A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study With Open-Label Extension Phase of Lorcaserin as Adjunctive Treatment in Subjects With Dravet Syndrome
Phase: PHASE3
Conditions: Epilepsies, Myoclonic
Sponsor: Eisai Inc.

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  Revisions to Version 1.0 
  New version /date: Version 2.0/09 Jul 2020
Change
Rationale
Affected Protocol Sections
Modified the exclusion criterion
related to fenfluramine 
Clarification
Section 2-Exclusion Criteria
Section 9.3.2
Mentioned a statement that the 
randomization will be stratified by 
previous treatment with 
fenfluramine (yes/no)
Clarification
Section 2-Study design
Section 2-Statistical Methods
Section 9.1
Section 9.1.2
Section 9.7.1.6.1
Section 9.7.1.6.2
Section 9.7.1.6.3

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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E2023-A001-304
Study Protocol 
Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group Study with Open-Label Extension Phase of 
Lorcaserin as Adjunctive Treatment in Subjects with Dravet 
Syndrome
Sponsor:
Eisai Inc.
100 Tice Boulevard, Woodcliff Lake, New Jersey 07677
United States (US)
Sponsor’s 
Investigational 
Product Name:
E2023/lorcaserin
Indication:
Dravet syndrome
Phase:
Phase 3
Approval Date:
Final (V1.0)
22 Jun 2020 (original protocol)
V2.0
09 Jul 2020
IND Number:
148085
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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according to the investigator’s clinical judgment, the dose may remain the same or can be decreased 
by 1 dose level, to the Target dose at any time during the Treatment Period.  If the dose had been 
decreased, it may be increased again if tolerability improves. 
All subjects who complete the Core Study will be eligible to enter the Extension Phase.  The last visit 
of the Treatment Period of the Core Study is considered to be the 1st visit of the Extension Phase.
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for subjects who do 
not enter the Extension Phase.
Extension Phase 
The Extension Phase will consist of a Treatment Period (12 weeks) and a Follow-up Period 
(4 weeks).  Subjects are eligible to complete the Extension Phase only if they have completed the 
Treatment Period of the Core Study.
All subjects will receive lorcaserin during the entire Extension Phase but the dose level will be 
blinded during the first 6 weeks.  During the first 6 weeks of the Extension Phase, subjects who 
received lorcaserin during the Core Study will receive the same dose of lorcaserin (the dose will 
remain flexible per weight category, based on clinical response and tolerability); subjects who 
received placebo during the Core Study will receive the target dose of lorcaserin per weight category.  
During the second 6 weeks of the Extension Phase, all subjects will receive lorcaserin at the 
maximum dose per weight category (the dose may be decreased due to tolerability reasons and
increased again if tolerability improves).  Addition, deletion, and dose changes to concomitant 
antiepileptic drugs (AEDs) are not allowed during the Treatment Period of the Extension Phase. 
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for subjects who will 
not participate in the Extended Access Program (Study E2023-A001-405) after completion of this 
study.  Subjects who complete the Extension Phase will be eligible to enter into 
Study E2023-A001-405.
Number of Subjects
Approximately 58 subjects will be randomized.
Inclusion Criteria
1.
Male or female, age ≥2 years at the time of informed consent (or assent)
2.
Confirmed diagnosis of epilepsy with Dravet syndrome per Recommendations from a North 
American Consensus Panel (2017)
3.
Has had at least 4 convulsive seizures during the 4 weeks of the Prerandomization Phase 
4.
Currently treated with at least 1 AED and the doses of all AEDs must be stable for at least 
4 weeks before Screening, and be expected to remain stable throughout the study.  
5.
If vagal nerve stimulator, responsive neurostimulator, or deep brain stimulator is used, it must be 
implanted at least 5 months before Screening, parameters must be stable for at least 4 weeks 
before Screening, and be expected to remain stable throughout the study  
6.
If a ketogenic diet is followed, it must be stable for at least 4 weeks before Screening and be 
expected to remain stable throughout the study
Exclusion Criteria
1.
Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
beta-human chorionic gonadotropin).  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
2.
Females of childbearing potential who:

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
Within 28 days before study entry, did not use a highly effective method of contraception, 
which includes any of the following:
o
Total abstinence (if it is their preferred and usual lifestyle)
o
An intrauterine device or intrauterine hormone-releasing system
o
A contraceptive implant
o
An oral contraceptive (Subject must have been on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and must agree to stay on the 
same dose of the oral contraceptive throughout the study and for 28 days after study drug 
discontinuation).
o
Have a vasectomized partner with confirmed azoospermia
Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
NOTE: All postmenarche 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.
Use of lorcaserin within 4 weeks before Screening, or any history of it being discontinued due to 
lack of efficacy or adverse reactions
4.
Use of fenfluramine within 2 months before Screening, any history of lack of fenfluramine 
efficacy, or any history of valvulopathy at baseline with history of fenfluramine use
5.
Use of serotonergic or other prohibited drugs administered within 7 days (or 5 half-lives, 
whichever is longer) or monoamine oxidase inhibitors within 30 days before dosing
6.
Has a history of status epilepticus that required hospitalization during the 6 months before 
Screening 
7.
Currently has progressive central nervous system disease, other than Dravet syndrome, including 
degenerative central nervous system diseases and progressive tumors
8.
Any history of malignancies
9.
Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal, liver
disease) that in the opinion of the investigator could affect the subject’s safety or interfere with 
the study assessments
10. Any history of or concomitant medical condition that in the opinion of the investigator would 
compromise the subject’s ability to safely complete the study 
11. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline 
prolonged QT/correct QT interval (eg, a repeated demonstration of a corrected QT interval 
>460 ms)
12. Any history of clinically significant bradycardia or other clinically significant conduction 
abnormality
13. Any suicidal ideation with intent with or without a plan at Screening or within 6 months of 
Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the 
Columbia-Suicide Severity Rating Scale [C-SSRS] or based on investigator’s clinical judgment 
for subjects unable to be evaluated by C-SSRS)
14. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS or based on 
investigator’s clinical judgment for subjects unable to be evaluated by C-SSRS)

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15. Hypersensitivity to the study drug and any of the excipients
16. Scheduled for surgery during the study
17. Use of illegal recreational drugs
18. Currently enrolled in another clinical study or used any investigational drug or device within 
4 weeks before Screening or within approximately 5 half-lives, whichever is longer.
Study Treatments
Test drug: E2023, oral, 10-mg tablets
Comparator Drug: placebo, oral tablets matching the test drug
Study drug will be taken as a suspension BID approximately 12 hours apart.  
To prepare the suspension of study drug before each administration, 2 tablets (from a blister pack, 
assigned by interactive voice and web response system [IxRS]) will first be suspended in 10 mL of 
water, after which 70 mL of sugar-free Ora-Sweet Syrup will be added and the suspension mixed 
thoroughly. For subjects with weight <20 kg, a 20 mL aliquot of this suspension, or for subjects with 
weight ≥20 kg, a 40 mL aliquot of this suspension will be taken orally and the remainder of the 
suspension should be discarded after each administration.
Duration of Treatment
14 weeks double-blind Treatment Period and 12 weeks open-label Extension Phase
Concomitant Drug/Therapy
Concomitant AEDs, including Epidiolex®, initiated before Screening are allowed; the dose must 
remain stable during the Prerandomization and Randomization Phase.
Benzodiazepines are allowed as AEDs or rescue medication for seizure control.
The following medications are prohibited during the Prerandomization and Randomization Phase: 
artisanal cannabidiol products, serotonergic drugs (due to the risk of serotonin syndrome), including 
selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine 
oxidase inhibitors, triptans, bupropion, dextromethorphan, centrally-acting anorectic agents including 
fenfluramine, and St. John’s Wort.
Drugs that are cytochrome P450 2D6 substrates should be used with caution, as lorcaserin can 
increase exposure of these drugs.
Investigational drugs or devices are prohibited during the participation in the study.
Assessments
Efficacy Assessments
Seizure diaries will be used to collect seizure counts.  
CGIC (clinician-rated) will be assessed.  CGIC is a 7-point scale that provides a clinician-determined 
summary measure of change from baseline of subject’s clinical status.
Pharmacokinetic Assessments
Blood samples for PK assessment will be collected during the Treatment Period. 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Data may be analyzed based on types of genetic mutations related to epilepsy (information on genetic 
mutation related to epilepsy will be collected, if available, based on review of epilepsy history).
Safety Assessments

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Prerandomization Phase will be conducted based on Cochran-Mantel-Haenszel test adjusted for 
fenfluramine and weight stratas and site.
Sequential Gatekeeping Procedure
In order to control for Type I error, a sequential gatekeeping approach will be used where the primary 
endpoint will be tested first at 0.05 level, if the null hypothesis is rejected, the key secondary endpoint 
will be tested at 0.05 significance level.  Otherwise no further testing will be performed.
Extension Phase: Descriptive statistics will be provided for the efficacy endpoints in the Extension 
Phase. Mean, standard deviation, median, minimum, and maximum will be provided for continuous 
endpoints and number and percentage will provide for categorical variables.  In addition, plots will be 
used to summarize the data.
Pharmacokinetic Analyses
Analysis of PK will be performed on the PK Analysis Set.  Plasma concentrations of lorcaserin will 
be listed.
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  For this approach, PK analysis data from this study will be pooled 
with relevant data from other lorcaserin studies as appropriate.  The effect of covariates, such as 
baseline characteristics/demographics, on PK will be explored.  Derived exposure parameters such as 
Cmax and AUC at steady-state will be calculated from the final PK model using individual posterior 
estimates of the PK parameters and from dosing history. 
Pharmacokinetic/Pharmacodynamic Analyses
Relationships between exposure to lorcaserin and selected efficacy and safety endpoints will be 
explored graphically if data permit.  Any emergent PK/pharmacodynamic relationship will be 
followed by population PK/pharmacodynamic modeling if data allow. 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Data may be analyzed based on types of genetic mutations related to epilepsy.
Safety Analyses
Safety analyses will be conducted on the Safety Analysis Set.  The data will be summarized by 
overall, treatment group, and by age group.
The incidence of TEAEs, serious adverse events (SAEs), AEs leading to discontinuation of study 
drug, and AEs leading to dose adjustment will be summarized.  The incidence of TEAEs will be 
summarized by severity (mild, moderate, or severe), as well as by relationship to treatment (related or 
not related).  Proportion of subjects with increased seizure frequency, weight and body mass index 
changes will be summarized.
Changes from baseline in laboratory values will be summarized for continuous variables.  Laboratory 
shift tables showing incidence of new or worsening clinically significant findings from baseline to the 
postbaseline visits will be displayed.  Shift from baseline to the highest postbaseline laboratory value 
and from baseline to the lowest postbaseline laboratory value will also be displayed.
Incidence of treatment-emergent markedly abnormal laboratory values in laboratory safety test 
variables will be summarized.  Treatment-emergent markedly abnormal laboratory values will be 
graded based on the Common Terminology Criteria for Adverse Events Version 5.0.  Incidence of 
Hy’s law will be summarized.
The change from baseline in vital signs and ECG parameters will be summarized.
Incidence of FDA-defined valvulopathy and pulmonary hypertension, and change from baseline of 
echocardiographic parameters will be summarized.  Incidence of bradycardia, new onset heart block, 

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new onset of other arrhythmias or conduction abnormalities, thickened valve leaflets, and restricted 
valve leaflet motion will be summarized.
The duration of treatment will be calculated as the number of days between the date the subject 
receives their 1st treatment dose and the date the subject receives the last dose of treatment.  These 
values will be used to summarize the extent of exposure to study drug.
Proportion of subjects with any treatment-emergent study-specific AEs will be summarized.
Other Analyses
The change from baseline in QOLIE-31 and PedsQL 4.0 Scale will be summarized.
Interim Analyses
No interim analysis is planned.
Sample Size Rationale
A sample size of 58 subjects (29 per group) will have 90% power to detect a difference of 50% 
reduction in convulsive seizure frequency per 28 days between lorcaserin and placebo assuming a 
standard deviation of 55, using a 2-group t-test with 0.05 two-sided significance level.  This sample 
size will have 90% power to detect an odds-ratio of at least 10 for the secondary endpoint 50% 
reduction in convulsive seizure frequency, assuming the placebo response is 12%, using a 2-group 
Chi-square test with 0.05 two-sided significance level. This sample size assumes a 7% dropout rate.

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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................2
2
CLINICAL PROTOCOL SYNOPSIS............................................................................3
3
TABLE OF CONTENTS.............................................................................................12
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................17
5
ETHICS.......................................................................................................................18
5.1
Institutional Review Boards/Independent Ethics Committees.............................18
5.2
Ethical Conduct of the Study..............................................................................18
5.3
Subject Information and Informed Consent ........................................................19
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................20
7
INTRODUCTION.......................................................................................................20
7.1
Compound Overview .........................................................................................20
7.2
Clinical Experience............................................................................................21
7.3
Study Rationale..................................................................................................21
8
STUDY OBJECTIVES................................................................................................22
8.1
Primary Objective..............................................................................................22
8.2
Secondary Objectives.........................................................................................22
8.2.1
Key Secondary Objective .........................................................................22
8.2.2
Other Secondary Objectives .....................................................................23
8.3
Exploratory Objectives.......................................................................................23
9
INVESTIGATIONAL PLAN ......................................................................................23
9.1
Overall Study Design and Plan...........................................................................23
9.1.1
Prerandomization Phase ...........................................................................25
9.1.1.1
Screening/Baseline Period ................................................................25
9.1.2
Randomization Phase ...............................................................................25
9.1.2.1
Treatment Period ..............................................................................26
9.1.2.2
Follow-Up Period .............................................................................26
9.1.3
Extension Phase .......................................................................................26
9.2
Discussion of Study Design, Including Choice of Control Groups......................27
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
9.4
Treatments.........................................................................................................30
9.4.1
Treatments Administered..........................................................................30
9.4.2
Identity of Investigational Products ..........................................................30

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9.4.2.1
Chemical Name of E2023.................................................................30
9.4.2.2
Comparator Drug..............................................................................30
9.4.2.3
Labeling for Study Drug...................................................................30
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 ...................................................................................................33
9.4.7
Prior and Concomitant Therapy................................................................33
9.4.8
Treatment Compliance .............................................................................34
9.4.9
Drug Supplies and Accountability ............................................................34
9.5
Study Assessments.............................................................................................35
9.5.1
Assessments .............................................................................................35
9.5.1.1
Screening Assessments .....................................................................35
9.5.1.1.1
Demography ...............................................................................35
9.5.1.1.2
Medical History ..........................................................................35
9.5.1.1.3
Epilepsy History .........................................................................36
9.5.1.2
Efficacy Assessments .......................................................................36
9.5.1.2.1
Seizure Counts............................................................................36
9.5.1.2.2
Clinical Global Impression..........................................................36
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................36
9.5.1.3.1
Pharmacokinetic Assessments.....................................................36
9.5.1.3.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments................................................................................37
9.5.1.4
Safety Assessments...........................................................................37
9.5.1.4.1
Adverse Events...........................................................................37
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................39
9.5.1.4.3
Study-Specific Adverse Events ...................................................40
9.5.1.4.4
Laboratory Measurements...........................................................40
9.5.1.4.5
Vital Signs and Weight Measurements........................................41
9.5.1.4.6
Physical Examinations ................................................................41
9.5.1.4.7
Neurological Examination...........................................................42
9.5.1.4.8
Electrocardiograms .....................................................................42
9.5.1.4.9
Echocardiograms ........................................................................42
9.5.1.4.10 Other Safety Assessments ...........................................................43

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9.5.1.5
Other Assessments............................................................................43
9.5.1.5.1
Quality of Life in Epilepsy Survey..............................................43
9.5.1.5.2
Pediatric Quality Of Life Inventory.............................................43
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 .............................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....................49
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................49
9.5.4.3.2
Reporting of Abnormal Hepatic Tests of Clinical Interest ...........50
9.5.4.3.3
Reporting of Study-Specific Events.............................................50
9.5.4.4
Expedited Reporting.........................................................................51
9.5.4.5
Breaking the Blind............................................................................51
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................51
9.5.5
Completion/Discontinuation of Subjects...................................................51
9.5.6
Abuse or Diversion of Study Drug............................................................52
9.5.7
Confirmation of Medical Care by Another Physician................................52
9.6
Data Quality Assurance......................................................................................52
9.6.1
Data Collection.........................................................................................52
9.6.2
Clinical Data Management .......................................................................53
9.7
Statistical Methods.............................................................................................53
9.7.1
Statistical and Analytical Plans.................................................................53
9.7.1.1
Study Endpoints................................................................................53
9.7.1.1.1
Primary Endpoint........................................................................53
9.7.1.1.2
Secondary Endpoints...................................................................53
9.7.1.1.3
Exploratory Endpoints ................................................................53
9.7.1.2
Definitions of Analysis Sets..............................................................54
9.7.1.3
Subject Disposition...........................................................................54
9.7.1.4
Demographic and Other Baseline Characteristics..............................54
9.7.1.5
Prior and Concomitant Therapy ........................................................54
9.7.1.6
Efficacy Analyses.............................................................................54

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9.7.1.6.1
Primary Efficacy Analysis...........................................................54
9.7.1.6.2
Secondary Efficacy Analyses......................................................55
9.7.1.6.3
Exploratory Efficacy Analyses....................................................55
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................56
9.7.1.7.1
Pharmacokinetic Analyses ..........................................................56
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .....................................................................................56
9.7.1.8
Safety Analyses ................................................................................56
9.7.1.8.1
Extent of Exposure......................................................................57
9.7.1.8.2
Adverse Events...........................................................................57
9.7.1.8.3
Laboratory Values.......................................................................58
9.7.1.8.4
Vital Signs..................................................................................58
9.7.1.8.5
Electrocardiograms .....................................................................58
9.7.1.8.6
Other Safety Analyses.................................................................58
9.7.1.9
Other Analyses .................................................................................58
9.7.2
Determination of Sample Size ..................................................................59
9.7.3
Interim Analysis.......................................................................................59
9.7.4
Other Statistical/Analytical Issues ............................................................59
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................59
10
REFERENCE LIST.....................................................................................................60
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......62
11.1
Changes to the Protocol......................................................................................62
11.2
Adherence to the Protocol..................................................................................62
11.3
Monitoring Procedures.......................................................................................62
11.4
Recording of Data..............................................................................................63
11.5
Identification of Source Data..............................................................................63
11.6
Retention of Records..........................................................................................64
11.7
Auditing Procedures and Inspection ...................................................................64
11.8
Handling of Study Drug.....................................................................................64
11.9
Publication of Results ........................................................................................65
11.10 Disclosure and Confidentiality ...........................................................................65
11.11 Discontinuation of Study....................................................................................65
11.12 Subject Insurance and Indemnity........................................................................66
12
APPENDICES.............................................................................................................67

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LIST OF IN-TEXT TABLES
Table 1
Selection of Dose....................................................................................33
Table 2
Clinical Laboratory Tests........................................................................41
Table 3
Schedule of Procedures/Assessments in Study E2023-A001-304:  Core 
Study......................................................................................................44
Table 4
Schedule of Procedures/Assessments in Study E2023-A001-304:  
Extension Phase......................................................................................73
Table 5 
Scheme of IxRS Study Drug Assignment and Preparation of Study 
Drug Suspension ....................................................................................78
LIST OF IN-TEXT FIGURES
Figure 1
Study Design:  E2023-A001-304 Core Study and Extension Phase.........24
LIST OF APPENDICES
Appendix 1
Sponsor’s Grading for Laboratory Values...............................................68
Appendix 2
Extension Phase......................................................................................71
Appendix 3
Scheme of IxRS Study Drug Assignment and Preparation of Study 
Drug Suspension ....................................................................................78

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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AED
antiepileptic drug
BID
twice daily
BMI
body mass index
CFR
Code of Federal Regulations
CGIC
Clinical Global Impression of Change
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
5-HT
5-hydroxytryptamine
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IRB
Institutional Review Board
IxRS
interactive voice and web response system
MedDRA
Medical Dictionary for Regulatory Activities
PBPK
physiologically-based pharmacokinetic
PD
pharmacodynamics(s)
PedsQL 4.0
Pediatric Quality of Life Inventory
PK
pharmacokinetic(s)
POPPK
population pharmacokinetic
PT
preferred term
QOLIE-31
Quality of Life in Epilepsy Survey
QTc
corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
ULN
upper limit of normal

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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent and assent forms, 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 (eg, 
Federal Regulations, Title 21 Code of Federal Regulations [CFR] Part 56).  Any protocol 
amendment or revision to the informed consent and assent forms 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.
Documented study approval from the IRB chairman must be sent to the principal investigator 
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 IRB annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB, he/she will forward a copy to the sponsor at the time of each periodic report.  The 
investigator(s) 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.
At the end of the study, the sponsor should notify the IRB within 90 days or sooner per the 
IRB requirements.  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 within 15 calendar days or sooner as per the IRB requirements, 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 (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki (2013) 

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
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, ICH

Title 21 of the 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 (or assent) document, the investigator must 
explain to each subject or guardian/legally authorized representative, in accordance with 
applicable professional standards and local laws/regulations, the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject (or guardian/legally authorized representative), and the 
extent of maintaining confidentiality of the subject’s records.  Each subject (or 
guardian/legally authorized representative) 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 
investigator.
This informed consent (or assent) should be given by means of a standard written statement, 
written in nontechnical language.  Electronic media may be used to replace paper-based 
informed consent processes (electronic Informed Consent), utilizing electronic 
signatures. An electronic Informed Consent may be used to provide the same information 
that is contained within the written informed consent (or assent) document, evaluate the 
subject’s comprehension of the information presented, and document the consent (or 
assent)of the subject or the subject’s guardian/legally authorized representative. The subject 
or the subject’s guardian/legally authorized representative should understand the statement 
before signing and dating it and will be given a copy of the signed document.  If a subject is 
unable to read or if a guardian/legally authorized representative is unable to read, an 
impartial witness should be present during the entire informed consent (or assent) discussion.  
After the informed consent form (ICF) (or assent form) and any other written information to 
be provided to subjects is read and explained to the subject or the subject’s guardian/legally 
authorized representative, and after the subject or the subject’s guardian/legally authorized 
representative has orally consented to the subject’s participation in the study and, if capable 
of doing so, has signed and personally dated the ICF, the witness should sign and personally 
date the consent form.  The subject or subject’s guardian/legally authorized representative 
will be asked to sign an ICF (or assent form) before any study-specific procedures are 
performed.  No subject can enter the study before his/her informed consent (or assent) has 
been obtained.  Informed consent from the subject’s legally acceptable representative is 
always required and informed consent (or assent) from the subject is optional (when age and 
condition allows) if not required by local regulations.  An informed consent will also be 
obtained from the guardian/legally authorized representative where applicable.

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An unsigned copy of an IRB-approved ICF must be prepared in accordance with ICH E6, 
Section 4, and all applicable local regulations (eg, Federal Regulations, Title 21 CFR 
Part 50).  Each subject or guardian/legally authorized representative must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.  
The subject or the subject’s guardian/legally authorized representative should be informed in 
a timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 20 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 organization(s) (CRO[s]) are listed in the 
Investigator Study File provided to each site.
7
INTRODUCTION
7.1
Compound Overview
Lorcaserin hydrochloride is a selective serotonin 5-hydroxytryptamine (5-HT)2C receptor 
agonist that is being developed for treatment of Dravet syndrome. Lorcaserin hydrochloride 
selectively mimics the effects of 5-HT at the 5-HT2C receptor and was designed to activate 
5-HT2C receptors without significant agonism of the 5-HT 2A (5-HT2A) or 5-HT 2B (5-HT2B) 
receptors at therapeutic doses.  Functional assays indicate that lorcaserin selectivity for the 
human 5-HT2C receptor is approximately 14- and 61-fold relative to the human 5-HT2A and 
5-HT2B receptors, respectively, and showed little or no appreciable interaction with other 
5-HT receptors, the 5-HT transporter, or a panel of additional receptors and ion channels. 
Lorcaserin was approved by the US FDA on 27 Jun 2012 as an adjunct to a reduced calorie 
diet and increased physical activity for chronic weight management in adults. 
During the review of a postmarketing required 12,000 patient cardiovascular outcome trial, 
the primary safety analysis showed no meaningful difference between lorcaserin and placebo 
in risk of major adverse cardiovascular events, demonstrating noninferiority 
(Bohula et al., 2018).  An assessment of malignancies in this study showed a small numerical 
imbalance (0.6%) in the lorcaserin arm with 462 (7.7%) lorcaserin-treated subjects diagnosed 
with 520 primary cancers and 423 (7.1%) placebo-treated subjects diagnosed with 
470 cancers (based on an FDA analysis).  While the data did not support a finding of 
causation with respect to such cancers, the FDA determined that this numerical imbalance in 
malignancies nonetheless resulted in an unfavourable benefit:risk for the weight management 

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indication and on 11 Feb 2020, the FDA requested that Eisai voluntarily withdraw BELVIQ®
from the market.
After the public announcement of the BELVIQ withdrawal, direct requests were made to 
Eisai and FDA by physicians, caregivers, and advocacy groups regarding the future 
availability of lorcaserin for the treatment of refractory epilepsies, such as Dravet syndrome.  
After consultation with the FDA, Eisai has made lorcaserin available via an Extended Access 
Program for refractory epilepsies to patients who were prescribed BELVIQ before the market 
withdrawal announcement and, based on their treating physician judgment, continue to 
derive clinical benefit.
For more details refer to the Global Investigator Brochure. 
7.2
Clinical Experience
Tolete et. al (2018) summarize a retrospective chart review (Jan 2014 – Jan 2018) of 
36 patients with childhood-onset refractory epilepsies (Dravet syndrome [20 patients], 
Lennox-Gastaut syndrome [9 patients], other treatment-resistant focal epilepsies [3 patients], 
and generalized epilepsies [3 patients]) administered lorcaserin.  Thirty-three (94.3%) 
patients were taking at least 1 antiseizure medication (mean = 3; clobazam [60%], valproic 
acid [57.1%], and cannabidiol [40%]).  Of the 35 patients analyzed, the median percentage 
reduction from baseline in the mean monthly frequency of motor seizures was 47.7% 
(z=−3.04, P<0.01; 46.9% in tonic-clonic, 62.3% in tonic, 60.1% in atonic, and 54.6% in focal 
seizures with motor features); 15 (42%) had greater than 50% reduction in motor seizures.  
Two (5.7%) patients had increased seizure frequency.  The mean lorcaserin dosage was 
15.7 mg/d (and 13.7 mg/d for children) and median treatment duration was 10.8 months.  
After 15 months, 50% of patients remained on lorcaserin.  The most common AEs reported 
were decreased appetite (19.6%), decreased attentiveness (17.1%), and weight loss (11.1%).  
The mean decline in body mass index (BMI) at last follow-up compared to baseline was 
−0.58 ± 0.24 kg/m2 (−2.7 ± 1.3%; P=0.02) and was similar among patients taking or not 
taking valproate.  Five patients stopped treatment before 30 days due to side effects.  The 
above nonclinical and clinical information on lorcaserin justifies the development of 
lorcaserin in Dravet.
The study design and duration of treatment was selected based on Guidelines for Industry on 
Clinical Evaluation of Antiepileptic Drugs (FDA, 1997) and is similar to the design of 
registration clinical studies of Epidiolex, drug approved for treatment of Dravet syndrome 
(Devinsky et al., 2017) and recently reported fenfluramine study in Dravet syndrome (Lagae
et al., 2020).  Sample size was estimated based on the percent reduction of convulsive 
seizures and standard deviation reported in fenfluramine study in Dravet syndrome (Lagae et 
al., 2020).
7.3
Study Rationale
Dravet syndrome is a severe refractory epilepsy syndrome with a reported incidence of 1 in 
40,000 (Wu et al., 2015), onset in the first year of life, and is characterized by frequent 

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convulsive seizures that may contribute to intellectual disability and impairments in 
coordination, behavior, and cognition (Dravet, 1978).  Most patients (70% to 85%) have 
mutation in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene.  The diagnosis 
of Dravet syndrome is based on electroclinical criteria (Wirrell et al., 2017).
Lorcaserin hydrochloride is a selective serotonin 5-HT2C receptor agonist.  The 5-HT2C
receptor is found primarily in the central nervous system (CNS). Autoradiographic studies in 
rats and other species have demonstrated that 5-HT2C binding sites are widely distributed in 
regions fundamental to the generation and propagation of seizures, including in the cortex 
(olfactory nucleus, pyriform, cingulate, and retrosplenial), limbic system (nucleus 
accumbens, hippocampus, and amygdala), and the basal ganglia (caudate nucleus and 
substantia nigra) (Isaac, 2005).  At the cellular level, 5-HT2C receptors are expressed on a 
subpopulation of inhibitory interneurons, and activation of these receptors increases gamma 
aminobutyric acid-mediated synaptic inhibition (Boothman et al., 2006).  As decreased 
inhibition plays a key role in the generation of seizures in Dravet syndrome, there is strong 
physiologic rationale for the therapeutic use of a selective 5-HT2C agonist, such as lorcaserin, 
in Dravet syndrome.  Fenfluramine, an agonist at the 5-HT2B and 5-HT2C receptors, has 
demonstrated efficacy in Dravet syndrome, further supporting the therapeutic rationale for 
lorcaserin (Lagae et al., 2020). 
Mice lacking 5-HT2C receptors, the target for lorcaserin, display spontaneous seizures that are 
occasionally lethal, and a decreased threshold for various convulsing stimuli 
(Venzi et al., 2016).  It has been demonstrated that the scn1labs552 zebrafish models the 
sodium channel mutation, convulsions, electrographic changes, and pharmacological 
responses to treatment of Dravet syndrome (Griffin, et al., 2018), and lorcaserin has been 
shown to reduce seizures in this zebrafish Dravet syndrome model (Griffin et al., 2017;
Griffin et al., 2018). These nonclinical and clinical data support development of lorcaserin as 
an antiseizure agent for treatment of Dravet syndrome.  
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to demonstrate that lorcaserin has superior efficacy 
compared to placebo on percent change in frequency of convulsive seizures per 28 days in 
subjects with Dravet syndrome.
8.2
Secondary Objectives
8.2.1
Key Secondary Objective

The key secondary objective of the study is to evaluate whether lorcaserin has superior 
efficacy compared to placebo on the 50% responder rate (percent of subjects with at least 
50% reduction in frequency of convulsive seizures per 28 days compared to baseline).

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OL = open-label, OLE = open-label extension, R = randomization.
9.1.1
Prerandomization Phase
The Prerandomization Phase will last for 4 weeks and will include a Screening/Baseline 
Period, during which the subjects will be assessed for eligibility.
9.1.1.1
Screening/Baseline Period
The Screening/Baseline Period will begin at Visit 1 (from Week –4 to Week 0).  The purpose 
of the Screening Period is to obtain informed consent and assent forms and to establish 
protocol eligibility.  Informed consent (or assent) will be obtained after the study has been 
fully explained to each subject and/or guardian/legally authorized representative and before 
the conduct of any screening procedures or assessments.  Procedures to be followed when 
obtaining informed consent (or assent) are detailed in Section 5.3.
Subjects must have a diagnosis of epilepsy with Dravet syndrome according to 
Recommendations from a North American Consensus Panel (2017) and confirmed by past 
EEG and clinical history.
During the 4-week Baseline Period, subjects must have at least 4 convulsive seizures based 
on seizure diary. Convulsive seizures are defined as hemiclonic, tonic, clonic, tonic-atonic, 
generalized tonic-clonic, and focal with clearly observable motor signs.
All concomitant treatment for epilepsy (including doses of antiepileptic drugs [AEDs], 
parameters of vagal nerve stimulator, responsive neurostimulator, or deep brain stimulator, 
and ketogenic diet, if followed) must be stable for at least 4 weeks before Screening and 
remain stable throughout the Core Study.
Once the Screening and Baseline procedures have been completed and eligibility has been 
established (Sections 9.3.1 and 9.3.2), the subjects will be randomized and begin treatment in 
the Randomization Phase.
9.1.2
Randomization Phase
The duration of the Randomization Phase will be 14 weeks and will include 2 periods:  
Treatment and Follow-up.  Subjects whose screening assessments and evaluations are 
completed and reviewed by the principal investigator and who continue to meet all of the 
inclusion/exclusion criteria will enter the Randomization Phase.  Approximately 58 subjects 
will be randomized to 1 of 2 treatment groups in a ratio of 1:1 and will receive lorcaserin or 
placebo for 14 weeks.  The randomization will be stratified by previous treatment with 
fenfluramine (yes/no) and by weight categories (10 to <20 kg, 20 to <40 kg, and ≥40 kg).

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9.1.2.1
Treatment Period
During the Treatment Period, all subjects will take study drug BID based on weight 
according to Section 9.4.1.
For lower weight categories, during the first 2 weeks of the Treatment Period, depending on 
the subject’s clinical response and tolerability, the dose may be increased (not earlier than 
after 1 week of treatment) by one dose level at a visit.  If the dose was increased, in the event 
of AEs, according to the investigator’s clinical judgment, the dose may remain the same or 
can be decreased by 1 dose level, to the target dose at any time during the Treatment Period.  
If the dose had been decreased, it may be increased again if tolerability improves. 
All subjects who complete the Core Study will be eligible to enter the Extension Phase.  The 
last visit of the Treatment Period of the Core Study is considered to be the 1st visit of the 
Extension Phase.
9.1.2.2
Follow-Up Period
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for subjects 
who do not enter the Extension Phase.
9.1.3
Extension Phase
The Extension Phase will consist of a Treatment Period (12 weeks) and a Follow-up Period 
(4 weeks).  Subjects are eligible to complete the Extension Phase only if they have completed 
the Treatment Period of the Core Study.
All subjects will receive lorcaserin during the entire Extension Phase but the dose level will 
be blinded during the first 6 weeks. During the first 6 weeks of the Extension Phase, subjects 
who received lorcaserin during the Core Study will receive the same dose of lorcaserin (the 
dose will remain flexible per weight category, based on clinical response and tolerability); 
subjects who received placebo during the Core Study will receive the target dose of 
lorcaserin per weight category. During the second 6 weeks of the Extension Phase, all 
subjects will receive lorcaserin at the maximum dose per weight category (the dose may be 
decreased due to tolerability reasons and increased again if tolerability improves).  Addition, 
deletion, and dose changes to concomitant AEDs are not allowed during the Treatment 
Period of the Extension Phase.
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for subjects 
who will not participate in the Extended Access Program (Study E2023-A001-405) after 
completion of this study.  Subjects who complete the Extension Phase will be eligible to 
enter into Study E2023-A001-405. See Appendix 2 for a full description of the Extension 
Phase. 

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9.2
Discussion of Study Design, Including Choice of Control Groups
The study design and duration of treatment was selected based on Guidelines for Industry on 
Clinical Evaluation of Antiepileptic Drugs (FDA, 1997) and is similar to the design of 
registration clinical studies of Epidiolex, a drug approved for treatment of Dravet syndrome 
(Devinsky et al., 2017) and a recently reported fenfluramine study in Dravet syndrome 
(Lagae et al., 2020).  Sample size was estimated based on the percent reduction of convulsive 
seizures and standard deviation reported in the fenfluramine study in Dravet syndrome 
(Lagae et al., 2020).
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints.
9.3
Selection of Study Population
Approximately 58 subjects will be randomized at approximately 20 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, age ≥2 years at the time of informed consent (or assent)
2. Confirmed diagnosis of epilepsy with Dravet syndrome per Recommendations from a 
North American Consensus Panel (2017)
3. Has had at least 4 convulsive seizures during the 4 weeks of the Prerandomization Phase
4. Currently treated with at least 1 AED and the doses of all AEDs must be stable for at 
least 4 weeks before Screening, and be expected to remain stable throughout the study.  
5. If vagal nerve stimulator, responsive neurostimulator, or deep brain stimulator is used, it 
must be implanted at least 5 months before Screening, parameters must be stable for at 
least 4 weeks before Screening, and be expected to remain stable throughout the study  
6. If a ketogenic diet is followed, it must be stable for at least 4 weeks before Screening and 
be expected to remain stable throughout the study
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:

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1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin).  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:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
o
Total abstinence (if it is their preferred and usual lifestyle)
o
An intrauterine device or intrauterine hormone-releasing system
o
A contraceptive implant
o
An oral contraceptive (Subject must have been on a stable dose of the same oral 
contraceptive product for at least 28 days before dosing and must agree to stay on 
the same dose of the oral contraceptive throughout the study and for 28 days after 
study drug discontinuation).
o
Have a vasectomized partner with confirmed azoospermia

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
NOTE: All postmenarche 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. Use of lorcaserin within 4 weeks before Screening, or any history of it being discontinued 
due to lack of efficacy or adverse reactions
4. Use of fenfluramine within 2 months before Screening, any history of lack of 
fenfluramine efficacy, or any history of valvulopathy at baseline with history of 
fenfluramine use
5. Use of serotonergic or other prohibited drugs administered within 7 days (or 5 half-lives, 
whichever is longer) or monoamine oxidase inhibitors within 30 days before dosing
6. Has a history of status epilepticus that required hospitalization during the 6 months 
before Screening
7. Currently has progressive CNS disease, other than Dravet syndrome, including 
degenerative CNS diseases and progressive tumors
8. Any history of malignancies
9. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal, 
liver disease) that in the opinion of the investigator could affect the subject’s safety or 
interfere with the study assessments
10. Any history of or concomitant medical condition that in the opinion of the investigator 
would compromise the subject’s ability to safely complete the study 

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11. A clinically significant electrocardiogram (ECG) abnormality, including a marked 
baseline prolonged QT/corrected QT interval (QTc; eg, a repeated demonstration of a 
QTc >460 ms)
12. Any history of clinically significant bradycardia or other clinically significant conduction 
abnormality
13. Any suicidal ideation with intent with or without a plan at Screening or within 6 months 
of Screening (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of 
the Columbia-Suicide Severity Rating Scale [C-SSRS] or based on investigator’s clinical 
judgment for subjects unable to be evaluated by C-SSRS)
14. Any lifetime suicidal behavior (per the Suicidal Behavior section of the C-SSRS or based 
on investigator’s clinical judgment for subjects unable to be evaluated by C-SSRS)
15. Hypersensitivity to the study drug and any of the excipients
16. Scheduled for surgery during the study
17. Use of illegal recreational drugs
18. Currently enrolled in another clinical study or used any investigational drug or device 
within 4 weeks before Screening or within approximately 5 half-lives, whichever is 
longer.
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.
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-Up Period and complete protocol-specified 
off-treatment visits and procedures.  The investigator should confirm whether a subject will 
withdraw from study treatment but agree to continue protocol-specified, off-treatment study 
visits, procedures, or whether the subject will withdraw from the study.  If a subject or 
guardian/legally authorized representative withdraws consent (or assent), the date will be 
documented in the source documents.
A subject who discontinues study treatment should be followed for subsequent 
protocol-specified visits and procedures.  If a subject discontinues study drug but remains in 
the study, the set of end-of-treatment procedures, Early Treatment Discontinuation according 
to Early Discontinuation Visit schedule, will be administered, and further information will be 
collected at visits according to regular Schedule of Procedures/Assessments.  The primary 
reason for discontinuation and all other reasons contributing to the subject’s discontinuation 
from study drug will be collected.  If a subject discontinues from study treatment and the 
study at the same time, Early Discontinuation Visit will be conducted followed by safety 
Follow-up Visit (see Section 9.5.5).

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9.4
Treatments
9.4.1
Treatments Administered
The following study drugs will be used in this study:

Test drug: E2023, oral, 10-mg tablets

Comparator drug: placebo, oral tablets matching the test drug
Selection of dose, timing, and instruction on how to prepare suspension for individual 
subjects is described in Section 9.4.5.
9.4.2
Identity of Investigational Products
Lorcaserin and matching placebo will be provided as a blue-colored, film-coated, 10-mg 
tablet, round, biconvex, debossed “A” on one side and “10” on the other side. 
Investigational products, ie, lorcaserin and placebo, will be supplied by the sponsor in 
blinded labeled containers.
The sponsor will provide the study drugs packaged in a double-blind configuration.  Each 
subject’s study drug will consist of either lorcaserin or placebo.
9.4.2.1
Chemical Name of E2023

Test drug code: 
E2023

Generic name:  
Lorcaserin 

Chemical name: 
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate

Molecular formula:  C11H14ClN·HCl·0.5 H2O

Molecular weight:
241.16 g/mol
9.4.2.2
Comparator Drug
The comparator drug is placebo, oral tablets matching the test drug.
9.4.2.3
Labeling for Study Drug
Lorcaserin or matching placebo will be labeled in accordance with text that is in full 
regulatory compliance with each participating country and is translated into the required 
language(s) for each of those countries.

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9.4.2.4
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee 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 treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
After the Baseline Period, subjects will be randomized to 1 of 2 treatment groups in a ratio of 
1:1.  Each treatment group will receive either lorcaserin or placebo BID.
Randomization will be performed centrally by an interactive voice and web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized bottle 
identification numbers.  At enrollment (and after successful completion of Visit 1), the 
investigator or designee will call the IxRS to register the subject information.  At 
randomization (Visit 2), the IxRS will assign each subject a unique 6-digit randomization 
number.  At every subsequent dose change, the investigator or a designee will call the IxRS 
to obtain dispensing instructions and register the subject’s visit.
9.4.4
Selection of Doses in the Study
Population pharmacokinetic (POPPK) modeling of lorcaserin in a pooled population of 
healthy adult volunteers from 2 Phase 1 studies, and overweight and obese adults from 
1 Phase 2 study and 3 Phase 3 studies (Report CMPS-APD356-003R), has identified that the 
PK profile of lorcaserin is best described by a 1-compartment model with first order 
absorption and elimination.  The analysis also identified that exposures to lorcaserin are a 
function of body weight, with allometric body weight effects on both clearance 
(exponent=0.75) and volume of distribution (exponent=1). 
In addition, a physiologically-based pharmacokinetic (PBPK) model was developed for 
lorcaserin using Simcyp V19.  Performance of the model in predicting lorcaserin PK was 
verified by plotting the model-predicted PK profiles over the observed lorcaserin PK profiles 
in healthy volunteers from Studies APD356-001 (single ascending dose), APD356-002 
(multiple ascending dose) and APD356-101 (immediate-release vs extended-release
bioequivalence study).  Overall, the model predicted the PK profiles of lorcaserin well and 
was considered suitable for predicting lorcaserin PK profiles in children. 

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Both the POPPK model and the PBPK model were used to simulate lorcaserin PK profiles 
for a range of doses and body weights in children (Centers for Disease Control and 
Prevention, 2020).  The lower limit of the body weight for Group 1 (10 kg), represents the 
10th percentile of body weight distribution in a 2 year-old child, according to the Centers for 
Disease Control and Prevention.  PBPK simulations of lorcaserin PK profiles were 
performed using the default values of the Simcyp Pediatric population file.  Both methods 
predicted similar PK profiles for lorcaserin in the age range evaluated (2 to 7 years). 
The doses of lorcaserin proposed for this study were selected based on the similarities of the 
predicted PK profile with those predicted after lorcaserin 10 mg BID administration in a 
70 kg adult.  
The doses proposed are further supported by data from a Good Laboratory Practice 
repeated-dose toxicity study in juvenile Sprague Dawley rats at doses of 0, 5, 50, and 100 
mg/kg/day.  Juvenile and adult Sprague Dawley rats tolerate lorcaserin at similar doses and 
exposures and the toxicity profile of lorcaserin is similar between juvenile and adult rats.  
Significant findings noted in the juvenile toxicity study were delayed sexual maturity in 
females and increased incidence and extent of tubuloalveolar glandular tissue of mammary 
gland in males compatible with increased prolactin levels at the highest dose tested (100 
mg/kg/day).  These findings were absent at the mid-dose (50 mg/kg/day) providing 15- and 
10-fold exposure margins in females and males, respectively, relative to the highest 
anticipated mean daily exposure in the proposed clinical study (10 mg BID for a 40 kg child).
9.4.5
Selection and Timing of Dose for Each Subject
During the Treatment Period, all subjects will take study drug as a suspension BID 
approximately 12 hours apart based on weight according to Table 1.

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Table 1
Selection of Dose
Subject’s Weight
10 to <20 kg
20 to <40 kg
≥40 kg
Target 
Dose(starting) 
2.5 mg BID (5 mg/day)
5 mg BID (10 mg/day)
10 mg BID (20 mg/day)
Dose Level Step 
(optional)
2.5 mg BID (5 mg/day)
5 mg BID (10 mg/day)
—
Maximum Dose
5 mg BID (10 mg/day)
10 mg BID (20 mg/day)
10 mg BID (20 mg/day)
BID = twice daily.
To prepare the suspension of study drug before each administration, 2 tablets (from a blister 
pack, assigned by IxRS) will first be suspended in 10 mL of water, after which 70 mL of 
sugar-free Ora-Sweet Syrup will be added and the suspension mixed thoroughly.  For 
subjects with weight <20 kg, a 20 mL aliquot of this suspension, or for subjects with weight 
≥20 kg, a 40 mL aliquot of this suspension will be taken orally and the remainder of the 
suspension should be discarded after each administration (for details see Appendix 3).
9.4.6
Blinding
During the Randomization Phase, subjects and all personnel involved with the conduct and 
interpretation of the study, including investigators, site personnel, and sponsor staff will be 
blinded to the treatment codes.  Randomization data will be kept strictly confidential, filed 
securely by an appropriate group with the sponsor or CRO and accessible only to authorized 
persons (eg, Eisai Global Safety) until the time of unblinding, per SOP.
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 (or assent) will be recorded.  
The AE or medical condition for which the concomitant medication or therapy was 
administered will be recorded.
Concomitant AEDs, including Epidiolex®, initiated before Screening are allowed; the dose 
must remain stable during the Prerandomization and Randomization Phase.
Benzodiazepines are allowed as AEDs or rescue medication for seizure control.
The following medications are prohibited during the Prerandomization and Randomization 
Phase: Artisanal cannabidiol products, serotonergic drugs (due to the risk of serotonin 
syndrome), including selective serotonin reuptake inhibitors, serotonin-norepinephrine 
reuptake inhibitors, monoamine oxidase inhibitors, triptans, bupropion, dextromethorphan, 
centrally-acting anorectic agents including fenfluramine, and St. John’s Wort.  
Drugs that are cytochrome P450 2D6 substrates should be used with caution, as lorcaserin 
can increase exposure of these drugs.

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Investigational drugs or devices are prohibited during the participation in the study.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during visits and at the completion of the study.
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

Drug Enforcement Agency license 

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

A copy of the certification and a table of the normal laboratory ranges for the reference
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated Form FDA 1572

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572 

A signed and dated curriculum vitae of the principal investigator including a copy of the 
principal investigator’s current medical license or medical registration number on the 
curriculum vitae

A signed and dated clinical site agreement
The investigator and the study staff will be responsible for the accountability of all treatment 
(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 treatment to be used other than as 
directed by this protocol.  Parent/guardian may be dispensed treatment for pediatric subjects. 
The site must maintain an accurate and timely record of the following:  receipt of all study 
treatment, dispensing of treatment to the subject, collection and reconciliation of unused 
study treatment of reconciled study treatment to the sponsor or (where applicable) destruction 
of reconciled study treatment at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study treatment, (b) treatment dispensing/return reconciliation 

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log, (c) treatment accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of treatment 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 treatment and inventory records must be made available, upon request, for inspection by 
a designated representative of the sponsor or a representative of a health authority.  As 
applicable, all unused treatment and empty and partially empty containers from used study 
treatment are to be returned to the investigator by the subject and, together with unused study 
treatment 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 treatment and containers at 
the site.  Destruction at the site will only occur under circumstances where regulation or 
supply type prohibits the return of treatment 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, treatment 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, 
treatment may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  Where treatment is 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 visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
Assessments will be performed as specified in Table 3.
9.5.1.1
Screening Assessments
9.5.1.1.1
DEMOGRAPHY 
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth, sex, race/ethnicity.
Height and weight will be measured at the Screening Visit. 
9.5.1.1.2
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All medical and surgical history within 1 year must be noted in the Medical History 
and Current Medical Conditions case report form (CRF).

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9.5.1.1.3
EPILEPSY HISTORY
Epilepsy history will be will be recorded at Screening Visit as designated in the Schedule of 
Procedures/Assessments (Table 3).  Epilepsy history will include information on genetic 
mutation related to epilepsy, if available. 
9.5.1.2
Efficacy Assessments
9.5.1.2.1
SEIZURE COUNTS
Seizure diaries will be used to collect seizure counts.  Diaries will be dispensed to all subjects 
at each visit as described in Table 3.  The diary is to be completed daily, by the 
parent/guardian. All seizures will be recorded.  At each visit the parent/guardian will be 
instructed by the site personnel as to how to complete the diary and reminded that they must 
return the diary at their next scheduled clinic visit and at the Early Discontinuation and 
Follow-up Visits (if applicable).  To ensure correct seizure classification, the medically 
qualified investigator should review the diary with the parent/guardian at all visits. 
Parents/guardians must be counseled if diary compliance is not satisfactory (ie, missed 3 or 
more consecutive daily diary entries).
9.5.1.2.2
CLINICAL GLOBAL IMPRESSION
CGIC (clinician-rated) will be assessed.  CGIC is a 7-point scale that provides a 
clinician-determined summary measure of change from baseline of subject’s clinical status.
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments
9.5.1.3.1
PHARMACOKINETIC ASSESSMENTS
Blood samples for PK assessment will be collected during the Treatment Period. 
Blood samples with sodium heparin as anticoagulant (1 mL each) will be collected as 
specified in Table 3.  See PK or laboratory manual for a description of collection, handling, 
and shipping procedures for PK samples.
Samples from all subjects receiving active treatment will be analyzed.  In addition, a 
predetermined percentage of placebo samples will be analyzed.  Remaining placebo samples 
will be held in storage in the event that further confirmatory analysis is requested.  Plasma 
concentrations of lorcaserin will be quantified by liquid chromatography with tandem mass 
spectrometry methodology using a previously validated assay.
Blood will also be drawn where possible at the first report of a serious adverse event (SAE) 
or severe unexpected AE and at its resolution.

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9.5.1.3.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Data may be analyzed based on types of genetic mutations related to epilepsy (information 
on genetic mutation related to epilepsy will be collected, if available, based on review of 
epilepsy history).
9.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, regular laboratory 
evaluation for hematology, blood chemistry, and urinalysis; periodic measurement of vital 
signs, weight, echocardiograms, and ECGs; and the performance of physical and 
neurological examinations, as detailed in Table 3.  
An assessment of suicidality using the C-SSRS (for subjects aged ≥6 years old) or based 
upon clinical assessment of the investigator (for subjects <6 years old) will be performed at 
every study visit.  The C-SSRS provides assessment of suicide risk including the severity and 
immediacy of that risk through a series of plain-language questions. 
Valvular regurgitation as assessed on echocardiogram will be rated absent, trace, mild, 
moderate, or severe for the aortic, mitral, tricuspid, and pulmonic valve. The evaluations will 
be based on the recommendations from the American Society of Echocardiography
(Zoghbi et al., 2017). Pulmonary artery pressure will be estimated by a comprehensive 
approach that includes the tricuspid regurgitation jet velocity (if present), right ventricular 
outflow tract flow acceleration time, pulmonic regurgitation peak early diastolic velocity (if 
present), right ventricular outflow tract flow acceleration time, pulmonic regurgitation peak 
early diastolic velocity (if present), and the eccentricity index that describes the 
interventricular septum position at end-systole (Jone and Ivy, 2014). 
9.5.1.4.1
ADVERSE EVENTS
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 E2023 or placebo. 
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.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression.

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 pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs, regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the study ICF through the last visit of the End of Treatment 
Phase.  Refer to Section 9.5.4.1 for the time period after the end of treatment for SAE 
collection.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTc using Fridericia’s formula) 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
using Fridericia’s formula is more than 460 ms and there is an increase of more than 60 ms 
from baseline.  If subject has a normal ECG baseline reading, but during any visit thereafter 
the QT is measured as more than 460 ms, 3 consecutive ECGs separated by 5 to 10 minutes 
will be performed to confirm the abnormality.  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 clinical assessment of 
suicidality, C-SSRS, in all subjects and determine if any result constitutes an AE.  Medical 
and scientific judgment should be exercised in deciding whether an isolated suicidality rating 
scale response should be classified as an AE. 
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its severity 
and its relationship to the study treatment.
Assessing Severity of Adverse Events
AEs will be graded on a 3-point scale (mild, moderate, severe) and reported in the detail 
indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity

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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 9.5.1.4.2 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
9.5.1.4.2
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. 
Refer to Section 9.5.1.4.3 for the list of study-specific events to be reported as SAEs.
In addition to study-specific events, 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 (or assent) (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
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.4.3
STUDY-SPECIFIC ADVERSE EVENTS
The following study-specific AEs will be considered as always serious as an important 
medical event, in the absence of other seriousness criteria:  serotonin syndrome, psychosis, 
suicidal behavior, priapism, new or worsened valvular heart disease, new or worsened 
pulmonary hypertension, new arrhythmia or conduction abnormality, severe symptomatic 
hypoglycemia, and malignant neoplasms.  The definitions of these study-specific AEs and 
the instructions for reporting are described in Section 9.5.4.3.3.
9.5.1.4.4
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 2.  Subjects should be in a seated position during blood collection.  

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The Schedule of Procedures/Assessments (Table 3) shows the visits and time points at which 
blood for clinical laboratory tests and urine for urinalysis will be collected in the study.
Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Calcium, 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, 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.
Clinical laboratory tests during the study will be performed by a central laboratory.  All 
blood and urine samples will be collected and sent to the central laboratory on the day of 
collection unless otherwise instructed.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.4.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF 
(see Section 9.5.4.3.2).
9.5.1.4.5
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [mmHg], pulse [beats per 
minute], respiratory rate [per minute], body temperature [in centigrade], and weight [kg]) 
will be obtained at the visits designated in the Schedule of Procedures/Assessments (Table 3) 
by a validated method.  Blood pressure and pulse will be measured after the subject has been 
sitting for 5 minutes.  All blood pressure measurements should be performed on the same 
arm, preferably by the same person.
9.5.1.4.6
PHYSICAL EXAMINATIONS
Physical examinations (comprehensive or symptom directed) will be performed as designated 
in the Schedule of Procedures/Assessments (Table 3).  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest 

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(including heart and lungs), abdomen, limbs, and skin.  A urogenital examination will only 
be required in the presence of clinical symptoms related to this region.  Documentation of the 
physical examination will be included in the source documentation at the site.  Significant 
findings at the Screening Visit will be recorded on the Medical History and Current Medical 
Conditions CRF.  Changes from screening physical examination findings that meet the 
definition of an AE will be recorded on the Adverse Events CRF.
9.5.1.4.7
NEUROLOGICAL EXAMINATION
Neurological examination will consist of assessment of mental status, sensory systems, 
cranial nerves, motor function, deep tendon reflexes, and cerebellar functions.  
9.5.1.4.8
ELECTROCARDIOGRAMS
ECGs will be obtained as designated in the Schedule of Procedures/Assessments (Table 3).  
If subject has a normal ECG baseline reading, but during any visit thereafter the QT is 
measured as more than 460 ms, 3 consecutive ECGs separated by 5 to 10 minutes will be 
performed to confirm the abnormality. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.4.9
ECHOCARDIOGRAMS
Echocardiograms will be obtained as designated in the Schedule of Procedures/Assessments 
(Table 3).  
In this study, echocardiographic images will be acquired as part of safety assessments. 
Standardized training will be provided for all echocardiographers, and centralized procedures 
for collecting, analyzing, and reporting echocardiographic data will be implemented. All 
echocardiograms will be over-read by 2 blinded central readers (primary and secondary). 
The baseline echocardiograms will be performed before randomization between Visits 1 and 
2 for subjects who are considered otherwise eligible for the study based on initial review of 
eligibility criteria. Valvular regurgitation as assessed on echocardiogram will be rated 
absent, trace, mild, moderate, or severe for the aortic, mitral, tricuspid, and pulmonic valves.  
The evaluations will be based on the recommendations from the American Society of 
Echocardiography (Zoghbi et al., 2017). Pulmonary artery pressure will be estimated by a 
comprehensive approach that includes the tricuspid regurgitation jet velocity (if present), 
right ventricular outflow tract flow acceleration time, pulmonic regurgitation peak early 
diastolic velocity (if present), right ventricular outflow tract flow acceleration time, pulmonic 
regurgitation peak early diastolic velocity (if present), and the eccentricity index that 
describes the interventricular septum position at end-systole (Jone and Ivy, 2014).

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9.5.1.4.10 OTHER SAFETY ASSESSMENTS
C-SSRS
An assessment of suicidality using the C-SSRS will be performed at Screening, Baseline, 
Day 1 postdosing, every visit, including after the last dose of study drug, and at the 
Termination Visit, as designated in the Schedule of Procedures/Assessments (Table 3).
Pregnancy Test
A serum β-hCG test will be performed for female subjects age 12 years old and above, or of 
child-bearing potential, only.  A sample of blood will be taken at Screening; at all other time 
points a urine pregnancy test will be performed as specified in the Schedule of 
Procedures/Assessments (Table 3).  If urine cannot be obtained for pregnancy testing after 
Screening, a serum pregnancy test will be performed.
9.5.1.5
Other Assessments
9.5.1.5.1
QUALITY OF LIFE IN EPILEPSY SURVEY
Quality of life will be assessed using Quality of Life in Epilepsy Survey (QOLIE-31).  The 
QOLIE-31 is a survey of health-related quality of life for adults that includes 31 questions 
about subject’s health and daily activities. 
9.5.1.5.2
PEDIATRIC QUALITY OF LIFE INVENTORY
The Pediatric Quality of Life Inventory (PedsQL 4.0) is a modular instrument for measuring 
health-related quality of life in children and adolescents ages 2 to 18 years. Generic Core 
Scales are multidimensional child self-report and parent proxy-report scales developed as the 
generic core measure to be integrated with the PedsQL Disease-Specific Modules.  The 
PedsQL 4.0 Generic Core Scales consist of 23 items applicable for healthy school and 
community populations, as well as pediatric populations with acute and chronic health 
conditions.
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the Schedule of Procedures/Assessments for the Core Study.

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Table 3
Schedule of Procedures/Assessments in Study E2023-A001-304:  Core Study
Phase
Prerandomization
Randomization
Period
Screening/Baseline
Treatmenta
Follow-
upb,c
Visit
1
2
3
4
5
6
7
8
EDd
Unschedulede
Week
From –4 Weeks to 
Week 0 
0
1
2
4
6
10
14
4 weeks 
after the 
last dose
Procedures/Assessments
Demography
X
Informed consent/assent
X
Inclusion/exclusion criteria
X
X
Medical history
X
Epilepsy historyf
X
Prior and concomitant medications 
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant AEDs
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Study drug compliance
X
X
X
X
X
X
X
Xe,g
Dispense study drug
X
X
X
X
X
X
Xh
Xe,g
Retrieve unused study drug
X
X
X
X
X
X
X
Xe,g
Dispense subject’s diary
X
X
X
X
X
X
X
Xh
Xe
Retrieve and review diary
X
X
X
X
X
X
X
X
Xe
Neurological examinationi
X
X
X

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Table 3
Schedule of Procedures/Assessments in Study E2023-A001-304:  Core Study
Phase
Prerandomization
Randomization
Period
Screening/Baseline
Treatmenta
Follow-
upb,c
Visit
1
2
3
4
5
6
7
8
EDd
Unschedulede
Week
From –4 Weeks to 
Week 0 
0
1
2
4
6
10
14
4 weeks 
after the 
last dose
Procedures/Assessments
Physical examinationi
X
X
X
Vital signs, and weight
X
X
X
X
X
X
X
X
X
Xe
Height
X
Clinical laboratory testsj
X
X
X
X
Xe,k
Serum β-hCG testl
X
Urine pregnancy testl
X
X
X
Xe
12-Lead ECGm
X
X
X
Xe,k
Echocardiogram
X
X
X
Xe,k
PK sampling (plasma)n
X
X
X
X
Xo
IxRS call
X
X
X
X
X
X
X
X
X
Xe
C-SSRS
X
X
X
X
X
X
X
X
X
QoL
X
X
X
Clinical Global Impressionp
X
X
X
AE = adverse event, AED = antiepileptic drug, β-hCG = beta-human chorionic gonadotropin, COVID-19 = Coronavirus disease 2019, 
C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, ED = early discontinuation, IxRS = interactive voice and web response system, 

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Table 3
Schedule of Procedures/Assessments in Study E2023-A001-304:  Core Study
Phase
Prerandomization
Randomization
Period
Screening/Baseline
Treatmenta
Follow-
upb,c
Visit
1
2
3
4
5
6
7
8
EDd
Unschedulede
Week
From –4 Weeks to 
Week 0 
0
1
2
4
6
10
14
4 weeks 
after the 
last dose
Procedures/Assessments
PedsQL = Pediatric Quality of Life Inventory, PK = pharmacokinetic, QoL = Quality of Life in Epilepsy Scale/Pediatric Quality of Life Inventory 4.0; 
QOLIE-31 = Quality of Life in Epilepsy Survey.
a:
All visits to be done within 3 days of the schedule.  If any of the visits after Visit 1 are conducted remotely due to the COVID-19 pandemic, at a 
minimum, the following assessments should be conducted: AEs, suicidality assessment, concomitant medications, review of seizure diary data, and study 
drug compliance (any missed or extra doses with dates).  Study drug and seizure diary may be picked up from the site by the subject/caregiver or shipped 
from the site to the subject’s location. C-SSRS and Clinical Global Impression may be conducted remotely over the phone by a qualified rater and 
QOLIE-31 and PedsQL based on input from subject over the phone.
b:
Visit to be done within ±7 days of the schedule.
c:
The Follow-up Visit only applies to those subjects who do not enter the Extension Phase after completion of this study.
d:
These assessments will be conducted for subjects who discontinue the study or treatment early for any reason after Visit 2.
e:
At Unscheduled Visits these assessments/procedures conducted if needed.
f:
Epilepsy history will include information on genetic mutation related to epilepsy, if available.
g:
Unused study drug to be retrieved and study drug dispensed only for subjects requiring dose change at Unscheduled Visits.
h:
Study drug and seizure diary will be dispensed only for subjects who enter the Extension Phase.
i:
Physical and neurological examinations will only be performed at the indicated visits.  For all other clinic visits during the study, the physical and the 
neurological examinations will only be performed when there is a complaint from the subject.  Clinically significant abnormal findings from the physical 
or the neurological examinations will be reported as AEs.
j:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
k:
At Unscheduled Visits, these assessments will only be done if the results from the previous visit were deemed clinically significant by the investigator.
l:
Only for female subjects of child-bearing potential (defined as all postmenarche females, unless postmenopausal or have been sterilized surgically).
m:
If subject has a normal ECG baseline reading, but during any visit thereafter the QT is measured as >460 ms, 3 consecutive ECGs separated by 
5 to 10 minutes will be performed to confirm the abnormality.
n:
One blood sample (approximately 1 mL) for determination of lorcaserin plasma concentrations will be collected at predose and between 1 to 2 hours 
postdose at Visit 4 and 6; 3 to 6 hours postdose only at Visit 5 and 7.

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Table 3
Schedule of Procedures/Assessments in Study E2023-A001-304:  Core Study
Phase
Prerandomization
Randomization
Period
Screening/Baseline
Treatmenta
Follow-
upb,c
Visit
1
2
3
4
5
6
7
8
EDd
Unschedulede
Week
From –4 Weeks to 
Week 0 
0
1
2
4
6
10
14
4 weeks 
after the 
last dose
Procedures/Assessments
o:
At ED Visit, 1 blood sample (approximately 1 mL) PK samples should only be collected only if can be drawn within 50 hours of the last dose of study 
drug.
p:
Clinical Global Impression of Severity is conducted At Visit 2, and Clinical Global Impression of Change at Visit 8 or ED.

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9.5.2.2
Description of Procedures/Assessments Schedule
Refer to the Schedule of Procedures/Assessments (Table 3) for procedures/assessments that 
will be performed during this study.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of epilepsy.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected for 28 days after the subject’s 
last dose.  All SAEs must be followed to resolution or, if resolution is unlikely, to 
stabilization.  Any SAE judged by the investigator to be related to the study treatment or any 
protocol-required procedure should be reported to the sponsor regardless of the length of 
time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB of the occurrence of the SAE in writing, if required 
by their institution.  A copy of this communication must be forwarded to the sponsor to be 
filed in the sponsor’s Trial Master File.

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9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in a female subject in which the estimated date of conception is either before 
the last visit or within 28 days of last study treatment, (or any partner’s pregnancy of a male 
subject in which the estimated date of conception is either before the last visit or within 
5 times the half-life of the study drug plus 90 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, a spontaneous abortion or an induced 
abortion done due to safety concerns for either mother or fetus 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 24 hours from the date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
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.  

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All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
and Intentional Overdose, even if asymptomatic, are always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF ABNORMAL HEPATIC TESTS OF CLINICAL INTEREST
The following combination of abnormal laboratory tests*, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing and whether 
nonserious or serious, should be entered on the Adverse Event CRF and reported using the 
procedures detailed in Reporting of Serious Adverse Events (Section 9.5.4.1).  If the event 
does not meet serious criteria, the seriousness criteria on the SAE form should be indicated as 
“nonserious.”  

Elevated aspartate aminotransferase or alanine aminotransferase laboratory value that 
is greater than or equal to 3× the upper limit of normal (ULN)
AND

Elevated total bilirubin laboratory value that is greater than or equal to 2× the ULN
AND AT THE SAME TIME

Alkaline phosphatase laboratory value that is less than 2× the ULN
*Note: These criteria are based upon available regulatory guidance documents.  The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require additional 
evaluation for an underlying etiology.  In addition to reporting the abnormal hepatic 
laboratory tests on a SAE form, the site should also consult the medical monitor for guidance 
on assessment and follow-up.  At a minimum, laboratory testing should be repeated at least 
once weekly until improvement or identification of a cause unrelated to study drug use that is 
unlikely to improve.
9.5.4.3.3
REPORTING OF STUDY-SPECIFIC EVENTS
The following study-specific AEs should always be considered as SAEs, and entered on the 
Adverse Event CRF and reported using the procedures detailed in Reporting of Serious 
Adverse Events (Section 9.5.4.1), as important medical events even if the event does not 
meet other seriousness criteria:

Serotonin syndrome (must have at least 1 of the following: spontaneous clonus; 
inducible clonus PLUS agitation or diaphoresis; ocular clonus PLUS agitation or 
diaphoresis; tremor PLUS hyperreflexia; hypertonia PLUS temperature above 38ºC 
PLUS ocular clonus or inducible clonus)

Psychosis

Suicidal behavior 

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
Priapism

New or worsened valvular heart disease 

New or worsened pulmonary hypertension

New arrhythmia or conduction abnormality 

Severe symptomatic hypoglycemia

Malignant neoplasms
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable regulatory requirements, on an expedited basis (ie, within 
specific time frames).  For this reason, it is imperative that sites provide complete SAE 
information in the manner described above.
9.5.4.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.4.6
Regulatory Reporting of Adverse Events
AEs will be reported by the sponsor or a third party acting on behalf of the sponsor to 
regulatory authorities in compliance with local and regional law and established guidance.  
The format of these reports will be dictated by the local and regional requirements.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 3).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, progression 
of disease, withdrawal of consent (or assent), pregnancy, study terminated by sponsor, or 

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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 on a study-phase basis.  
A subject removed from the study for any reason may be replaced if the reason for 
discontinuation is related to the Coronavirus Disease 2019 (COVID-19) pandemic.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.
AEs associated with abuse or diversion will be appropriately reported as AEs and monitored 
per Section 9.5.1.4.1.  Abuse is always to be captured as an AE.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent (or assent) of the subject, will inform the other 
physician that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s qualified compliance auditing team, which is an 
independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.

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new onset heart block, new onset of other arrhythmias or conduction abnormalities,
thickened valve leaflets, and restricted valve leaflet motion will be summarized.
Proportion of subjects with any treatment-emergent study-specific AEs will be summarized.
9.7.1.8.1
EXTENT OF EXPOSURE
The duration of treatment will be calculated as the number of days between the date the 
subject receives the 1st treatment dose and the date the subject receives the last dose of 
treatment.  These values will be used to summarize the extent of exposure to study drug.
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 23 or higher) lower level term 
closest to the verbatim term.  The linked MedDRA PT and primary system organ class (SOC) 
are also captured in the database.
A TEAE is defined as an AE that 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.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 
1 TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs 
will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  A subject data listing of all AEs leading to death will be provided.

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The number (percentage) of subjects with treatment-emergent SAEs will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all SAEs will be 
provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT for each treatment group.  A subject data 
listing of all AEs leading to discontinuation from study drug will be provided.
The number (percentage) of subjects with TEAEs leading to treatment dose adjustment will 
be summarized by MedDRA SOC and PT.  A subject data listing of all AEs leading to 
treatment dose adjustment will be provided.
9.7.1.8.3
LABORATORY VALUES
Changes from baseline in laboratory values will be summarized for continuous variables.  
Laboratory shift tables showing incidence of new or worsening clinically significant findings 
from baseline to the postbaseline visits will be displayed.  Shift from baseline to the highest 
postbaseline laboratory value and from baseline to the lowest postbaseline laboratory value 
will also be displayed.
Incidence of treatment-emergent markedly abnormal laboratory values in laboratory safety 
test variables will be summarized.  Treatment-emergent markedly abnormal laboratory 
values will be graded based on the Common Terminology Criteria for Adverse Events 
Version 5.0.  Incidence of Hy’s law will be summarized.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit 
and treatment group.
9.7.1.8.5
ELECTROCARDIOGRAMS
ECG assessments will be performed at Unscheduled, if needed (See Table 3).  Descriptive 
statistics for ECG parameters and changes from baseline will be presented by visit and 
treatment group.
9.7.1.8.6
OTHER SAFETY ANALYSES
The proportion of subjects with any treatment-emergent report of suicidal ideation and 
behavior and intensity of these behaviors will be summarized.
Listings from pregnancy tests will be prepared. 
9.7.1.9
Other Analyses
The change from baseline in QOLIE-31 and PedsQL 4.0 Scale will be summarized.

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9.7.2
Determination of Sample Size
A sample size of 58 subjects (29 per group) will have 90% power to detect a difference of 
50% reduction in convulsive seizure frequency per 28 days between lorcaserin and 
placebo assuming a standard deviation of 55, using a 2-group t-test with 0.05 two sided 
significance level.  This sample size will have 90% power to detect an odds-ratio of at least 
10 for the secondary endpoint 50% reduction in convulsive seizure frequency, assuming the 
placebo response is 12%, using a 2-group Chi-square test with 0.05 two-sided significance 
level.  This sample size assumes a 7% dropout rate. Sample size was estimated based on the 
percent reduction of convulsive seizures and standard deviation reported in fenfluramine 
study in Dravet syndrome (Lagae et al., 2020).
9.7.3
Interim Analysis
No 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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Recommendations for noninvasive evaluation of native valvular regurgitation: a report from 
the American Society of Echocardiography developed in collaboration with the Society for 
Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 2017;30(4):303-71.

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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 (if applicable) 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 (if 
applicable) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and 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

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
Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, 
rhythm strips, electroencephalography, 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 correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following items, the data recorded directly on the CRF are to be considered source data:

Reasons for discontinuation of study treatment 

Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome)

Reasons for dose modification

Indication for prior/concomitant medication

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
Sampling times for drug concentrations

Sampling times for clinical laboratory tests.
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 15 years following the completion of the study.
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 drug will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or, when approval is given by the sponsor, will destroy supplies and 
containers at the site.

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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.
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.

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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 – 2.5ULN if 
baseline was normal; 
2.0 – 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was 
normal; 
>20.0baseline if 
baseline was 
abnormal
ALT
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was 
normal; 
>20.0baseline if 
baseline was 
abnormal
AST
>ULN – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 5.0ULN if 
baseline was normal; 
3.0 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was 
normal; 
>20.0baseline if 
baseline was 
abnormal
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN if 
baseline was normal; 
1.0 – 1.5baseline if 
baseline was abnormal
>1.5 – 3.0ULN if 
baseline was normal; 
1.5 – 3.0baseline if 
baseline was abnormal
>3.0 – 10.0ULN if 
baseline was normal; 3.0 
– 10.0baseline if 
baseline was abnormal
>10.0ULN if 
baseline was 
normal; 
>10.0baseline if 
baseline was 
abnormal
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
Ionized calcium 
<LLN – 1.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
Ionized calcium 
<1.0 – 0.9 mmol/L; 
symptomatic
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
Ionized calcium 
<0.9 – 0.8 mmol/L; 
hospitalization indicated
<6.0 mg/dL
<1.5 mmol/L
Ionized calcium 
<0.8 mmol/L; 
life-threatening 
consequences

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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
Ionized calcium 
>ULN – 1.5 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
Ionized calcium 
>1.5 – 1.6 mmol/L; 
symptomatic
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
Ionized calcium 
>1.6 – 1.8 mmol/L; 
hospitalization indicated
>13.5 mg/dL
>3.4 mmol/L
Ionized calcium 
>1.8 mmol/L; 
life-threatening 
consequences
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baseline;
>1.5 – 3.0ULN
>3.0baseline;
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 2.5ULN if 
baseline was normal; 
2.0 – 2.5baseline if 
baseline was abnormal
>2.5 – 5.0ULN if 
baseline was normal; 
>2.5 – 5.0baseline if 
baseline was abnormal
>5.0 – 20.0ULN if 
baseline was normal; 
>5.0 – 20.0baseline if 
baseline was abnormal
>20.0ULN if 
baseline was 
normal; >20.0
baseline if baseline 
was abnormal
Glucose, serum-high (hyperglycemia)
Abnormal glucose 
above baseline with no 
medical intervention
Change in daily 
management from 
baseline for a diabetic; 
oral antiglycemic agent 
initiated; workup for 
diabetes
Insulin therapy initiated; 
hospitalization indicated
life-threatening 
consequences; 
urgent intervention 
indicated
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L; 
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
Laboratory finding only 
and intervention not 
indicated
Oral replacement 
therapy indicated
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated
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; 
intervention initiated
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
125 – 129 mmol/L and 
asymptomatic
<125 – 129  mmol/L 
symptomatic; 
120 – 124 mmol/L 
regardless of symptoms
<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 

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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Uric acid, serum-high (hyperuricemia)
>ULN without 
physiologic 
consequences 
N/A
>ULN with physiologic 
consequences 
life-threatening 
consequences
Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  Published: 27 Nov, 2017.
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, WBC = white blood cell.

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Appendix 2
Extension Phase
Study Design and Plan
The Extension Phase will consist of a Treatment Period (12 weeks) and a Follow-up Period 
(4 weeks).  Subjects are eligible to complete the Extension Phase only if they have completed 
the Treatment Period of the Core Study.
All subjects will receive lorcaserin during entire Extension Phase but the dose level will be 
blinded during the first 6 weeks.  During the first 6 weeks of the Extension Phase, subjects 
who received lorcaserin during the Core Study will receive the same dose of lorcaserin (the 
dose will remain flexible per weight category, based on clinical response and tolerability); 
subjects who received placebo during the Core Study will receive the target dose of 
lorcaserin per weight category. During the second 6 weeks of the Extension Phase, all 
subjects will receive lorcaserin at the maximum dose per weight category (the dose may be 
decreased due to tolerability reasons and increased again if tolerability improves).  Addition, 
deletion, and dose changes to concomitant antiepileptic drugs (AEDs) are not allowed during 
the Treatment Period of the Extension Phase.  
The Follow-up Visit will be conducted 4 weeks after the last dose of study drug for subjects 
who will not participate in the Extended Access Program (Study E2023-A001-405) after 
completion of this study. 
The objectives of the Extension Phase are:

To evaluate the safety and tolerability of lorcaserin

To characterize the pharmacokinetics (PK) of lorcaserin and the relationship between 
lorcaserin plasma concentrations, efficacy, and safety 

To summarize the efficacy of lorcaserin as measured by percent change in frequency of 
convulsive seizures

To summarize the efficacy of lorcaserin as measured by percent change in frequency of 
each type of seizure

To summarize the efficacy of lorcaserin as measured by proportion of subjects who are 
free from convulsive seizures

To summarize the efficacy of lorcaserin as measured by proportion of subjects who are 
seizure-free

To summarize the efficacy of lorcaserin as measured by percent change in frequency of 
clusters

To summarize the efficacy of lorcaserin as measured by Clinical Global Impression of 
Change

To summarize the efficacy of lorcaserin as measured by on quality of life

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Schedule of Procedures/Assessments
Table 4 presents the Schedule of Procedures/Assessments for the Extension Phase.

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Table 4
Schedule of Procedures/Assessments in Study E2023-A001-304:  Extension Phase
Phase
Extension
Period
Treatmenta
Follow-upb,c
Visit
9
10
11
12
13
EDd
Unschedulede
Week
15
17
20
23
26
4 weeks after the 
last dose
Procedures/Assessments
Prior and concomitant medications 
X
X
X
X
X
X
X
X
Prior and concomitant AEDs
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Study drug compliance
X
X
X
X
X
X
Xe,f
Dispense study drug
X
X
X
X
Xe,f
Retrieve unused study drug
X
X
X
X
X
X
Xe,f
Dispense subject’s diary
X
X
X
X
Xe
Retrieve and review diary
X
X
X
X
X
X
Xe
Neurological examinationg
X
X
Physical examinationg
X
X
Vital signs, and weight
X
X
X
X
X
X
Xe
Clinical laboratory testsh
X
X
Xe,i
Urine pregnancy testj
X
X
Xe
12-lead ECGk
X
X
Xe,i
IxRS call
X
X
X
X
X
X
Xe
C-SSRS
X
X
X
X
X
X
QoL
X
X

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Table 4
Schedule of Procedures/Assessments in Study E2023-A001-304:  Extension Phase
Phase
Extension
Period
Treatmenta
Follow-upb,c
Visit
9
10
11
12
13
EDd
Unschedulede
Week
15
17
20
23
26
4 weeks after the 
last dose
Procedures/Assessments
Clinical Global Impressionl
Xl
X
PK Sampling (plasma)m
X
X
X
X
X
Xn
AE = adverse event, AED = antiepileptic drug; COVID-19 = Coronavirus disease 2019, C-SSRS = Columbia-Suicide Severity Rating Scale, 
ECG = electrocardiogram, ED = early discontinuation, IxRS = interactive voice and web response system, PedsQL = Pediatric Quality of Life Inventory,
QoL = Quality of Life in Epilepsy Scale/Pediatric Quality of Life Inventory 4.0, QOLIE-31 = Quality of Life in Epilepsy Survey.
a:
All visits to be done within 3 days of the schedule.  If any of the visits after Visit 1 are conducted remotely due to the COVID-19 pandemic, at a 
minimum, the following assessments should be conducted:  AEs, suicidality assessment, concomitant medications, review of seizure diary data, and study 
drug compliance (any missed or extra doses with dates).  Study drug and seizure diary may be picked up from the site by the subject/caregiver or shipped 
from the site to the subject’s location.  C-SSRS and Clinical Global Impression may be conducted remotely over the phone by a qualified rater and 
QOLIE-31 and PedsQL based on input from subject over the phone.
b:
Visit to be done within ±7 days of the schedule.
c:
The Follow-up Visit only applies to those subjects who do not participate in the Extended Access Program (Study E2023-A001-405) after completion of 
this study.
d:
These assessments will be conducted for subjects who discontinue the study or treatment early for any reason after Visit 9.
e:
At Unscheduled Visits these assessments/procedures conducted if needed.
f:
Unused study drug to be retrieved and study drug dispensed only for subjects requiring dose change at Unscheduled Visits.
g:
Physical and neurological examinations will only be performed at the indicated visits.  For all other clinic visits during the study, the physical and the 
neurological examinations will only be performed when there is a complaint from the subject.  Clinically significant abnormal findings from the physical 
or the neurological examinations will be reported as AEs.
h:
Clinical laboratory tests include hematology, blood chemistry, and urinalysis.
i:
At Unscheduled Visits, these assessments will only be done if the results from the previous visit were deemed clinically significant by the investigator.
j:
Only for female subjects of child-bearing potential (defined as all postmenarche females, unless postmenopausal or have been sterilized surgically).
k:
If subject has a normal ECG baseline reading, but during any visit thereafter the QT is measured as >460 ms, 3 consecutive ECGs separated by 
5 to 10 minutes will be performed to confirm the abnormality.

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Table 4
Schedule of Procedures/Assessments in Study E2023-A001-304:  Extension Phase
Phase
Extension
Period
Treatmenta
Follow-upb,c
Visit
9
10
11
12
13
EDd
Unschedulede
Week
15
17
20
23
26
4 weeks after the 
last dose
Procedures/Assessments
l:
Clinical Global Impression of Change at Visit 13 or ED.
m:
One blood sample (approximately 1 mL) for determination of lorcaserin plasma concentration will be collected at predose and between 1 to 2 hours 
postdose at Visit 9, 11, and 13; 3 to 6 hours postdose only at Visit 10 and 12.
n:
At ED, 1 blood sample (approximately 1 mL) PK samples should be collected only if samples can be drawn within 50 hours of the last dose of study drug.

Clinical Study Protocol
               E2023-A001-304
Eisai
FINAL (V2.0):  09 Jul 2020 
Confidential
Page 76 of 80
Statistical Methods
Statistical analyses will be performed by the sponsor or designee after the study is completed, 
the database is locked and released, and a snapshot of the database is obtained and released. 
Analyses for regional submissions may be performed during the course of the study.  
Statistical analyses will be performed using SAS software or other validated statistical 
software, as required. Details of the statistical analyses will be included in a separate 
statistical analysis plan.
Statistical and Analytical Plans
The statistical analyses of Extension Phase data are described in this section.  Further details 
of the analytical plan will be provided in the statistical analysis plan, which will be finalized 
before database lock and treatment unblinding.
Study Endpoints

Safety and tolerability, including incidence of treatment-emergent adverse events

PK parameters of lorcaserin in the Treatment Period

Percent change in frequency of convulsive seizures

Percent change in frequency of each type of seizure

Proportion of subjects who are free from convulsive seizures

Proportion of subjects who are seizure-free

Percent change from baseline in frequency of clusters

Clinical Global Impression of Change

Change from baseline in QOLIE-31 and PedsQL 4.0 Scales
Analysis sets
Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 postdose safety assessment in the  Extension Phase.
Full Analysis Set is the group of subjects who received at least 1 dose of study drug and had 
at least 1 postdose seizure measurement in the Extension Phase.
Efficacy Analyses
Descriptive statistics will be provided for the efficacy endpoints in the Extension Phase.  
Mean, standard deviation, median, minimum, and maximum will be provided for continuous 
endpoints and number and percentage will provide for categorical variables.  In addition, 
plots will be used to summarize the data.
Safety Analyses

Clinical Study Protocol
               E2023-A001-304
Eisai
FINAL (V2.0):  09 Jul 2020 
Confidential
Page 77 of 80
All safety analyses will be performed on the Safety Analysis Set. Safety data that will be 
evaluated include monitoring and recording all adverse events; regular laboratory evaluation 
for hematology, blood chemistry, and urinalysis; periodic measurement of vital signs, weight 
and ECGs; and the performance of physical and neurological examinations.  Safety analyses 
will be performed similarly to the Core Study analyses and all analyses will be on the 
treatment duration (Core Study and Extension Phase).

Clinical Study Protocol
               E2023-A001-304
Eisai
FINAL (V2.0):  09 Jul 2020 
Confidential
Page 78 of 80
Appendix 3
Scheme of IxRS Study Drug Assignment and 
Preparation of Study Drug Suspension
Table 5
Scheme of IxRS Study Drug Assignment and Preparation of 
Study Drug Suspension
Weight 
Group
Daily 
Dose
Dose per 
Administration
Volume of 
Suspension per 
Administration
Volume 
of 
Water
Volume 
of Ora-
Sweet 
Syrup
Tablet 
A
Weight 
Group
10 to 
<20 kg
Placebo
Placebo
20 mL
10 mL
70 mL
Placebo
1 tablet
Placebo
1 tablet
10 to 
<20 kg
5 mg
2.5 mg
20 mL
10 mL
70 mL
10 mg
1 tablet
Placebo
1 tablet
10 to 
<20 kg
10 mg
5 mg
20 mL
10 mL
70 mL
10 mg
1 tablet
10 mg
1 tablet
20 to 
<40 kg
Placebo
Placebo
40 mL
10 mL
70 mL
Placebo
1 tablet
Placebo
1 tablet
20 to 
<40 kg
10 mg
5 mg
40 mL
10 mL
70 mL
10 mg
1 tablet
Placebo
1 tablet
20 to 
<40 kg
20 mg
10 mg
40 mL
10 mL
70 mL
10 mg
1 tablet
10 mg
1 tablet
≥40 kg
Placebo
Placebo
40 mL
10 mL
70 mL
Placebo
1 tablet
Placebo
1 tablet
≥40 kg
20 mg
10 mg
40 mL
10 mL
70 mL
10 mg
1 tablet
10 mg
1 tablet
IxRS = interactive voice and web response system

Clinical Study Protocol
               E2023-A001-304
Eisai
FINAL (V2.0):  09 Jul 2020 
Confidential
Page 79 of 80
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E2023-A001-304
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group Study with Open-Label Extension Phase of 
Lorcaserin as Adjunctive Treatment in Subjects with Dravet 
Syndrome
Investigational Product 
Name:
E2023/lorcaserin
IND Number:
148085
SIGNATURES
Authors:
 MD, PhD
Study Director and Medical Monitor
Director, Clinical Research
Neurology Business Group
Eisai Inc.
Date
 PhD
Clinical Pharmacologist
VP, Global Head of Clinical Pharmacology
Neurology Business Group
Eisai Inc.
Date
 PhD
Study Statistician
Senior Director, Biostatistics
Eisai Inc.
Date
PPD
PPD
PPD

Clinical Study Protocol
               E2023-A001-304
Eisai
FINAL (V2.0):  09 Jul 2020 
Confidential
Page 80 of 80
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E2023-A001-304
Study Protocol Title:
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group Study with Open-Label Extension Phase of 
Lorcaserin as Adjunctive Treatment in Subjects with Dravet 
Syndrome
Investigational Product 
Name:
E2023/lorcaserin
IND Number:
148085
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date