameters listed in Section 9.5.1.5.3 will be summarized using frequencies (number and 
percentage of subjects), and changes from baseline to each postbaseline visit and to end of 
treatment will be reported using shift tables.  Percentages will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during the 
Treatment Period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used to 
identify subjects with treatment-emergent markedly abnormal laboratory values (TEMAVs).  
Except for phosphate, a TEMAV is defined as a postbaseline value with an increase from 
baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a postbaseline value 
with an increase from baseline to a grade of 3 or higher.  When displaying the incidence of 
TEMAVs, each subject may be counted once in the laboratory parameter high and in the 
laboratory parameter low categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, heart rate, 
respiratory rate, and temperature) and changes from baseline will be presented by visit and 
treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit 
and treatment group.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG result 
in QTcF during the Treatment Period will be summarized.  Clinically abnormal ECG results in 
QTcF will be categorized as follows:

For the QT interval assessment, clinically abnormal ECG results for QT interval 
corrected for heart rate using QTcF will be categorized as follows:  QTcF values 
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>450 msec, >480 msec, and >500 msec, and time-matched change from baseline in QTcF 
>30 msec and >60 msec.
9.7.1.8.6
OTHER SAFETY ANALYSES
Proportion of subjects with any treatment-emergent report of suicidal ideation and behavior and 
intensity of these behaviors will be summarized.
9.7.2
Determination of Sample Size
Approximately 9 subjects with photosensitive epilepsy and a stable PPR will be needed to be 
randomized in the study in order to obtain 6 evaluable subjects.  Based on a similar study in 
subjects with photosensitive epilepsy (NCT02564029), an estimated standard deviation of the 
treatment group difference of the SPR in the subject’s most sensitive eye condition is 3.62.  The 
width of a 90% CI of the mean group difference based on this standard deviation assumption and 
6 subjects is 2.431.  Therefore, a sample size of 6 would be sufficient to detect a mean group 
difference of 3 or larger with 90% confidence.
Upon consultation with the sponsor, subjects who discontinue from the study early may be 
replaced.
9.7.3
Interim Analysis
No formal interim analysis is planned.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision will 
be documented and described in the clinical study report.
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10 REFERENCE LIST
Binnie CD, van Emde Boas W, Kasteleijn-Nolste- Trenité DG, de Korte RA, Meijer JW, 
Meinardi H, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia.
1986a;27:248-54.
Binnie CD, Kasteleijn-Nolst Trenité DG, de Korte R. Photosensitivity as a model for acute 
antiepileptic drug studies. Electroencephalogr Clin Neurophysiol. 1986b;63:35-41.
Binnie CD. Preliminary evaluation of potential anti-epileptic drugs by single dose 
electrophysiological and pharmacological studies in patients. J Neural Transm. 1988;72:259-66.
Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol. 
1974;47: 211-8.
French J, Krauss G. Effect of Marketed Antiepileptic Drugs and Placebo in the Human 
Photosensitivity Screening Protocol. Neurotherapeutics. 2014;11:412-18
Kasteleijn-Nolst Trenité, D. , Brandt, C. , Mayer, T. , Rosenow, F. , Schmidt, B. , Steinhoff, B. 
J., Gardin, A. , Imbert, G. , Johns, D. , Sagkriotis, A. and Kucher, K. (2015), Dose-dependent 
suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor 
antagonist BGG492: Clear PK/PD relationship. Epilepsia, 56: 924-932. doi:10.1111/epi.13008
Kasteleijn-Nolst Trenité DG, Genton P, Parain D, Masnou P, Steinhoff BJ, Jacobs T, et al. 
Evaluation of brivaracetam, a novel SV2A ligand, in the photosensitivity model. Neurology.
2007;69:1027-34.
Kasteleijn-Nolst Trenité DG, Marescaux C, Stodieck S, Edelbroek PM, Oosting J. Photosensitive 
epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam 
analogue, levetiracetam. Epilepsy Res. 1996;25:225-30.
Trenité DG, French JA, Hirsch E, Macher JP, Meyer BU, Grosse PA et al. Evaluation of 
carisbamate, a novel antiepileptic drug, in photosensitive patients: an exploratory, 
placebo-controlled study. Epilepsy Res. 2007;74:193-200.
Columbia-Suicide Severity Rating Scale (C-SSRS). Columbia University. Available from: 
http://www.cssrs.columbia.edu/scales_cssrs.html
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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.  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 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, but the health or regulatory authority and 
IRB 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 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 CRO’s CRA will maintain contact with the investigator and designated staff by telephone, 
letter, or email between study visits.  Monitoring visits to each site will be conducted by the 
assigned CRA as described in the monitoring plan.  The investigator will allow the CRA to 
inspect the clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the local 
auditing agency and to IRB 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 interactive response system, x-rays, 
and other imaging reports (eg, sonograms, computed tomography [CT] scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, 
pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives

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

CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except when a 
section of the CRF itself is used as the source document.  Any correction to entries made on the 
CRF must be documented in a valid audit trail where the correction is dated, the individual 
making the correction is identified, the reason for the change is stated, and the original data are 
not obscured.  Only data required by the protocol for the purposes of the study should be 
collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor and 
retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the investigator is 
responsible for retaining all study documents, including but not limited to the protocol, copies of 
CRFs, the IB, and regulatory agency registration documents (eg, Form FDA 1572, ICFs, and 
IRB correspondence).  In addition, the sponsor will send a list of treatment codes by study 
subject to the investigator after the clinical database for this study has been locked.  The site 
should plan to retain study documents, as directed by the sponsor, for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.
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It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s SOPs 
to evaluate compliance with the principles of ICH GCP and all applicable local regulations.  If a 
government regulatory authority requests an inspection during the study or after its completion, 
the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs 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, or upon 
notification of the sponsor, and as appropriate during the study, the investigator (or a designated 
pharmacist) will return all used and unused drug containers, drug labels, and a copy of the 
completed drug disposition form to the sponsor’s CRA or, when approval is given by the 
sponsor, will destroy supplies and containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission pursuant to 
the terms and conditions set forth in the executed Clinical Trial Agreement between the 
sponsor/CRO and the institution/investigator.  The review is aimed at protecting the sponsor's 
proprietary information existing either at the date of the commencement of the study or 
generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
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11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the investigator, the investigator’s staff, and the IRB 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 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 and provide the sponsor and the IRB with a 
detailed written explanation of the termination or suspension.  Study records must be retained as 
noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance with 
all applicable laws and regulations.
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12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
Note: Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2082-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Crossover, Single-
Dose Study with An Open-Label Treatment Period Evaluating 
Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy 
Investigational Product
Name:
E2082
IND Number:
134556
SIGNATURES
Authors:
 
 NBG
Eisai, Inc.
Date
 NBG
Eisai, Inc.
Date
 
NBG
Eisai, Inc.
Date
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PPD
PPD
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2082-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Crossover, Single-
Dose Study with An Open-Label Treatment Period Evaluating 
Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy
Investigational Product
Name:
E2082
IND Number:
134556
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good Clinical 
Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2082-A001-201
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Crossover, Single-Dose 
Study with An Open-Label Treatment Period Evaluating 
Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy
Sponsor:
Eisai Inc.
100 Tice Boulevard, Woodcliff Lake, New Jersey 07677, US
Investigational 
Product Name:
E2082
Indication:
Not applicable
Phase:
2
Approval Date:
V1.0
21 Aug 2018 (original protocol)
IND Number:
134556
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E2082
Name of Active Ingredient:  2-Fluoro-6-[3-fluoro-8-oxo-7-(pyridin-3-yl)-7,8-dihydro-6H-
pyrano[3,2-b:5,4-b′]dipyridin-9-yl]benzonitrile
Study Protocol Title
A Multicenter, Double-Blind, Randomized, Crossover, Single-Dose Study with An Open-Label 
Treatment Period Evaluating Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy
Principal Investigator
Gregory Krauss, MD
Sites
Approximately 6 sites in the US
Study Period and Phase of Development
The total study duration from first subject enrolled to last subject’s last visit/last assessment will be 
approximately 8 to 9 months.
Phase 2
Objectives
Primary Objective

To assess pharmacodynamic (PD) activity of E2082 as measured by suppression of epileptic 
photoparoxysmal response (PPR) in the subject’s most sensitive eye condition in the 
photosensitivity model as a proof of principle of efficacy in subjects with photosensitive
epilepsy, compared to placebo
Secondary Objectives

To assess the PD activity of E2082 as measured by suppression of PPR in each of the 3 eye
conditions (eye closure, eyes closed, and eyes open), compared to placebo

To assess PD activity of E2082 as measured by onset, maximum change, and duration of 
photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and eyes 
open)

To assess proportion of subjects with complete suppression, partial suppression, and no 
response of standardized photosensitivity response (SPR)

To assess other central nervous system (CNS)-related effects of E2082 based on Bond-Lader 
Visual Analogue Scale (BL-VAS) 

To assess the safety and tolerability of E2082 following single oral dose administration

To assess the pharmacokinetics (PK) of E2082 following single oral dose administration
Exploratory Objective

To explore relationships between PK and PD 
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Study Design
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period, crossover study 
with an Open-Label Treatment Period, in adult subjects with photosensitive epilepsy.  This study will 
use the photosensitivity proof of principle model to determine the potential of E2082 to reduce the 
photosensitive range in adult subjects.  
This study will have 2 phases: Pretreatment Phase and Treatment Phase.  The Pretreatment Phase 
will consist of a Screening Period (up to 3 weeks from Visit 1), during which each subject’s study 
eligibility will be determined.  The Treatment Phase will consist of 3 blinded Treatment Periods for a 
randomized crossover design, followed by an Open-label Treatment Period.  During the Randomized 
Crossover Treatment Periods, there will be 3 Treatment Visits (Visit 2 [Treatment Period 1], Visit 3 
[Treatment Period 2], and Visit 4 [Treatment Period 3]) evaluating single-dose administrations of 
either placebo, E2082 2.5 mg, or E2082 25 mg in a blinded manner.  During the Open-label 
Treatment Period, there will be 1 treatment visit (Visit 5 [Treatment Period 4]) evaluating single-dose 
administration of E2082 40 mg.  Treatment visits (ie, Visit 2, Visit 3, Visit 4, and Visit 5) will each 
be separated by a 2-week (±3 days) washout interval for a total of approximately 6 weeks, which will 
then be followed by a Follow-up Period of 2 weeks (±3 days) after the last day of study product 
administration.  The anticipated study participation duration for each subject is approximately 
11 weeks.  All visits will be conducted on an outpatient basis.    
Within 21 days of the Screening Visit (Visit 1), subjects will be asked to return to the study site for 
Visit 2 (Day 1), when the final determination of eligibility will be made.
Subjects meeting all eligibility criteria will enter into the Treatment Phase and be randomly assigned 
to 1 of 6 treatment sequences to receive, in a blinded fashion, a single oral dose of placebo control, 
E2082 2.5 mg, or E2082 25 mg during the Randomized Crossover Treatment Periods.  This is 
followed by the Open-Label Treatment Period, during which each subject will receive a single dose 
of E2082 40 mg.  
On the day of each Treatment Visit (ie, Visit 2, Visit 3, Visit 4, and Visit 5), subjects will arrive at the 
clinic in the morning following an overnight fast of at least 8 hours.  Baseline intermittent photic 
stimulation (IPS)-electroencephalogram (EEG) assessments will be conducted 30 minutes to 2 hours 
before study product administration on each treatment day, including determination of the lower and 
upper limit of photosensitivity to IPS threshold frequency for each eye condition.
After completion of the Open-label Treatment Period, subjects will enter the Follow-up Period, 
during which they will be required to complete a Follow-up visit (Visit 6) at 2 weeks ±3 days 
following the last day of study product administration.  
Subjects who discontinue early from the study for any reason after having been exposed to study drug
will undergo an Early Discontinuation Visit within 2 weeks ±3 days of their last dose of study drug.
Early Discontinuation visit is not required for subjects who discontinued from the study before 
receiving the first study drug administration.  Upon consultation with the sponsor, subjects who 
discontinue from the study early may be replaced. 
The end of study is defined as the last subject completing the Follow-up Visit. 
IPS-EEG specific Subject Withdrawal/Stopping Criteria
At the discretion of the investigator, a subject may be withheld from further IPS-EEG testing during a 
study visit or withdrawn from the study if any of the following 3 circumstances occur:
1.
If a subject experiences:
a) generalized tonic-clonic seizure (GTCS) on any study day, and the subject has not had a 
GTCS in the 6 months before enrollment, that subject will be discontinued from the study.
OR
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b) GTCS during photic stimulation, that subject will be discontinued from the study.
2.
If, in the opinion of the investigator, a subject has evidence of proconvulsive activity on the 
EEG (eg, increase in spike-wave activity) following administration of the study drug, that 
subject will be discontinued from the study.
Proconvulsive activity is defined as:
a) generalized spike and wave discharges greater than 5 seconds defined by absence seizures 
or isolated myoclonic jerks do not require stoppage of study drug or subject withdrawal; or 
b) change in the usual pattern of PPR that is typical for the subject such as: decrease in time 
to occurrence of PPRs at the same flash frequency; increase in the duration of the PPR; or, 
clear increase of PPR-related negative sensations (clinical signs) or appearance or increase of 
spontaneous epileptiform activity.
3.
If a subject has widening of the photosensitivity range (becomes more sensitive) by more 
than 3 points on 2 consecutive occasions after dosing compared to Screening, the IPS will be 
terminated and the subject will not be permitted to participate in further IPS-EEG testing on 
the same day.
Number of Subjects
Approximately 9 subjects will be randomized to achieve 6 evaluable subjects.  
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study: 
1.
Male or female 18 to 60 years of age at the time of informed consent. 
2.
A diagnosis and/or history of a PPR on EEG (ie, photosensitivity epilepsy).
3.
If currently being treated with antiepileptic drugs (AEDs), up to a maximum of 
3 concomitant AEDs is allowed provided that doses must have remained stable for at least
4 weeks before Screening.  In the case where a new AED regimen has been initiated for a 
subject, the dose must be stable for at least 8 weeks before Screening.  (See Exclusion 
Criteria #17-22 for AEDs that are exclusionary.)
4.
Reproducible IPS-induced PPR on EEG of at least 3 points on the SPR scale in at least 1 eye 
condition (eye closure, eyes closed, eyes open) on at least 3 of the EEGs performed at 
Screening.
5.
Body mass index (BMI) between 18 to 35 kg/m2 (inclusive) and a total body weight greater 
than or equal to 45 kg at Screening.
6.
Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour period 
before Screening and during the 24-hour period before each treatment day.
7.
Willing and able to comply with all aspects of the protocol.
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study: 
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]).  
A separate baseline assessment is required if a negative Screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug. 
2.
Females of childbearing potential who:
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a.
Within 30 days before study entry, have had unprotected sexual intercourse and did not 
use a highly effective method of contraception (eg, total abstinence, an intrauterine 
device, a double-barrier method [such as condom plus diaphragm with spermicide], a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) 
b.
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.  If 
currently abstinent, the subject must agree to use a double barrier method as described 
above if she becomes sexually active during the study period or for 28 days after study 
drug discontinuation.  Females who are using hormonal contraceptives must be on a 
stable dose of the same hormonal contraceptive product for at least 4 weeks before 
dosing and must continue to use the same contraceptive during the study and for 28 days 
after study drug discontinuation.
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). 
3.
Male subjects who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days after 
study drug discontinuation).  No sperm donation is allowed during the study period and for 
28 days after study drug discontinuation.
4.
History of nonepileptic seizures (eg, metabolic, structural, or pseudoseizures) while on any 
antiepileptic medication(s).
5.
History of status epilepticus while on any antiepileptic medication(s) within 2 years before
Screening.
6.
Ongoing or history of GTCS within 6 months before Screening.
7.
Subject who had developed a clinical seizure during previous PPR assessment, or who 
experiences a clinical seizure during the Screening IPS procedure. 
8.
Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening.
9.
Inability to follow restriction on watching television, or use of any device(s) with an 
animated screen (eg, computer, video games, tablets, or smart phone) from the time of arrival 
at the study center until study procedures are completed for that day.
10. Currently active clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) with the exception of epilepsy, which in the opinion of the investigator could affect 
the subject’s safety or interfere with the study assessments.
11. A history of prolonged QT syndrome or risk factors for torsade de pointes (eg, heart failure,
hypokalemia, family history of long QT Syndrome), or the use of concomitant medications 
that prolonged the QT/corrected QT using Fridericia formula (QTcF) interval; or prolonged 
QT/QTcF interval (QTcF >450 msec) demonstrated on ECG at Screening or Baseline (based 
on average of triplicate ECGs).
12. Presence of active CNS infection, demyelinating disease, degenerative neurological disease 
or any CNS disease deemed to be progressive during the course of the study that may 
confound the interpretation of the study results.
13. Current/ongoing clinically significant active liver disease, porphyria, or with a family history 
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of severe hepatic dysfunction indicated by abnormal liver function tests (LFTs) greater than 
3 times the upper limit of normal (ULN) (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
14. Any history of gastrointestinal conditions or surgery that may affect PK profiles of E2082 
(eg, hepatectomy, nephrectomy, and digestive organ resection).
15. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
16. Use of perampanel within 6 weeks before Screening.
17. Use of felbamate for less than 2 years or where the dose has not been stable for at least 
8 weeks before Visit 1.  Subject must not have a history of white blood cell (WBC) count 
below equal or less than 2500/μL (2.50 1E+09/L), platelet count below 100,000, LFTs above 
3 times the ULN, or other indication of hepatic or bone marrow dysfunction while receiving 
felbamate.  If subjects received felbamate in the past, it must have been discontinued 8 weeks 
before Visit 1 to be eligible for study participation.
18. Use of vigabatrin within 5 months before Screening.  Subjects who have discontinued 
vigabatrin for at least 5 months before Screening must have documentation showing no 
evidence of vigabatrin-associated clinically significant abnormality in a visual perimetry test 
in order to be eligible for the study.
19. Concomitant use of cannabinoids.
20. Use of benzodiazepines for epilepsy for which the dose has not been stable for greater than 
4 weeks before Screening.  Benzodiazepine use as rescue medication for seizure control is 
allowed; however, intermittent use of benzodiazepines for any other indication (eg, 
anxiety/sleep disorders) is prohibited.
21. Use of concomitant AEDs or other drugs that are known to be potent cytochrome P450 
(CYP)3A enzyme inducers (such as carbamazepine, oxcarbazepine, eslicarbazepine, 
phenytoin, phenobarbital, and primidone) or CYP3A inhibitors within 4 weeks or 
5 half-lives, whichever is longer.
22. Vagus nerve stimulation (VNS) implanted within 5 months or changes in parameter within 
4 weeks before Screening.
23. On a ketogenic diet for which the diet is not a stable regimen for at least 4 weeks before
Screening. 
24. History of drug or alcohol dependency or abuse within the 12 months before Screening, or 
those subjects who have a positive drug test or alcohol test at Screening.
25. History of or ongoing multiple drug allergies or severe drug reaction to AED(s), including 
dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
26. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption.
27. Any suicidal ideation with intent with or without a plan within 6 months before Screening or 
during Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the Columbia-Suicide Severity Rating Scale [C-SSRS]).
28. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
29. Any psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
30. Currently enrolled in another clinical study or used any investigational drug or device within 
28 days or 5 half-lives, whichever is longer, preceding informed consent, except the 
investigational study for the evaluation of commercial IPS machine.
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Study Treatments
Test Drug:  E2082
E2082 will be supplied as 0.5-mg and 5-mg tablets for oral administration.
Comparator Drug:  E2082-matched placebo
Randomized Crossover Treatment Periods
Each subject will receive a single oral dose of E2082 2.5 mg, E2082 25 mg, and matched-placebo in 
a cross-over sequence according to his/her randomization code.
Treatment A (Placebo): 5 x E2082-matched placebo tablets
Treatment B (E2082 2.5 mg): 5 x E2082 0.5-mg tablet
Treatment C (E2082 25 mg): 5 x E2082 5-mg tablets
Open-label Treatment Period
Each subject will receive a single oral dose of E2082 40 mg (8 x E2082 5-mg tablets). 
All Study Drug will be administered with approximately 240 mL (8 fluid ounces) of water.  
Additional water may be provided in increments of 50 mL (up to a maximum of 100 mL), if required.  
A light snack can be provided approximately 30 minutes predose (after clinical laboratory blood 
collection) and approximately 2 hours postdose.  Water will be permitted ad libitum except from the 
time of dosing until 1 hour postdose.
Duration of Treatment
Single dose
(ie, the Treatment Phase will consist of 4 Treatment Periods each with a single dose administration)
Concomitant Drug/Therapy
Up to 3 concomitant AEDs are allowed during the course of the study, provided that the dosage of 
concomitant AED(s) has remained stable for at least 4 weeks before Screening.  In the case where a 
new AED regimen has been initiated for a subject, the dose must be stable for at least 8 weeks before 
screening.  During the study, changes to concomitant AEDs (including dosage) are not permitted
unless medically necessary and upon consultation with the Sponsor. 
Use of the following AEDs during the course of the study is not allowed:

Perampanel

Vigabatrin

Cannabinoids

Benzodiazepines for non-epilepsy indications (eg, anxiety/sleep disorders)

Enzyme-inducing antiepileptic drugs (EIAEDs, eg, carbamazepine, oxcarbazepine, 
eslicarbazepine, phenytoin, phenobarbital, and primidone)
Concomitant use of medications known to be potent CYP3A inducers/inhibitors including, but not 
limited to, rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, modafinil, pioglitazone, and 
rifabutin will not be permitted and are to be discontinued within 28 days before Visit 1.  
Vagus nerve stimulation (VNS) is not considered as one of the 3 allowed concomitant AEDs.  
However, VNS implantation during the course of the study is prohibited.  For subjects who have 
VNS implanted before participation in this study, changes to VNS parameters are not allowed unless 
medically necessary.  
Changes to ketogenic diet (eg, median chain triglyceride level) are not allowed during the study.
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Assessments
Efficacy Assessments
Not applicable.
Pharmacokinetic Assessments
On each treatment day, blood samples for the determination of plasma concentrations of E2082 will 
be collected from each subject predose (within 2 hours), and at 1 (±10 min), 2 (±10 min),
4 (±15 min), 6 (±15 min), and 8 (±15 min) hours postdose.  
Pharmacodynamic Assessments
IPS-EEG
PD activity of E2082 will be assessed by suppression of PPR following IPS using the Grass PS 33 
photic stimulator with an unpatterned glass lamp and an intensity of 100 cd/m2/flash.  Each IPS-EEG
assessment will be conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open; each 
for a minimum of 2.5 minutes) at ascending and then descending photo stimulation frequencies. The 
lower and upper limit of photosensitivity to IPS threshold frequency will be determined for each eye 
condition.  PPR is expected to be within the range of 2 Hz to 60 Hz, depending on the subject’s 
sensitivity to IPS.  Qualified medical personnel for the management of acute seizures will be present 
during the day of IPS-EEG procedure throughout the study.
During the Screening Visit (Visit 1), IPS-EEG assessment will be performed at 5 time points, over a 
4-hour time period (0, 1, 2, 3, and 4 hours; within ±15 minutes of the scheduled time point).  Subjects 
with a reproducible PPR on EEG of at least 3 points on the SPR scale in at least 1 eye condition on at 
least 3 of the EEGs performed at Screening will be eligible for the study.  However, the final 
determination of study eligibility will include predose assessments when the subject returns to study 
site for Visit 2.  On each treatment day (ie, Visit 2, Visit 3, Visit 4, and Visit 5), IPS-EEG
assessments will be conducted predose (approximately 30 minutes to 2 hours), and at 1, 2, 4, 6, and 
8 hours (within ±15 minutes of each scheduled time point) postdose to characterize the time course of 
E2082 PD activity including the onset, maximum change from baseline, and duration of the reduction 
in PPR response. The predose assessment serves as the baseline on each treatment day.
Other PD assessments
The BL-VAS (Bond A, 1974) for CNS-related effects of E2082 (such as somnolence, sedation, 
dizziness, and body sway) for potential sedative effects of E2082 will be evaluated for each subject 
on each treatment day predose (within 2 hours) and at 1, 2, 4, 6, and 8 hour postdose. 
All PD assessments will be performed within ±15 minutes of the scheduled time point.
Pharmacogenomic and Other Biomarker Assessments
Not applicable.
Safety Assessments
Safety will be assessed by monitoring and recording all adverse events (AEs).  Additionally, safety 
assessments will consist of physical and neurological examinations, vital signs, 12-lead ECG, clinical 
laboratory test (hematology, blood chemistry, and urinalysis), and (for women of childbearing 
potential only) pregnancy test.  A full neurological examination will be conducted during the 
Screening Visit.  An abbreviated neurological examination will be performed on each treatment day 
(predose and at 4 hours postdose), and during Follow-up/Early Discontinuation visit.
An assessment of suicidality using the C-SSRS will be performed at Screening, during each 
Treatment visit (predose), and at the Follow-up/Early Discontinuation Visit.
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Other Assessments
Not applicable.
Bioanalytical Methods
Plasma concentrations of E2082 will be measured using a validated liquid chromatography coupled 
with tandem mass spectrometry (LC-MS/MS) method.
Statistical Methods
Descriptive statistics will be presented including mean and standard deviation of photosensitivity 
range for each subject at Screening and at each time point, for each Treatment visit day by treatment 
group. Graphical displays of the data for each subject will allow exploration of intersubject and 
intrasubject variability.
Details of statistical methods and analyses will be specified in the statistical analysis plan (SAP).
Study Endpoints
Primary Endpoint

Mean change from baseline in the PPR range in each subject’s most sensitive eye condition 
Secondary Endpoints

Mean change from baseline in the PPR range in each of the 3 eye conditions (eye closure, 
eyes closed, and eyes open) 

Onset, maximum change, and duration of response in each of the 3 eye conditions (eye 
closure, eyes closed, and eyes open) 

Frequency and percentage of subjects with complete suppression, partial response, and no 
response of SPR

Changes from baseline in BL-VAS 

Incidence of treatment-emergent adverse events (TEAEs)

Clinically significant changes from baseline in vital signs, serum chemistries, complete blood 
counts, or liver function tests after single doses of E2082, compared to placebo

PK parameters of E2082 (Cmax, time to reach Cmax following drug administration 
[tmax], area under concentration-time curve from time 0 to 8 hours postdose [AUC(0-8h)])
Exploratory Endpoints

Relationship between plasma exposure of E2082 (PK) and PD response (eg, onset, maximum 
change, and duration of photosensitivity response, BL-VAS)
Analysis Sets
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and have at 
least 1 postdose safety assessment.
The PK Analysis Set is the group of randomized subjects who receive at least 1 dose of study drug 
and have sufficient PK data to derive at least 1 PK parameter.
The PD Analysis Set is the group of randomized subjects who receive at least 1 dose of study drug 
and have sufficient PD data to derive at least 1 PD parameter.
Efficacy Analyses
Not Applicable.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacokinetic Analyses
The Safety Analysis Set will be used for listings of individual E2082 plasma concentrations.  The PK 
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analysis set will be used for summaries of plasma E2082 concentrations and for analyses, summaries, 
and listings of PK parameters.  Plasma concentrations will be tabulated by nominal sampling time 
and summarized by treatment dose using summary statistics. 
The following PK parameters will be derived by noncompartmental analysis using plasma 
concentrations of E2082.  These parameters will include, but are not limited to:
Cmax
maximum observed concentration
AUC(0-8h)
area under concentration x time curve from time 0 to 8 hours postdose
tmax
time to reach Cmax following drug administration
The PK of E2082 will be analyzed based on available data from this study.  The PK and PD Analysis 
Sets will be used to evaluate the relationship of PK of E2082 and change in SPR response.  PK-PD 
analyses may include the examination of the relationship of PK of E2082 and SPR (eg, time of onset, 
maximum change, and duration of response; and BL-VAS data) using model-based approaches, data 
permitting.  Details of the PK/PD analyses will be described in a separately prepared analysis plan 
and its report.
Pharmacodynamic Analyses
The PD analysis will be performed on the PD Analysis Set.  
No multiplicity adjustments will be made.  The 5 PPR measured postdose on a study day will be 
averaged and used for the primary endpoint.  The predose PPR data from the respective treatment 
period will be used as the baseline data.  
The primary and secondary endpoints of mean change from baseline of the average PPR in the most 
sensitive and 3 eye conditions will be analyzed using a mixed effects model for the crossover part of 
the study and summarized for each E2082 dose level and placebo regardless of crossover design.  The 
mixed effects model for the crossover part of the study will include treatment (E2082 2.5 mg, 25 mg, 
and placebo), period, and sequence as fixed effects, baseline (predose) measurement as a covariate, 
and subject nested within sequence as a random effect. Where data are normally distributed, least 
squares (LS) means, difference in LS means of each E2082 dose (2.5 mg or 25 mg) compared to 
placebo, and 90% CIs will be presented with no adjustments for multiplicity. 
Additional analysis by graphical exploration for the evaluation of onset, maximum change, and 
duration of photosensitivity response at each dose level will be performed for all 3 eye conditions for 
each treatment.  Similarly, frequency and percentage of subjects with complete suppression, partial 
suppression, and no response at each dose level of E2082 will be summarized descriptively and 
graphically for each treatment.
Sensitivity analyses may be conducted for photosensitivity response, for example, in subjects who 
completed all 3 Treatment Periods 1 through 3 versus those who are included in the PD Analysis Set.
Other exploratory analyses may be conducted as data permit.
All other PD data (ie, BL-VAS) will be listed and summarized by treatment, as appropriate, using 
standard summary statistics.  Descriptive summary statistics (eg, mean, SD, median, minimum, and 
maximum for continuous variables, and the number and percent for categorical variables) of each 
endpoint and the changes from baseline will be tabulated.
Pharmacogenomic and Other Biomarker Analyses
Not applicable.
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety data that will be evaluated 
include AEs, clinical laboratory results, vital signs, ECGs, and neurological/physical examinations.  
TEAEs will be summarized by presenting for each treatment group, the incidence of AEs.  An 
assessment of suicidal ideation and behavior using the C-SSRS will be performed throughout the 
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study.  
Descriptive summary statistics (eg, mean, SD, median, minimum, and maximum for continuous 
variables, and the number and percent for categorical variables) of the laboratory, vital signs, ECG 
parameters, and changes from baseline will be evaluated by treatment group.  The proportion of 
subjects with any treatment-emergent report of suicidal ideation and behavior and intensity of these 
behaviors will be summarized.
Interim Analyses
No formal interim analysis is planned.
Sample Size Rationale
Approximately 9 subjects with photosensitive epilepsy and a stable PPR will be needed to be 
randomized in the study in order to obtain 6 evaluable subjects.  Based on a similar study in subjects 
with photosensitive epilepsy (NCT02564029), an estimated standard deviation of the treatment group 
difference of the SPR in the subject’s most sensitive eye condition is 3.62.  The width of a 90% CI of 
the mean group difference based on this standard deviation assumption and 6 subjects is 2.431.  
Therefore, a sample size of 6 would be sufficient to detect a mean group difference of 3 or larger with 
90% confidence. 
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................12
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................19
5.1
Institutional Review Boards/Independent Ethics Committees ..............................19
5.2
Ethical Conduct of the Study.................................................................................19
5.3
Subject Information and Informed Consent...........................................................20
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................20
7
INTRODUCTION ...........................................................................................................21
7.1
Indication ...............................................................................................................21
7.1.1
Mechanism of Action – E2082 ....................................................................21
7.1.2
Clinical Experience With E2082 .................................................................21
7.1.2.1
Pharmacokinetics.................................................................................21
7.1.2.2
Pharmacodynamics ..............................................................................22
7.1.2.3
Safety and Tolerability.........................................................................22
7.2
Study Rationale......................................................................................................22
7.2.1
Photosensitivity Proof-of-Concept Model ...................................................22
8
STUDY OBJECTIVES....................................................................................................23
8.1
Primary Objective..................................................................................................23
8.2
Secondary Objectives.............................................................................................24
8.3
Exploratory Objective............................................................................................24
9
INVESTIGATIONAL PLAN..........................................................................................24
9.1
Overall Study Design and Plan..............................................................................24
9.1.1
Pretreatment Phase.......................................................................................25
9.1.1.1
Screening Period..................................................................................25
9.1.2
Treatment Phase...........................................................................................26
9.1.2.1
Randomized Crossover Treatment Periods (Treatment Periods 1 to 3)26
9.1.2.2
Open-label Treatment Period...............................................................27
9.1.3
Follow-Up Period.........................................................................................28
9.2
Discussion of Study Design, Including Choice of Control Groups.......................28
9.3
Selection of Study Population................................................................................28
9.3.1
Inclusion Criteria .........................................................................................28
9.3.2
Exclusion Criteria ........................................................................................29
9.3.3
Removal of Subjects From Therapy or Assessment....................................31
9.3.3.1
IPS-EEG-Specific Subject Withdrawal/Stopping Criteria...................31
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9.4
Treatments..............................................................................................................32
9.4.1
Treatments Administered.............................................................................32
9.4.1.1
Randomized Crossover Treatment Periods..........................................32
9.4.1.2
Open-label Treatment Period...............................................................32
9.4.2
Identity of Investigational Products.............................................................32
9.4.2.1
Chemical Name, Structural Formula of E2082....................................32
9.4.2.2
Comparator Drug .................................................................................33
9.4.2.3
Labeling for Study Drug......................................................................33
9.4.2.4
Storage Conditions...............................................................................33
9.4.3
Method of Assigning Subjects to Treatment Groups...................................33
9.4.3.1
Randomized Crossover Treatment Periods..........................................33
9.4.3.2
Open-Label Treatment Period..............................................................33
9.4.4
Selection of Doses in the Study...................................................................33
9.4.5
Selection and Timing of Dose for Each Subject..........................................34
9.4.6
Blinding........................................................................................................34
9.4.7
Prior and Concomitant Therapy...................................................................35
9.4.7.1
Prohibited Concomitant Therapies and Drugs.....................................36
9.4.7.2
Restrictions During the Study Period ..................................................36
9.4.8
Treatment Compliance.................................................................................36
9.4.9
Drug Supplies and Accountability...............................................................37
9.5
Study Assessments.................................................................................................38
9.5.1
Assessments.................................................................................................38
9.5.1.1
Demography.........................................................................................38
9.5.1.2
Screening Assessments ........................................................................38
9.5.1.2.1
Medical History and Epilepsy Medical History.............................38
9.5.1.2.2
Height Measurement and BMI computation..................................38
9.5.1.2.3
Urine Drug Test .............................................................................38
9.5.1.2.4
Serology.........................................................................................38
9.5.1.3
Efficacy Assessments...........................................................................39
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments.......................................................................39
9.5.1.4.1
Pharmacokinetic Assessments .......................................................39
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................39
9.5.1.5
Safety Assessments..............................................................................41
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...41
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................43
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9.5.1.5.3
Laboratory Measurements .............................................................44
9.5.1.5.4
Vital Signs and Weight Measurements..........................................45
9.5.1.5.5
Physical Examinations...................................................................46
9.5.1.5.6
Neurological Examinations............................................................46
9.5.1.5.7
Electrocardiograms ........................................................................46
9.5.1.5.8
Other Safety Assessments..............................................................46
9.5.2
Schedule of Procedures/Assessments ..........................................................47
9.5.2.1
Schedule of Procedures/Assessments ..................................................47
9.5.2.2
Description of Procedures/Assessments Schedule...............................52
9.5.3
Appropriateness of Measurements...............................................................53
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
With Special Situations................................................................................53
9.5.4.1
Reporting of Serious Adverse Events..................................................53
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................54
9.5.4.3
Reporting of Events Associated With Special Situations....................54
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................54
9.5.4.4
Expedited Reporting ............................................................................55
9.5.4.5
Breaking the Blind...............................................................................55
9.5.4.6
Regulatory Reporting of Adverse Events ............................................55
9.5.5
Completion/Discontinuation of Subjects.....................................................55
9.5.6
Abuse or Diversion of Study Drug ..............................................................56
9.5.7
Confirmation of Medical Care by Another Physician .................................56
9.6
Data Quality Assurance .........................................................................................56
9.6.1
Data Collection ............................................................................................56
9.6.2
Clinical Data Management ..........................................................................57
9.7
Statistical Methods.................................................................................................57
9.7.1
Statistical and Analytical Plans....................................................................57
9.7.1.1
Study Endpoints...................................................................................57
9.7.1.1.1
Primary Endpoint...........................................................................57
9.7.1.1.2
Secondary Endpoints .....................................................................58
9.7.1.1.3
Exploratory Endpoints ...................................................................58
9.7.1.2
Definitions of Analysis Sets.................................................................58
9.7.1.3
Subject Disposition..............................................................................58
9.7.1.4
Demographic and Other Baseline Characteristics ...............................58
9.7.1.5
Prior and Concomitant Therapy...........................................................59
9.7.1.6
Efficacy Analyses ................................................................................59
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9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses.............................................................................59
9.7.1.7.1
Pharmacokinetic Analyses.............................................................59
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................60
9.7.1.8
Safety Analyses....................................................................................60
9.7.1.8.1
Extent of Exposure.........................................................................61
9.7.1.8.2
Adverse Events ..............................................................................61
9.7.1.8.3
Laboratory Values..........................................................................61
9.7.1.8.4
Vital Signs......................................................................................62
9.7.1.8.5
Electrocardiograms ........................................................................62
9.7.1.8.6
Other Safety Analyses....................................................................62
9.7.2
Determination of Sample Size .....................................................................63
9.7.3
Interim Analysis...........................................................................................63
9.7.4
Other Statistical/Analytical Issues ...............................................................63
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................63
10
REFERENCE LIST .........................................................................................................64
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......65
11.1
Changes to the Protocol .........................................................................................65
11.2
Adherence to the Protocol......................................................................................65
11.3
Monitoring Procedures...........................................................................................65
11.4
Recording of Data..................................................................................................66
11.5
Identification of Source Data.................................................................................66
11.6
Retention of Records..............................................................................................66
11.7
Auditing Procedures and Inspection......................................................................67
11.8
Handling of Study Drug.........................................................................................67
11.9
Publication of Results ............................................................................................67
11.10 Disclosure and Confidentiality ..............................................................................68
11.11 Discontinuation of Study .......................................................................................68
11.12 Subject Insurance and Indemnity...........................................................................68
12
APPENDICES .................................................................................................................69
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LIST OF IN-TEXT TABLES
Table 1
Treatment Sequences .................................................................................27
Table 2
Treatment Description ...............................................................................32
Table 3
Clinical Laboratory Tests...........................................................................45
Table 4
Schedule of Procedures and Assessments in E2082-A001-201 ................48
Table 5
Time Windows for Study Assessments on Treatment Days......................52
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E2082-A001-201.................................................25
Figure 2
Individual plasma concentration-time profiles of E2082 (2.5 mg) 
following single oral dose administration in Study E2082-A001-001 ......34
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................69
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase 
AMPA
α amino 3 hydroxy-5-methyl-4-isoxazolepropionic acid
AST
aspartate aminotransferase
AUC(0-8h)
area under concentration-time curve from time 0 to 8 hours postdose
β-hCG
beta-human chorionic gonadotropin
BL
Bond-Lader
BMI
body mass index
BP
blood pressure
CFR
Code of Federal Regulations
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
EEG
electroencephalogram 
GTCS
generalized tonic-clonic seizure
hCG
human chorionic gonadotropin
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IPS
intermittent photic stimulation
IRB
Institutional Review Board
LFT
liver function test
LNH
low/normal/high
LS
least squares
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetics
POC
proof-of-concept
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Abbreviation
Term
PPR
photoparoxysmal response
PT
preferred term
QTc
corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SAD
single ascending dose
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure
SPR
standardized photosensitivity response
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory value
tmax
time at which the highest drug concentration occurs (time to reach Cmax
following drug administration)
ULN
upper limit of normal
WBC
white blood cell
VAS
Visual Analogue Scale
VNS
vagus nerve stimulation
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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) constituted and functioning in accordance 
with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E6 GCP, Section 3, and any local regulations (Code of Federal Regulations
[CFR], Title 21 CFR Parts 50 and 56).  Any protocol amendment or revision to the ICF will be 
resubmitted to the IRB for review and approval, except for changes involving only logistical or 
administrative aspects of the study (eg, change in clinical research associates [CRAs], change of 
telephone number[s]).  Documentation of IRB 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 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 decides to suspend or 
terminate the study, the investigator will immediately send the notice of study suspension or 
termination by the IRB to the sponsor.
Study progress is to be reported to the IRB annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to the 
IRB, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator or the sponsor will submit, depending on local regulations, periodic reports and 
inform the IRB of any reportable adverse events (AEs) per ICH guidelines and local IRB 
standards of practice.  Upon completion of the study, the investigator will provide the IRB with a 
brief report of the outcome of the study, if required.
The end of study is defined as the last subject completing the Follow-up Visit.  The sponsor 
should also provide the IRB with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB and Competent Authority within 15 calendar days, and a detailed written explanation of the 
reasons for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOP) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required by 
the following:

Principles of the World Medical Association Declaration of Helsinki 

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Pharmaceuticals for Human Use
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
Title 21 of the United States CFR (US 21 CFR) regarding clinical studies, including Part 
50 and Part 56 concerning informed subject consent and IRB regulations and applicable 
sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to each 
subject 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 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, 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, and after 
the subject 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 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-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations.  Each subject must sign an approved ICF before 
study participation.  The form must be signed and dated by the appropriate parties.  The original, 
signed ICF for each subject will be verified by the sponsor and kept on file according to local 
procedures at the site.
The subject should be informed in a timely manner if new information becomes available that 
may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 6 investigational sites in the US. 
The name and telephone and fax numbers of the medical monitor and other contact personnel at 
the sponsor and of the contract research organizations (CROs) will be provided to each site.
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7
INTRODUCTION
7.1
Indication 
The overall development plan of E2082 will be based on the potential role of 
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an 
antiepileptogenesis agent in a number of neurological disorders associated with 
glutamate-mediated neuronal overexcitation. 
7.1.1
Mechanism of Action – E2082
E2082 is a selective noncompetitive AMPA type glutamate receptor antagonist.  AMPA 
receptors, located on post-synaptic neurons, are responsible for fast glutamate-mediated 
excitation at synapses. Glutamate is the primary excitatory neurotransmitter in the central 
nervous system (CNS) and is implicated in a number of neurological disorders caused by 
neuronal overexcitation.
E2082 demonstrated potent in vitro inhibitory effect (AMPA receptor functional assay) and in 
vivo antiseizure effect in various animal models of epilepsy (audiogenic seizure, maximal 
electroshock [MES] seizure, and pharmacoresistant 6 Hz psychomotor seizure mouse models).  
Preclinical evidence suggests that E2082 showed a broad window between therapeutic effect and 
AMPA receptor antagonism-related CNS side effects (eg, sedation, ataxia) with a protective 
index (TD50 [rotarod test]/antiseizure ED50) of 3.2- to 20-fold.  Refer to the Investigator’s 
Brochure (IB) for detailed information. 
7.1.2
Clinical Experience With E2082
E2082 is currently under Phase 1 clinical development that comprises the first-in-human, 
double-blind, placebo-controlled, single- and multiple-ascending dose (SAD-MAD) study 
(E2082-J081-001; Study 001) in healthy male subjects in Japan.  The SAD portion of Study 001 
(Part A) evaluated pharmacokinetics (PK), safety and tolerability of E2082 in healthy male adult 
subjects at doses of 0.2, 0.5, 1, 2.5, 5, 10, 15, 25, and 40 mg under fasted condition, as well as at
5 mg under fed condition, and in elderly subjects at 10 mg.  E2082 was administered as oral 
tablets (0.5 or 5-mg dose strengths) in all dose cohorts, except for the 0.2-mg cohort (as oral 
solution).  The SAD portion of Study 001 is completed, in which a total of 60 subjects received a 
single dose of E2082 (0.2 through 40 mg) and 20 subjects received placebo.  The MAD portion 
of Study 001 is ongoing. 
7.1.2.1
Pharmacokinetics
Preliminary PK data suggest that E2082 was rapidly absorbed with median time to maximum 
plasma concentration (tmax) observed approximately 1 to 4 hours following oral administration of 
E2082 tablets over the dose range of 0.5 to 40 mg.  The average half life of E2082 was 
approximately 30 hours.  The mean plasma exposure (peak plasma concentration [Cmax] and area 
under the plasma concentration-time curve from zero time extrapolated to infinite time
[AUC(0-inf)]) increased approximately dose proportionally with increasing dose across the dose 
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range of 0.5 to 40 mg.  Food intake did not appear to affect the rate or extent of E2082 
absorption. Refer to the IB for a full description of PK.
7.1.2.2
Pharmacodynamics
Saccadic eye movements was included in Study 001 for evaluation of potential CNS-related side 
effects of E2082 as an exploratory pharmacodynamic (PD) parameter.   Preliminary results 
suggest a dose/concentration-dependent reduction in peak saccadic velocity following single 
dose administration of E2082.  Refer to the IB for detailed information. 
7.1.2.3
Safety and Tolerability
Preliminary safety data from Study 001 showed that E2082 was well-tolerated following single 
oral dose administration in healthy subjects. There were no deaths, serious adverse events 
(SAEs), or adverse events leading to discontinuation, and no medically significant findings from 
laboratory tests, ECG, or vital signs.  A total of 16 subjects experienced treatment-emergent 
adverse events (TEAEs); 15/60 (25%) subjects receiving E2082 and 1/20 (5%) in the placebo 
group.  The most common TEAEs reported were dizziness (14/60 [23.3%] subjects) and 
somnolence (6/60 [10.0%] subjects), followed by nausea (2/60 [3.3%] subjects), decreased
appetite (2/60 [3.3%] subjects), back pain (1/60 [1.7%] subjects), and nasopharyngitis (1/20 
[5.0%] subjects).  All TEAEs were deemed related to E2082, except for back pain and 
nasopharyngitis.  All TEAEs reported were mild to moderate in severity, and all resolved without 
any medical interventions. 
Please refer to IB for a full summary of TEAEs, including safety and tolerability information. 
7.2
Study Rationale
7.2.1
Photosensitivity Proof-of-Concept Model
Patients with epilepsy often have intermittent seizures that occur at variable times. Consequently, 
studies evaluating new antiseizure medications require that large numbers of subjects be 
evaluated over several months of treatment to accurately assess treatment effects. In such 
circumstances, it is extremely useful to conduct a “proof-of-concept” (POC) study, which would 
screen potential antiseizure agents for possible efficacy before proceeding to lengthy and 
expensive studies that expose many subjects to a new compound. The photosensitivity POC 
study design has been used successfully to evaluate potential antiseizure effects of new agents in 
early stage development in small groups of subjects with photically-induced generalized 
epileptiform responses on electroencephalogram (EEG), called photoparoxysmal responses 
(PPRs).
Photosensitivity describes the ability to produce epileptiform activities in response to intermittent 
photic stimulation.  This EEG pattern is called PPR.  Some subjects who are photosensitive have 
photosensitive epilepsy, and may have clinical events in response to photic stimulation. This 
response is also characterized as “reflex epilepsy” in the small group of subjects with epilepsy
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who have seizures in response to photic stimulation in the absence of adequate treatment.  Many 
other subjects will have PPR demonstrated only as an EEG pattern.  Photosensitivity is typically 
a genetic trait with a Mendelian autosomal dominant pattern.  When associated with epilepsy, the 
epilepsy type will almost always be classified as generalized idiopathic epilepsy, and the clinical 
seizure semiology will be characterized by absence, generalized tonic-clonic, or myoclonic 
seizures.  Any of these 3 generalized seizure types can be precipitated by photic stimulation.
In the photosensitivity study design model, subjects who have PPR in response to flickering 
diffuse white light are included.  A photosensitivity range for each subject can be determined by 
eliciting the upper and lower limits of sensitivity to intermittent photic stimulation (IPS) in order 
not to evoke seizures for that particular subject.  Subjects are usually sensitive to IPS within 
clearly defined limits of flash frequency (mostly between 10-30 Hz).  The photosensitivity range 
is relatively stable over time for each subject, although it can decrease or be eliminated by the 
use of AEDs. 
This photosensitivity range, defined as the difference between the highest and lowest flash rates 
that consistently elicit a PPR, can be used as a quantitative measure of photosensitivity and, 
therefore, epileptogenicity.  In photosensitivity studies, a stable baseline is defined as the 
baseline at the Screening and Predose on the day of each Treatment Period.  Usually during a 
photosensitivity study, the baseline is stable throughout the study.  The photosensitivity range is 
measured repeatedly (up to 8 times) over the course of a single day, and the range can be 
measured rapidly (over a 5-minute interval) in an EEG laboratory.  Reduction in the 
photosensitivity range can then be easily quantified after a single dose of an AED. This 
reduction has been used to demonstrate an antiepileptic effect for a number of AEDs currently 
marketed or in development, most notably valproate, levetiracetam, lamotrigine, brivaracetam, 
carisbamate, JZP4 (Jazz Pharmaceuticals), cenobamate (YKP3089, SK Life Sciences), and 
selurampanel (BGG492, Novartis).  This POC model has been successful in identifying multiple 
drugs in early phase drug development that were subsequently effective in large clinical studies 
(Binnie, et al., 1986a; Binnie, et al., 1986b; Binnie, 1988; Kasteleijn-Nolst Trenité, et al., 1996;
Kasteleijn-Nolst Trenité, et al., 2007; Trenité, et al., 2007; French and Krauss, 2014;
Kasteleijn-Nolst Trenité, et al., 2015).  
The intent of this study is to provide a POC signal and evidence of a dose-response relationship, 
and to inform the design and dose selection for Phase 2 of the clinical development program.
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to assess PD activity of E2082 as measured by suppression 
of epileptic PPR in the subject’s most sensitive eye condition in the photosensitivity model as a 
proof of principle of efficacy in subjects with photosensitive epilepsy, compared to placebo.
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8.2
Secondary Objectives
The secondary objectives of the study are: 

To assess the PD activity of E2082 as measured by suppression of PPR in each of the 
3 eye conditions (eye closure, eyes closed, and eyes open), compared to placebo

To assess PD activity of E2082 as measured by onset, maximum change, and duration of 
photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, and 
eyes open)

To assess proportion of subjects with complete suppression, partial suppression, and no 
response of standardized photosensitivity response (SPR)

To assess other CNS-related effects of E2082 based on Bond-Lader Visual Analogue
Scale (BL-VAS) 

To assess the safety and tolerability of E2082 following single oral dose administration

To assess the PK of E2082 following single oral dose administration
8.3
Exploratory Objective

To explore relationships between PK and PD 
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period, crossover 
study with an Open-label Treatment Period, in adult subjects with photosensitive epilepsy.  This 
study will use the photosensitivity proof of principle model to determine the potential of E2082 
to reduce the photosensitive range in adult subjects.  
This study will have 2 phases:  Pretreatment Phase and Treatment Phase.  The Pretreatment 
Phase will consist of a Screening Period (up to 3 weeks from Visit 1), during which each 
subject’s study eligibility will be determined.  The Treatment Phase will consist of 3 blinded 
Treatment Periods for a randomized crossover design, followed by an Open-label Treatment 
Period.  During the Randomized Crossover Treatment Periods, there will be 3 Treatment Visits 
(Visit 2 [Treatment Period 1], Visit 3 [Treatment Period 2], and Visit 4 [Treatment Period 3]) 
evaluating single-dose administrations of either placebo, E2082 2.5 mg, or E2082 25 mg in a 
blinded manner.  During the Open-label Treatment Period, there will be 1 treatment visit (Visit 5
[Treatment Period 4]) evaluating single-dose administration of E2082 40 mg.  Treatment visits 
(ie, Visit 2, Visit 3, Visit 4, and Visit 5) will each be separated by a 2-week (±3 days) washout 
interval for a total of approximately 6 weeks, which will then be followed by a Follow-up Period 
of 2 weeks (±3 days) after the last day of study product administration.  The anticipated study 
participation duration for each subject is approximately 11 weeks.  All visits will be conducted 
on an outpatient basis.
An overview of the study design is presented in Figure 1.
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Note: FU visit is a single visit at the end of the Follow-up Period.
FU = Follow-up, Pd = Period, R = Randomization, Trt = Treatment, WO = Washout.
Figure 1
Study Design for Study E2082-A001-201
9.1.1
Pretreatment Phase
The Pretreatment Phase will consist of a Screening Period (up to 3 weeks from Visit 1), during 
which each subject’s study eligibility will be determined.  
9.1.1.1
Screening Period
Screening will occur between Day –21 and Day –1.  The purpose of the Screening Period is to 
establish protocol eligibility.  Signed informed consent must be obtained before any study 
procedures (including screening procedures) can be conducted.  Procedures to be followed when 
obtaining informed consent are detailed in Section 5.3.
Subjects must have a diagnosis and/or history of a PPR on EEG (ie, photosensitive epilepsy) for 
which they may receive up to 3 concomitant AEDs (Section 9.4.7).
At the Screening Visit (Visit 1), subjects will undergo an IPS-EEG assessment in 3 eye
conditions (eye closure, eyes closed, and eyes open) at ascending and then descending 
photo-stimulation frequencies.  At the Screening Visit, each frequency will be assessed in 3 eye 
conditions (eye closure, eyes closed, and eyes open) commencing at 2 Hz.  As soon as 
generalized EEG epileptiform activity appears, the stimulation for that particular frequency in 
that particular eye condition will be instantly terminated.  For the other eye conditions, ascending 
frequencies will be used, until generalized epileptiform activity is seen.  This procedure will 
Visit:
Screening
-21 to -1
1
57±3
1
15±3
Period:
Phase:
Study Day:
WO Pd 1
(14±3 days)
2
3
4
5
29±3
Pretreatment
Trt Pd 2
(1 day)
WO Pd 2
(14±3 days)
Trt Pd 3
(1 day)
Treatment
Open-label
Treatment
FU Pd
(14±3 days)
6
43±3
Randomized Crossover
Treatment
Follow-Up
Trt Pd 1
(1 day)
WO Pd 3
(14±3 days)
R
Trt Pd 4
(1 day)
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determine the lower threshold frequencies for each eye condition.  Similar assessments will then 
be carried out starting at 60 Hz and descending through the standard frequencies.  To avoid 
occurrence of a seizure, the stimulator will be turned off immediately if a generalized response is 
observed, and the sequence will be stopped at that point in that specific eye condition.  In this 
manner, for each eye condition, the upper threshold frequencies are determined.  
During the Screening Visit (Visit 1), IPS-EEG assessment will be performed at 5 time points, 
over a 4-hour time period (0, 1, 2, 3, and 4 hours; within ±15 minutes of the scheduled time 
point).  Subjects with a reproducible PPR on EEG of at least 3 points on the SPR scale in at least 
1 eye condition on at least 3 of the EEGs performed at Screening will be eligible for the study.  
However, the final determination of study eligibility will include predose assessments when the 
subject returns to study site for Visit 2.  The Screening assessments will be conducted, including 
determination of the lower and upper limit of photosensitivity to IPS-EEG threshold frequency 
for each eye condition.  Qualified medical personnel for the management of acute seizures will 
be present during the day of IPS-EEG procedure throughout the study.  
Upon review by the investigator, subjects whose Screening assessments (including Day 1 
[Visit 2] predose procedures) continue to meet all of the inclusion/exclusion criteria will enter 
the Treatment Phase.
9.1.2
Treatment Phase
The duration of the Treatment Phase will be 6 weeks and will include 3 blinded Treatment
Periods for a randomized crossover design, followed by an Open-label Treatment Period.  
Up to 3 concomitant AEDs (Section 9.4.7) are allowed during the course of the study, provided 
that the dosage of concomitant AED(s) has remained stable for at least 4 weeks before
Screening.  In the case where a new AED regimen has been initiated for a subject, the dose must 
be stable for at least 8 weeks before screening.  During the study, changes to concomitant AEDs 
(including dosage) are not permitted unless medically necessary and upon consultation with the 
Sponsor.  Adherence to a stable AED regimen is critical as missed doses or changes during the 
study may affect the subject’s photosensitivity response. 
The Screening Disposition case report form (CRF) page must be completed to indicate whether 
the subject is eligible to participate in the study and to provide reasons for screen failure, if 
applicable.
9.1.2.1
Randomized Crossover Treatment Periods (Treatment Periods 1 to 3)
During the Randomized Crossover Treatment Periods, there will be 3 Treatment Visits (Visit 2
[Treatment Period 1], Visit 3 [Treatment Period 2], and Visit 4 [Treatment Period 3]) evaluating 
single-dose administrations of either placebo, E2082 2.5 mg, or E2082 25 mg.  Subjects will be 
randomly assigned to 1 of 6 treatment sequences to receive the 3 treatments, in a blinded manner
in a cross-over sequence according to his/her randomization code (Table 1).
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Table 1
Treatment Sequences
Sequence
Treatment Period 1
(Visit 2)
Treatment Period 2
(Visit 3)
Treatment Period 3
(Visit 4)
1: ABC
Placebo
E2082 2.5 mg
E2082 25 mg 
2: BCA
E2082 2.5 mg
E2082 25 mg 
Placebo
3: CAB
E2082 25 mg 
Placebo
E2082 2.5 mg
4: ACB
Placebo
E2082 25 mg 
E2082 2.5 mg
5: BAC
E2082 2.5 mg
Placebo
E2082 25 mg 
6: CBA
E2082 25 mg 
E2082 2.5 mg
Placebo
A = Placebo; B = E2082 2.5 mg; C = E2082 25 mg 
On the day of each Treatment Visit (ie, Visit 2, Visit 3, and Visit 4), subjects will arrive at the 
clinic in the morning following an overnight fast of at least 8 hours.  In order to enable 
discrimination between spontaneous and IPS evoked discharges, the subject will be assessed, at 
the start of each treatment day (ie, Visit 2, Visit 3, and Visit 4), for ≥2.5 minutes with each of the 
3 eye conditions without any stimulation.  Baseline IPS-EEG assessments will be conducted 
30 minutes to 2 hours before study product administration on each treatment day, including 
determination of the lower and upper limit of photosensitivity to IPS threshold frequency for 
each eye condition.  The predose assessment serves as the baseline on each treatment day.  
Trains of flashes at constant frequency will be delivered for 4 to 6 seconds.  Intervals between 
successive flash trains at a given frequency will last for at least 5 seconds.  Determination of the 
photosensitivity ranges will be assessed with separate trains of flashes of 4 to 6 seconds duration 
(or less if generalized epileptic activity occurs).  Flashes will be administered at standard 
frequencies of 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 60 Hz.  IPS-EEG assessments 
will be repeated at 1, 2, 4, 6, and 8 hours (within ±15 minutes of each scheduled time point) 
following study product administration.  PK, PD (B-L VAS), and vital signs assessments will be 
conducted predose, and at the same postdose time points as IPS-EEG measurements.  Other 
safety assessments will be performed on each treatment visit day either predose only (clinical 
laboratory tests, Columbia-Suicide Severity Rating Scale (C-SSRS), and urine pregnancy test 
[for women of childbearing potential only]), or both predose and at 4 hours postdose (brief 
neurological and 12-lead ECG examinations).
9.1.2.2
Open-label Treatment Period
There will be 1 treatment visit (Visit 5 [Treatment Period 4]) evaluating single-dose 
administration of E2082 40 mg.
Subjects will return to the study site after the 2-week [±3 days] washout interval following the 
Randomized Crossover Treatment Period 3 and will receive a single dose of 40 mg E2082. The 
same study procedures for Treatment Periods 1 through 3 (ie, Visit 2, Visit 3, and Visit 4) will 
apply to Treatment Period 4 (ie, Visit 5), except that study drug administration is not blinded.  
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Concomitant medication restrictions from the Randomized Crossover Treatment Period will 
apply to the Open-label Treatment Period.
9.1.3
Follow-Up Period
After completion of the Open-label Treatment period, subjects will enter the Follow-up Period,
during which they will be required to complete a Follow-up visit (Visit 6) at 2 weeks ±3 days 
following the last day of study product administration. 
At the end of the Follow-up Period, subjects will be required to complete a Follow-up visit.
9.2
Discussion of Study Design, Including Choice of Control Groups
Randomization will be used in this study in the Randomized Crossover Treatment Periods to 
avoid bias in the assignment of subjects to treatment, to increase the likelihood that known and 
unknown subject attributes (eg, demographics and baseline characteristics) are balanced across 
treatment groups, and to ensure the validity of statistical comparisons across treatment groups.  
Blinding to treatment will be used to reduce potential bias during data collection and evaluation 
of endpoints.
9.3
Selection of Study Population
Approximately 9 subjects will be randomized to achieve 6 evaluable subjects at approximately 
6 sites in the US.  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. Male or female 18 to 60 years of age at the time of informed consent. 
2. A diagnosis and/or history of a PPR on EEG (ie, photosensitivity epilepsy).
3. If currently being treated with AED(s), up to a maximum of 3 concomitant AEDs is allowed 
provided that doses must have remained stable for at least 4 weeks before Screening.  In the 
case where a new AED regimen has been initiated for a subject, the dose must be stable for at 
least 8 weeks before Screening.  (See Exclusion Criteria #17-22 for AEDs that are 
exclusionary.)
4. Reproducible IPS-induced PPR on EEG of at least 3 points on the SPR scale in at least 1 eye 
condition (eye closure, eyes closed, eyes open) on at least 3 of the EEGs performed at 
Screening.
5. Body mass index (BMI) between 18 to 35 kg/m2 (inclusive) and a total body weight greater 
than or equal to 45 kg at Screening.
6. Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour period 
before Screening and during the 24-hour period before each treatment day.
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7. Willing and able to comply with all aspects of the protocol.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [β-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]).  
A separate baseline assessment is required if a negative Screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug. 
2. Females of childbearing potential who:
a.
Within 30 days before study entry, have had unprotected sexual intercourse and did not 
use a highly effective method of contraception (eg, total abstinence, an intrauterine device, 
a double-barrier method [such as condom plus diaphragm with spermicide], a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) 
b. 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.  If 
currently abstinent, the subject must agree to use a double barrier method as described 
above if she becomes sexually active during the study period or for 28 days after study 
drug discontinuation.  Females who are using hormonal contraceptives must be on a stable 
dose of the same hormonal contraceptive product for at least 4 weeks before dosing and 
must continue to use the same contraceptive during the study and for 28 days after study 
drug discontinuation.
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). 
3. Male subjects who have not had a successful vasectomy (confirmed azoospermia) or they 
and their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days after 
study drug discontinuation).  No sperm donation is allowed during the study period and for 
28 days after study drug discontinuation.
4. History of nonepileptic seizures (eg, metabolic, structural, or pseudoseizures) while on any 
antiepileptic medication(s).
5. History of status epilepticus while on any antiepileptic medication(s) within 2 years before
Screening.
6. Ongoing or history of generalized tonic-clonic seizures (GTCS) within 6 months before
Screening.
7. Subject who had developed a clinical seizure during previous PPR assessment, or who 
experiences a clinical seizure during the Screening IPS procedure. 
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8. Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening.
9. Inability to follow restriction on watching television, or use of any device(s) with an 
animated screen (eg, computer, video games, tablets, or smart phone) from the time of arrival 
at the study center until study procedures are completed for that day.
10. Currently active clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal 
disease) with the exception of epilepsy, which in the opinion of the investigator could affect 
the subject’s safety or interfere with the study assessments.
11. A history of prolonged QT syndrome or risk factors for torsade de pointes (eg, heart failure, 
hypokalemia, family history of long QT Syndrome), or the use of concomitant medications 
that prolonged the QT/corrected QT using Fridericia formula (QTcF) interval; or prolonged 
QT/QTcF interval (QTcF >450 msec) demonstrated on ECG at Screening or Baseline (based 
on average of triplicate ECGs).
12. Presence of active CNS infection, demyelinating disease, degenerative neurological disease 
or any CNS disease deemed to be progressive during the course of the study that may 
confound the interpretation of the study results.
13. Current/ongoing clinically significant active liver disease, porphyria, or with a family history 
of severe hepatic dysfunction indicated by abnormal liver function tests (LFTs) greater than 
3 times the upper limit of normal (ULN) (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
14. Any history of gastrointestinal conditions or surgery that may affect PK profiles of E2082 
(eg, hepatectomy, nephrectomy, and digestive organ resection).
15. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
16. Use of perampanel within 6 weeks before Screening.
17. Use of felbamate for less than 2 years or where the dose has not been stable for at least 
8 weeks before Visit 1.  Subject must not have a history of white blood cell (WBC) count 
below equal or less than 2500/μL (2.50 1E+09/L), platelet count below 100,000, LFTs above 
3 times the ULN, or other indication of hepatic or bone marrow dysfunction while receiving 
felbamate.  If subjects received felbamate in the past, it must have been discontinued 8 weeks 
before Visit 1 to be eligible for study participation.
18. Use of vigabatrin within 5 months before Screening.  Subjects who have discontinued 
vigabatrin for at least 5 months before Screening must have documentation showing no 
evidence of vigabatrin associated clinically significant abnormality in a visual perimetry test 
in order to be eligible for the study.
19. Concomitant use of cannabinoids.
20. Use of benzodiazepines for epilepsy for which the dose has not been stable for greater than 
4 weeks before Screening.  Benzodiazepine use as rescue medication for seizure control is 
allowed; however, intermittent use of benzodiazepines for any other indication (eg, 
anxiety/sleep disorders) is prohibited.
21. Use of concomitant AEDs or other drugs that are known to be potent cytochrome P450 
(CYP)3A enzyme inducers (such as carbamazepine, oxcarbazepine, eslicarbazepine, 
phenytoin, phenobarbital, and primidone) or CYP3A inhibitors within 4 weeks or 
5 half-lives, whichever is longer.
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22. Vagus nerve stimulation (VNS) implanted within 5 months or changes in parameter within 
4 weeks before Screening.
23. On a ketogenic diet for which the diet is not a stable regimen for at least 4 weeks before
Screening. 
24. History of drug or alcohol dependency or abuse within the 12 months before Screening, or 
those subjects who have a positive drug test or alcohol test at Screening.
25. History of or ongoing multiple drug allergies or severe drug reaction to AED(s), including 
dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions. 
26. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption.
27. Any suicidal ideation with intent with or without a plan within 6 months before Screening or 
during Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the C-SSRS).
28. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
29. Any psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of 
antipsychotics or prior suicide attempt(s) within approximately the last 2 years.
30. Currently enrolled in another clinical study or used any investigational drug or device within 
28 days or 5 half-lives, whichever is longer, preceding informed consent, except the 
investigational study for the evaluation of commercial IPS machine. 
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or administrative 
reasons.  The subject may stop study drug or withdraw from the study at any time for any reason.
Subjects who discontinue from the study early may be replaced upon consultation with the 
sponsor.
9.3.3.1
IPS-EEG-Specific Subject Withdrawal/Stopping Criteria
The investigator will determine continued subject participation in the IPS assessments.  In 
individual situations, safety assessments will be completed as appropriate, determined by the 
investigator. 
At the discretion of the investigator, a subject may be withheld from further IPS-EEG testing 
during a study visit or withdrawn from the study if any of the following 3 circumstances occur:
1. If a subject experiences:
a) GTCS on any study day, and the subject has not had a GTCS in the 6 months before
enrollment, that subject will be discontinued from the study.
OR
b) GTCS during photic stimulation, that subject will be discontinued from the study.
2. If, in the opinion of the investigator, a subject has evidence of proconvulsive activity on the 
EEG (eg, increase in spike-wave activity), following administration of the study drug, that 
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subject will be discontinued from the study. 
Proconvulsive activity is defined as 
a) generalized spike and wave discharges greater than 5 seconds defined by absence seizures 
or isolated myoclonic jerks do not require stoppage of study drug or subject withdrawal; or 
b) change in the usual pattern of PPR that is typical for the subject such as: decrease in time 
to occurrence of PPRs at the same flash frequency; increase in the duration of the PPR; or, 
clear increase of PPR-related negative sensations (clinical signs) or appearance or increase of 
spontaneous epileptiform activity.
3. If a subject has widening of the photosensitivity range (becomes more sensitive) by more 
than 3 points on 2 consecutive occasions after dosing compared to Screening, the IPS will be 
terminated and the subject will not be permitted to participate in further IPS-EEG testing on 
the same day.
9.4
Treatments
9.4.1
Treatments Administered
9.4.1.1
Randomized Crossover Treatment Periods
The following treatments will be administered as a single oral dose (Table 2).  Each subject will 
receive each treatment in a sequence according to the randomization code (Table 1).   
Table 2
Treatment Description 
Treatment
Study Drug/Dose
Study Drug(s) to be 
Administered
A
Placebo
5 x E2082-matched placebo 
tablets
B
E2082 2.5 mg
5 x E2082 0.5-mg tablets
C
E2082 25 mg 
5 x E2082 5-mg tablets
9.4.1.2
Open-label Treatment Period
Each subject will receive a single oral dose of E2082 40 mg (8 x E2082 5-mg tablets).
9.4.2
Identity of Investigational Products
E2082 film-coated tablets (0.5 mg and 5 mg) and corresponding placebo are yellowish red, 
approximately 5.1 mm in diameter.  Test drug and placebo will be supplied by the sponsor in 
labeled containers.
9.4.2.1
Chemical Name, Structural Formula of E2082

Test drug code:  E2082

Generic name:  Not Applicable
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
Chemical name:  2-Fluoro-6-[3-fluoro-8-oxo-7-(pyridin-3-yl)-7,8-dihydro-6H-
pyrano[3,2-b:5,4-b′]dipyridin-9-yl]benzonitrile

Molecular formula:  C23H12F2N4O2

Molecular weight:  414.37
9.4.2.2
Comparator Drug
Placebo tablet with matching color and appearance to E2082 tablet will be supplied.
9.4.2.3
Labeling for Study Drug
E2082 will be labeled in accordance with text that is in full regulatory compliance.
9.4.2.4
Storage Conditions
E2082 will be stored in accordance with labeled storage conditions.  Temperature monitoring is 
required at the storage location to ensure that E2082 is maintained within 2ºC to 8ºC.  The 
investigator or designee is responsible for ensuring that the temperature is monitored throughout 
the total duration of the study and that records are maintained; the temperature should be 
monitored continuously by using either an in-house validated data acquisition system, a 
mechanical recording device, such as a calibrated chart recorder, or by manual means, such that 
minimum and maximum thermometric values over a specific time period can be recorded and 
retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
9.4.3.1
Randomized Crossover Treatment Periods
Subjects will be assigned to all 3 treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent, unblinded, statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
9.4.3.2
Open-Label Treatment Period
Not applicable, as each subject will receive a single oral dose of E2082 40 mg (8 x E2082 5-mg 
tablets).
9.4.4
Selection of Doses in the Study
Single oral doses of 2.5 mg and 25 mg are currently being proposed for this study.  A third dose 
of 40 mg, was selected as the highest dose in this photosensitivity study, and was determined 
following review of available PK/safety data from the 40-mg cohort in Study 001.
The low dose of 2.5 mg was selected based on the exposures observed at ED50 in preclinical 
mouse model (6 Hz psychomotor seizure model).  Based on preliminary SAD PK data from 
Study 001, a single dose of 2.5 mg is expected to achieve plasma concentrations at or above the 
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predicted minimum effective plasma concentration of 80 ng/mL for approximately 8 hours in the 
majority of the subjects (Figure 2).  
In the ongoing first-in-human study (Study 001), E2082 was well tolerated up to 40 mg (the 
highest dose level with PK and safety data evaluated).  The proposed dose range between 2.5 mg 
and the highest dose of 40 mg are expected to provide a wide range of exposure (approximately 
10- to 16-fold) to demonstrate POC and may also support exploratory PK/PD response analysis.
Figure 2
Individual plasma concentration-time profiles of E2082 (2.5 mg) 
following single oral dose administration in Study E2082-A001-001
conc = concentration
9.4.5
Selection and Timing of Dose for Each Subject
Following an overnight fast of at least 8 hours, subjects will be administered the study drug 
product with approximately 240 mL (8 fluid ounces) of water on the day of each Treatment Visit
(ie, Visit 2, Visit 3, Visit 4, and Visit 5).  A light snack can be provided at 30 minutes predose 
(after clinical laboratory blood collection) and at 2 hours postdose.  
9.4.6
Blinding
Central EEG reading of all EEG records (including Screening and Treatment Periods 1 through 
4) will be performed in a blinded and independent manner.  Investigator(s) may consult with the 
central read only during the Pretreatment Phase, if needed, for IPS-EEG eligibility 
determination.  
Subject ID
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During the Randomized Crossover Treatment Periods, subjects and all personnel involved with 
the conduct and interpretation of the study, including investigators, site personnel (with the 
exception of the pharmacist preparing and dispensing the study drug), and sponsor/designee 
(with the exception of the independent biostatistician and unblinded CRAs) will be blinded to the 
treatment codes.  Randomization code will be kept strictly confidential, filed securely by an 
appropriate group with the sponsor or CRO and accessible only to authorized persons (eg, Eisai 
Global Safety) until the time of unblinding, per SOP.
The E2082 drug substance and placebo will be provided to an unblinded pharmacist in an open-
label manner.  The unblinded pharmacist will be responsible for preparing and dispensing study 
drug tablets in accordance with subject randomization in a blinded manner.  A master list of all 
treatments and the subject numbers associated with them will be maintained in a sealed envelope 
by the sponsor.  In addition, master code breaker reports or envelopes identifying the treatment 
group of each subject number will be provided to the site and to the sponsor in sealed envelopes.  
These code breaker reports or envelopes are not to be opened unless an emergency occurs and 
knowledge of the subject’s randomization code may affect his/her medical treatment.  If 
possible, before breaking the blind, the investigator should consult with the sponsor to ascertain 
the necessity of breaking the code.  The investigator is to record the date and time of opening the 
code breaker report or envelope and the reason for breaking the code (see also Section 9.5.4.5).  
At the conclusion of the study, where possible, all unused drug supplies at the site, together with 
master code breaker reports or envelopes, are to be returned to the clinical supply vendor for 
final reconciliation and disposition.
Data from any completed cohort may be unblinded for review by the sponsor.
9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the subject 
during the study within 3 months before the Screening Visit and throughout the course of the 
study (starting at the date of informed consent) will be recorded on the Prior & Concomitant 
Medication CRF or Non-Pharmacological Procedures CRF.  
Up to 3 concomitant AEDs (with the exception of those AEDs listed in Section 9.4.7.1) are 
allowed during the course of the study, provided that the dosage of concomitant AED(s) has 
remained stable for at least 4 weeks before Screening.  In the case where a new AED regimen 
has been initiated for a subject, the dose must be stable for at least 8 weeks before screening.  
During the study, changes to concomitant AEDs (including dosage) are not permitted unless 
medically necessary and upon consultation with the Sponsor.
Vagus nerve stimulation (VNS) is not considered as one of the 3 allowed concomitant AEDs.  
However, VNS implantation during the course of the study is prohibited.  For subjects who have 
VNS implanted prior to participation in this study, changes to VNS parameters are not allowed 
unless medically necessary.  
Likewise, ketogenic diet is not considered as one of the 3 allowed concomitant AEDs.  However, 
changes to ketogenic diet (eg, median chain triglyceride level) are not allowed during the study.
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The investigator will record on the AE CRF any AE for which the concomitant 
medication/therapy was administered.  If the concomitant medication/therapy is being 
administered for a medical condition present at the time of entry into the study, the investigator 
will record the medical condition on the Medical History and Current Medical Condition CRF.
9.4.7.1
Prohibited Concomitant Therapies and Drugs
Use of the following AEDs during the course of the study is not allowed:

Perampanel

Vigabatrin

Cannabinoids

Benzodiazepines for non-epilepsy indications (eg, anxiety/sleep disorders) (Stable doses 
of benzodiazepine or intermittent benzodiazepine use as rescue medication for seizure 
control is allowed)

Enzyme-inducing antiepileptic drugs (EIAEDs, eg, carbamazepine, oxcarbazepine, 
eslicarbazepine, phenytoin, phenobarbital, and primidone)
Concomitant use of medications known to be potent CYP3A inducers/inhibitors including, but 
not limited to, rifampin, troglitazone, St John’s Wort, efavirenz, nevirapine, modafinil, 
pioglitazone, and rifabutin will not be permitted and are to be discontinued within 28 days before 
Visit 1.  
9.4.7.2
Restrictions During the Study Period
Study drug will be administered on the day of each Treatment Visit (ie, Visit 2, Visit 3, Visit 4, 
and Visit 5) after an overnight fast of at least 8 hours.  Treatments will be administered orally 
with approximately 240 mL (8 fluid ounces) of water.  Additional water may be provided in 
increments of 50 mL (up to a maximum of 100 mL), if required.  A light snack can be provided 
at 30 minutes predose (after clinical laboratory blood collection) and at 2 hours postdose.
Water will be allowed as desired except from the time of dosing until 1 hour after study drug 
administration.
For study visits where IPS-EEG assessments will be performed, subjects will be required to 
abstain from watching television or using any device with an animated screen (ie, computer, 
video games, tablets, or smart phone) from the time of arrival at the study center until study 
procedures are completed for that day.  Subjects will be required to refrain from strenuous 
exercise and alcohol consumption during the 24-hour period before Screening and during the 
24-hour period before each treatment day.  Subjects will be instructed to get similar amounts of 
sleep prior to each visit.
9.4.8
Treatment Compliance
Not applicable as study drug will be administered in the study site by study personnel and 
records will be maintained.
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9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB for the institution where the study is to be conducted

A copy of the IRB-approved ICF and any other documentation provided to the subjects to 
be used in this study

The IRB 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 

A signed and dated clinical studies agreement
The investigator/designee 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.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not enrolled 
in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study drugs, 
dispensing of study drugs to the subject, collection and reconciliation of unused study drugs that 
are either returned by the subjects or shipped to site but not dispensed to subjects, and return of 
reconciled study drugs to the sponsor or (where applicable) destruction of reconciled study drugs 
at the site.  This includes, but may not be limited to:  (a) documentation of receipt of study drugs, 
(b) study drugs dispensing/return reconciliation log, (c) study drugs accountability log, (d) all 
shipping service receipts, (e) documentation of returns to the sponsor, and (f) certificates of 
destruction for any destruction of study drugs that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs and inventory records must be made available, upon request, for inspection by a 
designated representative of the sponsor or a representative of a health authority (eg, FDA).  As 
applicable, all unused study drugs and empty and partially empty containers from used study 
drugs are to be returned to the investigator by the subject and, together with unused study drugs 
that were shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
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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
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, and race/ethnicity.
9.5.1.2
Screening Assessments
9.5.1.2.1
MEDICAL HISTORY AND EPILEPSY MEDICAL HISTORY
In addition to standard medical history, surgical, and epilepsy history and current medical 
conditions will be recorded at the Screening Visit.  All medical, surgical, and epilepsy history 
within 10 years must be noted in the Medical History and Current Medical Conditions CRF.
9.5.1.2.2
HEIGHT MEASUREMENT AND BMI COMPUTATION
Height (cm) will be recorded at the Screening Visit and BMI (kg/m2) will be computed from 
height and weight data at Screening.   
9.5.1.2.3
URINE DRUG TEST
A 30-mL urine sample will be collected at the Screening Visit (Visit 1), as specified in the 
Schedule of Procedures/Assessments (Table 4).  This sample will be tested for common drugs of 
use/abuse:  eg, ethyl alcohol, phencyclidine (PCP), benzodiazepines, cocaine, amphetamines, 
cannabinoids, opioids, barbiturates, and tricyclic antidepressant drugs.
9.5.1.2.4
SEROLOGY
A 6 mL sample of blood will be taken for hepatitis B surface antigen and hepatitis C antibodies 
at Screening.
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9.5.1.3
Efficacy Assessments
Not applicable.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples for the determination of plasma concentrations of E2082 will be collected from 
each subject.  PK sampling for plasma concentration will be collected predose (within 2 hours) 
and postdose at 1 (±10 min), 2 (±10 min), 4 (±15 min), 6 (±15 min), and 8 (±15 min) hours on 
each treatment day (ie, Visit 2, Visit 3, Visit 4, and Visit 5).  Plasma concentrations of E2082
will be measured using a validated liquid chromatography coupled with tandem mass 
spectrometry (LC-MS/MS) method.  Actual PK sampling date and time will be recorded at each 
scheduled and unscheduled sampling time point. Actual date and time of study drug 
administration will also be recorded for each dose administration during each Treatment Visit.  
See Table 5 for a description of assessment timings and window periods.
At time points when vital signs, ECGs, and blood sampling are to be performed at the same time 
point, these procedures will be performed in the following order:  ECGs, vital signs, and then 
blood sampling.  
Information on the PK sample collection, handling, and shipping procedures will be provided to 
the clinical site either as a stand-alone PK laboratory manual or as part of the (central)
Laboratory Manual.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
All PD assessments will be performed within ±15 minutes of the scheduled time point.  See 
Table 5 for a description of assessment timings and window periods.
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IPS-EEG
Throughout the study, the flash frequency will be recorded.  Three eye conditions (eye closure, 
eyes closed, and eyes open) per stimulus for assessment purposes will be recorded. The 
combination of lower and upper frequencies gives a total of 3 photosensitivity ranges, 1 per eye 
condition.  If there is any doubt of the interpretation during any of the assessments (for example 
blinking during the eyes open condition, provoking epileptiform activity) the stimulation in the 
same eye condition will be repeated.  In order to minimize the risk of inducing a seizure, photic 
stimulation will not be carried out between the upper and lower thresholds.  This method has 
been found to be the safest, as it prevents elicitation of seizures by avoiding stimulation of the 
subject at the most sensitive frequencies.  The range for each subject will be recorded in the 
CRF.  The most sensitive eye condition will be noted during every visit; however, assessments in 
all 3 eye conditions will be noted.
During the Screening Visit (Visit 1), IPS-EEG assessment will be performed at 5 time points, 
over a 4 hour time period (0, 1, 2, 3, and 4 hours; within ±15 minutes of the scheduled time 
point).  Subjects with a reproducible PPR on EEG of at least 3 points on the SPR scale in at least 
1 eye condition on at least 3 of the EEGs performed at Screening will be eligible for the study.  
However, the final determination of study eligibility will include predose assessments when the 
subject returns to study site for Visit 2.  
PD activity of E2082 will be assessed by suppression of PPR following IPS under 3 eye 
conditions (eye closure, eyes closed, and eyes open) using the Grass PS 33 photic stimulator with 
an unpatterned glass lamp and an intensity of 100 cd/m2/flash at approximately 30 minutes to 
2 hours predose, and at 1, 2, 4, 6, and 8 hours postdose (within ±15 minutes of each scheduled 
time point), on each treatment day, (ie, Visit 2, Visit 3, Visit 4, and Visit 5).  The time course 
(30 minutes to 2 hours predose to 8 hours postdose) will help assess the onset, maximum change
from baseline, and duration of the reduction in PPR response.  The predose assessment serves as 
the baseline on each treatment day.  PPR is expected to be within the range of 2 Hz to 60 Hz,
depending on the subject’s sensitivity to IPS.
Standard 19-21-channel EEG equipment will be used for recording including video monitoring 
and precise recording of duration and frequency of the flashes (sensor or connection with the 
photostimulator).  The international 10-20 system will be used, with 2 additional channels, 1 for 
eye movements (to detect changes in eye condition more easily) and 1 for flash frequencies.  A 
19-21-channel recording system will be used with a bipolar derivation with emphasis on the 
parieto-temporal-occipital area (maximum and spreading of epileptiform activity).  The display 
montage will include T4-T6-O2-O1-T5-T3 and T4-P4-Pz-P3-T3, apart from 2x4 (8) frontal to 
occipital leads. 
The following settings will be used: 

Amplification:  7-10 microV/mm

High Frequency Filter: 35-70 Hz

Time constant: 0.3-0.6 sec

Display speed: 30 mm/sec
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In order to enable discrimination between spontaneous and IPS evoked discharges, the subject 
will be assessed ,at the start of each treatment day, (ie, Visit 2, Visit 3, Visit 4, and Visit 5), for 
≥2.5 minutes with each of the 3 eye conditions without any stimulation.  Each IPS-EEG 
assessment will be conducted in all 3 eye conditions (eye closure, eyes closed, and eyes open; 
each for a minimum of 2.5 minutes) at ascending and then descending photo stimulation 
frequencies. The lower and upper limit of photosensitivity to IPS threshold frequency will be 
determined for each eye condition.  Trains of flashes at constant frequency will be delivered for 
4 to 6 seconds.  Intervals between successive flash trains at a given frequency will last for at least 
5 seconds.  Determination of the photosensitivity ranges will be assessed with separate trains of 
flashes of 4 to 6 seconds duration (or less if generalized epileptic activity occurs).  Flashes will 
be administered at standard frequencies of 2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50, and 
60 Hz.
Bond and Lader Visual Analogue Scale
The Bond and Lader VAS (Bond A, 1974) for CNS–related effects of E2082 (such as 
somnolence, sedation, dizziness, and body sway) will be evaluated for each subject predose 
(within 2 hours) and at 1, 2, 4, 6, and 8 hours postdose on each treatment day (ie, Visit 2, Visit 3, 
Visit 4, and Visit 5). 
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; laboratory evaluation for 
hematology, blood chemistry, and urine values; measurement of vital signs and ECGs; 
pregnancy test for women of childbearing potential only; and the performance of neurological 
and physical examinations as detailed in Table 4.
An assessment of suicidality using the C-SSRS will be performed as detailed in Table 4.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship 
with the medicinal product.  For this study, the study drug is E2082. 
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease 

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
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
Recurrence of an intermittent medical condition (eg, headache) not present at 
pretreatment (Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the subject 
signs the study ICF through the last visit (ie, Follow-up/Early Discontinuation Visit).  SAEs must 
be collected for 28 days after the last dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be part 
of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute an 
AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality considered to 
constitute an AE should be reported on the AE CRF. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QT interval corrected by the 
Fridericia formula (QTcF) is greater than 450 msec and there is an increase of more than 
60 msec from baseline.  Any ECG abnormality that the investigator considers as an AE should 
be reported as such.
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects and 
determine if any result constitutes an AE.  Medical and scientific judgment should be exercised 
in deciding whether an isolated suicidality rating scale response should be classified as an AE 
(see Section 9.5.1.5.8 for a description of the C-SSRS). 
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, whichever 
comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
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The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a reasonable 
possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An 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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Events associated with special situations include pregnancy or exposure to study drug through 
breastfeeding; AEs associated with study drug overdose, misuse, abuse, or medication error.  
These events associated with special situations are to be captured using the SAE procedures but 
are to be considered as SAEs only if they meet one of the above criteria.  All AEs associated 
with special situations are to be reported on the CRF whether or not they meet the criteria for 
SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, blood chemistry, and urinalysis, 
are summarized in Table 3.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 4) shows the visits and time points 
at which blood for clinical laboratory tests and urine for urinalysis will be collected in the study. 
Subjects will fast for at least 8 hours before blood is drawn for clinical laboratory assessments.  
Clinical laboratory blood collection must be performed before a subject can receive the light 
snack that can be provided at 30 minutes predose.  See Table 5 for a description of assessment 
timings and window periods.
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Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)
Blood Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, 
calcium, 
cholesterol, 
globulin, 
glucose, 
lactate 
dehydrogenase, phosphorus, total protein, triglycerides, uric acid
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
RBC = red blood cell, WBC = white blood cell.
All blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the laboratory abnormality will be recorded on the AE CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], heart rate [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 4).  
Vital signs are to be taken in the supine position after subjects have remained resting for at least 
5 minutes.  All BP measurements should be performed on the same arm, preferably by the same 
qualified healthcare professional.
When vital signs are to be obtained concurrently with PK or other blood samples, the vital sign 
measurements will be performed before drawing blood samples in order minimize the potential 
effects of blood drawing on recordings obtained during safety assessments.
At time points when vital signs, ECGs, and blood sampling are to be performed at the same time 
point, these procedures will be performed in the following order: ECGs, vital signs, and then 
blood sampling.  Subjects will remain rested in the supine position for 10 minutes before and 
5 minutes after ECG recordings, followed by recording of vital sign measurements.
See Table 5 for a description of assessment timings and window periods.
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9.5.1.5.5
PHYSICAL EXAMINATIONS
Full and abbreviated physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 4).  Documentation of the physical examination will be included 
in the source documentation at the site.  Significant findings at the Screening Visit will be 
recorded on the Medical History and Current Medical Conditions CRF.  Clinically significant 
abnormal findings from the physical examination will be recorded as an AE on the AE CRF.
Full Physical Examination
A full physical examination will include evaluations of the head, eyes, ears, nose, throat, neck, 
heart, chest, lungs, abdomen, extremities, skin, and neurological examination.  The subject will
be queried regarding physical status and subjective symptoms as well. A urogenital examination 
will only be required in the presence of clinical symptoms related to this region.
Abbreviated Physical Examination
Health status will be assessed by brief evaluation of the head, eyes, ears, nose, throat, and other 
physical conditions of note.  The subject must be queried regarding changes in physical status 
since the last examination.
9.5.1.5.6
NEUROLOGICAL EXAMINATIONS
Full and abbreviated neurological examinations will be performed as designated in the Schedule 
of Procedures/Assessments (Table 4).  Documentation of the neurological examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit will 
be recorded on the Medical History and Current Medical Conditions CRF.  Clinically significant 
abnormal findings from the neurological examination will be recorded as an AE on the AE CRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
ECGs (12-lead) will be obtained as designated in the Schedule of Procedures/Assessments 
(Table 4).  At time points when vital signs, ECGs, and blood sampling are to be performed at the 
same time point, these procedures will be performed in the following order:  ECGs, vital signs, 
and then blood sampling.  Subjects will remain rested in the supine position for 10 minutes 
before and 5 minutes after ECG recordings, followed by recording of vital sign measurements.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the AE CRF.
See Table 5 for a description of assessment timings and window periods.
9.5.1.5.8
OTHER SAFETY ASSESSMENTS
C-SSRS
An assessment of suicidality using the C-SSRS will be performed at Screening, during each 
Treatment visit (ie, Visit 2, Visit 3, Visit 4, and Visit 5), and at the Follow-up/Early 
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discontinuation visit, as designated in the Schedule of Procedures/Assessments (Table 4).  It is 
recommended that, for the Treatment Visits, C-SSRS be performed predose to ensure there is no 
increased risk of suicidality since last visit.
Pregnancy Test
For women of childbearing potential, a serum β-hCG or hCG test (6 mL blood sample) will be 
performed during Screening Visit (Table 4).  Subsequently, urine pregnancy test will be 
performed prior to dose administration on each treatment visit (ie, Visit 2, Visit 3, Visit 4, and 
Visit 5), and upon return to site during Follow-up/Early Discontinuation Visit.  Unscheduled 
pregnancy test (serum or urine) may be performed as medically necessary at the discretion of the 
investigator.
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 4 presents the schedule of procedures/assessments for the study.
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-
upa/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
Informed Consent
X
Demography 
X
Randomization
X
Inclusion/exclusion 
criteria
X
X
Medical and surgical 
history
X
Epilepsy medical history
X
Heightc and weight
X
X
X
(X)d
Physical examinatione
X
X
X
(X)d
Neurological 
examinationf
X
X
X
X
X
X
(X)d
Vital signsg,h
X
X
X
X
X
X
(X)d
12-Lead ECGi,h
X
X
X
X
X
X
(X)d
Clinical laboratory testsj,h
X
X
X
X
X
X
(X)d
Serology (HBsAg, HCV 
Ab) 
X
Urine drug testk
X
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-
upa/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
Serum β-hCG [or hCG]
testl
X
Urine pregnancy testl
X
X
X
X
X
(X)d
PK sampling (plasma)m,h
X
X
X
X
(X)d
IPS-EEG Assessment
Xn
Xo
Xo
Xo
Xo
BL-VASp
X
X
X
X
C-SSRSq
X
X
X
X
X
X
(X)d
Study drug
administration
X
X
X
X
Prior and concomitant 
medication(s)
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
β-hCG = beta-human chorionic gonadotropin (or hCG = human chorionic gonadotropin), BL-VAS = Bond and Lader Visual Analogue Scale, 
C-SSRS = Columbia-Suicide Severity Rating Scale, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody, IPS-EEG = intermittent photic 
stimulation electroencephalogram, Pd = Period, PK = pharmacokinetics, QTcF = QT interval corrected by the Fridericia formula, Trt = Treatment, 
VAS = visual analogue scale.
a:
For subjects who completed Open-label Treatment Period. Follow-up visit is to be conducted 2 weeks ±3 days following the last day of
study product administration.
b:
For subjects who discontinued early from the study after having been exposed to study drug, Early Discontinuation Visit is to be 
conducted 2 weeks ±3 days following the last dose administration. Early Discontinuation visit is not required for subjects who 
discontinued from the study before receiving the first study drug administration.
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-
upa/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
c:
Height will be assessed only during the Screening Visit.
d:
During the unscheduled visits, specific procedure(s) to be performed will be on an as-needed basis at the discretion of the investigator.  
For example, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the investigator.
e:
A full physical examination will be conducted at Screening.  Abbreviated physical examination will be performed during Visit 2 (before 
randomization) and Follow-up/Early Discontinuation Visit.  Additional physical examination may be conducted at any other visit(s), as 
medically deemed necessary.  Clinically significant abnormal findings from the physical examinations will be reported as AEs.
f:
A full neurological examination will be conducted at Screening. Abbreviated neurological examination will be performed during each 
treatment visit (predose and at 4 hours [±30 min] postdose) and Follow-up/Early Discontinuation Visit. Clinically significant abnormal 
findings from the neurological examinations will be reported as AEs.
g:
Vital signs (systolic and diastolic blood pressure [BP], heart rate [HR], respiratory rate, and body temperature) will be taken at Screening, 
during each treatment visit, and during Follow-up/Early Discontinuation Visit.  On each treatment day (ie, Visit 2, Visit 3, Visit 4, and 
Visit 5), vital sign measurements will be obtained predose (within 2 hours), and at 1, 2, 4, 6, and 8 hours postdose, with the window for 
collection postdose is (±15 min) at each scheduled timepoint.  Vital signs are to be taken in the supine position after subjects have 
remained resting for at least 5 minutes.  
h:
At time points when vital signs, ECG, and blood sampling are to be performed at the same time point, the following order must be 
followed: ECG, vital signs, and then blood sampling.
i:
ECG assessments will be performed at Screening, during each treatment visit (predose and at 4 hours [±30 min] postdose), and during 
Follow-up/Early Discontinuation Visit.  ECG measurements are to be taken in the supine position after subjects have remained resting for 
at least 5 minutes. If QTcF exceeds 450 msec during any visit, 3 consecutive ECG measurements each separated by 5 – 10 minutes will 
be performed to confirm the abnormality.  Any ECG abnormalities that the investigator deems to be clinically significant will be reported 
as AEs.
j:
Clinical laboratory tests include: hematology, blood chemistry, and urinalysis. Subjects will fast for at least 8 hours before blood is drawn 
for clinical laboratory assessments. Clinical laboratory blood collection must be performed before a subject can receive the light snack 
that can be provided at 30 minutes predose.
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Table 4
Schedule of Procedures and Assessments in E2082-A001-201
Phase
Pretreatment
Treatment
Follow-
upa/Early 
Discontinuationb
Unscheduled 
Visit
Period
Screening
Randomized Crossover
Open-
label
Trt Pd 1
Trt Pd 2
Trt Pd 3
Trt Pd 4
Visit
1
2
3
4
5
6a
Study Day
-21 to -1
1
15±3
29±3
43±3
57±3a
Procedures/Assessments
k:
Screening for common drugs of use/abuse (eg, ethyl alcohol, phencyclidine (PCP), benzodiazepines, cocaine, amphetamines, 
cannabinoids, opioids, barbiturates, and tricyclic antidepressant drug).
l:
For female subjects of childbearing potential only. 
m:
Blood samples for plasma PK will be obtained predose (within 2 hours) and at 1 (±10 min), 2 (±10 min), 4 (±15 min), 6 (±15 min), and 8
(±15 min) hours postdose on each treatment day (ie, Visit 2, Visit 3, Visit 4 and Visit 5).  
n:
During Screening Visit, IPS-EEG assessment will be performed at 5 time points over a 4-hour interval (0, 1, 2, 3, and 4 hours; within ±15 
minutes of the scheduled time point).
o:
On each treatment day (Visit 2, Visit 3, Visit 4, and Visit 5), IPS-EEG assessment will be performed predose (approximately within 
30 minutes to 2 hours), and at 1, 2, 4, 6, and 8 hours postdose (a window of ±15 minutes is allowed at each postdose timepoint).
p:
BL-VAS will be performed from each subject on each treatment day predose (within 2 hours) and at 1, 2, 4, 6, and 8 hours postdose.  
q:
C-SSRS will be performed at Screening, during each Treatment Visit (recommended to administer C-SSRS predose to ensure there is no 
increased risk of suicidality since last visit), and at the Follow-up/Early Discontinuation Visit.
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Table 5 presents the blood sampling schedule for pharmacokinetic assessments, in addition for 
window periods for study assessments on Treatment visits (ie, Visit 2, Visit 3, Visit 4, and 
Visit 5).  
Table 5
Time Windows for Study Assessments on Treatment Days
Visit (Window)
Time Relative to the 
Administration
Acceptable Time Window
PK
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Predose
–2 hours
1, 2 hours
±10 minutes
4, 6, and 8 hours
±15 minutes
Vital Signs
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Predose
–2 hours
1, 2, 4, 6, and 8 hours
±15 minutes
ECG
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Predose
–2 hours
4 hours
±30 minutes
Clinical Laboratory Tests
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Predose
–2 hours to -30 minutes (before light snack)
IPS-EEG Assessment
Visit 2
Visit 3 (±3 days),
Visit 4 (±3 days), 
Visit 5 (±3 days)
Predose
-2 hours to -30 minutes 
1, 2, 4, 6, and 8 hours
±15 minutes
IPS-EEG = intermittent photic stimulation electroencephalogram, PK = pharmacokinetics
9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in Table 4.
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9.5.3
Appropriateness of Measurements
Most of the clinical assessments are standard measurements commonly used in Phase 2 studies 
of epilepsy.  The safety assessments to be performed in this study, including monitoring and 
recording all AEs; laboratory evaluation for hematology, blood chemistry, and urine values; 
measurement of vital signs and ECGs; and the performance of neurological and physical 
examinations, are standard evaluations to ensure subject safety.
In addition to the standard safety measurements, CNS-related side effects (eg, somnolence, body 
sway, dizziness and sedation) known to be associated with AMPA receptor antagonism will also 
be assessed using BL-VAS (Bond A, 1974).  As BL-VAS measures effects of E2082 that are 
related to the underlying pharmacological activities of AMPA receptor antagonist, these 
measurements also serve as PD markers in this study.
The IPS-EEG procedure during this study will be performed based upon the protocol of 
Kastelejin et al (Kasteleijn-Nolst Trenité, et al., 1996).  The combination of lower and upper 
frequencies gives a total of 3 photosensitivity ranges, 1 per eye condition (eye closure, eyes 
closed, and eyes open).  In order to minimize the risk of inducing a seizure, photic stimulation 
will not be carried out between the upper and lower thresholds.  However, qualified medical 
personnel for the management of acute seizures will be present during the day of IPS-EEG
procedure throughout the duration of the study.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated With 
Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the last visit (ie, 
Follow-up/Early Discontinuation visit) and for 28 days after the last dose.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization. Any SAE judged by the 
investigator to be related to the study treatment or any protocol-required procedure should be 
reported to the sponsor regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality.
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Any follow-up information received on SAEs should be forwarded within 1 business day of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by the 
sponsor.
The investigator must notify his IRB of the occurrence of the SAE in writing, if required by his
institution.  A copy of this communication must be forwarded to the CRO to be filed in the 
sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or within 
28 days of last study treatment, or any exposure to study drug through breastfeeding during study 
treatment or within 28 days of last study treatment, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in the 
same format as all other SAEs (see Reporting of Serious Adverse Events [Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or email as 
soon as possible but no later than 1 business day from the date the investigator becomes aware of 
the pregnancy.  The contact information for the reporting of pregnancies and exposure to study 
drug through breastfeeding is provided in the Investigator Study File.  The Pregnancy Report 
Form must be used for reporting.  All pregnancies must be followed to outcome.  The outcome 
of the pregnancy must be reported as soon as possible but no later than 1 business day from the 
date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated With Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
AEs associated with study drug overdose, misuse, abuse, and medication error refer to AEs 
associated with uses of the study drug outside of that specified by the protocol.  Overdose,
misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose
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Misuse
Intentional and inappropriate use of study drug not in accordance with the
protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site personnel
or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on the 
AE CRF and also reported using the procedures detailed in Reporting of Serious Adverse Events 
(Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse is always to be captured as 
an AE.  If the AE associated with an overdose, misuse, abuse, or medication error does not meet 
serious criteria, it must still be reported using the SAE form and in an expedited manner but 
should be noted as nonserious on the SAE form and the AE CRF.
9.5.4.4
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
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code for 
an individual subject.  In all such cases, the AE necessitating the emergency blind break will be 
handled as an SAE in accordance with the procedures indicated above.  Any broken code will be 
clearly justified and documented.  The medical monitor must be notified immediately of the 
blind break.
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.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or administrative 
reasons.  A subject may elect to discontinue the study at any time for any reason.  All subjects 
who discontinue the study early after having been exposed to study drug are to complete the 
study’s early discontinuation procedures indicated in the Schedule of Procedures/Assessments 
(Table 4).  Early Discontinuation visit is not required for subjects who discontinued from the 
study before receiving the first study drug administration.
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The investigator will promptly explain to the subject involved that the study will be discontinued 
for that subject and provide appropriate medical treatment and other necessary measures for the 
subject.  A subject who has ceased to return for visits will be followed up by mail, phone, or 
other means to gather information such as the reason for failure to return, the status of treatment 
compliance, the presence or absence of AEs, and clinical courses of signs and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate 1 or 
more secondary reason(s) for discontinuation.  Study disposition information will be collected on 
the Subject Disposition CRF.
A subject removed from the study for any reason may be replaced.
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to receive 
medical care by another physician.  At each visit, the investigator will ask the subject whether 
he/she has received medical care by another physician since the last visit or is planning to do so 
in the future.  When the subject is going to receive medical care by another physician, the 
investigator, with the consent of the subject, will inform the other physician that the subject is 
participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, SOPs, 
working practice documents, and applicable regulations and guidelines.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 1572 
must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in any 
form to third parties without written permission from Eisai, except for authorized representatives 
of Eisai or appropriate regulatory authorities.
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9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All data, 
both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released for unblinding.  Statistical analyses will be performed 
using SAS software or other validated statistical software as required.  
Descriptive statistics will be presented including mean and standard deviation of photosensitivity 
range for each subject at Screening and at each time point, for each Treatment Visit day by 
treatment group.  Graphical displays of the data for each subject will allow exploration of 
intersubject and intrasubject variability.  Details of statistical methods and analyses will be 
included in a separate statistical analysis plan (SAP).  
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
The reduction in PPR response will be evaluated for 8 hours postdose during each Treatment 
Period.  A diminution in response is anticipated with the dose range.  .
The primary endpoint, the mean change from baseline of the average PPR in the most sensitive is 
analyzed using a mixed effects model for crossover part of the study and summarized for each 
E2082 dose level and placebo regardless of crossover design.  Another endpoint will include 
proportions of subjects with complete suppression, partial response, or no response   
Complete suppression is defined as an SPR reduction to 0 over at least 1 time point for all 3 eye 
conditions. Partial response is defined as a reduction in SPR of at least 3 units from baseline for 
at least 3 time points, and no time points with at least 3 units of increase, in the most sensitive 
eye condition; without meeting the complete suppression definition. The definition of no 
response is as follows: Did not meet complete suppression or partial response definitions.
9.7.1.1.1
PRIMARY ENDPOINT

The primary endpoint of this study is the mean change from baseline in the PPR range in 
each subject’s most sensitive eye condition.
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9.7.1.1.2
SECONDARY ENDPOINTS

Mean change from baseline in the PPR range in each of the 3 eye conditions (eye closure, 
eyes closed, and eyes open) 

Onset, maximum change, and duration of response in each of the 3 eye conditions (eye 
closure, eyes closed, and eyes open) 

Frequency and percentage of subjects with complete suppression, partial response, and no 
response of SPR

Changes from baseline in BL-VAS 

Incidence of TEAEs

Clinically significant changes from baseline in vital signs, serum chemistries, complete 
blood counts, or liver function tests after single doses of E2082, compared to placebo

PK parameters of E2082 (Cmax, tmax, area under concentration-time curve from time 0 to 
8 hours postdose [AUC(0-8h)])
9.7.1.1.3
EXPLORATORY ENDPOINTS

Relationship between plasma exposure of E2082 (PK) and PD response (eg, onset, 
maximum change, and duration of photosensitivity response, BL-VAS)
9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.
The PK Analysis Set is the group of randomized subjects who receive at least 1 dose of study 
drug and have sufficient PK data to derive at least 1 PK parameter.
The PD Analysis Set is the group of randomized subjects who receive at least 1 dose of study 
drug and have sufficient PD data to derive at least 1 PD parameter.
9.7.1.3
Subject Disposition
The number of subjects screened and the number failing Screening (overall and by reason for 
failure) will be summarized.  Screen failure data will be listed.  The number of subjects 
randomized along with the number of subjects administered each dose of E2082 will also be 
presented.
Subjects who prematurely terminate their participation in the study will be summarized by their 
primary reason for study termination.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be summarized 
by dose group for each part of the study using descriptive statistics.  Continuous demographic 
and baseline variables include age, height, and weight; categorical variables include sex, age 
group, and race.  
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9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary. The number (percentage) of subjects who 
took prior and concomitant medications will be summarized by treatment group, Anatomical 
Therapeutic Chemical (ATC) class, and World Health Organization Drug Dictionary preferred 
term (PT).  Prior medications will be defined as medications that stopped before the dose of 
study drug.  Concomitant medications will be defined as medications that started after the date of 
the dose of study drug up to 28 days after the subject’s dose.  All medications will be presented 
in subject data listings.
9.7.1.6
Efficacy Analyses
Not applicable.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The Safety Analysis Set will be used for listings of individual E2082 plasma concentrations.  The 
PK analysis set will be used for summaries of plasma E2082 concentrations and for analyses, 
summaries, and listings of PK parameters.  Plasma concentrations will be tabulated by nominal 
sampling time and summarized by treatment dose using summary statistics.  
The following PK parameters will be derived by noncompartmental analysis using plasma 
concentrations of E2082.  These parameters will include, but are not limited to:

Cmax
maximum observed concentration

AUC(0-8h) area under concentration-time curve from time 0 to 8 hours postdose

tmax
time to reach Cmax following drug administration
The PK of E2082 will be analyzed based on available data from this study.  The PK and PD 
Analysis Sets will be used to evaluate the relationship of PK of E2082 and change in SPR
response.  The PK-PD analyses may include the examination of the relationship of PK of E2082
and SPR (eg, time of onset, maximum change, and duration of response; and BL-VAS data) 
using model-based approaches, data permitting.  Details of the PK/PD analyses will be described 
in a separately prepared analysis plan and its report. 
Analysis variables:
Plasma concentrations of E2082
Analysis set:
The PK Analysis Set will be used for individual plasma concentration 
listings and summaries of plasma concentrations.
Analysis methods:
The PK of E2082 will be analyzed based on available data from this 
study.  Plasma concentrations will be tabulated by nominal sampling time 
and summarized by treatment dose using summary statistics.  
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9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The PD analysis will be performed on the PD Analysis Set.  
No multiplicity adjustments will be made. The 5 PPR measured postdose on a study day will be 
averaged and used for the primary endpoint.  The predose PPR data from the respective 
treatment period will be used as the baseline data.  
The primary and secondary endpoints of mean change from baseline of the average PPR in the 
most sensitive and 3 eye conditions will be analyzed using a mixed effects model for the
crossover part of the study and summarized for each E2082 dose level and placebo regardless of 
crossover design.  The mixed effects model for the crossover part of the study will include 
treatment (E2082 2.5 mg, 25 mg, and placebo), period, and sequence as fixed effects, baseline 
(predose) measurement as a covariate, and subject nested within sequence as a random effect. 
Where data are normally distributed, least squares (LS) means, difference in LS means of each 
E2082 dose (2.5 mg or 25 mg) compared to placebo, and 90% CIs will be presented with no 
adjustments for multiplicity. 
Additional analysis by graphical exploration for the evaluation of onset, maximum change, and 
duration of photosensitivity response at each dose level will be performed for all 3 eye 
conditions for each treatment.  Similarly, frequency and percentage of subjects with complete 
suppression, partial suppression, and no response at each dose level of E2082 will be 
summarized descriptively and graphically for each treatment.
Sensitivity analyses may be conducted for photosensitivity response, for example, in subjects 
who completed all 3 Treatment Periods 1 through 3 versus those who are included in the PD 
Analysis Set. Other exploratory analyses may be conducted as data permit.  
All other PD data (ie, BL-VAS data) will be listed and summarized by treatment, as appropriate, 
using standard summary statistics.  Descriptive summary statistics (eg, mean, SD, median, 
minimum, and maximum for continuous variables, and the number and percent for categorical 
variables) of each endpoint and the changes from baseline will be tabulated.
PK-PD analyses may include the examination of the relationship of PK of E2082 and SPR (eg, 
time of onset, maximum change, and duration of response; and BL-VAS data) using 
model-based approaches, data permitting.  Details of the PK/PD analyses will be described in a 
separately prepared analysis plan and its report.
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety data that will be 
evaluated include AEs, clinical laboratory results, vital signs, ECGs, and neurological/physical 
examinations.  TEAEs will be summarized by presenting for each treatment group, the incidence 
of AEs.  
An assessment of suicidal ideation and behavior using the C-SSRS will be performed throughout 
the study.  
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Descriptive summary statistics (eg, mean, SD, median, minimum, and maximum for continuous 
variables, and the number and percent for categorical variables) of the laboratory, vital signs, and 
ECG parameters, and changes from baseline will be evaluated by treatment group.  The 
proportion of subjects with any treatment-emergent report of suicidal ideation and behavior and 
intensity of these behaviors will be summarized.
9.7.1.8.1
EXTENT OF EXPOSURE
Extent of exposure will be presented by dose level.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA (Version 20.0 or higher) lower level term (LLT) 
closest to the verbatim term.  The linked MedDRA PT and primary system organ class (SOC) are 
also captured in the database.
A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment 
(Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment group, 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]).  A subject data listing of all SAEs, including 
deaths, will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last on-treatment 
value) will be summarized by visit and treatment group using descriptive statistics.  Qualitative 
parameters listed in Section 9.5.1.5.3 will be summarized using frequencies (number and 
percentage of subjects), and changes from baseline to each postbaseline visit and to end of 
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treatment will be reported using shift tables.  Percentages will be based on the number of 
subjects with both nonmissing baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment.  Similar shift tables will also compare the 
baseline LNH classification to the LNH classification for the highest and lowest value during the 
Treatment Period.
Appendix 1 (Sponsor’s Grading for Laboratory Values) presents the criteria that will be used to 
identify subjects with treatment-emergent markedly abnormal laboratory values (TEMAVs).  
Except for phosphate, a TEMAV is defined as a postbaseline value with an increase from 
baseline to a grade of 2 or higher.  For phosphate, a TEMAV was defined as a postbaseline value 
with an increase from baseline to a grade of 3 or higher.  When displaying the incidence of 
TEMAVs, each subject may be counted once in the laboratory parameter high and in the 
laboratory parameter low categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, heart rate, 
respiratory rate, and temperature) and changes from baseline will be presented by visit and 
treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by visit 
and treatment group.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG result 
in QTcF during the Treatment Period will be summarized.  Clinically abnormal ECG results in 
QTcF will be categorized as follows:

For the QT interval assessment, clinically abnormal ECG results for QT interval 
corrected for heart rate using QTcF will be categorized as follows:  QTcF values 
>450 msec, >480 msec, and >500 msec, and time-matched change from baseline in QTcF 
>30 msec and >60 msec.
9.7.1.8.6
OTHER SAFETY ANALYSES
Proportion of subjects with any treatment-emergent report of suicidal ideation and behavior and 
intensity of these behaviors will be summarized.
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9.7.2
Determination of Sample Size
Approximately 9 subjects with photosensitive epilepsy and a stable PPR will be needed to be 
randomized in the study in order to obtain 6 evaluable subjects.  Based on a similar study in 
subjects with photosensitive epilepsy (NCT02564029), an estimated standard deviation of the 
treatment group difference of the SPR in the subject’s most sensitive eye condition is 3.62.  The 
width of a 90% CI of the mean group difference based on this standard deviation assumption and 
6 subjects is 2.431.  Therefore, a sample size of 6 would be sufficient to detect a mean group 
difference of 3 or larger with 90% confidence.
Upon consultation with the sponsor, subjects who discontinue from the study early may be 
replaced.
9.7.3
Interim Analysis
No formal interim analysis is planned.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the revision 
impacts the study and how the revision should be implemented.  The details of the revision will 
be documented and described in the clinical study report.
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10 REFERENCE LIST
Binnie CD, van Emde Boas W, Kasteleijn-Nolste- Trenité DG, de Korte RA, Meijer JW, 
Meinardi H, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia.
1986a;27:248-54.
Binnie CD, Kasteleijn-Nolst Trenité DG, de Korte R. Photosensitivity as a model for acute 
antiepileptic drug studies. Electroencephalogr Clin Neurophysiol. 1986b;63:35-41.
Binnie CD. Preliminary evaluation of potential anti-epileptic drugs by single dose 
electrophysiological and pharmacological studies in patients. J Neural Transm. 1988;72:259-66.
Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol. 
1974;47: 211-8.
French J, Krauss G. Effect of Marketed Antiepileptic Drugs and Placebo in the Human 
Photosensitivity Screening Protocol. Neurotherapeutics. 2014;11:412-18
Kasteleijn-Nolst Trenité, D. , Brandt, C. , Mayer, T. , Rosenow, F. , Schmidt, B. , Steinhoff, B. 
J., Gardin, A. , Imbert, G. , Johns, D. , Sagkriotis, A. and Kucher, K. (2015), Dose-dependent 
suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor 
antagonist BGG492: Clear PK/PD relationship. Epilepsia, 56: 924-932. doi:10.1111/epi.13008
Kasteleijn-Nolst Trenité DG, Genton P, Parain D, Masnou P, Steinhoff BJ, Jacobs T, et al. 
Evaluation of brivaracetam, a novel SV2A ligand, in the photosensitivity model. Neurology.
2007;69:1027-34.
Kasteleijn-Nolst Trenité DG, Marescaux C, Stodieck S, Edelbroek PM, Oosting J. Photosensitive 
epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam 
analogue, levetiracetam. Epilepsy Res. 1996;25:225-30.
Löscher W, Luna-Tortós C, Römermann K, Fedrowitz M.  Do ATP-binding cassette transporters 
cause pharmacoresistance in epilepsy? Problems and approaches in determining which 
antiepileptic drugs are affected. Curr Pharm Des. 2011;17(26):2808-28.
Trenité DG, French JA, Hirsch E, Macher JP, Meyer BU, Grosse PA et al. Evaluation of 
carisbamate, a novel antiepileptic drug, in photosensitive patients: an exploratory, 
placebo-controlled study. Epilepsy Res. 2007;74:193-200.
Columbia-Suicide Severity Rating Scale (C-SSRS). Columbia University. Available from: 
http://www.cssrs.columbia.edu/scales_cssrs.html
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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.  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 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, but the health or regulatory authority and 
IRB 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 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 CRO’s CRA will maintain contact with the investigator and designated staff by telephone, 
letter, or email between study visits.  Monitoring visits to each site will be conducted by the 
assigned CRA as described in the monitoring plan.  The investigator will allow the CRA to 
inspect the clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the local 
auditing agency and to IRB 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 interactive response system, x-rays, 
and other imaging reports (eg, sonograms, computed tomography [CT] scans, magnetic 
resonance images, radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, 
pulmonary function tests) regardless of how these images are stored, including 
microfiche and photographic negatives

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

CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except when a 
section of the CRF itself is used as the source document.  Any correction to entries made on the 
CRF must be documented in a valid audit trail where the correction is dated, the individual 
making the correction is identified, the reason for the change is stated, and the original data are 
not obscured.  Only data required by the protocol for the purposes of the study should be 
collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor and 
retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the investigator is 
responsible for retaining all study documents, including but not limited to the protocol, copies of 
CRFs, the IB, and regulatory agency registration documents (eg, Form FDA 1572, ICFs, and 
IRB correspondence).  In addition, the sponsor will send a list of treatment codes by study 
subject to the investigator after the clinical database for this study has been locked.  The site
should plan to retain study documents, as directed by the sponsor, for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.
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It is requested that at the completion of the required retention period, or should the investigator 
retire or relocate, the investigator contact the sponsor, allowing the sponsor the option of 
permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s SOPs 
to evaluate compliance with the principles of ICH GCP and all applicable local regulations.  If a 
government regulatory authority requests an inspection during the study or after its completion, 
the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs 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, or upon 
notification of the sponsor, and as appropriate during the study, the investigator (or a designated 
pharmacist) will return all used and unused drug containers, drug labels, and a copy of the 
completed drug disposition form to the sponsor’s CRA or, when approval is given by the 
sponsor, will destroy supplies and containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by the sponsor in advance of submission pursuant to 
the terms and conditions set forth in the executed Clinical Trial Agreement between the 
sponsor/CRO and the institution/investigator.  The review is aimed at protecting the sponsor's 
proprietary information existing either at the date of the commencement of the study or 
generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
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11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study should 
be kept confidential by the investigator, the investigator’s staff, and the IRB 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 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 and provide the sponsor and the IRB with a 
detailed written explanation of the termination or suspension.  Study records must be retained as 
noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance with 
all applicable laws and regulations.
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12 APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
Note: Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2082-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Crossover, Single-
Dose Study with An Open-Label Treatment Period Evaluating 
Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy 
Investigational Product
Name:
E2082
IND Number:
134556
SIGNATURES
Authors:
 
 NBG
Eisai, Inc.
Date
 NBG
Eisai, Inc.
Date
 
NBG
Eisai, Inc.
Date
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PPD
PPD
PPD
PPD
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2082-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Crossover, Single-
Dose Study with An Open-Label Treatment Period Evaluating 
Pharmacodynamic Activity of E2082 in Adult Subjects with 
Photosensitive Epilepsy
Investigational Product
Name:
E2082
IND Number:
134556
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good Clinical 
Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
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SAP_001.pdf: 
Clinical Study Report 
E2082-A001-201 
 
16.1.9 
Documentation of Statistical Methods 
The final approved Statistical Analysis Plan for this study is provided in the following pages. 
 
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Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2082-A001-201
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamics Activity of E2082 in Adult Subjects 
with Photosensitive Epilepsy
Date:
4 September 2019
Version:
Final Version 1,0
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Statistical Analysis Plan
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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 Objective ................................................................................5
3.2
Overall Study Design and Plan.............................................................................5
4
DETERMINATION OF SAMPLE SIZE.......................................................................8
5
STATISTICAL METHODS..........................................................................................9
5.1
Study Endpoints...................................................................................................9
5.1.1
Primary Endpoint .......................................................................................9
5.1.2
Secondary Endpoints..................................................................................9
5.2
Study Subjects .....................................................................................................9
5.2.1
Definitions of Analysis Sets........................................................................9
5.2.2
Subject Disposition...................................................................................10
5.2.3
Protocol Deviations ..................................................................................10
5.2.4
Demographic and Other Baseline Characteristics......................................10
5.2.5
Prior and Concomitant Therapy................................................................10
5.2.6
Treatment Compliance .............................................................................10
5.3
Data Analysis General Considerations................................................................10
5.3.1
Pooling of Centers....................................................................................11
5.3.2
Adjustments for Covariates ......................................................................11
5.3.3
Multiple Comparisons/Multiplicity...........................................................11
5.3.4
Examination of Subgroups........................................................................11
5.3.5
Handling of Missing Data, Dropouts, and Outliers....................................11
5.3.6
Other Considerations................................................................................11
5.4
Efficacy Analyses ..............................................................................................12
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................12
5.5.1
Pharmacokinetic Analyses........................................................................12
5.5.2
Pharmacodynamic Analyses.....................................................................12
5.6
Safety Analyses..................................................................................................13
5.6.1
Extent of Exposure...................................................................................13
5.6.2
Adverse Events.........................................................................................13
5.6.3
Laboratory Values ....................................................................................14
5.6.4
Vital Signs................................................................................................15
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5.6.5
Electrocardiograms...................................................................................15
5.6.6
Other Safety Analyses ..............................................................................16
5.7
Other Analyses...................................................................................................16
6
INTERIM ANALYSES...............................................................................................16
7
CHANGES IN THE PLANNED ANALYSES ............................................................16
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................16
8.1
Definitions of Baseline Values...........................................................................16
8.2
Definitions of Treatment Periods........................................................................16
8.3
Definitions of Derived PPR Variables ................................................................16
8.4
Definitions of PK Data Handling........................................................................17
9
PROGRAMMING SPECIFICATIONS .......................................................................17
10
STATISTICAL SOFTWARE......................................................................................17
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................17
12
REFERENCES............................................................................................................17
13
APPENDICES.............................................................................................................18
13.1
Sponsor’s Grading for Laboratory Values ..........................................................18
13.2
SAS Code of Mixed Model for Primary PD Analyses ........................................19
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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ATC
anatomical therapeutic class
BMI
Body Mass Index
BP
blood pressure 
CI
confidence interval 
CRF
case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
EEG-IPS
electrocardiogram
electroencephalogram intermittent photic stimulation
EOT
end of treatment
LNH
low/normal/high
LS
least square
MedDRA
Medical Dictionary for Regulatory Activities
PD
PGx
pharmacodynamic(s)
pharmacogenomic
PK
pharmacokinetic(s)
PPR
photoparoxysmal response
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SD
SI
standard deviation
Système International
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 Eisai Protocol 
E2082-A001-201.
3.1
Study Objectives
3.1.1
Primary Objective
To assess pharmacodynamics (PD) activity of E2082 as measured by suppression of 
epileptic photoparoxysmal response (PPR) in the subject’s most sensitive eye condition 
in the photosensitivity model as a proof of principle of efficacy in subjects with 
photosensitive epilepsy, compared to placebo
3.1.2
Secondary Objectives
The secondary objectives of the study are: 

To assess the PD activity of E2082 as measured by suppression of PPR in each of the 
3 eye conditions (eye closure, eyes closed, and eyes open), compared to placebo

To assess PD activity of E2082 as measured by onset, maximum change, and duration 
of photosensitivity response in each of the 3 eye conditions (eye closure, eyes closed, 
and eyes open)

To assess proportion of subjects with complete suppression, partial suppression, and 
no response of standardized photosensitivity response (SPR)

To assess other central nervous system (CNS)-related effects of E2082 based on 
Bond-Lader Visual Analogue Scale (BL-VAS) 

To assess the safety and tolerability of E2082 following single oral dose 
administration

To assess the pharmacokinetics (PK) of E2082 following single oral dose 
administration
3.1.3
Exploratory Objective
To explore relationships between PK and PD.
3.2
Overall Study Design and Plan
This is a multicenter, double blind, randomized, 6-sequence, 3-treatment, 3-period, crossover 
study with an Open-Label Treatment Period, in adult subjects with photosensitive epilepsy.  
This study will have 2 phases:  Pretreatment Phase and Treatment Phase.  
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The Pretreatment Phase will consist of a Screening Period (up to 3 weeks from Visit 1), during 
which each subject’s study eligibility will be determined.  
The Treatment Phase will consist of 3 blinded Treatment Periods for a randomized crossover 
design, followed by an Open-label Treatment Period.  During the blinded Randomized
Crossover Treatment Periods, there will be 3 Treatment Visits (Visit 2 [Treatment Period 1], 
Visit 3 [Treatment Period 2], and Visit 4 [Treatment Period 3]) evaluating single-dose 
administrations of either placebo, E2082 2.5 mg, or E2082 25 mg in a blinded manner.  
During the open-label treatment period, subjects will be administrated a single dose of E2082 
40 mg.  
A recent protocol amendment (Amendment 01; V2.0) has modified the study design to allow 
for the evaluation of an open-label dose administration of E2082 10 mg in subjects as 
applicable, depending on the scenario the subject falls under and depending on the subject’s 
response (photoparoxysmal response [PPR]) during blinded Treatment Periods, as described 
below.  
Scenario 1:  Newly enrolled or ongoing subjects who have completed up to the Treatment 
Period 3 at the time of Protocol Amendment 01 implementation, will undergo 1 treatment 
visit (Visit 5 [Treatment Period 4]) during the Open-label treatment period to receive a
single-dose administration of E2082 40 mg or 10 mg; the dose to be administered will be 
provided by an independent unblinded biostatistician upon review of the subject’s response 
data collected during Treatment Periods 1 through 3.
Scenario 2:  Subjects who completed the open-label Treatment Period 4 (Visit 5), and have 
not completed the Follow-Up visit [Visit 6]) by the time of Protocol Amendment 01 
implementation may continue the study as originally planned (ie, process to Follow-up Visit 
[Visit 6]) or may continue in the study to receive an additional open-label, single oral dose of 
E2082 10 mg in the Treatment Period 5 (Visit 8) before proceeding to Follow-up Visit (Visit 
9).
Scenario 3: Subjects who completed the study (including Follow-Up visit [Visit 6]) before
the implementation of Protocol Amendment 01 may be allowed to re-enter the study to 
receive an open-label, single-dose administration of E2082 10 mg after Screening 2 (Visit 7) 
dependent on the subject’s response to treatment during the subject’s initial study 
participation.
Treatment visits (i.e., Visit 2, Visit 3, Visit 4, and Visit 5) will each be separated by a 2-week 
(±3 days) washout interval for a total of approximately 6 weeks. Treatment Period 5 (Visit 8) 
will be 2 weeks (±3 days) after Treatment Period 4 (Visit 5) for subjects in Scenario 2, and 
after Screening 2 for subjects in Scenario 3. All subjects will undergo a Follow-up Period of 
2 weeks (±3 days) after the last day of study product administration (Visit 5 and/or Visit 8, as 
applicable). (revised per Amendment 01). 
Each subject will receive a single oral dose in a crossover sequence according to his/her 
randomization code for the treatment sequence in 3 double-blinded treatment periods.
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Table of Treatment Sequences
Sequence
Double-Blind Treatment Periods
1 (V2)
2 (V3) 
3 (V4)
1: ABC
Placebo
E2082 2.5 mg
E2082 25 mg
2: BCA
E2082 2.5 mg
E2082 25 mg
Placebo
3: CAB
E2082 25 mg
Placebo
E2082 2.5 mg
4: ACB
Placebo
E2082 25 mg
E2082 2.5 mg
5: BAC
E2082 2.5 mg
Placebo
E2082 25 mg
6: CBA
E2082 25 mg
E2082 2.5 mg
Placebo
A = Placebo; B = E2082 2.5 mg; C = E2082 25 mg;
An overview of the study design is presented by Figure 1 in the study protocol as follows.
ED = Early discontinuation, FU = Follow Up, Pd = period, R = randomization, Trt = treatment, WO = washout.
Figure 1 : Design for a Crossover Study
Visit:
Screening
-21 to -1
1
57±3
1
15±3
Period:
Phase:
Study Day:
WO Pd 1
(14±3 days)
2
3
4
5
29±3
Pretreatment
Trt Pd 2
(1 day)
WO Pd 2
(14±3 days)
Trt Pd 3
(1 day)
Treatment
Open-label
Treatment
FU Pd
(14±3 days)
6
43±3
Randomized Crossover
Treatment
Follow-Up
Trt Pd 1
(1 day)
WO Pd 3
(14±3 days)
R
Trt Pd 4
(1 day)
Randomization
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An overview of the changes related to amendment is described below in Figure 2.
FU = Follow-up, SCR = screening, Pd = Period
a:
Study days are with respective to the day of Treatment Period 5 (Visit 8).
Figure 2 : Study Design for Subjects in E2082-A001-201 - Scenario 3 
(Revised per Amendment 01)
4
DETERMINATION OF SAMPLE SIZE
Based on a similar study in subjects with photosensitive epilepsy (NCT02564029), an 
estimated standard deviation of the treatment group difference of the SPR in the subject’s most 
sensitive eye condition is 3.62.  The width of a 90% CI of the mean group difference based on 
this standard deviation assumption and 6 subjects is 2.431.  Therefore, a sample size of 6 would 
be sufficient to detect a mean group difference of 3 or larger with 90% confidence.
Approximately 9 subjects with photosensitive epilepsy and a stable PPR will be needed to be 
randomized in the study in order to obtain 6 evaluable subjects.  
A subject will be defined as evaluable if the subject has completed at least 2 treatment periods
(including one with placebo) and has more than 50% non-missing postdose PPR data in each 
period to get the average PPR value (i.e., at least 3 of 5 posedose PPR data are valid in each 
period).   
Subjects who discontinue from the study early may be replaced after consultation with the 
sponsor.
Visit:
Screening 2 
(SCR-2)
7
Period:
Phase:
8
9
Pretreatment
Treatment
Open-label
Treatment
Trt Pd 5
(1 day) 
FU Pd
(14±3 days)
Follow-Up 2
(FU-2)
Study Daya:
-21 to -1
1
15±3
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5
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum unless otherwise specified. Categorical 
variables will be summarized as number (percentage) of subjects.
Study data will be unblinded once double-blind treatment period has completed. Two sets of 
analyses tables will be created: one set after the unblinding using all the available data until 
that point and another set after all the subjects have completed the last study visit.
5.1
Study Endpoints
5.1.1
Primary Endpoint
The primary endpoint is mean change from baseline in the PPR range in each subject’s most 
sensitive eye condition at each dose level of E2082 as compared to placebo.
5.1.2
Secondary Endpoints
•
Mean change from baseline in the PPR range in each of the 3 eye conditions (eye 
closure, eyes closed, and eyes open) at each dose level of E2082 compared to placebo
•
Onset, maximum change, and duration of response in each of the 3 eye conditions 
(eye closure, eyes closed, and eyes open) at each dose level of E2082
•
Frequency and percentage of subjects with complete suppression, partial response, 
and no response of SPR at each dose level of E2082
•
Changes from baseline in BL-VAS at each dose level of E2082
•
Incidence of TEAEs at each dose level of E2082
•
Clinically significant changes from baseline in vital signs, serum chemistries, 
complete blood counts, or liver function tests after single doses of E2082, compared 
to placebo
•
PK parameters of E2082 (Cmax, tmax, area under concentration-time curve from time 0 
to 8 hours postdose [AUC(0-8h)])
•
Relationship between PK parameters of E2082 onset, maximum change, and duration 
of impact on photosensitivity
5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who receive at least 1 dose of study drug and 
have at least 1 postdose safety assessment.
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The Pharmacokinetic Analysis Set is the group of randomized subjects who receive at least 
1 dose of study drug and have sufficient PK data to derive at least 1 PK parameter.
The Pharmacodynamic Analysis Set is the group of randomized subjects who receive at least 
1 dose of study drug and have sufficient PD data to derive at least 1 PD parameter.
5.2.2
Subject Disposition
Number of subjects screened and screening failures (overall and by reason for failure) will be 
summarized.  The number of subjects randomized along with the number of subjects received
each dose of E2082 will also be presented.
Subjects who prematurely terminate their participation in the study will be summarized by 
the primary reason as well as any other reasons(s) for discontinuation from the study. 
5.2.3
Protocol Deviations
Major protocol deviations will be presented as a listing.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized overall using descriptive statistics by treatment groups and overall.
Continuous demographic and baseline variables include age, height, and weight; 
categorical variables include sex, age group, race, and ethnicity.
5.2.5
Prior and Concomitant Therapy
Number (percentage) of subjects who took prior and concomitant medications, will be 
summarized by Anatomical Therapeutic Chemical (ATC) class and World Health 
Organization Drug Dictionary preferred term (PT).
Prior medications will be defined as medications that stopped before the dose of study drug in
treatment period 1. Concomitant medications for a treatment group will be defined as 
medications that started after the date of the dose of study drug up to 28 days after the subject’s
dose or the next dose date in next treatment period, whichever is earlier.  
Prior medications will be summarized overall and concomitant medications will be 
summarized by treatment group. The latest version before database lock will be used for 
analysis. 
5.2.6
Treatment Compliance
Not Applicable. 
5.3
Data Analysis General Considerations
Because of the crossover design of the study, analyses results will be presented by treatment 
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sequence (Sequence 1 to Sequence 6) and by treatment group (Placebo, E2082 2.5 mg, 
E2082 25 mg) as appropriate. For by treatment group summaries, data from subjects 
receiving a given treatment will be combined across various sequences. 
For listings or data summaries where change from baseline measurements will be 
calculated and presented, unless stated otherwise, the last observed measurement, 
including unscheduled assessments, prior to the first dose of study drug in the first period 
will be considered the baseline measurement for all assessments except PPR related 
endpoints.
All descriptive statistics for continuous variables will be reported using number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum 
unless otherwise specified. Categorical variables will be summarized as number and 
percentage of subjects.
Listings will include all subjects, unless specified otherwise, and will be presented 
by sequence, treatment and subject.  
5.3.1
Pooling of Centers 
Subjects from all centers will be pooled for all analyses.
5.3.2
Adjustments for Covariates
Predose (baseline) PPR values will be included in the mixed model as the adjustment for 
covariate. 
5.3.3
Multiple Comparisons/Multiplicity
Not applicable.
5.3.4
Examination of Subgroups
Not applicable. 
5.3.5
Handling of Missing Data, Dropouts, and Outliers
Missing values in PPR will not be imputed in this study.
For PD analyses, two summaries for the primary and secondary PPR endpoints will
be produced, if different, one for all data in PD analysis set and one for all completers.
For safety summaries, all data in Safety Analysis Set will be included.
5.3.6
Other Considerations
Not applicable.
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5.4
Efficacy Analyses
Not Applicable. 
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
5.5.1
Pharmacokinetic Analyses
The Safety Analysis Set will be used for individual listings of E2082plasma concentration-
time data. The PK Analysis set will be used for descriptive statistics of E2082 plasma 
concentration-time data.  Plasma concentrations will be tabulated by nominal sampling time 
and summarized by treatment group.
Various PK parameters will be derived and relationship between PK of E2082 and PD 
parameters will be explored.  These analyses will be specified in separate PK SAP/report.  
5.5.2
Pharmacodynamic Analyses
No multiplicity adjustments will be made. The PPR measurements collected at the 5 postdose 
timepoints on a given treatment day will be averaged and the arithmetic average value will be 
used for both primary endpoint and secondary endpoint analyses.  The predose PPR data 
from the respective treatment period will be used as the baseline data for that period.  The 
following PD analyses will be performed on the PD Analysis Set.  
Primary PD Analyses
The reduction in PPR response will be evaluated for 8 hours postdose during each Treatment 
Period.  A diminution in response is anticipated with the dose range.  
The primary endpoint, mean change from baseline of the average PPR in the most sensitive 
eye condition, will be summarized by treatment group, and analyzed using a mixed effects 
model for crossover part of the study.  The mixed effects model for the crossover part of the 
study will include treatment (E2082 2.5 mg, 25 mg, and placebo), period, and sequence as 
fixed effects, baseline (predose) measurement as a covariate, and subject nested within 
sequence as a random effect. Least squares (LS) means, difference in LS means of each 
E2082 dose (2.5 mg or 25 mg) compared to placebo, and 90% CIs will be presented with no 
adjustments for multiplicity. 
Secondary PD Analyses 
The secondary endpoints of mean change from baseline of the average PPR for each E2082 
dose for all 3 different eye conditions (eye closure, eyes closed, and eyes open) will be 
summarized by treatment group and compared with placebo by using the same mixed effects 
model as for primary PD analyses.  
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Table and figure for the proportions of subjects with complete suppression, partial response, 
or no response will be displayed by treatment group (see section 8.3 for definition of 
complete, partial suppression or no response).
Evaluation of onset, maximum change, and duration of photosensitivity response at each 
dose level will be performed for all 3 eye conditions for each treatment using summary and 
graphical displays.  
Sensitivity analyses may be conducted for photosensitivity response, for example, in subjects 
who completed all 3 Treatment Periods 1 through 3 versus those who are included in the PD 
Analysis Set.  Other exploratory analyses may be conducted as data permit.  
All other PD data (ie, BL-VAS data) may be summarized by treatment groups using standard 
summary statistics.
PK-PD analyses may include examination of relationship between PK of E2082 and SPR (eg, 
time of onset, maximum change, and duration of response; and BL-VAS data) using 
model-based approaches as permitted by data.  Details of the PK/PD analyses will be 
described in a separately prepared analysis plan and its report.
5.6
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety data that will be 
evaluated include adverse events (AEs), clinical laboratory results, vital signs, ECGs, C-SSRS, 
and neurological/physical examinations.  
Treatment-emergent adverse events (TEAEs) will be summarized for each treatment group by
incidence of each AE.  
Descriptive summary statistics of the laboratory, vital signs, and ECG parameters, and changes 
from baseline will be presented by treatment group.  The proportion of subjects with any 
treatment-emergent report of suicidal ideation and behavior and intensity of these behaviors 
will be summarized.
Study Day 1 for all safety analyses will be defined as the date of the dose of study
drug in treatment period 1.
5.6.1
Extent of Exposure
The number of subjects exposed to each study drug dose and placebo will be 
summarized descriptively by treatment group and treatment period.
5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  AEs will be coded to the MedDRA (Version 20.0 or higher) lower level term 
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(LLT) closest to the verbatim term.  The linked MedDRA PT and primary system organ class 
(SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment, having been present at pretreatment (Baseline) but 
stopped before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE 
is continuous.
Only TEAEs will be included in the summary tables.  All AEs, treatment-emergent or 
otherwise, will be presented in subject data listings.  
The TEAEs will be summarized by treatment group 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] or No [not related]).  
The number (percentage) of subjects with treatment-emergent SAEs will be summarized by
the latest edition of MedDRA SOC, and PT. A subject data listing of all SAEs, including 
deaths, will be provided. A subject data listing of all AEs leading to discontinuation from study 
drug will be provided.
5.6.3
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in protocol section 9.5.1.5.3, the actual value and the 
change from baseline to each postbaseline visit, and to the end of treatment (defined as the 
last on-treatment value at that dose) will be summarized by visit and treatment group using 
descriptive statistics.  Qualitative parameters listed in protocol section 9.5.1.5.3 will be 
summarized using frequencies (number and percentage of subjects), and changes from 
baseline to each postbaseline visit and to end of treatment visit via shift tables.  Percentages 
will be based on the number of subjects with both nonmissing baseline and relevant 
postbaseline results.
Number and percentage of subjects with markedly abnormal laboratory values will be 
summarized. Appendix 1 (Sponsor’s Grading for Laboratory Values) below presents the 
criteria that will be used to identify subjects with treatment-emergent markedly abnormal 
laboratory values (TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline 
value with an increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV 
was defined as a postbaseline value with an increase from baseline to a grade of 3 or higher.  
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Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range and presented in the listings.  
When displaying the incidence of TEMAVs, each subject may be counted once in the 
laboratory parameter high and in the laboratory parameter low categories, as applicable.
5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, respiratory 
rate, and temperature) and changes from baseline will be presented by visit and treatment 
group.
In addition, the number (percentage) of subjects with at least 1 clinically notable vital sign 
results will be summarized by treatment groups.  Clinically notable ranges are defined as 
follows:
Variable
Criterion valuea
Change relative to baselinea
Heart rate
>120 bpm
Increase of ≥15 bpm
<50 bpm
Decrease of ≥15 bpm
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
a Clinically notable means that a value must have met both the criterion value and satisfied the 
magnitude of change relative to baseline.
Clinically notable vital sign values will be identified on the listings as those above (H) 
or below (L) a clinically notable range.
5.6.5
Electrocardiograms 
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and treatment group.
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia during the treatment period will be summarized.  Clinically abnormal 
ECG results in QTc Fridericia will be categorized as follows:
For the QT interval assessment, clinically abnormal ECG results for QT interval corrected for 
heart rate using Fridericia’s formula (QTcF) will be categorized as follows: QTcF values 
>450 msec, >480 msec, and >500 msec, and time-matched change from baseline in QTcF 
>30 msec and >60 msec.
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5.6.6
Other Safety Analyses
The results of C-SSRS assessments will be listed for each subject. The incidence of 
suicidal ideation or suicidal behavior may be summarized by treatment group as 
appropriate.
5.7
Other Analyses
Not applicable.
6
INTERIM ANALYSES
No formal interim analyses are planned for this study.
7
CHANGES IN THE PLANNED ANALYSES
There are no changes to the statistical methods in this analysis plan compared to the latest protocol. However, 
there is no data with 10 mg thus the statistical analyses and TLGs do not include 10 mg.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
8.1
Definitions of Baseline Values
For PPR analyses in all treatment periods, the predose PPR data from the respective treatment 
period will be used as baseline data for that period. If predose PPR data is not valid, the average 
PPR value at screening visit will be used as baseline for PPR analyses. 
The baseline value for all safety endpoints will be the last non-missing measurement occurring 
prior to the first dose of study drug in the treatment period 1.
8.2
Definitions of Treatment Periods
Treatment periods 1 to 4 are one-day treatment periods which will include single dose of study 
drug on Day 1 (Visit 2) for treatment period 1, Day 15 (Visit 3) for treatment period 2, Day 29
(Visit 4) for treatment period 3, and Day 43 (Visit 5) for treatment period 4. 
8.3
Definitions of Derived PPR Variables
The followings are definitions for PPR related analyses:

Standard Photosensitivity Response (SPR): a standardized derived measure of the 
range of frequencies of IPS that elicits epileptiform EEG responses in a subject.  The 
range is assigned a number, representing the number of frequency steps, from 0 to 14 
between the lowest to the highest frequencies of IPS that elicits epileptiform activity 
by EEG.  If the upper and lower limit of measured frequencies is the same, SPR will 
be set = 1.
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
Most sensitive eye condition:  SPR is measured in each of 3 eye states: eye closure, 
eyes closed, and eyes open.  That eye condition that yields the largest SPR before 
dosing is defined as the most sensitive eye condition.

Duration of suppression: The difference in hours between the onset of suppression and 
the end of suppression of photosensitivity.  The onset of suppression is defined as the 
first time point at which the SPR was at least 3 units below the mean SPR at baseline.  
The end of suppression is defined as the last time (second time) with two successive 
reductions in SPR of at least 3 units lower than the mean SPR at baseline.

Response: Complete suppression is defined as a standardized photosensitivity response 
(SPR) reduction to 0 over at least 1 time point for all three eye conditions. Partial 
response is defined as a reduction in SPR of at least 3 units from baseline for at least 3 
time points, and no time points with at least 3 units of increase, in the most sensitive 
eye condition; without meeting the complete suppression definition. No response is 
defined as the response not meeting complete suppression or partial suppression 
definitions.
8.4
Definitions of PK Data Handling
Rules for handling PK data for derivation of PK parameters will be defined in separate PK 
report.  When presenting individual/raw values and summary statistics, the following rule 
will be applied: for drug concentrations and all summary statistics will have 3 significant 
digits except for tmax will have 2 decimal places. 
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. 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 Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
13.2 SAS Code of Mixed Model for Primary PD Analyses
proc mixed data= xxx;
  class USUBJID TRTPN PERIOD SEQUENCE ;
  model AVAL = TRTPN PERIOD SEQUENCE BASE /SOLUTION ddfm= kr; 
  random USUBJID(SEQUENCE) ; 
  lsmeans TRTPN/alpha= 0.1 PDIFF CL
  pdiff=control(‘Placebo’) ; 
run;
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SIGNATURE PAGE
Author:  
[electronic signature in eDMS]
Neurology Business Group
Date
Approval:
[electronic signature in eDMS]
Neurology Business Group
Date
[electronic signature in eDMS]
 
 NBG
Eisai, Inc.
Date
Page 21 of 21
PPD
PPD
PPD
PPD
PPD
PPD