Clinical trial NCT03603639
Conditions: Photosensitive Epilepsy
Keywords: E2730 Epilepsy Photosensitive Seizures PPR Anti-epileptic
Sponsor: Eisai Inc.
Start date: 2018-07-27; Completion date: 2019-02-14
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary purpose of the study is to assess the pharmacodynamic (PD) activity of E2730 as measured by suppression of epileptic photoparoxysmal response (PPR) in the participant's most sensitive eye condition in participants with photosensitive epilepsy.

Detailed description:
Adult participants with epilepsy will be enrolled in this study. This study will consist of 2 phases: Prerandomization and Randomization Phase.

The Prerandomization Phase will consist of a Screening Period (up to 3 weeks), during which each participant's study eligibility will be determined and baseline assessments will be conducted. The Randomization Phase will consist of 3 Treatment Periods with a single dose in each period (placebo, E2730 40 mg, or E2730 120 mg), each separated by a 3-week washout interval for a total of approximately 6 weeks, and a Follow-up Period (3 weeks after the last dose of study drug).

Arms: arm 1: Participants will receive a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 1 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 2 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods. arm 2: Participants will receive a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 1 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 2 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods. arm 3: Participants will receive a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 1 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 2 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods. arm 4: Participants will receive a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 1 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 2 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods. arm 5: Participants will receive a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 1 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 2 followed by a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods. arm 6: Participants will receive a single dose of E2730 120 mg, capsule, orally (Treatment C) in Treatment Period 1 followed by a single dose of E2730 40 mg, capsule, orally (Treatment B) in Treatment Period 2 followed by a single dose of E2730-matched placebo, capsule, orally (Treatment A) in Treatment Period 3. A wash-out phase of at least 3-weeks will be maintained between the treatment periods.
Interventions: intervention 1: Placebo intervention 2: E2730
Intervention descriptions: intervention 1: Participants will receive E2730-matched placebo capsule, orally. intervention 2: Participants will receive E2730 capsule, orally.

Protocol documents:
Prot_000.pdf: 
Clinical Study Report 
E2730-A001-201 
 
16.1.1 
Protocol and Protocol Amendments 
The latest version of the study protocol and previous version are provided on the following 
pages: 
• V2.0 Final, 17 Jun 2018 (per Amendment 01) 
• V1.0 Final, 30 May 2018 (original protocol) 
 
 
 
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REVISION HISTORY
Revisions to Version 1.0
Amended version/Date: FINAL:  v2.0, 17 June 2018 (per Administrative Change 01)
Change
Rationale
Affected Protocol Sections
Clarified that a light snack can be 
provided at 30 minutes predose (after 
clinical laboratory blood collection) and 
at 2 hours postdose)
Document quality
Synopsis – Study Design
Clarification of timing of full and brief 
neurological examinations during the 
study.
Document quality and clarity
Table 5, footnote b
Correction of footnote for IPS procedure
Document quality
Table 5
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2730-A001-201
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamic Activity of E2730 in Adult Subjects 
with Photosensitive Epilepsy
Sponsor: 
Eisai Inc.
100 Tice Boulevard, Woodcliff Lake, New Jersey 07677, US
Investigational 
Product Name:
E2730
Indication:
Not applicable
Phase:
2
Approval Date:
V2.0
17 June 2018 (revised original protocol)
V1.0
30 May 2018 (original protocol)
IND Number:
124728
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.:  E2730
Name of Active Ingredient:  
 
Study Protocol Title
A Multicenter, Double-Blind, Randomized, Cross-Over Study Evaluating Pharmacodynamic Activity 
of E2730 in Adult Subjects with Photosensitive Epilepsy
Principal Investigator
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 4 to 5 months.
Phase 2
Objectives
Primary Objective

To assess the pharmacodynamic (PD) activity of E2730 as measured by suppression of 
epileptic photoparoxysmal response (PPR) in the subject’s most sensitive eye condition as a 
proof of principle of efficacy in subjects with photosensitive epilepsy
Secondary Objectives

To assess the PD activity of E2730 as measured by suppression of epileptic PPR, onset, 
maximum change, and duration of response in 3 eye-conditions (eye closure, eyes closed, and 
eyes open) in subjects with photosensitive epilepsy. 

To assess the safety and tolerability of E2730 following a single oral dose in subjects with 
photosensitive epilepsy

To assess the pharmacokinetics (PK) of E2730 following a single oral dose in subjects with 
photosensitive epilepsy

To evaluate potential exposure-PD response relationships

 
 
Study Design
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period cross-over study 
in adult subjects with epilepsy.  This study will use the photosensitivity proof of principle model to 
determine the potential of E2730 to reduce the photosensitive range in adult subjects.  This study will 
have 2 phases: Prerandomization and Randomization.  The Prerandomization Phase will consist of a
Screening Period (up to 3 weeks), during which each subject’s study eligibility will be determined 
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and baseline assessments will be conducted.  The Randomization Phase will consist of 3 Treatment 
Periods with a single dose in each period (placebo, E2730 40 mg, or E2730 120 mg, each separated 
by a 3-week (±3 days) washout interval for a total of approximately 6 weeks), and a Follow-up Period
(a single visit, 3 weeks ±3 days after the last day of study product administration).  All visits will be 
conducted on an outpatient basis.  
At the Screening Visit (Visit 1), subjects will undergo an electroencephalogram intermittent photic 
stimulation (EEG-IPS) assessment in 3 eye-conditions (eye closure, eyes closed, and eyes open) at 
ascending and then descending photo-stimulation frequencies.  The Screening Visit EEG-IPS 
assessment will be performed at 5 time points, over an approximately 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 standardized photosensitivity response (SPR) scale in at least 1 eye 
condition on at least 3 of the EEGs performed at Screening will be eligible for the study.  The 
baseline assessments will be conducted, including determination of the lower and upper limit of 
photosensitivity to IPS threshold frequency for each eye condition.  Qualified medical personnel for 
the management of acute seizures will be present during the day of EEG-IPS procedure throughout 
the duration of the study.
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 will be 
randomized, enter the Randomization Phase, and will begin Treatment Period 1.  
Subjects meeting eligibility criteria will be randomized into 1 of 6 treatment sequences to receive, in 
a blinded fashion, a single oral dose of placebo control, E2730 40 mg, or E2730 120 mg and begin 
the Randomization Phase.  On the day of each Treatment Visit (ie, Day 1, Day 22, Day 43), subjects 
will arrive at the clinic in the morning following an overnight fast of at least 8 hours, and the baseline 
assessments will be conducted again at predose, including determination of the lower and upper limit 
of photosensitivity to IPS threshold frequency for each eye condition.  Study drug product 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 at at 30 minites pre-dose (after clinical laboratory blood collection) and 2 hours postdose
(revised per Administrative Change 01).  Water will be permitted ad libitum except from the time of 
dosing until 1 hour postdose. Each treatment period will be separated by a 3-week (±3 days) washout 
interval. 
The safety, tolerability, and PK of E2730 will be assessed.  A full neurological examination and vital 
signs evaluation will be performed at screening and a brief neurological examination will be 
performed at predose and at scheduled time points after dosing.  E2730 activity will be characterized 
by EEG-IPS, for a minimum of 2.5 minutes under all eye conditions (eye closure, eyes open, and
eyes closed) on each treatment day.  EEG-IPS sessions will be assessed on Day 1 (Visit 2), Day 22
(Visit 3), and Day 43 (Visit 4) at 30 minutes to 2 hours predose and 1, 2, 4, 6, and 8 hours postdose 
time points. The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered at 
screening, postdose at the end of every treatment visit, and at the Follow-up/Early discontinuation 
visit.  Bond and Lader scale for central nervous system (CNS)–related sedative adverse effects will be 
measured for each subject at predose, 1, 2, 4, 6, and 8 hours postdose at every visit.  There will be an 
interval of 21±3 days between scheduled subsequent visits between dosing days.  
After completing Treatment Period 3, all subjects will enter the Follow-up period during which they 
will be required to complete a Follow-up visit at 3 weeks ±3 days following the last day of study 
product administration.  The end of study is defined as the last subject completing the Follow-up 
Visit.  The anticipated study participation duration for each subject is approximately 12 weeks.  
Early Discontinuation
Subjects who discontinue study drug before completing all treatments in the study, for any reason,
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will undergo an Early Discontinuation (ED) Visit within 3 weeks ±3 days of their last dose of study 
drug.
Number of Subjects
Approximately 9 subjects will be randomized to achieve 6 evaluable subjects.  Subjects who 
discontinue from the study early may be replaced, after consultation with the sponsor.
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 history of a PPR on EEG with or without a diagnosis of epilepsy.
3.
Currently taking up to a maximum of 3 concomitant antiepileptic drugs (AEDs).  If taking 
concomitant AED(s), the dose must have remained stable for at least 4 weeks prior to 
screening.
4.
A reproducible IPS-induced PPR on EEG of at least 3 points on a frequency assessment scale 
(SPR) in at least 1 eye condition on at least 3 of the EEGs performed at Screening.
5.
A body mass index (BMI) between 18 to 35 kg/m2 and a total body weight greater than or 
equal to 45 kg at the time of Screening.
6.
Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour period 
before Screening and during the 24-hour period prior to 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: 
0.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).  
A separate baseline assessment is required if a negative screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug. 
1.
Females of childbearing potential who:
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) 
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 
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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). 
2.
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.
3.
History of nonepileptic seizures (eg, metabolic, structural, or pseudoseizures) while on any 
antiepileptic medication(s).
4.
History of status epilepticus while on any antiepileptic medication(s) within 2 years prior to 
Screening.
5.
Ongoing or history of generalized tonic-clonic seizures within 6 months prior to Screening.
6.
Previously developed or who experienced a clinical seizure during prior PPR assessment or 
screening IPS procedure, respectively. 
7.
 
8.
Multiple drug allergies or a severe drug reaction to AED(s), including dermatological (eg, 
Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
9.
Current evidence of 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.
10. An 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.
11. Current evidence of clinically significant active liver disease, porphyria, or with a family 
history of severe hepatic dysfunction indicated by abnormal liver function tests greater than 
3 times the upper limit of normal (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
12. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
13. Known to be human immunodeficiency virus (HIV) positive.
14. History of drug or alcohol dependency or abuse within the 12 months before Screening, or 
those who have a positive drug test or alcohol test at Screening.
15. Concomitant use of cannabinoids.  
16. Inability to follow restriction on watching television, or use of any device with an animated 
screen (ie, computer, video games, tablets) 24 hours before dosing.
17. 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 (QTc) interval; or prolonged QT/QTc interval 
(QTc >450 msec) demonstrated on ECG at Screening or Baseline (based on average of 
triplicate ECGs).  
18. 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).
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19. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
20. 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.
21. Currently enrolled in another clinical study or used any investigational drug or device within 
30 days or 5 half-lives, whichever is longer, preceding informed consent, except the 
investigational study for the evaluation of commercial IPS machine.
22. Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening.
Study Treatments
Test Drug:  E2730
E2730 will be supplied as active pharmaceutical ingredient in capsule at dose strengths of 40 mg and 
80 mg.
Comparator Drug:  E2730-matched placebo
Each subject will receive a single oral dose of E2730 40 mg, E2730 120 mg, and matched-placebo in 
a cross-over sequence according to his/her randomization code.  
E2730 40 mg: 1 E2730 40 mg capsule and 1 E2730-matched placebo capsule
E2730 120 mg: 1 E2730 80 mg capsule and 1 E2730 40 mg capsule   
Placebo: 2 E2730-matched placebo capsules
Duration of Treatment
Single dose (ie, the Randomization Phase will consist of 3 Treatment Periods with a single dose in 
each period)
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 prior to Screening.  During the study, 
changes to concomitant AEDs (including dosage) are not permitted. 
Assessments
Efficacy Assessments
Not applicable
Pharmacokinetic Assessments
Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite 
(M1) will be collected at predose and postdose at 1, 2, 4, 6, and 8 hours on Day 1 (Visit 2), Day 22
(Visit 3), and Day 43 (Visit 4). In case of early discontinuation, a PK sample will be taken.
Pharmacodynamic Assessments
PD activity of E2730 will be assessed by suppression of PPR following IPS under 3 conditions (eye 
closure, eyes closed, and eyes open) using the Grass PS 33 photic stimulator with an unpatterned 
glass lamp and an intensity of 100cd/m2/flash at 30 minutes to 2 hours predose, and at 1, 2, 4, 6, and 
8 hours postdose.  The time course (30 minutes to 2 hours predose to 8 hours postdose) will help 
assess the onset, maximum change, and duration of the reduction in PPR response.  PPR is expected 
to be within the range from 2 Hz to 60 Hz, depending on subject sensitivity to IPS.
The Bond and Lader Visual Analogue Scale (VAS) for CNS–related sedation effects will be 
measured for each subject at predose, 1, 2, 4, 6, and 8 hours postdose on Day 1 (Visit 2), Day 22 
(Visit 3), and Day 43 (Visit 4).
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All PD assessments will be performed within ±15 minutes of the scheduled time point.
 
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs); laboratory 
evaluation for hematology, blood chemistry, and urine values; measurement of vital signs and ECGs; 
and the performance of neurological and physical examinations.  
An assessment of suicidality using the C-SSRS will be performed at Screening, during each 
Treatment visit (postdose), and at the Follow-up/ED Visit.
Other Assessments
Not applicable
Bioanalytical Methods
Plasma concentrations of E2730 and the N-acetyl metabolite (M1) will be measured using validated 
liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) methods.
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 at each 
dose level of E2730 as compared to placebo
Secondary Endpoints

Mean changes from baseline in PPR ranges in each subject’s eye closure, eyes closed, and 
eyes open condition at each dose level of E2730 as compared to placebo

Onset, maximum change, and duration of photosensitivity response at each dose level in all 3 
eye conditions at the time course of E2730 as compared to placebo 

Frequency and percentage of subjects with Complete Suppression, Partial Response, and no 
Response of PPR at each dose level of E2730 as compared to placebo

Occurrence of AEs or changes in the neurological examination after single doses of E2730 
compared to placebo

Changes in vital signs, serum chemistries, complete blood counts, or liver function tests after 
single doses of E2730 compared to placebo

PK of E2730 and its N-acetyl metabolite, M1

Relationship between PK parameters of E2730 onset, maximum change, and duration of 
impact on photosensitivity
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 Pharmacokinetic Analysis Set is the group of randomized subjects who receive at least 1 dose of 
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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.
Efficacy Analyses
Not Applicable
Pharmacokinetic, Pharmacodynamic, 
 Analyses
Pharmacokinetic Analyses
The PK Analysis Set will be used for listings of individual E2730 and N-acetyl metabolite (M1) 
plasma concentrations, 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 E2730 and M1.  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 E2730 will be analyzed based on available data from this study.  The PK and PD Analysis 
datasets will be used to evaluate the relationship of PK of E2730 and change in PPR response.  The
PK-PD analyses may include the examination of the relationship of PK of E2730 and PPR response 
(eg, time of onset, maximum change, and duration of PPR; Bond and Lader data) using model-based 
approaches.
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 for each 
E2730 dose compared with placebo in the most sensitive and different eye conditions will be 
performed using a mixed effects model for crossover study.  The model will include treatment, 
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 E2730 dose compared to placebo, and 90% CIs will be 
presented with no adjustments for multiplicity. 
Additional analysis by graphical exploration on onset, maximum change, and duration of 
photosensitivity response at each dose level will be performed for all 3 eye conditions at the time 
course of E2730 as compared to placebo.  This analysis will provide further information on the 
frequency and percentage of subjects with Complete Suppression, Partial Response, and No Response 
of PPR at each dose level of E2730 as compared to placebo.
Sensitivity analyses for PPR may be conducted, for example, of PPR for subjects who completed 
Treatment Periods 1-3 versus those who are included in the PD Analysis Set.
 
All PD data (Bond and Lader) 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.
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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.  
Treatment-emergent adverse events (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.....................................................................................................................2
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................3
3
TABLE OF CONTENTS.................................................................................................11
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................16
5
ETHICS............................................................................................................................18
5.1
Institutional Review Boards/Independent Ethics Committees ..............................18
5.2
Ethical Conduct of the Study.................................................................................18
5.3
Subject Information and Informed Consent...........................................................19
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................19
7
INTRODUCTION ...........................................................................................................20
7.1
Indication ...............................................................................................................20
7.1.1
Mechanism of Action – E2730 ....................................................................20
7.1.2
Clinical Experience With E2730 .................................................................20
7.1.2.1
Pharmacokinetics.................................................................................21
7.1.2.2
Safety and Tolerability.........................................................................22
7.2
Study Rationale......................................................................................................22
7.2.1
Photosensitivity Proof of Concept Model....................................................22
8
STUDY OBJECTIVES....................................................................................................24
8.1
Primary Objective..................................................................................................24
8.2
Secondary Objectives.............................................................................................24
8.3
............................................................................................25
9
INVESTIGATIONAL PLAN..........................................................................................25
9.1
Overall Study Design and Plan..............................................................................25
9.1.1
Prerandomization Phase...............................................................................26
9.1.1.1
Screening Period..................................................................................26
9.1.2
Randomization Phase...................................................................................27
9.1.2.1
Treatment Periods................................................................................27
9.1.2.2
Follow-up Period .................................................................................27
9.2
Discussion of Study Design, Including Choice of Control Groups.......................27
9.3
Selection of Study Population................................................................................28
9.3.1
Inclusion Criteria .........................................................................................28
9.3.2
Exclusion Criteria ........................................................................................28
9.3.3
Removal of Subjects From Therapy or Assessment....................................30
9.3.3.1
Study-Specific Withdrawal Criteria.....................................................30
9.4
Treatment(s)...........................................................................................................31
9.4.1
Treatment(s) Administered..........................................................................31
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9.4.2
Identity of Investigational Product(s) ..........................................................32
9.4.2.1
Chemical Name, Structural Formula of E2730....................................32
9.4.2.2
Comparator Drug .................................................................................32
9.4.2.3
Labeling for Study Drug......................................................................32
9.4.2.4
Storage Conditions...............................................................................32
9.4.3
Method of Assigning Subjects to Treatment Groups...................................32
9.4.4
Selection of Doses in the Study...................................................................32
9.4.5
Selection and Timing of Dose for Each Subject..........................................33
9.4.6
Blinding........................................................................................................33
9.4.7
Prior and Concomitant Therapy...................................................................34
9.4.7.1
Prohibited Concomitant Therapies and Drugs.....................................34
9.4.7.2
Restrictions During the Study Period ..................................................34
9.4.8
Treatment Compliance.................................................................................34
9.4.9
Drug Supplies and Accountability...............................................................34
9.5
Study Assessments.................................................................................................36
9.5.1
Assessments.................................................................................................36
9.5.1.1
Demography.........................................................................................36
9.5.1.2
Baseline Assessments ..........................................................................36
9.5.1.2.1
Medical History and Epilepsy Medical History.............................36
9.5.1.2.2
Height Measurement and BMI computation..................................36
9.5.1.2.3
Urine Drug Test .............................................................................36
9.5.1.2.4
Serology.........................................................................................36
9.5.1.3
Efficacy Assessments...........................................................................37
9.5.1.4
Pharmacokinetic, Pharmacodynamic, 
 
 Assessments.............................................................37
9.5.1.4.1
Pharmacokinetic Assessments .......................................................37
9.5.1.4.2
Pharmacodynamic,
 
Assessments...................................................................................37
9.5.1.5
Safety Assessments..............................................................................38
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...38
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................40
9.5.1.5.3
Laboratory Measurements .............................................................41
9.5.1.5.4
Vital Signs and Weight Measurements..........................................42
9.5.1.5.5
Physical Examinations...................................................................43
9.5.1.5.6
Neurological Examinations............................................................43
9.5.1.5.7
Electrocardiograms ........................................................................43
9.5.1.5.8
Other Safety Assessments..............................................................44
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9.5.2
Schedule of Procedures/Assessments ..........................................................44
9.5.2.1
Schedule of Procedures/Assessments ..................................................44
9.5.2.2
Description of Procedures/Assessments Schedule...............................48
9.5.3
Appropriateness of Measurements...............................................................48
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated With Special Situations .............................................................48
9.5.4.1
Reporting of Serious Adverse Events..................................................48
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................49
9.5.4.3
Reporting of Events Associated With Special Situations....................50
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................50
9.5.4.4
Expedited Reporting ............................................................................50
9.5.4.5
Breaking the Blind...............................................................................50
9.5.4.6
Regulatory Reporting of Adverse Events ............................................51
9.5.5
Completion/Discontinuation of Subjects.....................................................51
9.5.6
Abuse or Diversion of Study Drug ..............................................................51
9.5.7
Confirmation of Medical Care by Another Physician .................................51
9.6
Data Quality Assurance .........................................................................................52
9.6.1
Data Collection ............................................................................................52
9.6.2
Clinical Data Management ..........................................................................52
9.7
Statistical Methods.................................................................................................52
9.7.1
Statistical and Analytical Plans....................................................................52
9.7.1.1
Study Endpoints...................................................................................53
9.7.1.1.1
Primary Endpoint...........................................................................53
9.7.1.1.2
Secondary Endpoints .....................................................................53
9.7.1.2
Definitions of Analysis Sets.................................................................53
9.7.1.3
Subject Disposition..............................................................................54
9.7.1.4
Demographic and Other Baseline Characteristics ...............................54
9.7.1.5
Prior and Concomitant Therapy...........................................................54
9.7.1.6
Efficacy Analyses ................................................................................54
9.7.1.7
Pharmacokinetic, Pharmacodynamic, 
 
 Analyses...................................................................54
9.7.1.7.1
Pharmacokinetic Analyses.............................................................54
9.7.1.7.2
Pharmacodynamic, 
 
Analyses.........................................................................................55
9.7.1.8
Safety Analyses....................................................................................56
9.7.1.8.1
Extent of Exposure.........................................................................56
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9.7.1.8.2
Adverse Events ..............................................................................56
9.7.1.8.3
Laboratory Values..........................................................................57
9.7.1.8.4
Vital Signs......................................................................................57
9.7.1.8.5
Electrocardiograms ........................................................................57
9.7.1.8.6
Other Safety Analyses....................................................................58
9.7.2
Determination of Sample Size .....................................................................58
9.7.3
Interim Analysis...........................................................................................58
9.7.4
Other Statistical/Analytical Issues ...............................................................58
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................58
10
REFERENCE LIST .........................................................................................................59
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......60
11.1
Changes to the Protocol .........................................................................................60
11.2
Adherence to the Protocol......................................................................................60
11.3
Monitoring Procedures...........................................................................................60
11.4
Recording of Data..................................................................................................61
11.5
Identification of Source Data.................................................................................61
11.6
Retention of Records..............................................................................................61
11.7
Auditing Procedures and Inspection......................................................................62
11.8
Handling of Study Drug.........................................................................................62
11.9
Publication of Results ............................................................................................62
11.10 Disclosure and Confidentiality ..............................................................................63
11.11 Discontinuation of Study .......................................................................................63
11.12 Subject Insurance and Indemnity...........................................................................63
12
APPENDICES .................................................................................................................64
LIST OF IN-TEXT TABLES
Table 1
PK Parameters In Study 001 (20 mg) and Study 002 (40 mg, 80 mg, 
and 120 mg) ...............................................................................................21
Table 2
Treatments Administered...........................................................................31
Table 3
Treatment Sequences .................................................................................31
Table 4
Clinical Laboratory Tests...........................................................................42
Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201.............45
Table 6
Blood Sampling Schedule for Pharmacokinetic Assessments...................48
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for a Crossover Study..........................................................26
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LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................65
Appendix 2
Prohibited Concomitant Medications ........................................................67
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
AUC(0-24)
area under the concentration-time curve from 0 time to fixed time 24 hours
AUC(0-inf)
area under the concentration-time curve from 0 time extrapolated to infinity
time
β-hCG
beta human chorionic gonadotropin
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
CV
coefficient of variance
ED
Early Discontinuation (Visit)
EEG-IPS
electroencephalogram intermittent photic stimulation
GM
geometric mean
hCG
human chorionic gonadotropin
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
LNH
low/normal/high
LS
least squares
M1
E2730 N-acetyl metabolite
MedDRA
Medical Dictionary for Regulatory Activities
Max
maximum
Min
minimum
n/a
not applicable
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Abbreviation
Term
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetics
POC
proof-of-concept
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
t1/2
terminal elimination phase half-life
tmax
time at which the highest drug concentration occurs
VAS
Visual Analogue Scale
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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 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 the study will be the date of the last study visit for the last subject in the study.  
The sponsor should also provide the IRB 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 Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject 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 initial goal is to develop E2730 as an antiepileptic drug (AED) in patients with a rare 
form of epilepsy, in parallel with partial-onset seizure studies in adolescents and adults.  The 
selection of the disease candidate for orphan drug treatment will be based on ongoing and 
planned preclinical studies in house and at external institutions.  
7.1.1
Mechanism of Action – E2730
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
7.1.2
Clinical Experience With E2730
The E2730 clinical program to date comprises 1 completed Phase 1 study in which 6 healthy 
subjects received single doses of E2730 (20 mg) and 2 healthy subjects received placebo.  
The first-in-human single ascending dose (SAD) study of E2730 (E2730-A001-001; 
Study 001), was initially planned to administer E2730 with dose escalation conducted in 
sequential dose groups consisting of 8 subjects per group randomized (3:1) to receive single 
ascending E2730 doses of 20, 40, or 80 mg or E2730-matched placebo.  Dose escalation 
could only occur if the available data supported an increase in dose that did not exceed 
plasma E2730 exposures predefined for Cmax=1.5 μg/mL or area under the 
concentration-time curve from zero time extrapolated to infinite time 
(AUC(0-inf))=20μg•h/mL.  This threshold was originally required by the Food and Drug 
Administration (FDA) and was reached with the first E2730 dose (20 mg).  Thus, no higher 
E2730 doses were administered.
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The SAD study (E2730-A001-002; Study 002) is currently ongoing, where doses of 40, 80, 
120, and 160 mg are planned in healthy subjects.  The proposed doses are anticipated not to 
exceed 3 μg/mL, per the FDA’s revised limit on the Cmax, and the data will be evaluated on 
an ongoing basis during each dose escalation.  The anticipated Cmax of the highest dose 
cohort (120 mg cohort) in the current study is likely not to exceed the prespecified threshold. 
7.1.2.1
Pharmacokinetics
In Study 001 and Study 002, which enrolled healthy subjects (18-50 years); E2730 was 
rapidly absorbed after a single oral administration of 20, 40, 80, and 120 mg.  Plasma E2730 
concentrations peaked at 1.25 to 5.5 hours.  The N-acetyl metabolite (M1) was sparsely 
detected just above or at the lower limit of quantification, thus a complete plasma M1 
pharmacokinetic (PK) profile could not be derived.  Pharmacokinetic parameters in Study 
001 and Study 002 are shown in Table 1.  Although Cmax and AUC(0-24) were less than dose 
proportional between 20 mg and 40 mg, there was almost dose proportional from 40 mg 
through 120 mg.  The highest individual Cmax value (2.930 μg/mL) of 120 mg was not to 
exceed the prespecified threshold of 3 μg/mL.  There was 1 subject who had low plasma 
E2730 concentration (Cmax: 0.222 μg/mL) in the 120 mg cohort.  The plasma E2730 
concentration declined with a mean terminal elimination phase half-life (t1/2) of 59.0 to 
69.8 hours. 
Table 1
PK Parameters In Study 001 (20 mg) and Study 002 (40 mg, 80 mg,
and 120 mg)
Dose
tmax (h)
Cmax (ng/mL)
AUC(0-24)
(ng•h/mL)
AUC(0-inf)
(ng•h/mL)
t½ (h)
20 mg
1.25
(0.50, 1.50)
351
(22.7) 
6330
(23.9) 
28600
(11.5) 
69.8
(21.9) 
40 mg
3.00
(1.50, 6.00)
496
(20.3)
9210
(19.6)
41300
(15.9)
69.7
(15.2)
80 mg
5.50
(1.00, 8.00)
899
(14) 
16900
(12.7) 
61100
(6.44) 
59.0
(15.8) 
120 mg
4.50
(0.50, 8.00)
1270
(116)
23300
(110)
n/aa
n/aa
AUC(0-24) = area under the concentration-time curve from 0 time to fixed time 24 hours; AUC(0-inf) = area under 
the concentration-time curve from 0 time extrapolated to infinity time; PK = pharmacokinetics, max = 
maximum; min = minimum; t1/2 = terminal elimination phase half-life; tmax = time at which the highest drug 
concentration occurs, n/a = not applicable; CV = coefficient of variance.
Note:  All PK parameters, except tmax, are presented as geometric mean (%CV).  tmax is presented as median 
(min, max).
a.
As of the data cut-off date of 22 May 2018, plasma concentrations of E2730 at 120 mg are available until 
24 hours post dose. 
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After administration of E2730 20 mg, the GM percent of recovered parent drug in urine 
collected up to 96 hours postdose was 21.8% and a smaller fraction (GM=0.728%) was 
excreted as M1.
7.1.2.2
Safety and Tolerability
E2730 was well tolerated in healthy adult subjects when administered as single oral doses 
across the dose range of 20 to 120 mg (Study 001 and Study 002).  The maximum tolerated 
dose (MTD) has not yet been reached (Study 002).
Among 6 subjects who received 20 mg E2730 (Study 001), 1 subject experienced a TEAE 
(postural orthostatic tachycardia syndrome) on the day of administration.  The event was 
mild in severity and resolved on the same day without treatment.  The investigator judged the 
event to be related to the study drug.  Another subject experienced a TEAE (dizziness) on the 
day of placebo administration.  The event was mild in severity and resolved on the same day 
without treatment.  The investigator judged the event to be related to the study drug.  
From the blinded preliminary safety results in 40 mg and 80 mg, 4 subjects experienced 
6 TEAEs (sleepiness, insomnia, nausea, drowsiness [2 subjects], and decrease appetite) and 4 
subjects experienced 8 TEAEs (orthostatic tachycardia [2 subjects], dermatitis contact, 
atrioventricular block, dizziness, headache, insomnia, and diarrhea), respectively.  There 
were no medically significant findings from vital signs in 40 mg and 80 mg cohorts.
In the 120 mg cohort, the safety data have been reviewed through Day 13.  Clinically 
significant findings in vital signs were reported for 2 subjects, which were characterized as 
AEs of orthostatic tachycardia and hypotension.  Both AEs were mild and in both cases, 
subjects were asymptomatic.  There were no deaths or SAEs, and no medically significant 
findings have been reported from EEG or ECG (no significant QT or QTc prolongations).  
There have been no clinically significant laboratory abnormalities.  There were no 
epileptiform discharges or clinically significant abnormalities of EEG observed in the 40 mg, 
80 mg, or 120 mg dose cohorts.
7.2
Study Rationale
7.2.1
Photosensitivity Proof of Concept Model
 
 
 
 
 
 
 
 
 
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to assess the PD activity of E2730 as measured by 
suppression of epileptic PPR in the subject’s most sensitive eye condition as a proof of 
principle of efficacy in subjects with photosensitive epilepsy.
8.2
Secondary Objectives
The secondary objectives of the study are: 

To assess the PD activity of E2730 as measured by suppression of epileptic PPR, 
onset, maximum change, and duration of response in 3 eye-conditions (eye closure, 
eyes closed, and eyes open) in subjects with photosensitive epilepsy. 
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
To assess the safety and tolerability of E2730 following a single oral dose in subjects
with photosensitive epilepsy.

To assess the PK of E2730 following a single oral dose in subjects with 
photosensitive epilepsy.

To evaluate potential exposure-PD response relationships.
8.3
 
 
 
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period cross-over 
study in adult subjects with epilepsy.  This study will use the photosensitivity proof of 
principle model to determine the potential of E2730 to reduce the photosensitive range in 
adult subjects.  This study will have 2 phases: Prerandomization and Randomization.  The 
Prerandomization Phase will consist of a Screening Period (up to 3 weeks), during which 
each subject’s study eligibility will be determined and baseline assessments will be 
conducted.  The Randomization Phase will consist of 3 Treatment Periods with a single dose 
in each period (placebo, E2730 40 mg, or E2730 120 mg, each separated by a 3-week
(±3 days) washout interval for a total of approximately 6 weeks), and a Follow-up Period (a 
single visit, 3 weeks ±3 days after the last day of study product administration).  All visits
will be conducted on an outpatient basis.  
An overview of the study design is presented in Figure 1.
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Figure 1
Study Design for a Crossover Study
ED = Early discontinuation, FU = Follow Up, Pd = period, R = randomization, Trt = treatment, WO = washout
9.1.1
Prerandomization Phase
The Prerandomization Phase will consist of a Screening Period (up to 3 weeks), during which 
each subject’s study eligibility will be determined and baseline assessments will be 
conducted.  
9.1.1.1
Screening Period
Screening will occur between Day –21 and Day –1.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.
Subjects must have a diagnosis and history of a PPR on EEG with or without a diagnosis of 
epilepsy for which they are receiving up to 3 concomitant AEDs.
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.
Visit:
Screening/Baseline
R
Trt Pd 1 
(1 day)
-21 to -1
1
64±3
Period 1
Period 2
1
22±3
Phase:
Period:
Study Day:
WO Pd 1 
(21±3 days)
2
3
4
5
43±3
Prerandomization
Trt Pd 2 
(1 day)
WO Pd 2
(21±3 days)
Trt Pd 3
(1 day)
WO Pd 3
(21±3 days)
Period 3
Treatment
Follow-up
FU Visit (or 
ED visit) 
(1 day)
Randomization
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At the Screening Visit (Visit 1), subjects will undergo an EEG-IPS assessment in 
3 eye-conditions (eye closure, eyes closed, and eyes open) at ascending and then descending 
photo-stimulation frequencies.  The Screening Visit EEG-IPS assessment will be performed 
at 5 time points, over an approximately 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.  The baseline assessments will be conducted, 
including determination of the lower and upper limit of photosensitivity to intermittent photic 
stimulation (EEG-IPS) threshold frequency for each eye condition.  Qualified medical 
personnel for the management of acute seizures will be present during the day of EEG-IPS 
procedure throughout the duration of the study.  
9.1.2
Randomization Phase
The duration of the Randomization Phase will be 9 weeks and will include 3 Treatment 
Periods (placebo, E2730 40 mg or E2730 120 mg, each separated by a 3-week (±3 days)
washout interval, for a total of approximately 6 weeks), and a Follow-up Period (a single 
visit, 3 weeks ±3 days after the last day of study product administration).  Subjects whose 
screening assessments and evaluations (including Day 1 [Visit 2] procedures) are completed 
and reviewed by the investigator and who continue to meet all of the inclusion/exclusion 
criteria will enter the Randomization Phase.  The baseline assessments will be conducted 
again at predose of each Treatment Period, including determination of the lower and upper 
limit of photosensitivity to IPS threshold frequency for each eye condition.
9.1.2.1
Treatment Periods
Subjects will be randomized into 1 of 6 treatment sequences to receive placebo, E2730 
40 mg, or E2730 120 mg. Each of the 3 treatment periods will be separated by a 3-week
(±3 days) washout interval. 
9.1.2.2
Follow-up Period
After completing Treatment Period 3, all subjects will enter the Follow-up period during 
which they will be required to complete a Follow-up visit.  The Follow-up Period is a single 
visit, 3 weeks ±3 days after the last day of study product administration.
9.2
Discussion of Study Design, Including Choice of Control Groups
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
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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 old at the time of informed consent. 
2. A diagnosis and history of a PPR on EEG with or without a diagnosis of epilepsy.
3. Currently taking up to a maximum of 3 concomitant antiepileptic drugs (AEDs).  If 
taking concomitant AED(s), the dose must have remained stable for at least 4 weeks prior 
to screening.
4. A reproducible IPS-induced PPR on EEG of at least 3 points on a frequency assessment 
scale (SPR) in at least 1 eye condition on at least 3 of the EEGs performed at Screening.
5. A body mass index (BMI) between 18 to 35 kg/m2 and a total body weight greater than or 
equal to 45 kg at the time of Screening.
6. Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour
period before Screening and during the 24-hour period prior to each treatment day.
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 [ß-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or 
hCG]).  A separate baseline assessment is required if a negative screening pregnancy test 
was obtained more than 72 hours before the 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 
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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 prior 
to Screening.
6. Ongoing or history of generalized tonic-clonic seizures within 6 months prior to 
Screening.
7. Previously developed or who experienced a clinical seizure during prior PPR assessment
or screening IPS procedure, respectively. 
8.
 
9. Multiple drug allergies or a severe drug reaction to AED(s), including dermatological (eg, 
Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
10. Current evidence of 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. An active central nervous system (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.
12. Current evidence of clinically significant active liver disease, porphyria, or with a family 
history of severe hepatic dysfunction indicated by abnormal liver function tests greater 
than 3 times the upper limit of normal (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
13. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
14. Known to be human immunodeficiency virus (HIV) positive.
15. History of drug or alcohol dependency or abuse within the 12 months before Screening, 
or those who have a positive drug test or alcohol test at Screening.
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16. Concomitant use of cannabinoids.  
17. Inability to follow restriction on watching television, or use of any device with an 
animated screen (ie, computer, video games, tablets) 24 hours before dosing.
18. 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 (QTc) interval; or prolonged QT/QTc 
interval (QTc >450 msec) demonstrated on ECG at Screening or Baseline (based on 
average of triplicate ECGs).  
19. 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).
20. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
21. 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.
22. Currently enrolled in another clinical study or used any investigational drug or device 
within 30 days or 5 half-lives, whichever is longer, preceding informed consent, except 
the investigational study for the evaluation of commercial IPS machine.
23. Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening. 
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.
9.3.3.1
Study-Specific Withdrawal 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. 
A subject may be withdrawn from the study if any of the following circumstances occur:
1. If a subject experiences a generalized tonic-clonic seizure on any study day, and the 
subject has not had a generalized tonic-clonic seizure in the 6 months prior to enrollment, 
that subject will be discontinued from the study.
OR
1. If a subject experiences a generalized tonic-clonic seizure during IPS, 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.
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3. If a subject has widening of the photosensitivity range by more than 3 points on 
2 consecutive occasions after dosing as compared to Screening, the IPS will be 
terminated and the subject will not be permitted to participate in further testing on the 
same day.
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. 
9.4
Treatment(s)
9.4.1
Treatment(s) Administered
E2730 is the test drug and will be supplied as active pharmaceutical ingredient in capsule at 
dose strengths of 40 mg and 80 mg.  Study site personnel will administer capsules containing 
E2730 or matched placebo (Table 2) as single oral doses according to the study design.  
Filled capsules will be packed, labelled, and shipped by the contract manufacturer to each 
site. 
Each subject will receive a single oral dose in a cross-over sequence according to his/her 
randomization code (Table 3). The following treatments will be administered as a single dose 
to subjects.  

E2730 40 mg: 1 E2730 40 mg capsule and 1 E2730-matched placebo capsule

E2730 120 mg: 1 E2730 80 mg capsule and 1 E2730 40 mg capsule   

Placebo: 2 E2730-matched placebo capsules 
Table 2
Treatments Administered
Treatment
Study Drug Administered
A
Placebo
B
E2730 40 mg
C
E2730 120 mg
Table 3
Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
Treatment Period 3
1: ABC
Placebo
E2730 40 mg
E2730 120 mg
2: BCA
E2730 40 mg
E2730 120 mg
Placebo
3: CAB
E2730 120 mg
Placebo
E2730 40 mg
4: ACB
Placebo
E2730 120 mg
E2730 40 mg
5: BAC
E2730 40 mg
Placebo
E2730 120 mg
6: CBA
E2730 120 mg
E2730 40 mg
Placebo
A = Placebo; B = E2730 40 mg; C = E2730 120 mg
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9.4.2
Identity of Investigational Product(s)
E2730 will be supplied in powder form as the free base.
9.4.2.1
Chemical Name, Structural Formula of E2730

Test drug code:  E2730
9.4.2.2
Comparator Drug
Placebo capsule matched to E2730 capsule will be administered.
9.4.2.3
Labeling for Study Drug
E2730 will be labeled in accordance with text that is in full regulatory compliance.
9.4.2.4
Storage Conditions
E2730 will be stored in accordance with labeled storage conditions.  Temperature monitoring 
is required at the storage location to ensure that E2730 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
Subjects will be assigned to all 3 treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
9.4.4
Selection of Doses in the Study
E2730 is currently studied in the SAD study (Study 002).  In rat amygdala kindling model, 
which is considered the most clinically relevant animal model for investigating the effect of 
compound on partial-onset seizures, E2730 showed a significant and dose-dependent 
antiseizure effect after the single oral administration.    
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Two doses are currently being considered for this study.  Based on the data from the ongoing 
Study 002, the anticipated exposure at the dose of 120 mg will be within the exposure limits 
imposed by the FDA.  An additional, lower dose of 40 mg is being considered to provide 
exposure data to further evaluate PK/PD relationship of E2730.  The data from this study will 
also support initial dose response analysis and provide a dose for future studies. 
The doses in this study will be finalized after all cohorts in Study 002 have been evaluated.
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, Day 1, Day 22, and Day 43).  A light snack can be provided at 30 minutes predose 
(after clinical laboratory blood collection) and at 2 hours postdose.  
9.4.6
Blinding
During the Prerandomization and Randomization Phases, central EEG reading will be 
performed in a blinded and independent manner.  Investigator(s) may consult with the central 
read only during the Prerandomization Phase, if needed, for EEG-IPS eligibility 
determination.  
During the Randomization Phase, 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 staff 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 E2730 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 capsules 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.  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.
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9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent) will be recorded on the 
Prior & Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  Up to 
3 concomitant AEDs (Appendix 2) are allowed during the course of the study, provided that 
the dosage of concomitant AED(s) has remained stable for at least 4 weeks prior to 
screening.  During the study, changes to concomitant AEDs (including dosage) are not 
permitted.
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
 
 
9.4.7.2
Restrictions During the Study Period
Study drug will be administered on the day of each Treatment Visit (ie, Day 1, Day 22, and 
Day 43) after an overnight fast of at least 8 hours.  Treatments will be administered orally 
with approximately 240 mL (8 fluid ounces) of water.  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.
Subjects will be required to abstain from watching television or using any device with an 
animated screen (ie, computer, video games, tablets) within the 24 hour period prior to each 
dosing.  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 prior to each 
treatment day.  
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
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
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 and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
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 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 
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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, race/ethnicity.
9.5.1.2
Baseline 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 designated time points as specified in the 
Schedule of Procedures/Assessments (Table 5).  This sample will be tested for common 
drugs of use/abuse:  eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, opioids (as a 
group), benzodiazepines, barbiturates, and amphetamines.
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, 
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples for determination of plasma concentrations of E2730 and its metabolite, M1,
will be collected from each subject.  PK sampling for plasma concentration will be collected 
at predose and postdose at 1, 2, 4, 6, and 8 hours on Day 1 (Visit 2), Day 22 (Visit 3), and 
Day 43 (Visit 4).  In case of early discontinuation, a PK sample will be taken.  Plasma 
concentrations of E2730 and M1 will be measured using validated liquid chromatography 
coupled with tandem mass spectrometry (LC-MS/MS) methods.
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,
ASSESSMENTS
All PD assessments will be performed within ±15 minutes of the scheduled time point.
EEG-IPS
PD activity of E2730 will be assessed by suppression of PPR following IPS under 
3 conditions (eye closure, eye closed, eye open) using the Grass PS 33 photic stimulator with 
an unpatterned glass lamp and an intensity of 100cd/m2/flash at 30 minutes to 2 hours 
predose, and at 1, 2, 4, 6, and 8 hours postdose.  The time course (30 minutes to 2 hours 
predose to 8 hours postdose) will help assess the onset, maximum change, and duration of the 
reduction in PPR response.  PPR is expected to be within the range, from 2 Hz to 60 Hz,
depending on subject 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 
EA).  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
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
Display speed: 30 mm/sec
Bond and Lader Visual Analogue Scale
The Bond and Lader visual analogue scale (VAS) for CNS–related sedation effects will be 
measured for each subject at predose, 1, 2, 4, 6, and 8 hours postdose on Day 1 (Visit 2), Day 
22 (Visit 3), and Day 43 (Visit 4).  
 
 
 
 
 
  
 
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; 
and the performance of neurological and physical examinations as detailed in Table 5.
An assessment of suicidality using the C-SSRS will be performed as detailed in 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 E2730. 
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 in the Randomization Phase and for 5× the 
half-life of E2730 (mean terminal elimination phase half-life following a single 
administration of 20 mg E2730 was 71.2 hours in Study 001).  Subjects who fail screening 
primarily due to AE(s) must have the AE(s) leading to screen failure reported on the 
Screening Disposition CRF.  Serious adverse events (SAEs) must be collected through the 
last visit in the Randomization Phase and for 5× the half-life of E2730 (mean terminal 
elimination phase half-life following a single administration of 20 mg E2730 was 71.2 hours
in Study 001)..
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 QTc interval 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
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Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 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)
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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. 
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, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 5) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study. 
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Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, 
calcium, 
cholesterol, 
globulin, 
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], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 5) 
by a validated method.  BP and pulse will be measured after the subject has been supine for 
10 minutes.  Triplicate reading of supine vital signs will be measured at all visits except for 
Screening.  All BP measurements should be performed on the same arm, preferably by the 
same person.
At Screening and during Visit 2, Visit 3, and Visit 4, after supine measurements are 
completed, subjects will be asked to stand up for 2 minutes, and BP and pulse will be taken 
in the standing position. 
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 to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
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At time points when vital signs, ECGs, and blood sampling are performed concurrently, 
procedures will be performed in the following order: ECGs, vital signs, and then blood 
sampling. Subjects will rest in the supine position for 10 minutes before and 5 minutes after 
ECG recordings followed by recording of vital signs in the supine position and in standing 
position (BP and pulse only), and lastly blood sampling.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Comprehensive and abbreviated physical examinations will be performed as designated in 
the Schedule of Procedures/Assessments (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.  Changes from screening physical examination findings that meet the definition of an 
AE will be recorded on the AE CRF.
Comprehensive Physical Examination
A comprehensive 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
Comprehensive and abbreviated neurological examinations will be performed as designated 
in the Schedule of Procedures/Assessments (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.  Changes from screening neurological examination findings that meet the definition of 
an AE will be recorded on the AE CRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
Electrocardiograms (12-lead) will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 5).  
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the AE CRF.
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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, postdose at 
the end of every treatment visit, and at the Follow-up/Early discontinuation visit, as 
designated in the Schedule of Procedures/Assessments (Table 5).
Pregnancy Test
A serum β-hCG or hCG test will be performed for all women of childbearing potential.  A 
6-mL sample of blood will be taken at designated time points as specified in the Schedule of 
Procedures/Assessments (Table 5).
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 5 presents the schedule of procedures/assessments for the study.
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Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201
Phase
Prerandomization
Randomization
Unscheduled
Period
Screening
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-up /Early 
Discontinuationa
Visit
1
2
3
4
5
Study Day
-21 to -1
1
22±3
43±3
64±3
Procedures/Assessments
Informed Consent
X
Demography 
X
Randomization
X
Inclusion/exclusion criteria
X
X
Medical history
X
Epilepsy medical history
X
Physical examinationb
X
X
X
Neurological examinationb
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
Height and weightd
X
X
X
12-Lead ECGe
X
X
X
X
X
Xf
Clinical laboratory testsg
X
X
X
X
X
X
Urine drug test
X
Urine pregnancy testh
X
X
X
X
Serum β-hCG [or hCG] testh
X
Serology (HCVAb, HBsAg)
X
PK sampling (plasma)i
X
X
X
X
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Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201
Phase
Prerandomization
Randomization
Unscheduled
Period
Screening
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-up /Early 
Discontinuationa
Visit
1
2
3
4
5
Study Day
-21 to -1
1
22±3
43±3
64±3
Procedures/Assessments
X
C-SSRS
X
X
X
X
X
EEG-IPS Assessmentk
Xl
Xm
Xm
Xm
Bond and Lader VASk,n
X
X
X
Administer study drug
X
X
X
Prior and concomitant medication(s)
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
ß-hCG = beta-human chorionic gonadotropin (or hCG = human chorionic gonadotropin), BP = blood pressure, C-SSRS = Columbia-Suicide Severity Rating Scale, EEG-IPS= 
electroencephalogram- intermittent photic stimulation, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody,
PK = pharmacokinetics, QTc = corrected QT interval, VAS = visual analogue scale.
a:
To be completed for all subjects, including those who discontinue the study early.
b:
A full physical examination will be carried out at Screening. A brief physical examination may be carried out at other visits, as deemed necessary by the 
investigator.  A full neurological examination will be performed at screening.  A brief neurological examination will be performed during each treatment 
visit (predose and at 4 hours [±30 minutes] postdose), and during the Follow up/Early Discontinuation visit.  Clinically significant abnormal findings from 
the physical or the neurological examinations will be reported as AEs.
c:
Vital signs measurements will be taken at screening.  In addition, on each dosing day, vital sign (BP, pulse, body temperature, respiratory rate) 
measurements will be obtained at predose, 1, 2, 4, 6, and 8 hours postdose.  Subjects will need to rest for 10 minutes before vital signs are taken in the 
supine position.  Triplicate reading of supine vital signs will be measured at all visits except for Screening.  At Screening and during the Treatment 
periods, after supine measurements are completed, subjects will be asked to stand up for 2 minutes, and BP and pulse will be taken in the standing 
position.  At time points when vital signs, ECGs, and blood sampling are performed concurrently, procedures will be performed in the following order:  
ECGs, vital signs, and then blood sampling.  Subjects will rest in the supine position for 10 minutes before and 5 minutes after ECG recordings followed 
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Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201
Phase
Prerandomization
Randomization
Unscheduled
Period
Screening
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-up /Early 
Discontinuationa
Visit
1
2
3
4
5
Study Day
-21 to -1
1
22±3
43±3
64±3
Procedures/Assessments
by recording of vital signs in the supine position and in standing position (BP and pulse only), and lastly blood sampling.
d:
At Screening, both height and weight will be measured.  At all other visits, only weight will be measured. 
e:
ECG assessments will be performed in the supine position at predose and 4 hours postdose (on each dosing day). If during any visit the QTc was 
measured as >450 msec, 3 consecutive ECGs separated by 5 – 10 minutes will be performed to confirm the abnormality.  
f:
During the unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the investigator.
g:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
h:
Female subjects of childbearing potential only. 
i:
Blood samples for plasma PK will be obtained at predose and postdose at 1, 2, 4, 6, and 8 hours on Days 1, 22, and 43.  In case of early discontinuation, a 
PK sample will be taken. 
j:
 
k:
All PD assessments will be performed within ±15 minutes of the scheduled time point.
l:
EEG-IPS assessment will be performed at 5 time points, over an approximately 4-hour time period (0, 1, 2, 3, and 4 hours).
m:
EEG-IPS assessment will be performed 30 minutes to 2 hours predose and repeated at approximately 1, 2, 4, 6, and 8 hours postdose on Days 1, 22, and 
43.
n:
The Bond and Lader VAS for CNS–related sedation side effects will be measured from each subject at predose, 1, 2, 4, 6, and 8 hours postdose on Days 1, 
22, and 43.  
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Table 6 presents the blood sampling schedule for pharmacokinetic assessments.  In case of 
early discontinuation, a PK sample will be taken. 
Table 6
Blood Sampling Schedule for Pharmacokinetic Assessments
Days
Time Relative to the Administration
Acceptable Time Window
Day 1 (Visit 2),
Day 22 (Visit 3) (±3 days),
Day 43 (Visit 4) (±3 days)
Predose
–2 hours
1 and 2 hours
±5 minutes
4, 6, and 8 hours
±15 minutes
9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in 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, Bond and Lader VAS will be conducted in 
this study.  The Bond and Lader VAS (Bond, 1974) is a sensitive tool to assess CNS side 
effects (somnolence, body sway, dizziness and sedation etc.).  Since CNS related side effects 
were observed in nonclinical studies of E2730, Bond and Lader VAS is included for 
assessment of CNS-related sedation effects in this study.
The EEG-IPS procedure during this study will be performed based upon the protocol of 
Kastelejin et al (Kastelejin-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 EEG-IPS 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.
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SAEs, regardless of causality assessment, must be collected through the last visit in the 
Randomization Phase and for 5× the half-life of E2730 (mean terminal elimination phase 
half-life following a single administration of 20 mg E2730 was 71.2 hours in Study 001).  All 
SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE 
judged by the investigator to be related to the study treatment or any protocol-required 
procedure should be reported to the sponsor regardless of the length of time that has passed 
since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
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 
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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
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 
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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 are to complete the study’s ED procedures 
indicated in the Schedule of Procedures/Assessments (Table 5).
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.
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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.
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.
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9.7.1.1
Study Endpoints
The reduction in PPR response will be evaluated for 8 hours postdose for the entire time 
period.  A diminution in response is anticipated with the dose range.  A statistical difference 
of treatment doses versus placebo will be evaluated.
The primary endpoint, the change in the PPR range, is evaluated using mixed effects model 
for comparing low and high treatment doses versus placebo.  Another endpoint will include 
proportions of subjects responding to treatment versus placebo.  Most patients have strong 
responses to effective treatments compared to placebo, which can be evaluated by graphs of 
partial response (ie, 3 steps narrowing) and abolition of PPR.  
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 at each dose level of E2730 as compared to 
placebo.
9.7.1.1.2
SECONDARY ENDPOINTS

Mean changes from baseline in PPR ranges in each subject’s eye closure, eyes closed, 
and eyes open condition at each dose level of E2730 as compared to placebo

Onset, maximum change, and duration of photosensitivity response at each dose level in 
all 3 eye conditions at the time course of E2730 as compared to placebo

Frequency and percentage of subjects with Complete Suppression, Partial Response, and 
no Response of PPR at each dose level of E2730 as compared to placebo

Occurrence of AEs or changes in the neurological examination after single doses of 
E2730 compared to placebo

Changes in vital signs, serum chemistries, complete blood counts, or liver function tests
after single doses of E2730 compared to placebo

PK of E2730 and its N-acetyl metabolite, M1

Relationship between PK parameters of E2730 onset, maximum change, and duration of 
impact on photosensitivity
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 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.
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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.
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 E2730 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.  
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, 
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for listings of individual E2730 and M1 plasma 
concentrations, 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 E2730 and M1.  These parameters will include, but are not limited to:
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
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 E2730 will be analyzed based on available data from this study.  The PK and PD 
Analysis datasets will be used to evaluate the relationship of PK of E2730 and change in PPR 
response.  The PK-PD analyses may include the examination of the relationship of PK of 
E2730 and PPR response (eg, time of onset, maximum change, and duration of PPR; Bond 
and Lader data) using model-based approaches.
Analysis variables:
Plasma concentrations of E2730 and N-acetyl metabolite (M1)
Analysis set:
The Pharmacokinetic Analysis Set will be used for individual plasma 
concentration listings and summaries of plasma concentrations.
Analysis methods:
The PK of E2730 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,
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 for 
each E2730 dose compared with placebo in the most sensitive and different eye conditions 
will be performed using a mixed effects model for crossover study.  The model will include 
treatment, 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 E2730 dose compared 
to placebo, and 90% CIs will be presented with no adjustments for multiplicity. 
Additional analysis by graphical exploration on onset, maximum change, and duration of 
photosensitivity response at each dose level will be performed for all 3 eye conditions at the 
time course of E2730 as compared to placebo.  This analysis will provide further information 
on the frequency and percentage of subjects with Complete Suppression, Partial Response, 
and No Response of PPR at each dose level of E2730 as compared to placebo.
Sensitivity analyses for PPR may be conducted, for example, of PPR for subjects who 
completed Treatment Periods 1-3 versus those who are included in the PD Analysis Set. 
  All PD data (Bond and Lader) 
will be listed and summarized by treatment, as appropriate, using standard summary 
statistics.  Descriptive summary statistics (eg, mean, SD, median, minimum, and maximum 
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for continuous variables, and the number and percent for categorical variables) of each 
endpoint and the changes from baseline will be tabulated.
 
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.  Treatment-emergent adverse events (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 
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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 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, pulse, 
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.
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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 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.
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.
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
 
 
 
 
Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br. J. med. 
Psychol. 1974; 47: 211-8.
 
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.
 
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, 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 Investigator's Brochure, 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 
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ICH region or at least 3 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department 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 principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused
drug supply before approval to do so by the sponsor.  At the conclusion of the study, 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
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
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; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Prohibited Concomitant Medications 
Prohibited Concomitant Medication
The above list of prohibited concomitant medications is not exhaustive. 
The investigator should provide further guidance before switching any of the concomitant medications 
mentioned in the above list.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2730-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamic Activity of E2730 in Adult 
Subjects with Photosensitive Epilepsy 
Investigational Product
Name:
E2730
IND Number:
124728
SIGNATURES
Authors:
Eisai, Inc.
Date
Eisai, Inc.
Date
Eisai, Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2730-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamic Activity of E2730 in Adult 
Subjects with Photosensitive Epilepsy
Investigational Product
Name:
E2730
IND Number:
124728
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:
E2730-A001-201
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamic Activity of E2730 in Adult Subjects 
with Photosensitive Epilepsy
Sponsor: 
Eisai Inc.
100 Tice Boulevard, Woodcliff Lake, New Jersey 07677, US
Investigational 
Product Name:
E2730
Indication:
Not applicable
Phase:
2
Approval Date:
V1.0
30 May 2018 (original protocol)
IND Number:
124728
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.:  E2730
Name of Active Ingredient:  
 
Study Protocol Title
A Multicenter, Double-Blind, Randomized, Cross-Over Study Evaluating Pharmacodynamic Activity 
of E2730 in Adult Subjects with Photosensitive Epilepsy
Principal Investigator
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 4 to 5 months.
Phase 2
Objectives
Primary Objective

To assess the pharmacodynamic (PD) activity of E2730 as measured by suppression of 
epileptic photoparoxysmal response (PPR) in the subject’s most sensitive eye condition as a 
proof of principle of efficacy in subjects with photosensitive epilepsy
Secondary Objectives

To assess the PD activity of E2730 as measured by suppression of epileptic PPR, onset, 
maximum change, and duration of response in 3 eye-conditions (eye closure, eyes closed, and 
eyes open) in subjects with photosensitive epilepsy. 

To assess the safety and tolerability of E2730 following a single oral dose in subjects with 
photosensitive epilepsy

To assess the pharmacokinetics (PK) of E2730 following a single oral dose in subjects with 
photosensitive epilepsy

To evaluate potential exposure-PD response relationships

 
 
Study Design
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period cross-over study 
in adult subjects with epilepsy.  This study will use the photosensitivity proof of principle model to 
determine the potential of E2730 to reduce the photosensitive range in adult subjects.  This study will 
have 2 phases: Prerandomization and Randomization.  The Prerandomization Phase will consist of a
Screening Period (up to 3 weeks), during which each subject’s study eligibility will be determined 
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and baseline assessments will be conducted.  The Randomization Phase will consist of 3 Treatment 
Periods with a single dose in each period (placebo, E2730 40 mg, or E2730 120 mg, each separated 
by a 3-week (±3 days) washout interval for a total of approximately 6 weeks), and a Follow-up Period
(a single visit, 3 weeks ±3 days after the last day of study product administration).  All visits will be 
conducted on an outpatient basis.  
At the Screening Visit (Visit 1), subjects will undergo an electroencephalogram intermittent photic 
stimulation (EEG-IPS) assessment in 3 eye-conditions (eye closure, eyes closed, and eyes open) at 
ascending and then descending photo-stimulation frequencies.  The Screening Visit EEG-IPS 
assessment will be performed at 5 time points, over an approximately 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 standardized photosensitivity response (SPR) scale in at least 1 eye 
condition on at least 3 of the EEGs performed at Screening will be eligible for the study.  The 
baseline assessments will be conducted, including determination of the lower and upper limit of 
photosensitivity to IPS threshold frequency for each eye condition.  Qualified medical personnel for 
the management of acute seizures will be present during the day of EEG-IPS procedure throughout 
the duration of the study.
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 will be 
randomized, enter the Randomization Phase, and will begin Treatment Period 1.  
Subjects meeting eligibility criteria will be randomized into 1 of 6 treatment sequences to receive, in 
a blinded fashion, a single oral dose of placebo control, E2730 40 mg, or E2730 120 mg and begin 
the Randomization Phase.  On the day of each Treatment Visit (ie, Day 1, Day 22, Day 43), subjects 
will arrive at the clinic in the morning following an overnight fast of at least 8 hours, and the baseline 
assessments will be conducted again at predose, including determination of the lower and upper limit 
of photosensitivity to IPS threshold frequency for each eye condition.  Study drug product 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 at 2 hours postdose.  Water will be permitted ad libitum except from the time of dosing until
1 hour postdose. Each treatment period will be separated by a 3-week (±3 days) washout interval. 
The safety, tolerability, and PK of E2730 will be assessed.  A full neurological examination and vital 
signs evaluation will be performed at screening and a brief neurological examination will be 
performed at predose and at scheduled time points after dosing.  E2730 activity will be characterized 
by EEG-IPS, for a minimum of 2.5 minutes under all eye conditions (eye closure, eyes open, and
eyes closed) on each treatment day.  EEG-IPS sessions will be assessed on Day 1 (Visit 2), Day 22
(Visit 3), and Day 43 (Visit 4) at 30 minutes to 2 hours predose and 1, 2, 4, 6, and 8 hours postdose 
time points. The Columbia-Suicide Severity Rating Scale (C-SSRS) will be administered at 
screening, postdose at the end of every treatment visit, and at the Follow-up/Early discontinuation 
visit.  Bond and Lader scale for central nervous system (CNS)–related sedative adverse effects will be 
measured for each subject at predose, 1, 2, 4, 6, and 8 hours postdose at every visit.  There will be an 
interval of 21±3 days between scheduled subsequent visits between dosing days.  
After completing Treatment Period 3, all subjects will enter the Follow-up period during which they 
will be required to complete a Follow-up visit at 3 weeks ±3 days following the last day of study 
product administration.  The end of study is defined as the last subject completing the Follow-up 
Visit.  The anticipated study participation duration for each subject is approximately 12 weeks.  
Early Discontinuation
Subjects who discontinue study drug before completing all treatments in the study, for any reason,
will undergo an Early Discontinuation (ED) Visit within 3 weeks ±3 days of their last dose of study 
drug.
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Number of Subjects
Approximately 9 subjects will be randomized to achieve 6 evaluable subjects.  Subjects who 
discontinue from the study early may be replaced, after consultation with the sponsor.
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 history of a PPR on EEG with or without a diagnosis of epilepsy.
3.
Currently taking up to a maximum of 3 concomitant antiepileptic drugs (AEDs).  If taking 
concomitant AED(s), the dose must have remained stable for at least 4 weeks prior to 
screening.
4.
A reproducible IPS-induced PPR on EEG of at least 3 points on a frequency assessment scale 
(SPR) in at least 1 eye condition on at least 3 of the EEGs performed at Screening.
5.
A body mass index (BMI) between 18 to 35 kg/m2 and a total body weight greater than or 
equal to 45 kg at the time of Screening.
6.
Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour period 
before Screening and during the 24-hour period prior to 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 [ß-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).  
A separate baseline assessment is required if a negative screening pregnancy test was 
obtained more than 72 hours before the 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, 
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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 prior to 
Screening.
6.
Ongoing or history of generalized tonic-clonic seizures within 6 months prior to Screening.
7.
Previously developed or who experienced a clinical seizure during prior PPR assessment or 
screening IPS procedure, respectively. 
8.
 
9.
Multiple drug allergies or a severe drug reaction to AED(s), including dermatological (eg, 
Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
10. Current evidence of 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. An 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.
12. Current evidence of clinically significant active liver disease, porphyria, or with a family 
history of severe hepatic dysfunction indicated by abnormal liver function tests greater than 
3 times the upper limit of normal (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
13. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
14. Known to be human immunodeficiency virus (HIV) positive.
15. History of drug or alcohol dependency or abuse within the 12 months before Screening, or 
those who have a positive drug test or alcohol test at Screening.
16. Concomitant use of cannabinoids.  
17. Inability to follow restriction on watching television, or use of any device with an animated 
screen (ie, computer, video games, tablets) 24 hours before dosing.
18. 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 (QTc) interval; or prolonged QT/QTc interval 
(QTc >450 msec) demonstrated on ECG at Screening or Baseline (based on average of 
triplicate ECGs).  
19. 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).
20. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
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21. 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.
22. Currently enrolled in another clinical study or used any investigational drug or device within 
30 days or 5 half-lives, whichever is longer, preceding informed consent, except the 
investigational study for the evaluation of commercial IPS machine.
23. Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening.
Study Treatments
Test Drug:  E2730
E2730 will be supplied as active pharmaceutical ingredient in capsule at dose strengths of 40 mg and 
80 mg.
Comparator Drug:  E2730-matched placebo
Each subject will receive a single oral dose of E2730 40 mg, E2730 120 mg, and matched-placebo in 
a cross-over sequence according to his/her randomization code.  
E2730 40 mg: 1 E2730 40 mg capsule and 1 E2730-matched placebo capsule
E2730 120 mg: 1 E2730 80 mg capsule and 1 E2730 40 mg capsule   
Placebo: 2 E2730-matched placebo capsules
Duration of Treatment
Single dose (ie, the Randomization Phase will consist of 3 Treatment Periods with a single dose in 
each period)
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 prior to Screening.  During the study, 
changes to concomitant AEDs (including dosage) are not permitted. 
Assessments
Efficacy Assessments
Not applicable
Pharmacokinetic Assessments
Blood samples for the determination of E2730 plasma concentrations and its N-acetyl metabolite 
(M1) will be collected at predose and postdose at 1, 2, 4, 6, and 8 hours on Day 1 (Visit 2), Day 22
(Visit 3), and Day 43 (Visit 4). In case of early discontinuation, a PK sample will be taken.
Pharmacodynamic Assessments
PD activity of E2730 will be assessed by suppression of PPR following IPS under 3 conditions (eye 
closure, eyes closed, and eyes open) using the Grass PS 33 photic stimulator with an unpatterned 
glass lamp and an intensity of 100cd/m2/flash at 30 minutes to 2 hours predose, and at 1, 2, 4, 6, and 
8 hours postdose.  The time course (30 minutes to 2 hours predose to 8 hours postdose) will help 
assess the onset, maximum change, and duration of the reduction in PPR response.  PPR is expected 
to be within the range from 2 Hz to 60 Hz, depending on subject sensitivity to IPS.
The Bond and Lader Visual Analogue Scale (VAS) for CNS–related sedation effects will be 
measured for each subject at predose, 1, 2, 4, 6, and 8 hours postdose on Day 1 (Visit 2), Day 22 
(Visit 3), and Day 43 (Visit 4).
All PD assessments will be performed within ±15 minutes of the scheduled time point.
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Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs); laboratory 
evaluation for hematology, blood chemistry, and urine values; measurement of vital signs and ECGs; 
and the performance of neurological and physical examinations.  
An assessment of suicidality using the C-SSRS will be performed at Screening, during each 
Treatment visit (postdose), and at the Follow-up/ED Visit.
Other Assessments
Not applicable
Bioanalytical Methods
Plasma concentrations of E2730 and the N-acetyl metabolite (M1) will be measured using validated 
liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) methods.
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 at each 
dose level of E2730 as compared to placebo
Secondary Endpoints

Mean changes from baseline in PPR ranges in each subject’s eye closure, eyes closed, and 
eyes open condition at each dose level of E2730 as compared to placebo

Onset, maximum change, and duration of photosensitivity response at each dose level in all 3 
eye conditions at the time course of E2730 as compared to placebo 

Frequency and percentage of subjects with Complete Suppression, Partial Response, and no 
Response of PPR at each dose level of E2730 as compared to placebo

Occurrence of AEs or changes in the neurological examination after single doses of E2730 
compared to placebo

Changes in vital signs, serum chemistries, complete blood counts, or liver function tests after 
single doses of E2730 compared to placebo

PK of E2730 and its N-acetyl metabolite, M1

Relationship between PK parameters of E2730 onset, maximum change, and duration of 
impact on photosensitivity
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 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.
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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.
Efficacy Analyses
Not Applicable
Pharmacokinetic, Pharmacodynamic, 
 Analyses
Pharmacokinetic Analyses
The PK Analysis Set will be used for listings of individual E2730 and N-acetyl metabolite (M1) 
plasma concentrations, 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 E2730 and M1.  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 E2730 will be analyzed based on available data from this study.  The PK and PD Analysis 
datasets will be used to evaluate the relationship of PK of E2730 and change in PPR response.  The
PK-PD analyses may include the examination of the relationship of PK of E2730 and PPR response 
(eg, time of onset, maximum change, and duration of PPR; Bond and Lader data) using model-based 
approaches.
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 for each
E2730 dose compared with placebo in the most sensitive and different eye conditions will be 
performed using a mixed effects model for crossover study.  The model will include treatment, 
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 E2730 dose compared to placebo, and 90% CIs will be 
presented with no adjustments for multiplicity. 
Additional analysis by graphical exploration on onset, maximum change, and duration of 
photosensitivity response at each dose level will be performed for all 3 eye conditions at the time 
course of E2730 as compared to placebo.  This analysis will provide further information on the 
frequency and percentage of subjects with Complete Suppression, Partial Response, and No Response 
of PPR at each dose level of E2730 as compared to placebo.
Sensitivity analyses for PPR may be conducted, for example, of PPR for subjects who completed 
Treatment Periods 1-3 versus those who are included in the PD Analysis Set.
 
All PD data (Bond and Lader) 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.
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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.  
Treatment-emergent adverse events (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.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................10
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................15
5
ETHICS............................................................................................................................17
5.1
Institutional Review Boards/Independent Ethics Committees ..............................17
5.2
Ethical Conduct of the Study.................................................................................17
5.3
Subject Information and Informed Consent...........................................................18
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................18
7
INTRODUCTION ...........................................................................................................19
7.1
Indication ...............................................................................................................19
7.1.1
Mechanism of Action – E2730 ....................................................................19
7.1.2
Clinical Experience With E2730 .................................................................19
7.1.2.1
Pharmacokinetics.................................................................................20
7.1.2.2
Safety and Tolerability.........................................................................21
7.2
Study Rationale......................................................................................................21
7.2.1
Photosensitivity Proof of Concept Model....................................................21
8
STUDY OBJECTIVES....................................................................................................23
8.1
Primary Objective..................................................................................................23
8.2
Secondary Objectives.............................................................................................23
8.3
...........................................................................................24
9
INVESTIGATIONAL PLAN..........................................................................................24
9.1
Overall Study Design and Plan..............................................................................24
9.1.1
Prerandomization Phase...............................................................................25
9.1.1.1
Screening Period..................................................................................25
9.1.2
Randomization Phase...................................................................................26
9.1.2.1
Treatment Periods................................................................................26
9.1.2.2
Follow-up Period .................................................................................26
9.2
Discussion of Study Design, Including Choice of Control Groups.......................26
9.3
Selection of Study Population................................................................................27
9.3.1
Inclusion Criteria .........................................................................................27
9.3.2
Exclusion Criteria ........................................................................................27
9.3.3
Removal of Subjects From Therapy or Assessment....................................29
9.3.3.1
Study-Specific Withdrawal Criteria.....................................................29
9.4
Treatment(s)...........................................................................................................30
9.4.1
Treatment(s) Administered..........................................................................30
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9.4.2
Identity of Investigational Product(s) ..........................................................31
9.4.2.1
Chemical Name, Structural Formula of E2730....................................31
9.4.2.2
Comparator Drug .................................................................................31
9.4.2.3
Labeling for Study Drug......................................................................31
9.4.2.4
Storage Conditions...............................................................................31
9.4.3
Method of Assigning Subjects to Treatment Groups...................................31
9.4.4
Selection of Doses in the Study...................................................................31
9.4.5
Selection and Timing of Dose for Each Subject..........................................32
9.4.6
Blinding........................................................................................................32
9.4.7
Prior and Concomitant Therapy...................................................................33
9.4.7.1
Prohibited Concomitant Therapies and Drugs.....................................33
9.4.7.2
Restrictions During the Study Period ..................................................33
9.4.8
Treatment Compliance.................................................................................33
9.4.9
Drug Supplies and Accountability...............................................................33
9.5
Study Assessments.................................................................................................35
9.5.1
Assessments.................................................................................................35
9.5.1.1
Demography.........................................................................................35
9.5.1.2
Baseline Assessments ..........................................................................35
9.5.1.2.1
Medical History and Epilepsy Medical History.............................35
9.5.1.2.2
Height Measurement and BMI computation..................................35
9.5.1.2.3
Urine Drug Test .............................................................................35
9.5.1.2.4
Serology.........................................................................................35
9.5.1.3
Efficacy Assessments...........................................................................36
9.5.1.4
Pharmacokinetic, Pharmacodynamic, 
 
 Assessments.............................................................36
9.5.1.4.1
Pharmacokinetic Assessments .......................................................36
9.5.1.4.2
Pharmacodynamic,
 
Assessments...................................................................................36
9.5.1.5
Safety Assessments..............................................................................37
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...37
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................39
9.5.1.5.3
Laboratory Measurements .............................................................40
9.5.1.5.4
Vital Signs and Weight Measurements..........................................41
9.5.1.5.5
Physical Examinations...................................................................42
9.5.1.5.6
Neurological Examinations............................................................42
9.5.1.5.7
Electrocardiograms ........................................................................42
9.5.1.5.8
Other Safety Assessments..............................................................43
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9.5.2
Schedule of Procedures/Assessments ..........................................................43
9.5.2.1
Schedule of Procedures/Assessments ..................................................43
9.5.2.2
Description of Procedures/Assessments Schedule...............................47
9.5.3
Appropriateness of Measurements...............................................................47
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated With Special Situations .............................................................47
9.5.4.1
Reporting of Serious Adverse Events..................................................47
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................48
9.5.4.3
Reporting of Events Associated With Special Situations....................49
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................49
9.5.4.4
Expedited Reporting ............................................................................49
9.5.4.5
Breaking the Blind...............................................................................49
9.5.4.6
Regulatory Reporting of Adverse Events ............................................50
9.5.5
Completion/Discontinuation of Subjects.....................................................50
9.5.6
Abuse or Diversion of Study Drug ..............................................................50
9.5.7
Confirmation of Medical Care by Another Physician .................................50
9.6
Data Quality Assurance .........................................................................................51
9.6.1
Data Collection ............................................................................................51
9.6.2
Clinical Data Management ..........................................................................51
9.7
Statistical Methods.................................................................................................51
9.7.1
Statistical and Analytical Plans....................................................................51
9.7.1.1
Study Endpoints...................................................................................52
9.7.1.1.1
Primary Endpoint...........................................................................52
9.7.1.1.2
Secondary Endpoints .....................................................................52
9.7.1.2
Definitions of Analysis Sets.................................................................52
9.7.1.3
Subject Disposition..............................................................................53
9.7.1.4
Demographic and Other Baseline Characteristics ...............................53
9.7.1.5
Prior and Concomitant Therapy...........................................................53
9.7.1.6
Efficacy Analyses ................................................................................53
9.7.1.7
Pharmacokinetic, Pharmacodynamic, 
 
 Analyses...................................................................53
9.7.1.7.1
Pharmacokinetic Analyses.............................................................53
9.7.1.7.2
Pharmacodynamic, 
 
Analyses.........................................................................................54
9.7.1.8
Safety Analyses....................................................................................55
9.7.1.8.1
Extent of Exposure.........................................................................55
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9.7.1.8.2
Adverse Events ..............................................................................55
9.7.1.8.3
Laboratory Values..........................................................................56
9.7.1.8.4
Vital Signs......................................................................................56
9.7.1.8.5
Electrocardiograms ........................................................................56
9.7.1.8.6
Other Safety Analyses....................................................................57
9.7.2
Determination of Sample Size .....................................................................57
9.7.3
Interim Analysis...........................................................................................57
9.7.4
Other Statistical/Analytical Issues ...............................................................57
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................57
10
REFERENCE LIST .........................................................................................................58
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......59
11.1
Changes to the Protocol .........................................................................................59
11.2
Adherence to the Protocol......................................................................................59
11.3
Monitoring Procedures...........................................................................................59
11.4
Recording of Data..................................................................................................60
11.5
Identification of Source Data.................................................................................60
11.6
Retention of Records..............................................................................................60
11.7
Auditing Procedures and Inspection......................................................................61
11.8
Handling of Study Drug.........................................................................................61
11.9
Publication of Results ............................................................................................61
11.10 Disclosure and Confidentiality ..............................................................................62
11.11 Discontinuation of Study .......................................................................................62
11.12 Subject Insurance and Indemnity...........................................................................62
12
APPENDICES .................................................................................................................63
LIST OF IN-TEXT TABLES
Table 1
PK Parameters In Study 001 (20 mg) and Study 002 (40 mg, 80 mg, 
and 120 mg) ...............................................................................................20
Table 2
Treatments Administered...........................................................................30
Table 3
Treatment Sequences .................................................................................30
Table 4
Clinical Laboratory Tests...........................................................................41
Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201.............44
Table 6
Blood Sampling Schedule for Pharmacokinetic Assessments...................47
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for a Crossover Study..........................................................25
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LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values.................................................64
Appendix 2
Prohibited Concomitant Medications ........................................................66
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase 
AST
aspartate aminotransferase
AUC(0-24)
area under the concentration-time curve from 0 time to fixed time 24 hours
AUC(0-inf)
area under the concentration-time curve from 0 time extrapolated to infinity
time
β-hCG
beta human chorionic gonadotropin
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
CV
coefficient of variance
ED
Early Discontinuation (Visit)
EEG-IPS
electroencephalogram intermittent photic stimulation
GM
geometric mean
hCG
human chorionic gonadotropin
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
LNH
low/normal/high
LS
least squares
M1
E2730 N-acetyl metabolite
MedDRA
Medical Dictionary for Regulatory Activities
Max
maximum
Min
minimum
n/a
not applicable
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Abbreviation
Term
PD
pharmacodynamic
PI
principal investigator
PK
pharmacokinetics
POC
proof-of-concept
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
t1/2
terminal elimination phase half-life
tmax
time at which the highest drug concentration occurs
VAS
Visual Analogue Scale
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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 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 the study will be the date of the last study visit for the last subject in the study.  
The sponsor should also provide the IRB 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 Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject 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 initial goal is to develop E2730 as an antiepileptic drug (AED) in patients with a rare 
form of epilepsy, in parallel with partial-onset seizure studies in adolescents and adults.  The 
selection of the disease candidate for orphan drug treatment will be based on ongoing and 
planned preclinical studies in house and at external institutions.  
7.1.1
Mechanism of Action – E2730
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
7.1.2
Clinical Experience With E2730
The E2730 clinical program to date comprises 1 completed Phase 1 study in which 6 healthy 
subjects received single doses of E2730 (20 mg) and 2 healthy subjects received placebo.  
The first-in-human single ascending dose (SAD) study of E2730 (E2730-A001-001; 
Study 001), was initially planned to administer E2730 with dose escalation conducted in 
sequential dose groups consisting of 8 subjects per group randomized (3:1) to receive single 
ascending E2730 doses of 20, 40, or 80 mg or E2730-matched placebo.  Dose escalation 
could only occur if the available data supported an increase in dose that did not exceed 
plasma E2730 exposures predefined for Cmax=1.5 μg/mL or area under the 
concentration-time curve from zero time extrapolated to infinite time 
(AUC(0-inf))=20μg•h/mL.  This threshold was originally required by the Food and Drug 
Administration (FDA) and was reached with the first E2730 dose (20 mg).  Thus, no higher 
E2730 doses were administered.
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The SAD study (E2730-A001-002; Study 002) is currently ongoing, where doses of 40, 80, 
120, and 160 mg are planned in healthy subjects.  The proposed doses are anticipated not to 
exceed 3 μg/mL, per the FDA’s revised limit on the Cmax, and the data will be evaluated on 
an ongoing basis during each dose escalation.  The anticipated Cmax of the highest dose 
cohort (120 mg cohort) in the current study is likely not to exceed the prespecified threshold. 
7.1.2.1
Pharmacokinetics
In Study 001 and Study 002, which enrolled healthy subjects (18-50 years); E2730 was 
rapidly absorbed after a single oral administration of 20, 40, 80, and 120 mg.  Plasma E2730 
concentrations peaked at 1.25 to 5.5 hours.  The N-acetyl metabolite (M1) was sparsely 
detected just above or at the lower limit of quantification, thus a complete plasma M1 
pharmacokinetic (PK) profile could not be derived.  Pharmacokinetic parameters in Study 
001 and Study 002 are shown in Table 1.  Although Cmax and AUC(0-24) were less than dose 
proportional between 20 mg and 40 mg, there was almost dose proportional from 40 mg 
through 120 mg.  The highest individual Cmax value (2.930 μg/mL) of 120 mg was not to 
exceed the prespecified threshold of 3 μg/mL.  There was 1 subject who had low plasma 
E2730 concentration (Cmax: 0.222 μg/mL) in the 120 mg cohort.  The plasma E2730 
concentration declined with a mean terminal elimination phase half-life (t1/2) of 59.0 to 
69.8 hours. 
Table 1
PK Parameters In Study 001 (20 mg) and Study 002 (40 mg, 80 mg,
and 120 mg)
Dose
tmax (h)
Cmax (ng/mL)
AUC(0-24)
(ng•h/mL)
AUC(0-inf)
(ng•h/mL)
t½ (h)
20 mg
1.25
(0.50, 1.50)
351
(22.7) 
6330
(23.9) 
28600
(11.5) 
69.8
(21.9) 
40 mg
3.00
(1.50, 6.00)
496
(20.3)
9210
(19.6)
41300
(15.9)
69.7
(15.2)
80 mg
5.50
(1.00, 8.00)
899
(14) 
16900
(12.7) 
61100
(6.44) 
59.0
(15.8) 
120 mg
4.50
(0.50, 8.00)
1270
(116)
23300
(110)
n/aa
n/aa
AUC(0-24) = area under the concentration-time curve from 0 time to fixed time 24 hours; AUC(0-inf) = area under 
the concentration-time curve from 0 time extrapolated to infinity time; PK = pharmacokinetics, max = 
maximum; min = minimum; t1/2 = terminal elimination phase half-life; tmax = time at which the highest drug 
concentration occurs, n/a = not applicable; CV = coefficient of variance.
Note:  All PK parameters, except tmax, are presented as geometric mean (%CV).  tmax is presented as median 
(min, max).
a.
As of the data cut-off date of 22 May 2018, plasma concentrations of E2730 at 120 mg are available until 
24 hours post dose. 
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After administration of E2730 20 mg, the GM percent of recovered parent drug in urine 
collected up to 96 hours postdose was 21.8% and a smaller fraction (GM=0.728%) was 
excreted as M1.
7.1.2.2
Safety and Tolerability
E2730 was well tolerated in healthy adult subjects when administered as single oral doses 
across the dose range of 20 to 120 mg (Study 001 and Study 002).  The maximum tolerated 
dose (MTD) has not yet been reached (Study 002).
Among 6 subjects who received 20 mg E2730 (Study 001), 1 subject experienced a TEAE 
(postural orthostatic tachycardia syndrome) on the day of administration.  The event was 
mild in severity and resolved on the same day without treatment.  The investigator judged the 
event to be related to the study drug.  Another subject experienced a TEAE (dizziness) on the 
day of placebo administration.  The event was mild in severity and resolved on the same day 
without treatment.  The investigator judged the event to be related to the study drug.  
From the blinded preliminary safety results in 40 mg and 80 mg, 4 subjects experienced 
6 TEAEs (sleepiness, insomnia, nausea, drowsiness [2 subjects], and decrease appetite) and 4 
subjects experienced 8 TEAEs (orthostatic tachycardia [2 subjects], dermatitis contact, 
atrioventricular block, dizziness, headache, insomnia, and diarrhea), respectively.  There 
were no medically significant findings from vital signs in 40 mg and 80 mg cohorts.
In the 120 mg cohort, the safety data have been reviewed through Day 13.  Clinically 
significant findings in vital signs were reported for 2 subjects, which were characterized as 
AEs of orthostatic tachycardia and hypotension.  Both AEs were mild and in both cases, 
subjects were asymptomatic.  There were no deaths or SAEs, and no medically significant 
findings have been reported from EEG or ECG (no significant QT or QTc prolongations).  
There have been no clinically significant laboratory abnormalities.  There were no 
epileptiform discharges or clinically significant abnormalities of EEG observed in the 40 mg, 
80 mg, or 120 mg dose cohorts.
7.2
Study Rationale
7.2.1
Photosensitivity Proof of Concept Model
 
 
 
 
 
 
 
 
 
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to assess the PD activity of E2730 as measured by 
suppression of epileptic PPR in the subject’s most sensitive eye condition as a proof of 
principle of efficacy in subjects with photosensitive epilepsy.
8.2
Secondary Objectives
The secondary objectives of the study are: 

To assess the PD activity of E2730 as measured by suppression of epileptic PPR, 
onset, maximum change, and duration of response in 3 eye-conditions (eye closure, 
eyes closed, and eyes open) in subjects with photosensitive epilepsy. 
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
To assess the safety and tolerability of E2730 following a single oral dose in subjects
with photosensitive epilepsy.

To assess the PK of E2730 following a single oral dose in subjects with 
photosensitive epilepsy.

To evaluate potential exposure-PD response relationships.
8.3
 
 
 
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period cross-over 
study in adult subjects with epilepsy.  This study will use the photosensitivity proof of 
principle model to determine the potential of E2730 to reduce the photosensitive range in 
adult subjects.  This study will have 2 phases: Prerandomization and Randomization.  The 
Prerandomization Phase will consist of a Screening Period (up to 3 weeks), during which 
each subject’s study eligibility will be determined and baseline assessments will be 
conducted.  The Randomization Phase will consist of 3 Treatment Periods with a single dose 
in each period (placebo, E2730 40 mg, or E2730 120 mg, each separated by a 3-week
(±3 days) washout interval for a total of approximately 6 weeks), and a Follow-up Period (a 
single visit, 3 weeks ±3 days after the last day of study product administration).  All visits
will be conducted on an outpatient basis.  
An overview of the study design is presented in Figure 1.
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Figure 1
Study Design for a Crossover Study
ED = Early discontinuation, FU = Follow Up, Pd = period, R = randomization, Trt = treatment, WO = washout
9.1.1
Prerandomization Phase
The Prerandomization Phase will consist of a Screening Period (up to 3 weeks), during which 
each subject’s study eligibility will be determined and baseline assessments will be 
conducted.  
9.1.1.1
Screening Period
Screening will occur between Day –21 and Day –1.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.
Subjects must have a diagnosis and history of a PPR on EEG with or without a diagnosis of 
epilepsy for which they are receiving up to 3 concomitant AEDs.
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.
Visit:
Screening/Baseline
R
Trt Pd 1 
(1 day)
-21 to -1
1
64±3
Period 1
Period 2
1
22±3
Phase:
Period:
Study Day:
WO Pd 1 
(21±3 days)
2
3
4
5
43±3
Prerandomization
Trt Pd 2 
(1 day)
WO Pd 2
(21±3 days)
Trt Pd 3
(1 day)
WO Pd 3
(21±3 days)
Period 3
Treatment
Follow-up
FU Visit (or 
ED visit) 
(1 day)
Randomization
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At the Screening Visit (Visit 1), subjects will undergo an EEG-IPS assessment in 
3 eye-conditions (eye closure, eyes closed, and eyes open) at ascending and then descending 
photo-stimulation frequencies.  The Screening Visit EEG-IPS assessment will be performed 
at 5 time points, over an approximately 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.  The baseline assessments will be conducted, 
including determination of the lower and upper limit of photosensitivity to intermittent photic 
stimulation (EEG-IPS) threshold frequency for each eye condition.  Qualified medical 
personnel for the management of acute seizures will be present during the day of EEG-IPS 
procedure throughout the duration of the study.  
9.1.2
Randomization Phase
The duration of the Randomization Phase will be 9 weeks and will include 3 Treatment 
Periods (placebo, E2730 40 mg or E2730 120 mg, each separated by a 3-week (±3 days)
washout interval, for a total of approximately 6 weeks), and a Follow-up Period (a single 
visit, 3 weeks ±3 days after the last day of study product administration).  Subjects whose 
screening assessments and evaluations (including Day 1 [Visit 2] procedures) are completed 
and reviewed by the investigator and who continue to meet all of the inclusion/exclusion 
criteria will enter the Randomization Phase.  The baseline assessments will be conducted 
again at predose of each Treatment Period, including determination of the lower and upper 
limit of photosensitivity to IPS threshold frequency for each eye condition.
9.1.2.1
Treatment Periods
Subjects will be randomized into 1 of 6 treatment sequences to receive placebo, E2730 
40 mg, or E2730 120 mg. Each of the 3 treatment periods will be separated by a 3-week
(±3 days) washout interval. 
9.1.2.2
Follow-up Period
After completing Treatment Period 3, all subjects will enter the Follow-up period during 
which they will be required to complete a Follow-up visit.  The Follow-up Period is a single 
visit, 3 weeks ±3 days after the last day of study product administration.
9.2
Discussion of Study Design, Including Choice of Control Groups
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
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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 old at the time of informed consent. 
2. A diagnosis and history of a PPR on EEG with or without a diagnosis of epilepsy.
3. Currently taking up to a maximum of 3 concomitant antiepileptic drugs (AEDs).  If 
taking concomitant AED(s), the dose must have remained stable for at least 4 weeks prior 
to screening.
4. A reproducible IPS-induced PPR on EEG of at least 3 points on a frequency assessment 
scale (SPR) in at least 1 eye condition on at least 3 of the EEGs performed at Screening.
5. A body mass index (BMI) between 18 to 35 kg/m2 and a total body weight greater than or 
equal to 45 kg at the time of Screening.
6. Agrees to refrain from strenuous exercise and alcohol consumption during the 24-hour
period before Screening and during the 24-hour period prior to each treatment day.
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 [ß-hCG] (or human chorionic gonadotropin 
[hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or 
hCG]).  A separate baseline assessment is required if a negative screening pregnancy test 
was obtained more than 72 hours before the 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 
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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 prior 
to Screening.
6. Ongoing or history of generalized tonic-clonic seizures within 6 months prior to 
Screening.
7. Previously developed or who experienced a clinical seizure during prior PPR assessment
or screening IPS procedure, respectively. 
8.
 
9. Multiple drug allergies or a severe drug reaction to AED(s), including dermatological (eg, 
Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
10. Current evidence of 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. An active central nervous system (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.
12. Current evidence of clinically significant active liver disease, porphyria, or with a family 
history of severe hepatic dysfunction indicated by abnormal liver function tests greater 
than 3 times the upper limit of normal (aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT]).
13. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening.
14. Known to be human immunodeficiency virus (HIV) positive.
15. History of drug or alcohol dependency or abuse within the 12 months before Screening, 
or those who have a positive drug test or alcohol test at Screening.
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16. Concomitant use of cannabinoids.  
17. Inability to follow restriction on watching television, or use of any device with an 
animated screen (ie, computer, video games, tablets) 24 hours before dosing.
18. 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 (QTc) interval; or prolonged QT/QTc 
interval (QTc >450 msec) demonstrated on ECG at Screening or Baseline (based on 
average of triplicate ECGs).  
19. 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).
20. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS).
21. 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.
22. Currently enrolled in another clinical study or used any investigational drug or device 
within 30 days or 5 half-lives, whichever is longer, preceding informed consent, except 
the investigational study for the evaluation of commercial IPS machine.
23. Frequent spontaneous background burst or current evidence of proconvulsive activity on 
EEG (eg, increase in spike-wave activity) at Screening. 
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.
9.3.3.1
Study-Specific Withdrawal 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. 
A subject may be withdrawn from the study if any of the following circumstances occur:
1. If a subject experiences a generalized tonic-clonic seizure on any study day, and the 
subject has not had a generalized tonic-clonic seizure in the 6 months prior to enrollment, 
that subject will be discontinued from the study.
OR
1. If a subject experiences a generalized tonic-clonic seizure during IPS, 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.
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3. If a subject has widening of the photosensitivity range by more than 3 points on 
2 consecutive occasions after dosing as compared to Screening, the IPS will be 
terminated and the subject will not be permitted to participate in further testing on the 
same day.
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. 
9.4
Treatment(s)
9.4.1
Treatment(s) Administered
E2730 is the test drug and will be supplied as active pharmaceutical ingredient in capsule at 
dose strengths of 40 mg and 80 mg.  Study site personnel will administer capsules containing 
E2730 or matched placebo (Table 2) as single oral doses according to the study design.  
Filled capsules will be packed, labelled, and shipped by the contract manufacturer to each 
site. 
Each subject will receive a single oral dose in a cross-over sequence according to his/her 
randomization code (Table 3). The following treatments will be administered as a single dose 
to subjects.  

E2730 40 mg: 1 E2730 40 mg capsule and 1 E2730-matched placebo capsule

E2730 120 mg: 1 E2730 80 mg capsule and 1 E2730 40 mg capsule   

Placebo: 2 E2730-matched placebo capsules 
Table 2
Treatments Administered
Treatment
Study Drug Administered
A
Placebo
B
E2730 40 mg
C
E2730 120 mg
Table 3
Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
Treatment Period 3
1: ABC
Placebo
E2730 40 mg
E2730 120 mg
2: BCA
E2730 40 mg
E2730 120 mg
Placebo
3: CAB
E2730 120 mg
Placebo
E2730 40 mg
4: ACB
Placebo
E2730 120 mg
E2730 40 mg
5: BAC
E2730 40 mg
Placebo
E2730 120 mg
6: CBA
E2730 120 mg
E2730 40 mg
Placebo
A = Placebo; B = E2730 40 mg; C = E2730 120 mg
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9.4.2
Identity of Investigational Product(s)
E2730 will be supplied in powder form as the free base.
9.4.2.1
Chemical Name, Structural Formula of E2730

Test drug code:  E2730
9.4.2.2
Comparator Drug
Placebo capsule matched to E2730 capsule will be administered.
9.4.2.3
Labeling for Study Drug
E2730 will be labeled in accordance with text that is in full regulatory compliance.
9.4.2.4
Storage Conditions
E2730 will be stored in accordance with labeled storage conditions.  Temperature monitoring 
is required at the storage location to ensure that E2730 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
Subjects will be assigned to all 3 treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
9.4.4
Selection of Doses in the Study
E2730 is currently studied in the SAD study (Study 002).  In rat amygdala kindling model, 
which is considered the most clinically relevant animal model for investigating the effect of 
compound on partial-onset seizures, E2730 showed a significant and dose-dependent 
antiseizure effect after the single oral administration.    
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Two doses are currently being considered for this study.  Based on the data from the ongoing 
Study 002, the anticipated exposure at the dose of 120 mg will be within the exposure limits 
imposed by the FDA.  An additional, lower dose of 40 mg is being considered to provide 
exposure data to further evaluate PK/PD relationship of E2730.  The data from this study will 
also support initial dose response analysis and provide a dose for future studies. 
The doses in this study will be finalized after all cohorts in Study 002 have been evaluated.
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, Day 1, Day 22, and Day 43).  A light snack can be provided at 30 minutes predose 
(after clinical laboratory blood collection) and at 2 hours postdose.  
9.4.6
Blinding
During the Prerandomization and Randomization Phases, central EEG reading will be 
performed in a blinded and independent manner.  Investigator(s) may consult with the central 
read only during the Prerandomization Phase, if needed, for EEG-IPS eligibility 
determination.  
During the Randomization Phase, 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 staff 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 E2730 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 capsules 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.  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.
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9.4.7
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent) will be recorded on the 
Prior & Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  Up to 
3 concomitant AEDs (Appendix 2) are allowed during the course of the study, provided that 
the dosage of concomitant AED(s) has remained stable for at least 4 weeks prior to 
screening.  During the study, changes to concomitant AEDs (including dosage) are not 
permitted.
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
 
 
9.4.7.2
Restrictions During the Study Period
Study drug will be administered on the day of each Treatment Visit (ie, Day 1, Day 22, and 
Day 43) after an overnight fast of at least 8 hours.  Treatments will be administered orally 
with approximately 240 mL (8 fluid ounces) of water.  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.
Subjects will be required to abstain from watching television or using any device with an 
animated screen (ie, computer, video games, tablets) within the 24 hour period prior to each 
dosing.  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 prior to each 
treatment day.  
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
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
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 and the study staff will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
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 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 
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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, race/ethnicity.
9.5.1.2
Baseline 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 designated time points as specified in the 
Schedule of Procedures/Assessments (Table 5).  This sample will be tested for common 
drugs of use/abuse:  eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, opioids (as a 
group), benzodiazepines, barbiturates, and amphetamines.
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, 
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples for determination of plasma concentrations of E2730 and its metabolite, M1,
will be collected from each subject.  PK sampling for plasma concentration will be collected 
at predose and postdose at 1, 2, 4, 6, and 8 hours on Day 1 (Visit 2), Day 22 (Visit 3), and 
Day 43 (Visit 4).  In case of early discontinuation, a PK sample will be taken.  Plasma 
concentrations of E2730 and M1 will be measured using validated liquid chromatography 
coupled with tandem mass spectrometry (LC-MS/MS) methods.
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,
ASSESSMENTS
All PD assessments will be performed within ±15 minutes of the scheduled time point.
EEG-IPS
PD activity of E2730 will be assessed by suppression of PPR following IPS under 
3 conditions (eye closure, eye closed, eye open) using the Grass PS 33 photic stimulator with 
an unpatterned glass lamp and an intensity of 100cd/m2/flash at 30 minutes to 2 hours 
predose, and at 1, 2, 4, 6, and 8 hours postdose.  The time course (30 minutes to 2 hours 
predose to 8 hours postdose) will help assess the onset, maximum change, and duration of the 
reduction in PPR response.  PPR is expected to be within the range, from 2 Hz to 60 Hz,
depending on subject 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 
EA).  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
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
Display speed: 30 mm/sec
Bond and Lader Visual Analogue Scale
The Bond and Lader visual analogue scale (VAS) for CNS–related sedation effects will be 
measured for each subject at predose, 1, 2, 4, 6, and 8 hours postdose on Day 1 (Visit 2), Day 
22 (Visit 3), and Day 43 (Visit 4).  
 
 
 
 
 
  
 
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; 
and the performance of neurological and physical examinations as detailed in Table 5.
An assessment of suicidality using the C-SSRS will be performed as detailed in 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 E2730. 
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 in the Randomization Phase and for 5× the 
half-life of E2730 (mean terminal elimination phase half-life following a single 
administration of 20 mg E2730 was 71.2 hours in Study 001).  Subjects who fail screening 
primarily due to AE(s) must have the AE(s) leading to screen failure reported on the 
Screening Disposition CRF.  Serious adverse events (SAEs) must be collected through the 
last visit in the Randomization Phase and for 5× the half-life of E2730 (mean terminal 
elimination phase half-life following a single administration of 20 mg E2730 was 71.2 hours
in Study 001)..
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 QTc interval 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
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Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 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)
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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. 
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, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 5) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study. 
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Table 4
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, 
calcium, 
cholesterol, 
globulin, 
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], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 5) 
by a validated method.  BP and pulse will be measured after the subject has been supine for 
10 minutes.  Triplicate reading of supine vital signs will be measured at all visits except for 
Screening.  All BP measurements should be performed on the same arm, preferably by the 
same person.
At Screening and during Visit 2, Visit 3, and Visit 4, after supine measurements are 
completed, subjects will be asked to stand up for 2 minutes, and BP and pulse will be taken 
in the standing position. 
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 to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
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At time points when vital signs, ECGs, and blood sampling are performed concurrently, 
procedures will be performed in the following order: ECGs, vital signs, and then blood 
sampling. Subjects will rest in the supine position for 10 minutes before and 5 minutes after 
ECG recordings followed by recording of vital signs in the supine position and in standing 
position (BP and pulse only), and lastly blood sampling.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Comprehensive and abbreviated physical examinations will be performed as designated in 
the Schedule of Procedures/Assessments (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.  Changes from screening physical examination findings that meet the definition of an 
AE will be recorded on the AE CRF.
Comprehensive Physical Examination
A comprehensive 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
Comprehensive and abbreviated neurological examinations will be performed as designated 
in the Schedule of Procedures/Assessments (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.  Changes from screening neurological examination findings that meet the definition of 
an AE will be recorded on the AE CRF.
9.5.1.5.7
ELECTROCARDIOGRAMS
Electrocardiograms (12-lead) will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 5).  
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the AE CRF.
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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, postdose at 
the end of every treatment visit, and at the Follow-up/Early discontinuation visit, as 
designated in the Schedule of Procedures/Assessments (Table 5).
Pregnancy Test
A serum β-hCG or hCG test will be performed for all women of childbearing potential.  A 
6-mL sample of blood will be taken at designated time points as specified in the Schedule of 
Procedures/Assessments (Table 5).
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 5 presents the schedule of procedures/assessments for the study.
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Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201
Phase
Prerandomization
Randomization
Unscheduled
Period
Screening
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-up /Early 
Discontinuationa
Visit
1
2
3
4
5
Study Day
-21 to -1
1
22±3
43±3
64±3
Procedures/Assessments
Informed Consent
X
Demography 
X
Randomization
X
Inclusion/exclusion criteria
X
X
Medical history
X
Epilepsy medical history
X
Physical examinationb
X
X
X
Neurological examinationb
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
Height and weightd
X
X
X
12-Lead ECGe
X
X
X
X
X
Xf
Clinical laboratory testsg
X
X
X
X
X
X
Urine drug test
X
Urine pregnancy testh
X
X
X
X
Serum β-hCG [or hCG] testh
X
Serology (HCVAb, HBsAg)
X
PK sampling (plasma)i
X
X
X
X
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Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201
Phase
Prerandomization
Randomization
Unscheduled
Period
Screening
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-up /Early 
Discontinuationa
Visit
1
2
3
4
5
Study Day
-21 to -1
1
22±3
43±3
64±3
Procedures/Assessments
X
C-SSRS
X
X
X
X
X
EEG-IPS Assessmentk
Xl
Xm
Xl
Xl
Bond and Lader VASk,n
X
X
X
Administer study drug
X
X
X
Prior and concomitant medication(s)
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
ß-hCG = beta-human chorionic gonadotropin (or hCG = human chorionic gonadotropin), BP = blood pressure, C-SSRS = Columbia-Suicide Severity Rating Scale, EEG-IPS= 
electroencephalogram- intermittent photic stimulation, HBsAg = hepatitis B surface antigen, HCVAb = hepatitis C virus antibody,
PK = pharmacokinetics, QTc = corrected QT interval, VAS = visual analogue scale.
a:
To be completed for all subjects, including those who discontinue the study early.
b:
A full physical examination will be carried out at Screening. A brief physical examination may be carried out at other visits, as deemed necessary by the 
investigator.  A neurological examination will be performed at screening, at each treatment visit (predose and at 4 hours postdose), and during the Follow 
up/Early Discontinuation visit (as applicable).  Clinically significant abnormal findings from the physical or the neurological examinations will be 
reported as AEs.
c:
Vital signs measurements will be taken at screening.  In addition, on each dosing day, vital sign (BP, pulse, body temperature, respiratory rate) 
measurements will be obtained at predose, 1, 2, 4, 6, and 8 hours postdose.  Subjects will need to rest for 10 minutes before vital signs are taken in the 
supine position.  Triplicate reading of supine vital signs will be measured at all visits except for Screening.  At Screening and during the Treatment 
periods, after supine measurements are completed, subjects will be asked to stand up for 2 minutes, and BP and pulse will be taken in the standing 
position.  At time points when vital signs, ECGs, and blood sampling are performed concurrently, procedures will be performed in the following order:  
ECGs, vital signs, and then blood sampling.  Subjects will rest in the supine position for 10 minutes before and 5 minutes after ECG recordings followed 
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Table 5
Schedule of Procedures/Assessments in Study E2730-A001-201
Phase
Prerandomization
Randomization
Unscheduled
Period
Screening
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Follow-up /Early 
Discontinuationa
Visit
1
2
3
4
5
Study Day
-21 to -1
1
22±3
43±3
64±3
Procedures/Assessments
by recording of vital signs in the supine position and in standing position (BP and pulse only), and lastly blood sampling.
d:
At Screening, both height and weight will be measured.  At all other visits, only weight will be measured. 
e:
ECG assessments will be performed in the supine position at predose and 4 hours postdose (on each dosing day). If during any visit the QTc was 
measured as >450 msec, 3 consecutive ECGs separated by 5 – 10 minutes will be performed to confirm the abnormality.  
f:
During the unscheduled visits, ECG will only be done if the results from the previous visit were deemed to be clinically significant by the investigator.
g:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
h:
Female subjects of childbearing potential only. 
i:
Blood samples for plasma PK will be obtained at predose and postdose at 1, 2, 4, 6, and 8 hours on Days 1, 22, and 43.  In case of early discontinuation, a 
PK sample will be taken. 
j:
 
k:
All PD assessments will be performed within ±15 minutes of the scheduled time point.
l:
EEG-IPS assessment will be performed at 5 time points, over an approximately 4-hour time period (0, 1, 2, 3, and 4 hours).
m:
EEG-IPS assessment will be performed 30 minutes to 2 hours predose and repeated at approximately 1, 2, 4, 6, and 8 hours postdose on Days 1, 22, and 
43.
n:
The Bond and Lader VAS for CNS–related sedation side effects will be measured from each subject at predose, 1, 2, 4, 6, and 8 hours postdose on Days 1, 
22, and 43.  
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Table 6 presents the blood sampling schedule for pharmacokinetic assessments.  In case of 
early discontinuation, a PK sample will be taken. 
Table 6
Blood Sampling Schedule for Pharmacokinetic Assessments
Days
Time Relative to the Administration
Acceptable Time Window
Day 1 (Visit 2),
Day 22 (Visit 3) (±3 days),
Day 43 (Visit 4) (±3 days)
Predose
–2 hours
1 and 2 hours
±5 minutes
4, 6, and 8 hours
±15 minutes
9.5.2.2
Description of Procedures/Assessments Schedule
The scheduling of study procedures and assessments is shown in 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, Bond and Lader VAS will be conducted in 
this study.  The Bond and Lader VAS (Bond, 1974) is a sensitive tool to assess CNS side 
effects (somnolence, body sway, dizziness and sedation etc.).  Since CNS related side effects 
were observed in nonclinical studies of E2730, Bond and Lader VAS is included for 
assessment of CNS-related sedation effects in this study.
The EEG-IPS procedure during this study will be performed based upon the protocol of 
Kastelejin et al (Kastelejin-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 EEG-IPS 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.
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SAEs, regardless of causality assessment, must be collected through the last visit in the 
Randomization Phase and for 5× the half-life of E2730 (mean terminal elimination phase 
half-life following a single administration of 20 mg E2730 was 71.2 hours in Study 001).  All 
SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE 
judged by the investigator to be related to the study treatment or any protocol-required 
procedure should be reported to the sponsor regardless of the length of time that has passed 
since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
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 
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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
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 
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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 are to complete the study’s ED procedures 
indicated in the Schedule of Procedures/Assessments (Table 5).
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.
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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.
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.
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9.7.1.1
Study Endpoints
The reduction in PPR response will be evaluated for 8 hours postdose for the entire time 
period.  A diminution in response is anticipated with the dose range.  A statistical difference 
of treatment doses versus placebo will be evaluated.
The primary endpoint, the change in the PPR range, is evaluated using mixed effects model 
for comparing low and high treatment doses versus placebo.  Another endpoint will include 
proportions of subjects responding to treatment versus placebo.  Most patients have strong 
responses to effective treatments compared to placebo, which can be evaluated by graphs of 
partial response (ie, 3 steps narrowing) and abolition of PPR.  
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 at each dose level of E2730 as compared to 
placebo.
9.7.1.1.2
SECONDARY ENDPOINTS

Mean changes from baseline in PPR ranges in each subject’s eye closure, eyes closed, 
and eyes open condition at each dose level of E2730 as compared to placebo

Onset, maximum change, and duration of photosensitivity response at each dose level in 
all 3 eye conditions at the time course of E2730 as compared to placebo

Frequency and percentage of subjects with Complete Suppression, Partial Response, and 
no Response of PPR at each dose level of E2730 as compared to placebo

Occurrence of AEs or changes in the neurological examination after single doses of 
E2730 compared to placebo

Changes in vital signs, serum chemistries, complete blood counts, or liver function tests 
after single doses of E2730 compared to placebo

PK of E2730 and its N-acetyl metabolite, M1

Relationship between PK parameters of E2730 onset, maximum change, and duration of 
impact on photosensitivity
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 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.
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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.
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 E2730 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.  
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, 
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The PK Analysis Set will be used for listings of individual E2730 and M1 plasma 
concentrations, 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 E2730 and M1.  These parameters will include, but are not limited to:
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
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 E2730 will be analyzed based on available data from this study.  The PK and PD 
Analysis datasets will be used to evaluate the relationship of PK of E2730 and change in PPR 
response.  The PK-PD analyses may include the examination of the relationship of PK of 
E2730 and PPR response (eg, time of onset, maximum change, and duration of PPR; Bond 
and Lader data) using model-based approaches.
Analysis variables:
Plasma concentrations of E2730 and N-acetyl metabolite (M1)
Analysis set:
The Pharmacokinetic Analysis Set will be used for individual plasma 
concentration listings and summaries of plasma concentrations.
Analysis methods:
The PK of E2730 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,
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 for 
each E2730 dose compared with placebo in the most sensitive and different eye conditions 
will be performed using a mixed effects model for crossover study.  The model will include 
treatment, 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 E2730 dose compared 
to placebo, and 90% CIs will be presented with no adjustments for multiplicity. 
Additional analysis by graphical exploration on onset, maximum change, and duration of 
photosensitivity response at each dose level will be performed for all 3 eye conditions at the 
time course of E2730 as compared to placebo.  This analysis will provide further information 
on the frequency and percentage of subjects with Complete Suppression, Partial Response, 
and No Response of PPR at each dose level of E2730 as compared to placebo.
Sensitivity analyses for PPR may be conducted, for example, of PPR for subjects who 
completed Treatment Periods 1-3 versus those who are included in the PD Analysis Set. 
  All PD data (Bond and Lader) 
will be listed and summarized by treatment, as appropriate, using standard summary 
statistics.  Descriptive summary statistics (eg, mean, SD, median, minimum, and maximum 
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for continuous variables, and the number and percent for categorical variables) of each 
endpoint and the changes from baseline will be tabulated.
 
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.  Treatment-emergent adverse events (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 
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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 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, pulse, 
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.
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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 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.
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.
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
 
 
 
 
Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br. J. med. 
Psychol. 1974; 47: 211-8.
 
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.
 
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, 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 Investigator's Brochure, 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 
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ICH region or at least 3 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department 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 principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused
drug supply before approval to do so by the sponsor.  At the conclusion of the study, 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
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
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; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Prohibited Concomitant Medications 
Prohibited Concomitant Medication
The above list of prohibited concomitant medications is not exhaustive. 
The investigator should provide further guidance before switching any of the concomitant medications 
mentioned in the above list.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2730-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamic Activity of E2730 in Adult 
Subjects with Photosensitive Epilepsy 
Investigational Product
Name:
E2730
IND Number:
124728
SIGNATURES
Authors:
Eisai, Inc.
Date
Eisai, Inc.
Date
Eisai, Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2730-A001-201
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamic Activity of E2730 in Adult 
Subjects with Photosensitive Epilepsy
Investigational Product
Name:
E2730
IND Number:
124728
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
Page 138 of 138

SAP_001.pdf: 
Clinical Study Report 
E2730-A001-201 
 
16.1.9 
Documentation of Statistical Methods 
The final approved Statistical Analysis Plan and other statistical documents, as applicable, for 
this study are provided in the following pages. 
 
Eisai
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E2730-A001-201
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Cross-Over Study 
Evaluating Pharmacodynamic Activity of E2730 in Adult Subjects 
with Photosensitive Epilepsy
Date:
13 FEB 2019
Version:
Version 1.0
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...................................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................4
3
INTRODUCTION .............................................................................................................5
3.1
Study Objectives ......................................................................................................5
3.1.1
Primary Objective..........................................................................................5
3.1.2
Secondary Objectives.....................................................................................5
3.1.3
....................................................................................5
3.2
Overall Study Design and Plan................................................................................5
4
DETERMINATION OF SAMPLE SIZE..........................................................................7
5
STATISTICAL METHODS..............................................................................................7
5.1
Study Endpoints.......................................................................................................7
5.1.1
Primary Endpoint...........................................................................................7
5.1.2
Secondary Endpoints .....................................................................................7
5.2
Study Subjects..........................................................................................................8
5.2.1
Definitions of Analysis Sets...........................................................................8
5.2.2
Subject Disposition........................................................................................8
5.2.3
Protocol Deviations........................................................................................8
5.2.4
Demographic and Other Baseline Characteristics .........................................8
5.2.5
Prior and Concomitant Therapy.....................................................................9
5.2.6
Treatment Compliance...................................................................................9
5.3
Data Analysis General Considerations ....................................................................9
5.3.1
Pooling of Centers..........................................................................................9
5.3.2
Adjustments for Covariates..........................................................................10
5.3.3
Multiple Comparisons/Multiplicity .............................................................10
5.3.4
Examination of Subgroups...........................................................................10
5.3.5
Handling of Missing Data, Dropouts, and Outliers .....................................10
5.3.6
Other Considerations ...................................................................................10
5.4
Efficacy Analyses ..................................................................................................10
5.5
Pharmacokinetic, Pharmacodynamic, 
 
 Analyses...............................................................................................10
5.5.1
Pharmacokinetic Analyses...........................................................................10
5.5.2
Pharmacodynamic Analyses........................................................................11
5.6
Safety Analyses......................................................................................................12
5.6.1
Extent of Exposure.......................................................................................12
5.6.2
Adverse Events ............................................................................................12
5.6.3
Laboratory Values........................................................................................13
5.6.4
Vital Signs....................................................................................................13
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5.6.5
Electrocardiograms ......................................................................................14
5.6.6
Other Safety Analyses..................................................................................14
5.7
Other Analyses.......................................................................................................14
6
INTERIM ANALYSES...................................................................................................14
7
CHANGES IN THE PLANNED ANALYSES...............................................................15
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................15
8.1
Definitions of Baseline Values ..............................................................................15
8.2
Definitions of Treatment Periods...........................................................................15
8.3
Definitions of Derived PPR Variables...................................................................15
8.4
Definitions of PK Data Handling...........................................................................16
8.4.1
Lower Limit of Quantification (LLOQ) of E2730 Plasma Concentration ..16
8.4.2
Below Limit of Quantification (BLQ) Handling for Calculation of PK 
Parameters....................................................................................................16
8.4.3
BLQ Handling for Developing Concentration-Time Profiles .....................16
8.4.4
Handling of Anomalous Concentration Values...........................................16
8.4.5
General Rules for Presentation of Drug Concentration and PK 
Parameters....................................................................................................16
9
PROGRAMMING SPECIFICATIONS ..........................................................................16
10
STATISTICAL SOFTWARE..........................................................................................16
11
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................16
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
pharmacodynamic(s)
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 E2730-
A001-201.
3.1
Study Objectives
3.1.1
Primary Objective
The primary objective of the study is to assess the pharmacodynamics (PD) activity of 
E2730 as measured by suppression of epileptic PPR in the subject’s most sensitive eye 
condition as a proof of principle of efficacy in subjects with photosensitive epilepsy.
3.1.2
Secondary Objectives
The secondary objectives of the study are: 
•
To assess the PD activity of E2730 as measured by suppression of epileptic PPR, 
onset, maximum change, and duration of response in 3 eye-conditions (eye closure, 
eyes closed, and eyes open) in subjects with photosensitive epilepsy. 
•
To assess the safety and tolerability of E2730 following a single oral dose in subjects 
with photosensitive epilepsy.
•
To assess the pharmacokinetics (PK) of E2730 following a single oral dose in 
subjects with photosensitive epilepsy.
•
To evaluate potential exposure-PD response relationships.
3.1.3
 
  
 
3.2
Overall Study Design and Plan
This is a multicenter, double-blind, randomized, 6-sequence, 3-treatment, 3-period cross-over 
study in adult subjects with epilepsy.  This study will use the photosensitivity proof of 
principle model to determine the potential of E2730 to reduce the photosensitive range in 
adult subjects.  This study will have 2 phases: Prerandomization and Randomization.  The 
Prerandomization Phase will consist of a Screening Period (up to 3 weeks), during which 
each subject’s study eligibility will be determined and baseline assessments will be 
conducted.  The Randomization Phase will consist of 3 Treatment Periods with a single dose 
in each period (placebo, E2730 40 mg, or E2730 120 mg, each separated by a 3-week 
(±3 days) washout interval for a total of approximately 6 weeks), and a Follow-up Period (a 
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single visit, 3 weeks ±3 days after the last day of study product administration).  All visits
will be conducted on an outpatient basis. Each subject will receive a single oral dose in a 
cross-over sequence according to his/her randomization code for the treatment sequence.
Table of Treatment Sequences
Sequence
Treatment Period 1
Treatment Period 2
Treatment Period 3
1: ABC
Placebo
E2730 40 mg
E2730 120 mg
2: BCA
E2730 40 mg
E2730 120 mg
Placebo
3: CAB
E2730 120 mg
Placebo
E2730 40 mg
4: ACB
Placebo
E2730 120 mg
E2730 40 mg
5: BAC
E2730 40 mg
Placebo
E2730 120 mg
6: CBA
E2730 120 mg
E2730 40 mg
Placebo
A = Placebo; B = E2730 40 mg; C = E2730 120 mg
An overview of the study design is presented by Figure 1 in the study protocol as follows.
Figure of Study Design for a Crossover Study
ED = Early discontinuation, FU = Follow Up, Pd = period, R = randomization, Trt = treatment, WO = washout.
Visit:
Screening/Baseline
R
Trt Pd 1 
(1 day)
-21 to -1
1
64±3
Period 1
Period 2
1
22±3
Phase:
Period:
Study Day:
WO Pd 1 
(21±3 days)
2
3
4
5
43±3
Prerandomization
Trt Pd 2 
(1 day)
WO Pd 2
(21±3 days)
Trt Pd 3
(1 day)
WO Pd 3
(21±3 days)
Period 3
Treatment
Follow-up
FU Visit (or 
ED visit) 
(1 day)
Randomization
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4
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.
Subjects who discontinue from the study early may be replaced, after consultation with the 
sponsor. 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 (ie, at least 3 of 5 posedose PPR data 
are valid in each period).   
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.
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 E2730 as compared to placebo.
5.1.2
Secondary Endpoints
•
Mean changes from baseline in PPR ranges in each subject’s eye closure, eyes closed, 
and eyes open condition at each dose level of E2730 as compared to placebo
•
Onset, maximum change, and duration of photosensitivity response at each dose level in 
all 3 eye conditions at the time course of E2730 as compared to placebo
•
Frequency and percentage of subjects with Complete Suppression, Partial Response, and 
no Response of PPR at each dose level of E2730 as compared to placebo
•
Occurrence of AEs or changes in the neurological examination after single doses of 
E2730 compared to placebo
•
Changes in vital signs, serum chemistries, complete blood counts, or liver function tests 
after single doses of E2730 compared to placebo
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•
PK of E2730 and its N-acetyl metabolite, M1
•
Relationship between PK parameters of E2730 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.
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
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 E2730 will also be 
presented.
Subjects who prematurely terminate their participation in the study will be summarized by 
their primary reason as well as any other reasons(s) for study termination.
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. Continuous demographic and baseline 
variables include age, height, and weight; categorical variables include sex, age group, 
race, and ethnicity.
Medical History
The number (percentage) of subjects in the Safety Analysis Set reporting a history of any 
medical condition, as recorded on the CRF, will be summarized overall.  A subject data 
listing of medical and surgical history will be provided.
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5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD). The latest version before 
database lock will be used for analysis. The number (percentage) of subjects who took prior 
and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) class, and World Health Organization Drug Dictionary preferred term (PT). Prior 
medications will be summarized overall and concomitant medications will be summarized by 
treatment group.  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 which is 
earlier.  All prior and concomitant medications will be presented in subject data listings.
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 summarized by 
treatment sequence (Sequence 1 to Sequence 6) and by treatment group (Placebo, E2730 
40 mg, E2730 120 mg) as appropriate. When results are summarized by treatment, data 
from subjects receiving a given treatment in the corresponding period are combined. For 
example, placebo treatment comprises data from Treatment Period 1 of Sequence 1, 
Treatment Period 3 of Sequence 2, Treatment Period 2 of Sequence 3, Treatment Period 1
of Sequence 4, Treatment Period 2 of Sequence 5, and Treatment Period 3 of Sequence 6
(see Table of Treatment Sequences).
For those 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.
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5.3.2
Adjustments for Covariates
Predose PPR value as baseline 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
If there are more than 3 dropouts in the study, a subject discontinuing/discontinued from 
the study for any reason may be replaced at the discretion of the sponsor. 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.
5.4
Efficacy Analyses
Not Applicable. 
5.5
Pharmacokinetic, Pharmacodynamic, 
 
 Analyses
5.5.1
Pharmacokinetic Analyses
The Safety Analysis Set will be used for individual E2730 and M1 plasma concentration-
time listings. The PK Analysis set will be used for summaries of E2730 and M1 plasma 
concentrations, 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 E2730 and M1.  These parameters will include, but are not limited to:
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•
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 E2730 will be analyzed based on available data from this study.  The PK and PD 
Analysis datasets will be used to evaluate the relationship of PK of E2730 and change in PPR 
response.  The PK-PD analyses may include the examination of the relationship of PK of 
E2730 and PPR response (eg, time of onset, maximum change, and duration of PPR; Bond 
and Lader data) using model-based approaches.
5.5.2
Pharmacodynamic Analyses
The following PD analyses will be performed on the PD Analysis Set.  
No multiplicity adjustments will be made. The 5 PPR measured postdose on a treatment day 
will be averaged and used for both primary endpoint and secondary endpoints.  The predose 
PPR data from the respective treatment period will be used as the baseline data for that 
period.  
Primary PD Analyses
The primary endpoint of mean change from baseline of the average PPR for each E2730 dose 
compared with placebo in the most sensitive eye condition will be performed using a mixed 
effects model for crossover study.  The model will include treatment, 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 E2730 dose 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 E2730 
dose compared with placebo in all 3 different eye conditions (eye closure, eyes closed, and 
eyes open) will be analyzed and summarized by using the same mixed effects model as for 
primary PD analyses.  
Additional analysis by graphical exploration on onset, maximum change, and duration of 
photosensitivity response at each dose level will be performed for all 3 eye conditions at the 
time course of E2730 as compared to placebo.  This analysis will provide further information 
on the frequency and percentage of subjects with Complete Suppression, Partial Response, 
and No Response of PPR (see Section 8.3 Definitions of Derived PPR Variables) at each 
dose level of E2730 as compared to placebo.
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Sensitivity analyses for PPR may be conducted, for example, of PPR for subjects who 
completed all Treatment Periods 1-3 versus those who are included in the PD Analysis Set.  
  
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 by presenting for each treatment group, the incidence of AEs.  
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.
All safety data will be presented in listings. 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 and treatment period and provided in a listing.
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 
(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 
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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 patients 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) 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 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.  
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.  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.
Clinically notable ranges are defined as follows.
Variable
Criterion valuea
Change relative to baselinea
Heart rate
>120 bpm
Increase of ≥15 bpm
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<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.
Vital sign values will be listed on an individual basis by sequence, treatment and 
subject. 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.
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 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.
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 will 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.
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7
CHANGES IN THE PLANNED ANALYSES
There are no changes to the statistical methods in this analysis plan compared to the latest 
protocol. Any future changes to the analysis will be documented separately and will be 
addressed in the Clinical Study Report.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
8.1
Definitions of Baseline Values
For PPR analyses in all 3 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 3 are one-day treatment periods which will include single dose of 
study drug on Day 1 (Visit 2) for treatment period 1, Day 22 (Visit 3) for treatment period 2, 
and Day 43 (Visit 4) for treatment period 3. 
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.

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.

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 
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defined as the response not meeting complete suppression or partial suppression 
definitions.
8.4
Definitions of PK Data Handling
8.4.1
Lower Limit of Quantification (LLOQ) of E2730 Plasma Concentration
The LLOQ of E2730 plasma concentration is 1.00 ng/mL. The LLOQ of M1 plasma 
concentration is 0.300 ng/mL. 
8.4.2
Below Limit of Quantification (BLQ) Handling for Calculation of PK 
Parameters
While calculating PK parameters in Phoenix-WinNonlin, BLQ values will be handled 
according to the NCA-MNL.
8.4.3
BLQ Handling for Developing Concentration-Time Profiles
When developing individual concentration-time profiles, BLQ values will be handled 
according to the NCA-MNL. 
8.4.4
Handling of Anomalous Concentration Values
The handling of anomalous concentration values will follow the guidance in the NCA-MNL. 
8.4.5
General Rules for Presentation of Drug Concentration and PK Parameters
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.
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12 REFERENCES
1. Columbia-Suicide Severity Rating Scale (C-SSRS). Columbia University. Available 
from: http://www.cssrs.columbia.edu/scales_cssrs.html
2. NCA-MNL: 302-104.01-MNL Non-Compartmental Analysis User Manual, June 
2018
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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
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
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 ; 
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]
Neurology Business Group
Date
Page 21 of 21
PPD
PPD
PPD