Clinical trial NCT03338296
Conditions: Obesity
Keywords: body mass index weight loss adolescents lifestyle modification
Sponsor: Eisai Inc.
Start date: 2017-09-28; Completion date: 2020-04-03
Enrollment: 278 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to demonstrate weight loss efficacy by change in body mass index (BMI) and safety in adolescents age 12 to 17 years (inclusive) during 52 weeks of treatment with Belviq XR 20 milligrams (mg) administered once daily (QD) as compared to placebo.

Detailed description:

Arms: arm 1: Participants will receive lorcaserin hydrochloride extended release (XR) 20 milligrams (mg) once daily (QD) for up to 52 weeks. arm 2: Participants will receive placebo QD for up to 52 weeks.
Interventions: intervention 1: lorcaserin hydrochloride XR intervention 2: Placebo
Intervention descriptions: intervention 1: oral tablet intervention 2: oral tablet

Protocol documents:
Prot_000.pdf: 
Clinical Study Report 
APD356-A001-403 
 
16.1.1 
Protocol and Protocol Amendments 
The latest version of the study protocol and all previous versions are provided on the following 
pages: 
• V10.0, 12 Feb 2018 (per Amendment 04) 
• V9.0, 12 Dec 2017 (per administrative corrections) 
• V8.0, 12 Dec 2017 (per Amendment 03) 
• v7.0, 11 Jul 2017 (per Amendment 02) 
• v6.0, 17 May 2017 (per Amendment 01) 
• v5.0. 22 Feb 2017 (Revision) 
• v4.0, 03 Nov 2016 (Revision) 
• v3.0, 14 Sep 2016 (Revision) 
• v2.0, 22 Jul 2016 (Revision) 
• v1.0, 16 Apr 2015 (original protocol) 
Eisai
Confidential
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Revision History
Previous Version (Revision): v9.0
Current Version (Revision):  v10.0
Date of Revisions: 12 Feb 2018 (per Amendment 04)
Change
Rationale
Affected Protocol Section(s)
Revised rescreening 
requirement
To facilitate recruitment
Section 2, Synopsis-Study Design
Section 9.1
Section 9.3
Revised measurements of 
fasting glucose to fasting 
plasma glucose
Document consistency
Section 2, Synopsis-Other 
Secondary Objectives
Section 8.2
Section 9.7.1.1.2
Revised in-text reference to 
cardiovascular disease from 
Exclusion Criterion #3 to 
Exclusion Criterion #4
Document quality
Section 2, Synopsis-Assessments
Revised safety analyses text for 
consistency throughout 
document
Document quality
Section 2, Synopsis-Assessments
Revised DEXA assessment to 
specify only in a subset of 
subjects and addition of Z-score 
for assessment 
Clarification 
Section 2, Synopsis-Objectives
Section 2, Synopsis-Assessments
Section 9.7.1.8
Section 9.7.1.8.6
Section 8.2
Section 9.5.1.5
Revised ordering of numbering 
of Exclusion Criteria in body 
for consistency in document
Document quality
Section 9.3.2
Addition of footnote “e”in 
assessment table to clarify 
procedure; subsequent 
renumbering of successive 
criteria
Clarification
Table 2
Removal of “US” designation 
from unscheduled laboratory 
tests as additional assessments 
are indicated in the clinical 
judgment of the investigator
Clarification
Table 2
Table 3
Clarifications of blood sample 
volumes
Clarification 
Table 3
Grammatical, typographical, 
stylistic, and formatting changes 
were also made
Document quality
Throughout the document 
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Revision History
Previous Version (Revision): v8.0
Current Version (Revision):  v9.0
Date of Revisions: 12 Dec 2017 (per administrative corrections)
Change
Rationale
Affected Protocol Section(s)
Revised assignment of 
assessment table footnotes
Clarity
Table 2
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Revised secondary objectives to 
assess effects of glycemia to 
fasting glucose in subjects with 
Type 2 diabetes and those 
without Type 2 diabetes
Per FDA request
Synopsis – Objective
Section 8.2
Section 9.7.1.1.2
Added secondary objective to 
assess the effects on body fat 
and lean mass compostion by 
DEXA in a subset of subjects at 
selected sites
Per FDA request
Synopsis – Objective
Synopsis - Efficacy Assessment
Synopsis – Other Safety 
Assessments
Synopsis – Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.1.2
Table 2
Section 9.7.1.8.6
Revised secondary objective for 
cardiovascular risk factors 
associated with obesity to 
include blood pressure and heart 
rate
Synopsis – Objective
Section 8.2
Revised secondary objective to 
evaluate bone density by DEXA 
in a subset of subjects at 
baseline and Week 52/EOT
Per FDA request
Synopsis – Objective
Synopsis - Other Safety 
Assessment
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.10
Table 2
Section 9.7.1.6
Section 9.7.1.8.6
Added requirement to evaluate 
drug compliance (via pill count)
Per FDA request
Synopsis – Other Secondary 
Efficacy Endpoints
Section 9.4.7
Section 9.7.1.1.2
Revised to specifiy that at least 
20% of all study subjects 
enrolled are younger (12 to 13 
year of age)
Per FDA request
Synopsis - Study Design
Section 9.1
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Added requirement that 80% of 
randomized subject will have 
primary endpoint assessments
Per FDA request
Synopsos – Study Design
Section 9.5.1.3
Revised to specify that study 
sites will be selected to ensure 
adequate representation of 
adolescents of ethnic and racial 
minorities
Per FDA request
Synopsis - Efficacy Assessments
Section 9.7.1.8.6
Added requirement for Data 
Monitoring Committee
Per FDA request
Synopsis - Study Design
Section 9.1
Added assessment of 
anthropometric measure (waist 
circumfereance)
Per FDA request
Synopsis – Efficacy Assessments
Section 9.5.1.3
Section 9.5.1.5.7
Revised inclusion criteria (#1) 
to define population at baseline 
with regard to Type 2 diabetes
diagnosis
To ensure PPSR requirements are met
Synopsis - Inclusion Criteria
Synopsis – Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.3.1
Added exclusion criteria (#3) 
for subjects with Type 2 
diabetes who are hypoglycemia 
unaware
To ensure PPSR requirements are met
Synopsis - Exclusion Criteria
Section 9.3.2
Revised concomitant 
medication guidelines
To provide futher clarity
Synopsis – Concomitant 
Drug/Therapy
Section 9.4.6
Revised instructions on height 
and body weight measurements
Per FDA request
Synopsis – Study Design
Section 9.1
Section 9.5.1.3
Section 9.5.1.5.5
Added instructions for 
investigator to monitor specific 
list of AEs that have occurred 
since the last visit
Per FDA request
Section 9.5.1.5.1
Added requirement for report 
hypoglycemic events for the 
subjects with type 2 diabetes
Per PPSR requirements
Section 9.5.1.5.1
Revised requirements for AE 
monitoring
Per PPSR requirements
Section 9.5.1.5.1
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Revised list of events that 
should be considered SAEs and 
reported as important medical 
events
Per PPSR requirements
Section 9.5.1.5.2
Section 9.5.4.3.2
Added requirement for querying 
sites for all relevant information 
for subjects lost to follow-up 
Per FDA request
Section 9.5.5
Added requirement to provide 
proper training to all study 
participants and their 
parent/guardian, in order to 
achieve optimal subject 
retention and prevent missing 
data
Per FDA request
Section 9.5.5
Revised assessment timepoints 
for Tanner Staging, 
Testosterone/Estradiol, TSH, 
fasting prolactic, 
echocardiogram, 
OC/PICP/Hydroxy-proline,
ECG, and Hand X-rays
Per FDA requeset
Table 2
Revised Other Secondary 
Efficacy Analyses text MMRM
Section 9.7.1.6
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Revision History
Previous Version (Revision): v6.0
Current Version (Revision):  v7.0
Date of Revisions: 11 Jul 2017 (per Amendment 02)
Change
Rationale
Affected Protocol Section(s)
Revised statistical power from 
90% to 80%
80% statistical power would provide 
sufficent sample size to detect weight 
loss effects and evaluate lorcaserin 
safety in the population selected.
Synopsis – Study Design
Synopsis – Number of Subjects
Synopsis – Sample Size Rationale
Section 7.1.2
Section 9.1
Section 9.2
Section 9.3
Section 9.7.2
Revised Other Secondary 
Endpoints
To align with recently submitted 
PPSR
Synopsis – Other Secondary 
Efficacy Endpoints
Section 9.7.1.1.2
Added clarification on timing of 
PK samples taken during an 
early discontinuation visit
Clarification
Table 2
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Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Revised scale for measuring of 
cognition from Wide Range 
Assessment of Memory and 
Learning-2 (WRAML-2) to 
Leiter-3
Leiter-3 is selected to replace 
WRAML-2 for the evaluation of the 
change in cognition for the following 
reasons:Lack of availability of 
WRAML-2 in Spanish, Leiter-3’s 
high scientific validity, non-verbal 
format to offer less biased assessment 
for subjects whose second language is 
English, easier and shorter 
administration and short test time 
reducing investigator burden, as well 
as increase probability of the 
subjects’ retention in the study.
Synopsis – Objectives
Synopsis – Other Safety 
Assessments
Synopsis – Other Safety Analyses
List of Abbreviations
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Added requirement that 
qualified personnel must 
evaluate positive responses on 
the C-SSRS and take 
appropriate action as detailed in 
the training and certification 
process for administering the 
C-SSRS
To provide guidance that qualified 
personnel must evaluate positive 
responses on the C-SSRS and take 
appropriate action as detailed in the 
training and certification process for 
administering the C-SSRS.
Synopsis – Other Safety 
Assessments
Section 9.5.1.5.10
Revised timing of initial C-
SSRS from Baseline to 
Screening
Operational efficiencies
Table 2
Section 9.3.2
Section 9.5.1.5.10
Correct formatting of Synopsis, 
Other Secondary Objectives
Consistency
Synopsis – Objectives
Section 8.2
Revised exclusion criteria for 
viral hepatitis (B or C) (#17) 
whereby active testing will not 
be performed 
To clarify that the subjects will be 
excluded if they are known to have
active hepatitis (B or C). Hepatitis (B 
or C) tests will not be conducted for 
the screening purpose.
Synopsis – Exclusion Criteria
Section 9.3.2
Added footnotes regarding 
collection of PK samples at 
EOT and Early Discontinuation 
visits
To ensure appropriate timing of
sampling relative to administration of 
last dose of study drug
Table 2
Added clarification for
Unscheduled visits, such that 
they may be conducted at any 
time that additional assessments 
are clinically indicated in the 
judgment of the investigator.
Provide additional guidance to 
investigators
Table 2
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Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Added clarification that 
prolactin testing should be 
fasting
Clarification
Table 2
Added requirement for 
pregnancy test and AM serum 
cortisol to Early 
Discontinuation Visit
Correction
Table 2
Table 3
Added requirement for lifestyle 
modification counseling Visit at 
Week 16
To ensure all visits are 4 weeks apart
Table 2
General alignment of text 
throughout
Clarity
Throughout
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Revision History
Previous Version (Revision): v4.0
Current Version (Revision):  v5.0
Date of Revisions: 22 Feb 2017
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
A full physical examination will 
be performed at Week 1
Correction
Synopsis - Safety Assessment
Section 9.5.1.5
PHQ-9 questionnaire has been 
added to every scheduled visit.
Per FDA recommendation
Synopsis - Safety Assessment 
Section 9.5.1.5
Section 9.5.2.1
The mixed model repeated 
measures (MMRM) model was 
replaced with the analysis of 
covariance (ANCOVA) model
analyzing Week 52 only.
Per FDA recommendation
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
All postdiscontinuation data 
will be used in the primary 
analysis
Clarification per FDA feedback
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Labeling information for study 
drug was updated
Correction as the study will only be 
conducted in the US
Section 9.4.2.3
The order of assessments was 
reorganized in the Schedule of 
Assessments 
To better align the assessments by 
grouping them
Section 9.5.2.1
Urinalysis will be performed at 
Visit 2 instead of Visit 9
Correction
Section 9.5.2.1
Assessment for testosterone, 
estradiol will be performed at 
Week 28, not Week 20
Correction
Section 9.5.2.1
Section 9.5.2.3
Prior/concomitant medication 
assessment will be performed at 
Week 56
Correction
Section 9.5.2.1
Assessments performed at early 
discontinuation from the study
Correction
Section 9.5.2.1
Summary of blood volumes 
table was updated
Correction
Section 9.5.2.3
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Subject population to include 
children ages 12 to 17 years
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Title Page
Synopsis - Study Protocol Title
Synopsis - Design
Synopsis - Inclusion Criteria
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.7.1.6
Section 9.7.1.8
Protocol Signature Page
Investigator Signature Page
All subjects will be evaluated 
for cardiac valvular disease or 
pulmonary hypertension via 
echocardiographic assessment.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Other Secondary 
Objectives
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.3.2
Section 9.5.1.5.10
Section 9.5.2
Section 9.7.1.8
Section 9.7.1.8.6
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Study drug administration will 
be taken at approximately the 
same time each day.  On the 
days of PK sampling and the 
day before the subjects come to 
the clinic for PK sampling, 
study drug will be taken in the 
morning and doses recorded 2 
days prior to the clinic visit.
This will ensure lower variability 
with regard to PK/PD measurements.
Synopsis - Pharmacokinetic 
Assessments
Section 9.4.1
Section 9.4.4
Section 9.5.1.4.1
Section 9.5.2.1
Screening, diagnosing, 
monitoring, and measuring the 
severity of depression will be 
assessed using the Patient 
Health Questionnaire (PHQ-9), 
and not the Children’s 
Depression Inventory 2 (CDI-
2).
The PHQ-9 was originally proposed 
by the FDA for the population in the 
current study.
Synopsis - Other Secondary 
Objectives
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Primary analysis changed from 
MMRM to using a pattern 
mixture model utilizing 
multiple imputations (MI) to 
impute missing values.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Clarified fasting lipids
Fasting lipid levels provide 
uniformity in lipid measurements for 
definition of dyslipidemia
Synopsis - Other Secondary 
Objectives
Synopsis - Efficacy Assessments
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Removed Appendix 3
The current study will not conduct 
any biomarker or pharmacogenomic
evaluation. PK/PD measurements 
will be done during study.
Appendix 3
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Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Prehypertension was deleted 
from the inclusion criterion.  
Subjects with Stage 1 primary 
hypertension, with an upper 
limit defined as 99% plus 5 
mmHg for age, sex, and height 
are included in the study. 
Prehypertension does not qualify as a 
comorbid condition.  The limitation 
on BP is to further define the proper 
study population.
Synopsis - Inclusion Criteria
Section 9.3.1
Removed the restriction that 
subjects need to have less than 
44 kg/m2 BMI for study entry
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Synopsis - Analysis Sets
Synopsis - Pharmacodynamic 
Analyses
Synopsis -
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study entry 
requirement that the caregiver 
cannot have a history of ADD, 
substance abuse, depression, 
suicidal ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Section 9.3.1
The secondary efficacy 
objective and endpoint were 
revised
To explore the predictability of 12-
week responders for long-term 
sustainable weight loss effect
Synopsis - Secondary Efficacy 
Objectives
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with symptoms or 
signs of cardiac valvular disease 
or pulmonary hypertension are 
not required to have further 
evaluation by centralized 
echocardiogram assessment.  In 
addition, no adjudication will be 
performed.  Local 
echocardiograms can be 
performed if deemed medically 
necessary by the investigator.
This 
change 
allows 
for 
the 
investigator to make the decision to 
perform local echocardiograms on a 
pediatric subject if deemed medically 
indicated rather than burden the 
subject to undergo a mandated, 
unnecessary procedure. 
Synopsis - Safety Assessments
Section 9.5.1.5
Updated study rationale
Clarification 
Section 7.1.1.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will replace the
IR formulation in the United States
market to support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to include 
children ages 9 to 17 years
Expand the age of the population due 
to the change of pediatric development 
strategy
A single dose pharmacokinetic study 
in pediatric obese subjects (APD356-
A001-026) indicated that patients with 
body weight greater than or equal to 
60 kg can be administered a dose 
similar to that given to adults and 
adolescents.  Based on Centers for 
Disease Control and Prevention 
(CDC) growth chart data, almost all 
subjects over 9 years of age are likely 
to be at or over 60 kg body weight.  
Therefore, children age 9 to 11 years 
have been included in the current 
study.
Title Page
Synopsis - Study Protocol Title
Synopsis - Objectives
Synopsis - Study Design
Synopsis - Inclusion Criteria
Synopsis - Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.10
Section 9.7.1.6
Section 9.7.1.8
Additional safety assessments 
including cognitive function, 
serotonin syndrome 
components, bone health and 
endocrine function, priapism, 
and symptoms associated with 
hyperprolactinemia were added.
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Efficacy Assessments
Synopsis - Pharmacokinetic 
Assessments
Synopsis - Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.1
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Change to primary and key 
secondary endpoints
Per FDA request
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary endpoint 
changed
Per FDA request
Synopsis - Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of study-
specific adverse events
To provide clearer guidance for the 
correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and prohibited 
prior and concomitant therapies
For clarification
Synopsis - Exclusion Criteria
Synopsis - Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of adverse 
events
To provide clearer guidance for the 
correct reporting of adverse events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
Update to Introduction and to 
Completion/ Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of Belviq XR® in Conjunction 
With Lifestyle Modification for Weight Loss in Obese Adolescents, Age 
12 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
v4.0
03 Nov 2016 (Revision)
v5.0
22 Feb 2017 (Revision)
v6.0
17 May 2017 (per Amendment 01)
v7.0
11 Jul 2017 (per Amendment 02)
V8.0
12 Dec 2017 (per Amendment 03)
V9.0
12 Dec 2017 (per administrative corrections)
V10.0
12 Feb 2018 (per Amendment 04)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use and all applicable local Good Clinical 
Practice (GCP) and regulations.  All required study documentation will be 
archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of Eisai 
(the sponsor).  Any viewing or disclosure of such information that is not 
authorized in writing by the sponsor is strictly prohibited.  Such information 
may be used solely for the purpose of reviewing or performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and 
Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in Obese Adolescents, Age 
12 to 17 Years
Investigators
TBD
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
Approximately 24 months from the first subject enrolled to last subject’s last visit or last assessment 
Phase 4
Objectives
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks of treatment 
with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD as compared to 
placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg administered QD compared 
to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of treatment with 
Belviq XR 20 mg administered QD is predictive of sustained change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 52 weeks of 
treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% BMI reduction, 
change in waist circumference) at the end of 52 weeks of treatment
-
Effects on fasting plamsa glucose, hemoglobin A1c (HbA1C), insulin levels, and Homeostatic Model 
Assessment of Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) in subjects with 
Type 2 Diabetes Mellitus (T2DM) at baseline during 52 weeks of treatment (revised per Amendments
03 and 04)
-
Effects on fasting plasma glucose, HbA1c, insulin levels, and HOMA-IR; glucose [mg/dL] × insulin 
[mU/L]/405 in subjects without T2DM at baseline during 52 weeks of treatment (revised per 
Amendments 03 and 04)
-
Effects on body fat and lean mass composition by Dual-energy X-ray Absorptiometry (DEXA) in a 
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subset of subjects (selected prior to randomization at selected sites) during 52 weeks of treatment
(revised per Amendment 03)
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, dyslipidemia)
including fasting lipid changes (total cholesterol, triglycerides, high density lipoprotein [HDL], low 
density lipoprotein [LDL]), systolic and diastolic blood pressure, and heart rate during 52 weeks of 
treatment (revised per Amendment 03)

To assess the safety of Belviq XR, including the effects on cognition with the Leiter-3 International 
Performance Scale (Leiter-3), depression with the Patient Health Questionnaire (PHQ-9), signal of suicidal 
ideation or behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by
Centers for Disease Control and Prevention (CDC) growth chart, sexual maturation (pubescence) measured 
by Tanner Staging scores, and other growth and development parameters by measuring sex hormones, 
thyroid function, adrenal function, bone age, and biochemical markers of bone health, bone mineral density 
and content, total body fat mass, and total body lean mass using DEXA in a subset of subjects (selected 
prior to randomization at selected sites), valvular function, and pulmonary arterial pressure.  (revised per 
Amendments 01 and 03)

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) parameters 
including but not limited to reduction from baseline in BMI and probability of achieving at least a 5% and 
at least a 10% reduction in BMI from baseline at Week 52 using population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese adolescents, 
ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 1:1 ratio to Belviq XR 20 mg QD
(130 subjects) and placebo (130 subjects).  Subjects will be stratified by sex.  Subjects will receive Belviq XR
20 mg or matched placebo QD in a 1:1 ratio for up to 52 weeks. A recruitment plan will be developed to ensure 
at least 20% of younger subjects (12 to 13 years of age) are enrolled in the study.  Throughout the duration of 
the study, subjects will be encouraged to adhere to a lifestyle modification program that includes a 
standardized, age-appropriate diet and exercise counseling. (revised per Amendments 02 and 03)
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization Phase will 
last up to 30 days and consist of 1 visit during which subjects will be screened for eligibility.  The 
Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The Treatment Period will last 
for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52.  The Follow-Up Period will 
extend from the End of Treatment (EOT) visit to the End of Study visit.
Subjects who screen fail can be re-screened only once.  All subjects will continue in the study until the 52-week 
evaluation is completed.  Subjects who discontinue treatment prematurely will be followed up until study 
completion.  All attempts will be made to capture height and weight in all subjects whether or not they are still 
on study drug at the end of the study.  (revised per Amendments 03 and 04)
Study sites will be selected to ensure adequate representation of adolescents of ethnic and racial minorities.  
(revised per Amendment 03)
Data Monitoring Committee (revised per Amendment 03)
A Data Monitoring Committee (DMC) will be established to monitor and conduct periodic safety review of 
unblinded data. DMC members will be chosen based on their expertise in evaluating these clinical events. A 
separate DMC charter will be established.
Number of Subjects
Approximately 500 subjects will be screened to provide 260 randomized subjects.  (revised per Amendment 02)
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years (inclusive) at Screening, with an initial BMI that is 
greater than or equal to the United States (US)-weighted mean of the 95th percentile based on age and sex
with a body weight greater than 60 kg.  Subjects with T2DM may have a pre-existing or new diagnosis of 
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T2DM.
Subjects with pre-existing T2DM should have prior documentation consistent with the diagnosis and/or be 
on active pharmacotherapy for T2DM.  
Subjects with a new diagnosis of T2DM (ie, diagnosed at Screening) should be based on the 2016 
American Diabetes Association (ADA) guidelines.  The diagnostic criteria are met if a subject has 
unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of 
hyperglycemia or hyperglycemic crisis) OR any of the following criteria are observed and confirmed:
◦
HbA1c ≥6.5% 
◦
fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 
◦
2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) by an oral glucose tolerance test (OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being or need to be treated 
with antidiabetic agents, the T2DM treatment regimen must be stable for at least 3 months before 
randomization.  A single rescreen is allowed following stabilization.  Stable control refers to minimal dose 
changes to existing medications for glycemic control and no medications being initiated for glycemic 
control in the 3 months before Randomization.  Minimal changes are defined as a change without any 
change in dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject has not 
been hospitalized due to hypo- or hyperglycemic events. (revised per Amendment 03)
2.
Subjects and their families not planning to move away from the area for the duration of the study
3.
Able and willing to comply with all aspects of the study, including a standardized, reduced-calorie diet and 
an age-appropriate, increased physical activity program
4.
Considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the investigator,
including consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study requirements for the 
caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the subject’s ability 
to fulfill the study requirements or significantly confound the assessments
2.
Who cannot swallow investigational products
3.
With T2DM who have hypoglycemia unawareness (revised per Amendment 03)
4.
Any of the following findings on Screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, mean gradient 
>25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean gradient >5 mm Hg and mitral valve 
area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure (SPAP) >40 mmHg (and/or tricuspid regurgitation (TR) jet 
velocity >2.9 m/s)
In cases where an actual SPAP value is not measurable due to lack of adequate TR jet, the pulmonary flow 
acceleration time measured at the right ventricular outflow tract (RVOTAT), will be used to assess 
eligibility. Subjects with a RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those subjects with RVOTAT between 100 and 120 msec will be determined based on 
combined assessment of the TR jet, septal motion and right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease
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
Clinically significant pericardial effusion (eg, moderate or larger or with hemodynamic compromise)
5.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper limit of 
normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater than 1.5×ULN in 
absence of Gilbert’s syndrome
6.
Any suicidal ideation with intent with or without a plan, at the time of or within 6 months of Screening, as 
indicated by answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS
7.
Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
8.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit Hyperactivity 
Disorder (ADHD), any Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)
depressive disorder, suicidal ideation or behavior, bipolar disorder, or schizophrenia
9.
Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi syndrome, Bardet 
Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, Cushing’s syndrome, daily systemic 
corticosteroid exposure for longer than 30 days, history of significant exposure to corticosteroids for 
chronic illness during the past year; inhaled steroids will be allowed) (revised per Amendment 03)
10. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, 
and herbal preparations within 1 month before Screening 
11. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine oxidase inhibitors 
(MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin®, Concerta®, biphetamine, and Dexedrine®)

benzodiazepines
12. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before Screening, 
including but not limited to pergolide, ergotamine, methysergide, and cabergoline
13. History or evidence of clinically significant disease (eg, malignancy, cardiac, respiratory, gastrointestinal, 
renal, or psychiatric disease) other than prediabetes (impaired fasting glucose or impaired glucose 
tolerance), T2DM treated with oral antidiabetic agents (excluding sulfonylurea) or non-insulin injectable 
antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
14. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any of the 
excipients
15. Significant change in diet or level of physical activity within 1 month before dosing or change in weight of 
more than 5 kg within 3 months before Screening
16. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before Screening
17. History of alcohol or drug dependence or abuse
18. Recreational drug use within 2 years before Screening
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19. Known to be human immunodeficiency virus (HIV) positive
20. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
21. Malignancy within 5 years before Screening
22. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or guardian to supervise 
study participation
23. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to profound 
mental retardation [IQ <70], moderate to severe cognitive developmental delay, pervasive development 
disorders, autism)
24. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder within 6 months of 
screening or any time between screening and randomization
25. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate readings recorded 
on 2 separate days.  Those subjects who had hypertension at Screening can be rescreened more than
1 month after initiation or adjustment of antihypertensive therapy 1 time.
26. Currently enrolled in another clinical study or has used any investigational drug or device within 30 days 
before providing informed consent
27. Planned bariatric surgery during the study or prior bariatric surgical procedures (revised per 
Amendment 03)
28. Not suitable to participate in the study in the opinion of the investigator, including consideration of any 
existing physical, medical, or mental condition that prevents compliance with the protocol
29. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
β-human chorionic gonadotropin test).  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.
30. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a 
highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier 
method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire 
study period and for 28 days after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described above) or refrain 
from sexual activity during the study period and for 28 days after study drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during 
the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]).
Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated, biconvex tablets
with one 20-mg tablet administered orally QD.
Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  up to 30 days
Randomization Phase: approximately 56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal preparations, are 
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prohibited as concomitant medications.  OTC cold medicines containing dextromethorphan can be used for up 
to 7 days with study medication temporarily stopped for that time period and resumed the next day after the 
OTC cold medicine is stopped.  Any of the following serotonergic agents or other agents in combination with 
Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
The following concomitant medication guidelines/restrictions will apply:

Medications for the treatment of hypertension, dyslipidemia, or diabetes may be started, discontinued, or 
adjusted during the study according to local standards of care if, in the judgment of the investigator or the 
subject’s physician, such a change is medically indicated.

For diabetic subjects treated with sulfonylureas, insulin (note that subjects should not be enrolled as 
indicated in exclusion criteria), or other antidiabetic agents with hypoglycemic risk, the risk of 
hypoglycemic events may be higher if the subjects experience rapid and significant weight loss (more than 
10% weight reduction than at the previous visit).  It is recommended that the physician advise the subject 
to monitor their blood glucose more frequently and adjust their antidiabetic medications and diet 
accordingly. 

The antihyperglycemic medication dose would be considered for reduction in the event of 1 documented 
and otherwise unexplained hypoglycemic event (blood glucose concentration <65 mg/dL) or 2 
undocumented and otherwise unexplained suspected hypoglycemic events between any 2 scheduled visits. 
For subjects on more than 1 antihyperglycemic medication, it is recommended to reduce insulin first (if 
applicable), then the oral and/or other injectable antidiabetic agents.  If the previous criteria are met again 
following dose reduction, further dose reductions or cessation of 1 or more antihyperglycemic agents, are 
suggested.  See Section 9.5.4.2 for the definition and reporting of hypoglycemic events. 
To minimize the risk of cardiac valve toxicity, subjects must not initiate use of agents that have documented 
correlation with increased incidence of valvulopathy and/or pulumonary hypertension (eg, pergolide, 
ergotamine, methysergide, or cabergoline) during the study.  If any of the above agents are clinically warranted, 
and subjects initiate any of these agents, lorcaserin HCl should be discontinued but can be restarted on 
lorcaserin HCl after being off the medications above for 1 month.  Otherwise, the study medication should not 
be restarted, but the subject should continue all study visits.  (revised per Amendment 03)
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Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to calculate the 
proportion (%) of subjects achieving at least a 5% and at least a 10% BMI reduction

Waist circumference (revised per Amendment 03)

Total body fat mass and total body lean mass will be determined centrally using DEXA in a subset of 
subjects (selected prior to randomization at selected sites) at baseline and Week 52/EOT (revised per 
Amendment 03)

Measurement of systolic and diastolic BP, heart rate (taken after resting for 5 minutes), fasting lipids (total 
cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), fasting plasma glucose, fasting insulin,
HbA1c, and Homeostasis Model Assessment of Insulin Resistance (HOMA–IR) to assess cardiovascular
and metabolic risk profiles from baseline to Week 52 (revised per Amendment 03)

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents
Every effort will be made to ensure that at least 80% of randomized subjects will have an assessment of the 
primary efficacy endpoint regardless of whether or not the subject remained on study drug or completed other 
study assessments.  (revised per Amendment 03)
Pharmacokinetic Assessments
Blood samples (approximately 4 mL each) for PK assessment will be collected at Weeks 12, 28, 36, and 52 for 
analysis of Population PK. (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at 
home before the visit, but to bring their study drug to the clinic visit, and take their daily dose at the clinic.  
Two blood samples for determination of plasma concentrations of lorcaserin will be taken: 1 predose (within 
30 minutes before dosing), and 1 within 1 to 3 hours after dosing.  Dose times must be recorded for the last 
2 dosing times before the day of clinic visit. Week 52 PK samples should only be collected if the sample can be 
drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at home, and will be 
asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for for PK 
assessments will be collected. Dose times must be recorded for the last 2 dosing times prior to the clinic visit.
(revised per Amendment 01)
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their relationships 
with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious adverse events 
(SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, metabolic function (fasting plasma
glucose, fasting lipids, and thyroid), adrenal function and biochemical blood and urine bone health assessments;
blood chemistry and urine values; neuropsychiatric events; periodic measurement of vital signs, neuromuscular 
signs for screening potential serotonin syndrome, and signs or symptoms of priapism and hyperprolactinemia;
and performance of physical examinations.
In subjects with potential prolactin-related AEs, such as 
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galactorrhea, changes in libido, or changes to menstrual cycle, fasting prolactin level will be measured and 
assessed.
Other Safety Assessments
Effect on growth will be evaluated using the CDC growth chart and bone age determination by x-ray of the 
hand. Sexual maturation will be evaluated by assessing sex hormones and Tanner Staging.
The C-SSRS will be used to assess all subjects in the study for any signal of depression or suicidal ideation or 
behavior at every visit.  Additionally, screening, diagnosing, monitoring, and measuring the severity of 
depression will be assessed using the PHQ-9 and effects on cognition will be assessed using the Leiter-3.  
(revised per Amendment 01)
Bone mineral density and content, total body fat mass and total body lean mass will be determined using DEXA 
in a subset of subjects (selected prior to randomization at selected sites).  (revised per Amendment 03)
Echocardiographic assessments will be used to exclude subjects with US Food and Drug Administration 
(FDA)-defined valvulopathy, pulmonary hypertension, and other major cardiovascular disease (as outlined in
Exclusion Criterion No. 4) during the Screening Period.  Additionally, cardiac valvular function and pulmonary 
systolic pressure changes at Weeks 28 and 52 will be assessed.
Valvular regurgitation as assessed in the 
echocardiogram will be rated absent, trace, mild, moderate, or severe for the aortic, mitral, and tricuspid valves; 
the rating will be absent or present for the pulmonic valve. The evaluations will be based on guidelines from the 
American Society of Echocardiography. Pulmonary artery pressure will be estimated from the TR jet velocity.  
(revised per Amendments 03 and 04)
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography coupled with tandem mass 
spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from baseline to Week 52

Association between change and percentage change in BMI from baseline to Week 52 with the outcome of 
achieving at least a 5% BMI reduction at Week 12 (revised per Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI reduction at 
Week 52 with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Change in waist circumference from baseline to Week 52

Change in total body composition (total fat and lean mass) in a subset of randomized subjects at end of 
52 weeks of treatment (revised per Amendment 03)

Change in HbA1c from baseline to Week 52 for subjects with T2DM at baseline (revised per 
Amendment 03)

Change in fasting plasma glucose, fasting insulin, and HOMA-IR from baseline to Week 52 for subjects 
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with T2DM at baseline (revised per Amendments03 and 04)

Change in fasting plamsa glucose, fasting insulin, and HOMA-IR from baseline to Week 52 for the 
subjects without T2DM at baseline (revised per Amendments 03 and 04)

Change in BP (systolic and diastolic) and heart rate from baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) from 
baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52

Subjects compliance rate at each visit by pill count during 52 week treatment (revised per Amendment 03)
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and had at least 
1 post dose safety assessment.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater compliant 
with study medication, completed the study, have no major protocol deviations, have no violations of 
inclusion or exclusion criteria, and have BMI data at baseline and Week 52.  The determination of subjects 
to be excluded from this population based on the above criteria and a list of major protocol violations will 
be included in the statistical analysis plan (SAP) and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid lorcaserin plasma 
concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who have at least 
1 adequately documented measurement of BMI.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as a 
supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in all efficacy 
analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from baseline to Week 52.  The change from baseline in 
BMI will be analyzed using analysis of covariance model (ANCOVA) with factors of treatment,  sex (male and 
female) as fixed effect, and the baseline age and BMI as covariates.  The missing values will be imputed using a 
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are missing not at 
random (MNAR).  The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model and missing value 
imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on the PP.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy analyses described 
above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed and will be
described in the SAP.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI reduction at 
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Week 52. The secondary efficacy endpoint will be analyzed only if the test for the primary efficacy endpoint is 
statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using a logistic 
regression model with factors of treatment, sex (male and female), and baseline BMI as a covariate using FAS.  
Subjects with any missing assessment at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed using 
mixed effect model repeated measurement analysis (MMRM) and categorical variables will be analyzed using
the Cochran Mantel Haenszel test, Chi-square test, or logistic regression as appropriate.  Additional analysis 
may be performed as needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male and female), and 
race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific 
Islander, or White) and age.  Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using nonlinear mixed 
effects modeling. The effect of covariates such as baseline characteristics or demographics on PK will be 
explored. Derived exposure parameters such as the maximum observed concentration and the area under the 
concentration-time curve from time 0 to 24 hours at steady-state will be calculated from the final PK model 
using individual posterior estimates of the PK parameters and from dosing history. The PK analysis set will be 
used for this analysis.
Pharmacodynamic Analyses
Change from baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will be used for this 
analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of subjects achieving ≥5% and ≥10% BMI 
reduction, and change in waist circumference from baseline) will also be assessed as part of the PD analysis.  
The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure and 
response, including but not limited to change in BMI from baseline and the probability of achieving at least a 
5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, exposure-safety relationships 
for select safety parameters may be explored graphically depending on the data at the end of study.  Any 
emergent relationship may be modeled as appropriate.  Any parameters based on the study data may be 
considered for exploratory assessment for its relationship to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the incidence 
of AEs (including changes from baseline in physical examination, neuromuscular sign assessment for serotonin 
syndrome, and signs and symptoms of priapism and hyperprolactinemia), out-of-normal-range laboratory safety 
test values, change from baseline in laboratory safety test values, ECGs, vital sign measurements, bone mineral 
density and content, total body fat mass and total body lean mass by DEXA, FDA-defined valvulopathy, and 
pulmonary hypertension assessed by echocardiograph will be summarized by treatment group using descriptive 
statistics or frequency count as appropriate.
No hypothesis testing will be performed for the safety assessment.  (Revised per Amendment 04)
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Other Safety Analyses
In addition, cognition will be evaluated by the Leiter-3, depression will be evaluated by the PHQ-9, and suicidal 
ideation and behavior will be evaluated by the C-SSRS, and will also be summarized by treatment group using 
descriptive statistics or frequency count as appropriate. For echocardiographic assessments, the proportion of 
subjects who develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
hypertension [pulmonary hypertension is defined when the subject’s systolic pulmonary artery pressure 
(SPAP) ≥40 mmHg evaluated by echocardiograph], and change from baseline in SPAP will be summarized by 
treatment group at Week 28 and Week 52 using descriptive statistics or frequency count as appropriate. (revised 
per Amendment 01)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in BMI from 
baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  Assuming a SD of 
2.2 kg/m2 and a 40% dropout rate, a sample size of 260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg 
treatment group; n=130 in the placebo group) will have at least 80% power to detect a treatment difference of 
1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at least a 5% 
BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, this sample of 260 subjects 
(130 subjects for Belviq XR 20 mg and 130 subjects for placebo) will also have greater than 78% power to 
detect an absolute difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 
2-sided Chi-Square test with α=0.05.
The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................20
5.1
Institutional Review Boards/Independent Ethics Committees ..............................20
5.2
Ethical Conduct of the Study.................................................................................21
5.3
Subject Information and Informed Consent...........................................................21
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................23
7
INTRODUCTION ...........................................................................................................24
7.1
Indication ...............................................................................................................24
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................25
7.1.1.1
Mechanism of Action...........................................................................25
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................25
7.1.2
Study Rationale............................................................................................26
8
STUDY OBJECTIVES....................................................................................................28
8.1
Primary Objective..................................................................................................28
8.2
Secondary Objectives.............................................................................................28
9
INVESTIGATIONAL PLAN..........................................................................................30
9.1
Overall Study Design and Plan..............................................................................30
9.1.1
Prerandomization Phase...............................................................................30
9.1.1.1
Screening Period..................................................................................30
9.1.2
Randomization Phase...................................................................................31
9.1.3
Extension Phase ...........................................................................................31
9.2
Discussion of Study Design, Including Choice of Control Groups.......................31
9.3
Selection of Study Population................................................................................32
9.3.1
Inclusion Criteria .........................................................................................32
9.3.2
Exclusion Criteria ........................................................................................33
9.3.3
Removal of Subjects From Therapy or Assessment....................................36
9.4
Treatments..............................................................................................................36
9.4.1
Treatments Administered.............................................................................36
9.4.2
Identity of Investigational Product...............................................................37
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................37
9.4.2.2
Comparator Drug .................................................................................37
9.4.2.3
Labeling for Study Drug......................................................................37
9.4.2.4
Storage Conditions...............................................................................38
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9.4.3
Method of Assigning Subjects to Treatment Groups...................................38
9.4.4
Selection and Timing of Dose for Each Subject..........................................39
9.4.5
Blinding........................................................................................................39
9.4.6
Prior and Concomitant Therapy...................................................................39
9.4.7
Treatment Compliance.................................................................................41
9.4.8
Drug Supplies and Accountability...............................................................41
9.5
Study Assessments.................................................................................................43
9.5.1
Assessments.................................................................................................43
9.5.1.1
Demography.........................................................................................43
9.5.1.2
Baseline Assessments ..........................................................................43
9.5.1.2.1
Medical History .............................................................................43
9.5.1.2.2
Urine Drug Screen .........................................................................43
9.5.1.3
Efficacy Assessments...........................................................................43
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................44
9.5.1.4.1
Pharmacokinetic Assessments .......................................................44
9.5.1.4.2
Pharmacodynamic Assessments ....................................................45
9.5.1.4.3
Pharmacogenomic and Other Biomarker Assessments .................45
9.5.1.5
Safety Assessments..............................................................................45
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...45
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................48
9.5.1.5.3
Laboratory Measurements .............................................................49
9.5.1.5.4
Vital Signs and Weight Measurements..........................................51
9.5.1.5.5
Height Measurements ....................................................................51
9.5.1.5.6
CDC Growth Measurements..........................................................51
9.5.1.5.7
Waist Circumference .....................................................................51
9.5.1.5.8
Physical Examinations...................................................................51
9.5.1.5.9
Electrocardiograms ........................................................................52
9.5.1.5.10
Other Safety Assessments..............................................................52
9.5.1.6
Other Assessments...............................................................................53
9.5.1.6.1
Pregnancy Test...............................................................................53
9.5.2
Schedule of Procedures/Assessments ..........................................................53
9.5.2.1
Schedule of Procedures/Assessments ..................................................53
9.5.2.2
Description of Procedures/Assessments Schedule...............................57
9.5.2.3
Total Volume of Blood Sampling........................................................57
9.5.3
Appropriateness of Measurements...............................................................57
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................58
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9.5.4.1
Reporting of Serious Adverse Events..................................................58
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................58
9.5.4.3
Reporting of Events Association with Special Situations....................59
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................59
9.5.4.3.2
Reporting of Study-Specific Events...............................................60
9.5.4.4
Expedited Reporting ............................................................................61
9.5.4.5
Breaking the Blind...............................................................................61
9.5.4.6
Regulatory Reporting of Adverse Events ............................................61
9.5.5
Completion/Discontinuation of Subjects.....................................................61
9.5.6
Abuse or Diversion of Study Drug ..............................................................62
9.5.7
Confirmation of Medical Care by Another Physician .................................62
9.6
Data Quality Assurance .........................................................................................62
9.6.1
Data Collection ............................................................................................63
9.6.2
Clinical Data Management ..........................................................................63
9.7
Statistical Methods.................................................................................................63
9.7.1
Statistical and Analytical Plans....................................................................63
9.7.1.1
Study Endpoints...................................................................................63
9.7.1.1.1
Primary Efficacy Endpoint ............................................................63
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................63
9.7.1.2
Definitions of Analysis Sets.................................................................64
9.7.1.3
Subject Disposition..............................................................................65
9.7.1.4
Demographic and Other Baseline Characteristics ...............................65
9.7.1.5
Prior and Concomitant Therapy...........................................................65
9.7.1.6
Efficacy Analyses ................................................................................66
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................67
9.7.1.7.1
Pharmacokinetic Analyses.............................................................67
9.7.1.7.2
Pharmacodynamic Analyses..........................................................68
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................68
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................68
9.7.1.8
Safety Analyses....................................................................................68
9.7.1.8.1
Extent of Exposure.........................................................................68
9.7.1.8.2
Adverse Events ..............................................................................69
9.7.1.8.3
Laboratory Values..........................................................................70
9.7.1.8.4
Vital Signs......................................................................................70
9.7.1.8.5
Electrocardiograms ........................................................................70
9.7.1.8.6
Other Safety Analyses....................................................................71
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9.7.2
Determination of Sample Size .....................................................................71
9.7.3
Interim Analysis...........................................................................................72
9.7.4
Other Statistical/Analytical Issues ...............................................................72
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................72
10
REFERENCE LIST .........................................................................................................73
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......75
11.1
Changes to the Protocol .........................................................................................75
11.2
Adherence to the Protocol......................................................................................75
11.3
Monitoring Procedures...........................................................................................75
11.4
Recording of Data..................................................................................................76
11.5
Identification of Source Data.................................................................................76
11.6
Retention of Records..............................................................................................77
11.7
Auditing Procedures and Inspection......................................................................77
11.8
Handling of Study Drug.........................................................................................77
11.9
Publication of Results ............................................................................................78
11.10 Disclosure and Confidentiality ..............................................................................78
11.11 Discontinuation of Study .......................................................................................78
11.12 Subject Insurance and Indemnity...........................................................................79
12
APPENDIX......................................................................................................................80
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests (revised per Amendments 01, 03, and 04) .......50
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 
(revised per Amendments 01, 02, 03, and 04)...........................................54
Table 3
Summary of Blood Sample Volumes (revised per Amendments 01, 
03, and 04) .................................................................................................57
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
(revised per Amendments 01 and 03)
Abbreviation
Term
ADA
American Diabetes Association
AE
adverse event
AS
aortic stenosis
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
DEXA
Dual-energy X-ray Absorptiometry
DMC
Data Monitoring Committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
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Abbreviation
Term
IxRS
interactive voice or web response system
LDL
low density lipoprotein
Leiter-3
Leiter-3 International Performance Scale
LNH
low/normal/high
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
MAR
missing at random
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OGTT
oral glucose tolerance test
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PH
pulmonary hypertension
PHQ-9
Patient Health Questionnaire
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
RVOTAT
acceleration time measured at right ventricular outflow tract
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SPAP
systolic pulmonary artery pressure  
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T2DM
Type 2 Diabetes Mellitus
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
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Abbreviation
Term
TR
tricuspid regurgitation
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity has become a global epidemic, causing a serious public health concern.  In the 
United States, the prevalence of obesity in adolescents ages 12 and 19 years has almost 
doubled over the past 2 decades.  The rate increased from 10.5% between 1988 and 1994 to 
20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, defined in the 
United States as greater than or equal to the 95th percentile in gender- and age-specific body 
mass index (BMI), continues to grow at an alarming rate in the United States and globally.  
Based on data (Wang and Lobstein, 2006) using various criteria for the definition of obesity 
that included more than 30 countries in Europe, North America, Asia, and the West Pacific, 
prevalence of obesity in these countries has also increased significantly, at a rate comparable 
to that in the United States.
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may 
result in a decrease in life expectancy for the first time in 200 years (Peeters, et al., 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese adolescents are likely to become 
tomorrow’s obese adults (Whitaker, et al., 1997).
Current approaches to weight management in adults include lifestyle modification, 
pharmacotherapy, and invasive bariatric procedures.  Lifestyle modification involves a 
combination of diet, exercise, and behavioral change, and is the preferred and essential 
strategy for weight management in obese and overweight individuals, including adolescents.  
Although lifestyle modification can be very efficacious in some patients, adherence to the 
prescribed regimens is often poor.  As such, lifestyle modification alone is often not adequate 
and the weight loss is often transient.  On the other hand, bariatric surgery and various other 
invasive procedures are generally reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise, but are rarely used 
for adolescents.
The current standard of care for treatment of obesity in adolescent subjects ranges from
behavioral therapy including lifestyle intervention to the rare use of pharmacotherapy in 
adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
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(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies may be used in 
the present study to help retain participants.  These include a highly trained and competent 
site staff, ample waiting area, readily available parking (at no cost), access to mass transit, 
and reminder and follow-up calls.  In addition, sites may utilize fun and interactive group 
sessions with games and hands-on nutrition and physical activity demonstrations, random 
raffle drawings, social events, birthday and holiday cards, and newsletters to further 
encourage subject retention.  Furthermore, we may make home visits for primary efficacy 
assessments, as needed, to maximize data collection. 
By incorporating some of these 
retention strategies, we hope that we will maximize participant retention, which will help us 
cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 Diabetes Mellitus (T2DM), demonstrated clinically 
meaningful efficacy and a safety profile that includes minimal and easily managed risks.  In
each of the individual studies and in the pooled efficacy analyses, the Belviq dose met the 
following prespecified endpoints:

A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) was 
significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
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studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
used for adolescent subjects with body weight greater than 60 kg.
In adolescent obese populations, it is anticipated that Belviq XR will result in similar effects.
As part of FDA postmarketing requirements, this study is designed to characterize the 
efficacy and safety of Belviq XR in adolescent obese populations in the United States.  It is 
also intended to support an indication for chronic weight management for obese adolescents 
ages 12 to 17 years old. 
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of subjects 
in the placebo-treated group who lose at least 5% of baseline body weight, and the 
difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in obese adolescents, where weight loss will be assessed using BMI
measurements to account for growth. In this study, the objective is to demonstrate that BMI
reduction will be achieved during 52 weeks of treatment with Belviq XR 20 mg administered 
once daily (QD) compared to placebo in obese adolescents.
In the Phase 3 orlistat study in obese adolescents mentioned above, the proportion of subjects 
who lost at least 5% body weight is relatively low. At the end of the study at Week 52, only 
26.5% of the subjects achieved a 5% or greater BMI reduction compared to 15.7% in the 
placebo group. The placebo-corrected BMI reduction was about 0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years
(Peirson, et al, 2015).  Thirty-one studies (29 behavioral, 2 pharmacological and behavioral) 
were included in a meta-analysis of randomized studies conducted in primary care centers in 
overweight and obese children and youth ages 2 to 18 years using behavioral (diet, exercise,
and lifestyle) and pharmacological interventions and providing 6-month postbaseline BMI or 
prevalence of overweight or obesity. Both interventions showed a significant effect on BMI 
in favor of treatment (behavioral: 
standardized mean difference [SMD] -0.54, 
95% confidence interval [CI]
-0.73, -0.36; orlistat plus behavioral: 
SMD -0.43, 
95% CI -0.60, -0.25). The studies reported no significant difference between groups in the 
likelihood of reduced prevalence of overweight or overweight and obese. A great deal of 
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variation was noted across efficacious interventions.
In conclusion, this meta-analysis 
demonstrated low-quality evidence that behavioral treatments alone are associated with a 
smaller effect in terms of reduced BMI compared with the effect shown by combined 
behavioral and pharmacological interventions. This may be because the effect size in the 
randomized, double blind, placebo controlled, phase 3 orlistat study in adolescents was 
relatively low and there was a lack of maintenance effect. These subjects started to regain 
their BMI after 6 months of treatment. At end of the study, only 26.5% of subjects achieved 
a 5% or greater BMI reduction compared to 15.7% in placebo group. In a sibutramine 
Phase 3 study in obese adolescents, a substantially higher proportion of subjects (69%) 
treated with sibutramine achieved at least a 5% BMI reduction compared to 21% of subjects 
in the placebo group. In addition, sibutramine resulted in a substantial reduction in mean 
BMI (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 
8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the weight loss effect of Belviq
in adults and sibutramine in adolescents, subjects in the orlistat study started to increase their 
BMI after 6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of 260 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
sibutramine, and liraglutide 3 mg) (FDA, 2003; Chanoine, et al., 2005; Berkowitz, et al,
2006; CT.gov NCT02918279) and other metabolic or dyslipidemia medication products
(ezetimibe, simvastatin) (FDA, 2007).  (revised per Amendment 02)
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8
STUDY OBJECTIVES
8.1
Primary Objective

To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment with 
Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR
20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in 
BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo
(revised per Amendment 01)

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% 
BMI reduction, change in waist circumference) at the end of 52 weeks of treatment
-
Effects on fasting plasma glucose, hemoglobin A1c (HbA1c), insulin levels, and 
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR); glucose [mg/dL] 
× insulin [mU/L]/405) in subjects with T2DM at baseline during 52 weeks of 
treatment (revised per Amendments 03 and 04)
-
Effects on fasting plasma glucose, HbA1c, insulin levels, and HOMA-IR; glucose 
[mg/dL] × insulin [mU/L]/405 in subjects without T2DM at baseline during 52 weeks 
of treatment (revised per Amendments 03 and 04)
-
Effects on body fat and lean mass composition by Dual-energy X-ray Absorptiometry 
(DEXA) in a subset of subjects (selected prior to randomization at selected sites)
during 52 weeks of treatment (revised per Amendment 03)
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high 
density lipoprotein [HDL], low density lipoprotein [LDL]), systolic and diastolic 
blood pressure, and heart rate) during 52 weeks of treatment (revised per 
Amendment 03)
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•
To assess the safety of Belviq XR, including the effects on cognition by Leiter-3 
International Performance Scale (Leiter-3), depression with the Patient Health 
Questionnaire 
(PHQ-9), 
signal 
of 
suicidal 
ideation 
or 
behavior 
with 
the 
Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by CDC growth 
chart, sexual maturation (pubescence) measured by Tanner Staging scores, and other 
growth and development parameters by measuring sex hormones, thyroid function, 
adrenal function, bone age, and biochemical markers of bone health, bone mineral 
density and content, total body fat mass and total body lean mass by DEXA in a subset of 
subjects (selected prior to randomization at selected sites), valvular function, pulmonary 
arterial pressure. (revised per Amendments 01 and 03)
•
To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling
•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
probability of achieving at least a 5% and at least a 10% reduction in BMI from baseline
at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (130 subjects) and placebo (130 subjects).  Subjects will be 
stratified by sex.  Subjects will receive Belviq XR 20 mg or matched placebo QD in a 1:1 
ratio for up to 52 weeks. A recruitment plan will be developed to ensure at least 20% of 
younger subjects (12 to 13 years of age) are enrolled in the study.  Throughout the duration 
of the study, subjects will be encouraged to adhere to a lifestyle modification program that 
includes a standardized, age-appropriate diet and exercise counseling (see Appendix 2).  
(revised per Amendments 02 and 03)
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be rescreened only once.  All subjects will continue in the study 
until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely 
will be followed up until study completion.  All attempts will be made to capture height and 
weight in all subjects whether or not they are still on study drug at the end of the study.  
(revised per Amendments 03 and 04)
Study sites will be selected to ensure adequate representation of adolescents of ethinic and 
racial minorities.  (revised per Amendment 03)
A Data Monitoring Committee (DMC) will be established to monitor and conduct periodic 
safety review of unblinded data. DMC members will be chosen based on their expertise in 
evaluating these clinical events. A separate DMC charter will be established.  (revised per 
Amendment 03)
9.1.1
Prerandomization Phase
Screening will occur during the Prerandomization Phase at Visit 1.
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
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description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
9.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025.  Overall, the PK parameters of Belviq and its main 
metabolites, M1 and M5, were similar to those in adults.  Following a single, oral 
administration of Belviq 10 mg to a total of 8 healthy adolescent (ages 12 to 17 years old) 
obese subjects, the mean maximum concentration observed and the area under the 
concentration-time curve from time zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 
464 hr×ng/mL, respectively.  The mean Belviq terminal phase half-life was 9.70 hours, 
similar to that observed in adults, thus supporting a similar dosing frequency (QD) in 
adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric or adolescent subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of subjects who are older than 12 years of age 
having a body weight of less than 60 kg is very low; therefore, the current study as designed 
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to enroll subjects between 12 to 17 years of age with body weight at least 60 kg, will cover
majority of the population of interest.  The targeted study population comprises 260 obese 
adolescents 12 to 17 years of age, with a body weight at least 60 kg.  (revised per 
Amendment 02)
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
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, 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 500 subjects will be screened to ensure that 260 subjects will be randomized.  
(revised per Amendment 02)
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug. Subjects who screen fail can be rescreened only once and
without repeating the screening echocardiogram for up to 90 days after the previous 
echocardiogram.  All other screening assessments must be repeated when a subject is 
rescreened.  Subjects that rescreen more than 90 days after the previous echocardiogram must 
repeat all screening assessments including the screening echocardiogram.  (revised per 
Amendments 03 and 04)
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, ages 12 to 17 years old (inclusive) at Screening, with 
an initial BMI that is greater than or equal to the United States (US)-weighted mean of 
the 95th percentile based on age and sex with a body weight greater than 60 kg.  Subjects 
with T2DM may have a pre-existing or new diagnosis of T2DM.  
Subjects with pre-existing T2DM should have prior documentation consistent with the 
diagnosis and/or be on active pharmacotherapy for T2DM.  
Subjects with a new diagnosis of T2DM (ie, diagnosed at Screening) should be based on 
the 2016 American Diabetes Association (ADA) guidelines.  The diagnostic criteria are 
met if a subject has unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL 
(11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis) OR any 
of the following criteria are observed and then confirmed:
o
HbA1c ≥6.5% 
o
fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 
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o
2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) by an oral glucose tolerance 
test (OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being or 
need to be treated with antidiabetic agents, the T2DM treatment regimen must be stable 
for at least 3 months before randomization.  A single rescreen is allowed following 
stabilization.  Stable control refers to minimal dose changes to existing medications for 
glycemic control and no medications being initiated for glycemic control in the 3 months 
before Randomization.  Minimal changes are defined as a change without any change in 
dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject 
has not been hospitalized due to hypo- or hyperglycemic events.  (revised per 
Amendment 03)
2. Subjects and their families are not planning to move away from the area for the duration 
of the study
3. Able and willing to comply with all aspects of the study, including a standardized,
reduced-calorie diet and an age-appropriate, increased physical activity program
4. Considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may affect 
the subject’s ability to fulfill the study requirements or significantly confound the 
assessments
2. Who cannot swallow investigational products
3. With T2DM who have hypoglycemia unawareness (revised per Amendment 03)
4. Any of the following findings on screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, 
mean gradient >25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean 
gradient >5 mm Hg and mitral valve area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure
(SPAP) >40 mm Hg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
-
In cases where an actual SPAP value is not measurable due to lack of adequate 
TR jet, the pulmonary flow acceleration time measured at the right ventricular 
outflow tract (RVOTAT), will be used to assess eligibility.   Subjects with a 
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RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those subjects with RVOTAT between 100 and 120 msec will 
be determined based on combined assessment of the TR jet, septal motion and 
right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with 
hemodynamic compromise)
5. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
6. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months 
of Screening, as indicated by answering “Yes” to questions 4 or 5 on the Suicidal 
Ideation section of the C-SSRS
7. Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
8. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder (ADHD), any Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition (DSM-5) depressive disorder, bipolar disorder, or schizophrenia
9. Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi 
syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, 
Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 30 days, 
history of significant exposure to corticosteroids for chronic illness during the past year; 
inhaled steroids will be allowed) (revised per Amendment 03)
10. Use of other products intended for weight loss including prescription drugs,
over-the-counter (OTC) drugs, and herbal preparations within 1 month before Screening
11. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 

bupropion

triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
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b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin®, Concerta®, biphetamine and Dexedrine®)

benzodiazepines
12. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and 
cabergoline
13. History or evidence of clinically significant disease (eg, malignancy, cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), T2DM treated with oral antidiabetic agents 
(excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive sleep 
apnea, dyslipidemia, and nonalcoholic fatty liver disease
14. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or 
any of the excipients
15. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
16. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 6 months
before Screening
17. History of alcohol or drug dependence or abuse
18. Recreational drug use within 2 years before Screening
19. Known to be human immunodeficiency virus (HIV) positive
20. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
21. Malignancy within 5 years before Screening
22. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
23. Special needs subjects who are unable to comprehend study-related instructions (eg, mild 
to profound mental retardation [IQ <70], moderate to severe cognitive developmental 
delay, pervasive development disorders, autism)
24. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
25. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate 
readings recorded on 2 separate days.  Those subjects who had uncontrolled hypertension 
at Screening can be rescreened more than 1 month after initiation or adjustment of 
antihypertensive therapy 1 time.
26. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
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27. Planned bariatric surgery during the study or prior bariatic surgical procedures (revised 
per Amendment 03)
28. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
29. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
30. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 
28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after 
study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use 
the same contraceptive during the study and for 28 days after study drug 
discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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.
Investigators should do their best to bring all subject who discontinued early from the study
in for the their primary endpoint collection regardless of the reason for ED. (revised per 
Amendment 01)
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD at 
approximately the same time each day.
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Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled with text that is in full regulatory compliance with each 
participating country. As the study is being conducted in US only, the study drug label will 
be printed in English. 
The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal (US) law to 
investigational use.”
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All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug was 
dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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.
Subjects will be centrally stratified by sex (male and female).  Within each stratum, subjects 
will be randomized to receive either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  
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Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily at approximately the same time of 
every day, and be encouraged to take the study medication with an adequate amount of water 
(8 oz. or 240 mL).  For information on dosing on visits associated with PK sampling, see 
Section 9.5.1.4.1.  (revised per Amendment 03)
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
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Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
The following concomitant medication guidelines/restrictions will apply:

Medications for the treatment of hypertension, dyslipidemia, or diabetes may be 
started, discontinued, or adjusted during the study according to local standards of care 
if, in the judgment of the investigator or the subject’s physician, such a change is 
medically indicated.

For diabetic subjects treated with sulfonylureas, insulin (note that subjects should not 
be enrolled as indicated in exclusion criteria), or other antidiabetic agents with 
hypoglycemic risk, the risk of hypoglycemic events may be higher if the subjects 
experience rapid and significant weight loss (more than 10% weight reduction than at 
the previous visit).  It is recommended that the physician advise the subject to 
monitor their blood glucose more frequently and adjust their antidiabetic medications 
and diet accordingly. 
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
The antihyperglycemic medication dose would be considered for reduction in the 
event of 1 documented and otherwise unexplained hypoglycemic event (blood 
glucose concentration <65 mg/dL) or 2 undocumented and otherwise unexplained 
suspected hypoglycemic events between any 2 scheduled visits.  For subjects on more 
than 1 antihyperglycemic medication, it is recommended to reduce insulin first (if 
applicable), then the oral and/or other injectable antidiabetic agents.  If the previous 
criteria are met again following dose reduction, further dose reductions or cessation 
of 1 or more antihyperglycemic agents, are suggested.  See Section 9.5.4.2 for the 
definition and reporting of hypoglycemic events. 
To minimize the risk of cardiac valve toxicity, subjects must not initiate use of agents that 
have documented correlation with increased incidence of valvulopathy and/or PH (eg, 
pergolide, ergotamine, methysergide, or cabergoline) during the study. 
(revised per 
Amendment 01)  If any of the above agents are clinically warranted, and subjects initiate any 
of these agents, Belviq XR should be discontinued but can be restarted on Belviq XR after 
being off the medications above for 1 month.  Otherwise, the study medication should not be 
restarted, but the subject should continue all study visits.  (revised per Amendments 03 and 
04)
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Subjects will 
be asked to bring their study drug bottles to each visit.  The CRAs will review treatment 
compliance during site visits and at the completion of the study.  (revised per 
Amendment 03)
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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
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•
An investigator-signed and dated Form FDA 1572, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 (US 
sites only).  Must be appropriate to handle schedule IV products and not be expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
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at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.2.2
URINE DRUG SCREEN
A 30-mL urine sample will be collected at Screening, as specified in the Schedule of 
Procedures/Assessments (Table 2).  This sample will be tested for common drugs of 
use/abuse (eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, nicotine/cotinine, opioids 
[as a group], benzodiazepines, barbiturates, amphetamines). (revised per Amendment 01)
9.5.1.3
Efficacy Assessments

Body weight and height: will be measured using a standard stadiometer method (Lohman 
T, et al, 1988) to calculate changes in BMI.
Body weight will be measured in the 
morning after at least 8 hours of fasting and voiding using a calibrated scale and 
standardized instructions for clothing (ie, a hospital gown). Weight will be measured to 
the nearest 0.1 kg. Height will be measured in triplicate utilizing a stadiometer with a 
standardized process (eg, subjects should not be wearing shoes). Height must be 
measured to the nearest 0.1 cm.  BMI will then be used to calculate the proportion (%) of 
subjects achieving at least a 5% and at least a 10% BMI reduction.  (revised per 
Amendment 03)
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
Waist circumference: will be determined by measurement taken with a tape measure 
positioned horizontally, parallel to the floor, at one finger width above the iliac crest. The 
subject should be standing erect with relaxed abdominal muscles.  The tape measure 
should be snug but not compress the skin. The waist circumference should be taken to the 
nearest 1.0 cm, at the end of normal expiration. Three measurements will be taken and 
the average will be calculated. (revised per Amendment 03)

Total body fat mass and total body lean mass:  will be determined centrally using DEXA 
in a subset of subjects (selected prior to randomization at selected sites) at bBseline and 
Week 52/EOT.  (revised per Amendment 03)

Measurement of systolic and diastolic BP, heart rate (taken after resting for 5 minutes), 
fasting lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), 
fasting plasma glucose, fasting insulin, HbA1c, and HOMA-IR to assess changes in 
cardiovascular and metabolic risk profiles from baseline to Week 52 (revised per 
Amendment 03)

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 
(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents, 2011)

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011)
Every effort will be made to ensure that at least 80% of randomized subjects will have an 
assessment of the primary efficacy endpoint regardless of whether or not the subject 
remained on study drug or completed other study assessments.  (revised per Amendment 03)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for Population PK analyses.  (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take 
their study drug at home before the visit, but to bring their study drug to the clinic visit and 
take their daily dose at the clinic.  Two blood samples for determination of plasma 
concentrations of lorcaserin will be taken 1 predose (within 30 minutes before dosing) and 1 
within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times 
before the day of clinic visit. Week 52 PK samples should only be collected if the sample can 
be drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug at home, and will 
be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood 
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sample for PK assessment will be collected.  Dose times must be recorded for the last 2 
dosing times prior to the clinic visit. (revised per Amendment 01)
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
coupled with tandem mass spectrometry method. The collection, handling, and shipping 
procedures for PK samples will be described in a manual to be provided to the study sites.
At Unscheduled Visits, PK samples should only be collected if subject has experienced a 
serious adverse event (SAE) while on study drug and the sample can be drawn within 60 
hours of the initiation of the SAE. (revised per Amendment 01)
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Lorcaserin plasma exposure from PK analysis and population PK/PD modeling will be used 
to explore the relationship between lorcaserin plasma exposure and following response to 
lorcaserin: 

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC AND OTHER BIOMARKER ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; electrocardiograms 
(ECGs); laboratory evaluations for hematology, metabolic function (fasting plasma glucose, 
lipids, and thyroid), adrenal functions, and biochemical blood and urine bone health
assessments;
blood chemistry and urine values; neuropsychiatric events;
periodic 
measurements of vital signs, neuromuscular signs for screening potential serotonin 
syndrome, and signs and symptoms of priapism and hyperprolactinemia; and performance of 
physical examinations.  In subjects with potential prolactin-related AEs, such galactorrhea,
changes in libido, or changes to menstrual cycle, fasting prolactin level will be measured and 
assessed.  (revised per Amendments 03 and 04)
Bone mineral density and content, total body fat mass and total body lean mass will be 
determined using DEXA in a subset of subjects (selected prior to randomization at selected 
sites).  (revised per Amendment 03)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
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relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present at 
pretreatment (baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
At each visit, the investigator should actively assess as to whether any of the following 
adverse events have occurred during the interval since the last visit:
•
Serotonin syndrome and signs or symptoms of serotonergism
•
Signs or symptoms of valvular heart disease or pulmonary hypertension, including 
dyspnea, dependent edema, congestive heart failure, or a new cardiac murmur
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•
Impairments in attention and memory, and confusion, somnolence, and fatigue
•
Psychiatric disorders
•
Hypoglycemia in subjects with diabetes on concomitant antidiabetes medications (using 
ADA definitions)
•
Priapism and hyperprolactinemia signs and symptoms should be recorded at each visit 
and whenever reported
•
Hypersensitivity reactions
Any such events should be recorded as adverse events.  Serotonin syndrome, valvular heart 
disease, pulmonary hypertension, and priapism should always be reported as serious adverse 
events (SAEs) (See Section 9.5.1.5.2 for a complete list of adverse events that should always 
be considered as Serious).  (revised per Amendment 03)
Events of hypoglycemia in subjects with diabetes on concomitant antidiabetes medication 
should be captured as per Section 9.5.2.  Severe symptomatic events of hypoglycemia should 
always be reported as an SAE as per Section 9.5.1.5.2.  (revised per Amendment 03)
It is the responsibility of the investigator to review the results of the Leiter-3, C-SSRS, and 
PHQ-9 for all subjects and determine if any result constitutes an AE.  Medical and scientific 
judgment should be exercised in deciding whether an isolated suicidality rating scale 
response should be classified as an AE (see Section 9.5.1.5.10 for a description of the 
C-SSRS).  (revised per Amendment 01)
All AEs must be monitored until symptom resolution, or until the condition stabalizes.  
(revised per Amendment 03)
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
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
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•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of the 
event
•
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious criteria:
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•
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
•
Priapism
•
New onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms (revised per Amendment 03)
•
Fibroadenomas of the breast or ductal carcinoma in situ
•
Severe symptomatic hypoglycemia (revised per Amendment 03)
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
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the study.
Laboratory testing should be conducted on an unscheduled basis if clinically 
indicated.  (revised per Amendment 03)
Table 1
Clinical Laboratory Tests (revised per Amendments 01, 03, and 
04)
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium, bicarbonate
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
Thyroid function
T4, TSH
Adrenal function
AM serum Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects)
Bone health assessments
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other (revised per Amendments 01
and 04)
Albumin, calcium, globulin, fasting plasma glucose, HbA1c, HDL 
cholesterol, fasting insulin, lactate dehydrogenase, LDL cholesterol,
fasting lipid panel, phosphorus, total protein, total cholesterol,
triglycerides, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
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9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained in triplicate to the nearest 0.1 cm as designated 
in the Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 03)
9.5.1.5.6
CDC GROWTH MEASUREMENTS
Investigators will calculate the height for age percentile and weight for age percentile 
utilizing the most recent CDC 95th Percentile Growth Chart and the height and weight 
measurements obtained, as designated in the Schedule of Procedures/Assessments (Table 2).  
(revised per Amendment 01)
9.5.1.5.7
WAIST CIRCUMFERENCE
Waist circumference (cm) measurements will be obtained in triplicate to the nearest 1.0 cm 
taken 3 times at each visit as designated in the Schedule of Procedures/Assessments 
(Table 2).  (revised per Amendments 01 and 03)
9.5.1.5.8
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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 eCRF.
As part of the physical examination, a neuromuscular sign assessment for serotonin 
syndrome will be performed for potential serotonergic syndrome components.  Serotonergic 
syndromes that meet the diagnostic criteria will be captured by AE eCRF.
(revised per 
Amendment 01)
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will also be captured in the AE eCRF. (revised per 
Amendment 01)
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9.5.1.5.9
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events eCRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.10 OTHER SAFETY ASSESSMENTS
Leiter-3
The Leiter International Performance Scale–Third Edition (Leiter-3) is widely used 
non verbal measure of intelligence, memory, and attention in those between the ages of 3 and 
75 years. 
The Attention/Memory Battery consists of 5 subtests: 2 measure nonverbal 
attention; 2 measure memory; and 1 measures cognitive interference (nonverbal Stroop test). 
These subtests are combined to produce a Memory and Processing Speed composite scores, 
normalized to a mean of 100 and standard deviation of 15. The Leiter-3 will be used to 
assess lorcaserin effects on cognition, specifically, attention and memory. In addition, signs 
and symptoms of cognition-related AEs, including impairments in attention, memory, and 
adverse effects on schoolwork will be captured in the eCRF. (revised per Amendment 01)
PHQ-9
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and 
measuring the severity of depression:

The PHQ-9 incorporates Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV) depression diagnostic criteria with other leading major depressive 
symptoms into a brief self-report tool.

The tool rates the frequency of the symptoms which factors into the scoring severity 
index.

Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.

A follow-up, non-scored question on the PHQ-9 assigns weight to the degree to which 
depressive problems have affected the subject’s level of function. 
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at Baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. Qualified personnel must evaluate positive 
responses on the C-SSRS and take appropriate action as detailed in the training and 
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certification process for administering the C-SSRS.  It will be performed at Screening and at 
study visits as designated in the Schedule of Procedures/Assessments (Table 2). (revised per 
Amendment 01)
DEXA for the Assessment of Bone Mineral Density
Bone mineral density body composition determination by DEXA whole body composition, to 
include bone mineral density and content, total body fat mass and total body lean mass will 
be determined using DEXA in a subset of subjects (selected prior to randomization at 
selected sites).  A contracted vendor will provide all administration and project management 
services for DEXA scanning.  This will include site and image data management services, as 
well as site training and certification.  (revised per Amendment 03)
A mininum of 30 subjects ages 12-17 years (selected prior to randomization at selected sites) 
should have bone density evaluated with DEXA at baseline and week 52/EOT.  (revised per 
Amendments 03 and 04)
Hand X-Ray
A hand x-ray for evaluation of any potential negative effect on bone age will be performed 
on the same hand at each visit as designated in the Schedules/Assessments (Table 2).  
(revised per Amendment 01)
Tanner Staging
The pubic hair growth (both sexes), genital (males only) and breast (females only) 
development of subjects will be using Tanner Staging by a trained clinician (Marshall, 1970).
Subjects will be examined by the investigator as designated in the Schedules/Assessments 
(Table 2). (revised per Amendments 01 and 03)
Echocardiogram
Echocardiograms will be obtained on the Schedule of Procedures/Assessments (Table 2). 
Valvular regurgitation in echocardiogram will be rated absent, trace, mild, moderate, or 
severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve.  The evaluations will be based on guidelines from the American Society of 
Echocardiography. Pulmonary artery systolic pressure will be estimated from the TR
regurgitant jet velocity.  (revised per Amendment 03)
9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at every visit as specified in the 
Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 03)
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 (revised per Amendments 01, 02,
03, and 04)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examinationd
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, insulin, and HbA1c sampling
X
X
X
X
X
X
T4 and TSH
X
X
X
X
X
Testosterone, Estradiole
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 (revised per Amendments 01, 02,
03, and 04)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Pregnancy test (urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting prolactin
X
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Fasting lipid panel
X
X
X
X
Urine NTX
X
X
X
X
PK/PD blood sampling
Xf
Xf
Xf
Xf,g
Xh
Xg
AM serum cortisol
X
X
X
ECG
X
X
X
X
Echocardiograph
Xi
X
X
DEXAj
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
Leiter-3
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 (revised per Amendments 01, 02,
03, and 04)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Standardized age-appropriate lifestyle modification 
counselingk
X
X
X
X
X
X
X
X
X
X
AE = adverse event, AM = morning; CDC = Centers for Disease Control and Prevention, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, ED = 
early discontinuation, EOS = End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, IxRS = interactive voice or web response system, NTX = N-telopeptide, OC 
= osteocalcin; PHQ-9 = The Patient Health Questionnaire, PICP = carboxyterminal propeptide of type I procollagen,  PD = pharmacodymanic, PK = pharmacokinetics, SAE = 
serious adverse event; T4 = thyroxine, TSH = thyroid stimulating hormone, US = unscheduled.
a: Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b: Window ±7 days for all visits. (revised per Amendments 01 and 03)
c: Unscheduled visits may be conducted at any time that additional assessments are indicated in the clinical judgment of the investigator.  Note that not all assessments listed 
under Unscheduled Visit need to be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs.  At 
Unscheduled Visits, PK samples should only be collected if subject has experienced a serious adverse event (SAE) while on study drug and the sample can be drawn within 
60 hours of the initiation of the SAE. (revised per Amendments 01 and 03)
d: Includes a neuromuscular assessment for serotonin syndrome, and signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle abnormalities 
or galactorrhea) (revised per Amendments 01 and 03)
e: Testosterone will only be drawn in males, and estradiol will only be drawn in females. (revised per Amendment 04)
f: On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at home before the visit, but to bring their study drug to the clinic 
visit and take their daily dose at the clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken:  1 predose (within 30 minutes before 
dosing) and 1 within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times before the day of clinic visit. Week 52 PK samples should only be 
collected if the sample can be drawn within 60 hours of the last dose of study drug.  On the day of the Week 36 clinic visit, subjects will take the morning dose at home, and 
will be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for PK assessments will be collected  Dose times must be recorded for the 
last 2 dosing times prior to the clinic visit. (revised per Amendment 01)
g: PK samples should only be collected if the sample can be drawn within 60 hours of the last dose of study drug.
h: PK samples should only be collected if subject has experienced an SAE while on study drug and the sample can be drawn within 60 hours of the initiation of the SAE.
i: Echocardiographic assessments will be performed during screening period after subjects have met all other inclusion and exclusion criteria.
j: Only subjects in selected sites will have this assessment done.  (revised per Amendment 03)
k: Lifestyle modification counseling will also be performed at Weeks 3, 16, 24, 32, 40, and 48 in addition to counseling at the scheduled visits in Appendix 2.
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes (revised per Amendments
01, 03, and 04)
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
(Chemistry and Hematology)
5
Screening: 1
Visits 2, 3, 4, 6, 8, 11 (EOT),
EOS or ED
58=40
T4, TSH 
2.5
Screening:  1
Visits 2, 8, 11 (EOT), or ED
2.5×4=10
Testosterone, estradiol
0.5
Visits 2, 8, 11 (EOT)
0.5x3=1.5
AM serum cortisol
0.5
Visits 2, 11 (EOT), or ED
0.5x2=1
Serum OC and PICP, 
Hydroxy-proline; Fasting 
lipid panel (HDL cholesterol, 
LDL cholesterol, total 
cholesterol, triglycerides)
8
Visits 2, 8, 11 (EOT), or ED
8×3=24
Fasting Prolactin, FPG, 
fasting insulin, and HbA1c
sampling
5
Screening:  1
Visits 2, 6, 8, 11 (EOT) or ED
5×6=30
PK/PD blood sampling
4
Visits 6, 8, and 11 (EOT) or ED
(2 samples each); Visit  9 (1 
sample only)
4×7=28
Total
134.5
ED= early discontinuation from study, EOS = End of Study, EOT = End of Treatment, FPG = fasting plasma glucose, 
HbA1c = hemoglobin A1c, OC = osteocalcin, PD = pharmacodynamic, PICP = carboxyterminal propeptide of type I 
procollagen, PK = pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported.
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If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms (revised per Amendment 03)

Fibroadenomas of the breast or ductal carcinoma in situ

Severe symptomatic hypoglycemia (revised per Amendment 03)
Subject-reported episodes of hypoglycemia or decreased blood sugar should be captured on 
the eCRF according to the following guidelines:

Pseudo-hypoglycemia:  An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia 
with a measured plasma glucose concentration >70 mg/dL (>3.9 mmol/L) but 
approaching that level.  (revised per Amendment 03)

Probable symptomatic hypoglycemia:  An event during which symptoms typical of 
hypoglycemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 70 mg/dL (≤ 3.9 mmol/L)
(revised per Amendment 03)

Asymptomatic hypoglycemia: 
An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dL (≤ 
3.9 mmol/L) (revised per Amendment 03)
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
Documented symptomatic hypoglycemia: An event during which typical hypoglycemia 
symptoms are accompanied by a measured plasma glucose ≤70 mg/dL (≤3.9 mmol/L) 
(revised per Amendment 03)

Severe hypoglycemia: 
An event requiring assistance of another person to actively 
administer carbohydrate, glucagon or other resuscitation actions. Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration (revised per 
Amendment 03)
See Section 9.4.6 (Prior and Concomitant Therapy) for directions on the recommendations 
for possible adjustment to antihyperglycemic medication doses in response to reported 
episodes of hypoglycemia.  (revised per Amendment 03)
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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue study drug prematurely will continue to be evaluated for all study 
assessments until study completion.  All attempts will be made to capture height and weight 
in all subjects whether or not they are still on IP at the end of the study.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments Table 2). (revised per Amendment 03)
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The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be contacted by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of the secondary reasons for discontinuation.  Study disposition information will 
be collected on the Subject Disposition CRF. If “lost to follow-up” is recorded in clinical 
database, appropriate queries will be sent to investigators in order to collect all the relevant 
reasons for missing data.  (revised per Amendment 03)
Every effort, including proper training of all study participants and their parent/guardian, 
should be made in order to achieve optimal subject retention and prevent missing data, 
especially for the Week 52 primary endpoint.  A retention plan to help avoid missing data 
will be developed and included in study manual. (revised per Amendment 03)
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.  The DEA Registrant has 
the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
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9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
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OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from baseline to Week 52

Association between change and percentage change in BMI from baseline to Week 52 
with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI 
reduction at Week 52 with the outcome of achieving at least a 5% BMI reduction at 
Week 12 (revised per Amendment 02)

Change in waist circumference from baseline to Week 52

Change in total body composition (total fat and lean mass) in a subset of randomized 
subjects at end of 52 weeks of treatment (revised per Amendment 03)

Change in HbA1c from baseline to Week 52 for subjects with T2DM at baseline (revised 
per Amendment 03)

Change in fasting plasma glucose, fasting insulin, and HOMA-IR from baseline to 
Week 52 for subjects with T2DM at baseline (revised per Amendments 03 and 04)

Change in fasting plasma glucose, fasting insulin, and HOMA-IR from baseline to Week 
52 for the subjects without T2DM at baseline (revised per Amendments 03 and 04)

Change in BP (systolic and diastolic) and heart rate from baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52

Subject compliance rate at each visit by pill count during 52 weeks of treatement (per 
Amendment 03)
9.7.1.2
Definitions of Analysis Sets

The 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.
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
The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or 
greater compliant with study medication, completed the study, have no major protocol 
deviations, have no violations of inclusion or exclusion criteria, and have BMI data at 
baseline and Week 52.  The determination of subjects to be excluded from this population 
based on the above criteria and list of major protocol violations will be included in the 
SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 
1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and 
who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline
variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
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medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from baseline to Week 52.  The change 
from baseline in BMI will be analyzed using analysis of covariance model (ANCOVA) with 
factors of treatment, sex (male and female) as fixed effect, and the baseline age and BMI as 
covariates.  The missing values will be imputed using a pattern mixture model utilizing 
multiple imputation (MI) assuming the missing values are missing not at random (MNAR).  
The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model 
and missing value imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated based 
on the PP.

Change from baseline in standardized BMI score (Z-score): The same primary efficacy 
analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed 
and will be described in the SAP.  
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Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, and sex (male and 
female), and baseline BMI as a covariate using FAS.  Subjects with any missing assessment 
at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using mixed effect model repeated measurement analysis (MMRM) on the FAS for 
study treatment compared to placebo, as appropriate. The model will include all data and will 
include treatment, time, and the interaction of treatment by time as fixed effects, with 
adjustment for sex (male versus female), BMI and age at baseline, and subject as a random 
effect.  (revised per Amendment 03)
Treatment by time interaction will be used to construct the treatment comparisons at a 
specific time.  The MMRM model assumes that the missing data are missing at random and 
makes use of all available data even if a subject has missing data at some postbaseline visits.  
An unstructured covariance matrix will be used, and if the model fails to converge, then an 
autoregressive matrix will be used.  (revised per Amendment 03)
Categorical variables will be analyzed using the Cochran Mantel Haenszel test, Chi-square 
test, or logistic regression as appropriate.  Additional analysis may be performed as needed 
using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male 
and female), race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or other Pacific Islander, or White), and age. Additional subgroups may be 
explored, if deemed necessary.  (revised per Amendment 03)
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
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posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Change from baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will 
be used for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of subjects achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also be 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination, 
neuromuscular sign assessment for serotonin syndrome, and signs and symptoms of priapism 
and hyperprolactinemia), out-of-normal-range laboratory safety test values, change from 
baseline in laboratory safety test values, ECGs, vital sign measurements, bone mineral 
density and content, total body fat mass and total body lean mass by DEXA, FDA-defined 
valvulopathy, and pulmonary hypertension by echocardiograph will be summarized by 
treatment group using descriptive statistics or frequency count as appropriate.  (revised per 
Amendments 01, 03, and 04)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the first dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the first dose of study drug and the date the subject received the last dose of study 
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drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (baseline) or
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No [not 
related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
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The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will
be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, 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
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
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and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and greater 
than 60 msec from the baseline visit.
9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including adolescent growth evaluations using 95th percentile CDC 
growth charts and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, study drug effect on cognition assessed by Leiter-3, assessment of suicidality using 
C-SSRS, depression assessment using PHQ-9, will be summarized by treatment group at 
each scheduled visit.  In a subset of subjects, bone mineral density and content, total body fat 
mass, and total body lean mass using DEXA and their z-score will be summarized by 
treatment group at baseline and Week 52. For echocardiographic assessments, the proportion 
of subjects who develop FDA-defined valvulopathy, the proportion of subjects who develop 
pulmonary hypertension (defined as when a subject’s SPAP is ≥40 mmHg evaluated by 
echocardiograph], and change from baseline in SPAP will also be summarized by treatment 
group at Week 28 and Week 52. (revised per Amendments 01, 03, and 04)
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg treatment group; n=130 in the 
placebo group) will have at least 80% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 260 subjects (130 subjects for Belviq XR 20 mg and 130 subjects for placebo) 
will also have greater than 78% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Chi-Square test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
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9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.
Lohman T, Roche AF, Martorell R. Anthropometric Standardization Reference Manual.  
Champaign, IL:  Human Kinetics Books; 1988.
Marshall WA, Tanner JM. Variation in pattern of pubertal changes in boys. Arch. 
Dis.Childhd 1970; 45, 13-23.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.
CT.gov Study NCT02918279. (revised per Amendment 02)
Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L.  
NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
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Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A 
Life-Table Analysis. Ann Intern Med. 2003; 138:24-32.
Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al. A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
Whitaker RC, et al. Predicting obesity in young adulthood from childhood and parental 
obesity. N Engl J Med. 1997 Sep 25;337(13):869-73.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
<LLN – 2.5 mg/dL
<2.5 – 2.0 mg/dL
<2.0 – 1.0 mg/dL
<1.0 mg/dL
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
(hypophosphatemia) 
<LLN – 0.8 mmol/L
<0.8 – 0.6 mmol/L
<0.6 – 0.3 mmol/L
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will be 
encouraged to participate in a standardized weight management program for adolescents 
consisting of multicomponent behavior therapy.  The therapy will focus on healthy eating, 
physical activity, and lifestyle changes that will facilitate weight loss and weight loss 
maintenance. The role of the caregivers is to support their child or adolescents’ lifestyle 
changes and their taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress but 
caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neurology Business Group
Eisai Inc.
Date
 Medicine Development Group
Eisai Inc.
Date
Neurology Business Group
Eisai Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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Revision History
Previous Version (Revision): v8.0
Current Version (Revision):  v9.0
Date of Revisions: 12 Dec 2017 (per administrative corrections)
Change
Rationale
Affected Protocol Section(s)
Revised assignment of 
assessment table footnotes
Clarity
Table 2
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Revised secondary objectives to 
assess effects of glycemia to 
fasting glucose in subjects with 
Type 2 diabetes and those 
without Type 2 diabetes
Per FDA request
Synopsis – Objective
Section 8.2
Section 9.7.1.1.2
Added secondary objective to 
assess the effects on body fat 
and lean mass compostion by 
DEXA in a subset of subjects at 
selected sites
Per FDA request
Synopsis – Objective
Synopsis - Efficacy Assessment
Synopsis – Other Safety 
Assessments
Synopsis – Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.1.2
Table 2
Section 9.7.1.8.6
Revised secondary objective for 
cardiovascular risk factors 
associated with obesity to 
include blood pressure and heart 
rate
Synopsis – Objective
Section 8.2
Revised secondary objective to 
evaluate bone density by DEXA 
in a subset of subjects at 
baseline and Week 52/EOT
Per FDA request
Synopsis – Objective
Synopsis - Other Safety 
Assessment
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.10
Table 2
Section 9.7.1.6
Section 9.7.1.8.6
Added requirement to evaluate 
drug compliance (via pill count)
Per FDA request
Synopsis – Other Secondary 
Efficacy Endpoints
Section 9.4.7
Section 9.7.1.1.2
Revised to specifiy that at least 
20% of all study subjects 
enrolled are younger (12 to 13 
year of age)
Per FDA request
Synopsis - Study Design
Section 9.1
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Added requirement that 80% of 
randomized subject will have 
primary endpoint assessments
Per FDA request
Synopsos – Study Design
Section 9.5.1.3
Revised to specify that study 
sites will be selected to ensure 
adequsate representation of 
adolescents of ethnic and racial 
minorities
Per FDA request
Synopsis - Efficacy Assessments
Section 9.7.1.8.6
Added requirement for Data 
Monitoring Committee
Per FDA request
Synopsis - Study Design
Section 9.1
Added assessment of 
anthropometric measure (waist 
circumfereance)
Per FDA request
Synopsis – Efficacy Assessments
Section 9.5.1.3
Section 9.5.1.5.7
Revised inclusion criteria (#1) 
to define population at baseline 
with regard to Type 2 diabetes
diagnosis
To ensure PPSR requirements are met
Synopsis - Inclusion Criteria
Synopsis – Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.3.1
Added exclusion criteria (#3) 
for subjects with Type 2 
diabetes who are hypoglycemia 
unaware
To ensure PPSR requirements are met
Synopsis - Exclusion Criteria
Section 9.3.2
Revised concomitant 
medication guidelines
To provide futher clarity
Synopsis – Concomitant 
Drug/Therapy
Section 9.4.6
Revised instructions on height 
and body weight measurements
Per FDA request
Synopsis – Study Design
Section 9.1
Section 9.5.1.3
Section 9.5.1.5.5
Added instructions for 
investigator to monitor specific 
list of AEs that have occurred 
since the last visit
Per FDA request
Section 9.5.1.5.1
Added requiirement for report 
hypoglycemic events for the 
subjects with type 2 diabetes
Per PPSR requirements
Section 9.5.1.5.1
Revised requirements for AE 
monitoring
Per PPSR requirements
Section 9.5.1.5.1
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Revised list of events that 
should be considered SAEs and 
reported as important medical 
events
Per PPSR requirements
Section 9.5.1.5.2
Section 9.5.4.3.2
Added requirement for querying 
sites for all relevant information 
for subjects lost to follow-up 
Per FDA request
Section 9.5.5
Added requirement to provide 
proper training to all study 
participants and their 
parent/guardian, in order to 
achieve optimal subject 
retention and prevent missing 
data
Per FDA request
Section 9.5.5
Revised assessment timepoints 
for Tanner Staging, 
Testosterone/Estradiol, TSH, 
fasting prolactic, 
echocardiogram, 
OC/PICP/Hydroxy-proline,
ECG, and Hand X-rays
Per FDA requeset
Table 2
Revised Other Secondary 
Efficacy Analyses text MMRM
Section 9.7.1.6
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Revision History
Previous Version (Revision): v6.0
Current Version (Revision):  v7.0
Date of Revisions: 11 Jul 2017 (per Amendment 02)
Change
Rationale
Affected Protocol Section(s)
Revised statistical power from 
90% to 80%
80% statistical power would provide 
sufficent sample size to detect weight 
loss effects and evaluate lorcaserin 
safety in the population selected.
Synopsis – Study Design
Synopsis – Number of Subjects
Synopsis – Sample Size Rationale
Section 7.1.2
Section 9.1
Section 9.2
Section 9.3
Section 9.7.2
Revised Other Secondary 
Endpoints
To align with recently submitted 
PPSR
Synopsis – Other Secondary 
Efficacy Endpoints
Section 9.7.1.1.2
Added clarification on timing of 
PK samples taken during an 
early discontinuation visit
Clarification
Table 2
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Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Revised scale for measuring of 
cognition from Wide Range 
Assessment of Memory and 
Learning-2 (WRAML-2) to 
Leiter-3
Leiter-3 is selected to replace 
WRAML-2 for the evaluation of the 
change in cognition for the following 
reasons:Lack of availability of 
WRAML-2 in Spanish, Leiter-3’s 
high scientific validity, non-verbal 
format to offer less biased assessment 
for subjects whose second language is 
English, easier and shorter 
administration and short test time 
reducing investigator burden, as well 
as increase probability of the 
subjects’ retention in the study.
Synopsis – Objectives
Synopsis – Other Safety 
Assessments
Synopsis – Other Safety Analyses
List of Abbreviations
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Added requirement that 
qualified personnel must 
evaluate positive responses on 
the C-SSRS and take 
appropriate action as detailed in 
the training and certification 
process for administering the 
C-SSRS
To provide guidance that qualified 
personnel must evaluate positive 
responses on the C-SSRS and take 
appropriate action as detailed in the 
training and certification process for 
administering the C-SSRS.
Synopsis – Other Safety 
Assessments
Section 9.5.1.5.10
Revised timing of initial C-
SSRS from Baseline to 
Screening
Operational efficiencies
Table 2
Section 9.3.2
Section 9.5.1.5.10
Correct formatting of Synopsis, 
Other Secondary Objectives
Consistency
Synopsis – Objectives
Section 8.2
Revised exclusion criteria for 
viral hepatitis (B or C) (#17) 
whereby active testing will not 
be performed 
To clarify that the subjects will be 
excluded if they are known to have
active hepatitis (B or C). Hepatitis (B 
or C) tests will not be conducted for 
the screening purpose.
Synopsis – Exclusion Criteria
Section 9.3.2
Added footnotes regarding 
collection of PK samples at 
EOT and Early Discontinuation 
visits
To ensure appropriate timing of
sampling relative to administration of 
last dose of study drug
Table 2
Added clarification for
Unscheduled visits, such that 
they may be conducted at any 
time that additional assessments 
are clinically indicated in the 
judgment of the investigator.
Provide additional guidance to 
investigators
Table 2
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Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Added clarification that 
prolactin testing should be 
fasting
Clarification
Table 2
Added requirement for 
pregnancy test and AM serum 
cortisol to Early 
Discontinuation Visit
Correction
Table 2
Table 3
Added requirement for lifestyle 
modification counseling Visit at 
Week 16
To ensure all visits are 4 weeks apart
Table 2
General alignment of text 
throughout
Clarity
Throughout
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Revision History
Previous Version (Revision): v4.0
Current Version (Revision):  v5.0
Date of Revisions: 22 Feb 2017
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
A full physical examination will 
be performed at Week 1
Correction
Synopsis - Safety Assessment
Section 9.5.1.5
PHQ-9 questionnaire has been 
added to every scheduled visit.
Per FDA recommendation
Synopsis - Safety Assessment 
Section 9.5.1.5
Section 9.5.2.1
The mixed model repeated 
measures (MMRM) model was 
replaced with the analysis of 
covariance (ANCOVA) model
analyzing Week 52 only.
Per FDA recommendation
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
All postdiscontinuation data 
will be used in the primary 
analysis
Clarification per FDA feedback
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Labeling information for study 
drug was updated
Correction as the study will only be 
conducted in the US
Section 9.4.2.3
The order of assessments was 
reorganized in the Schedule of 
Assessments 
To better align the assessments by 
grouping them
Section 9.5.2.1
Urinalysis will be performed at 
Visit 2 instead of Visit 9
Correction
Section 9.5.2.1
Assessment for testosterone, 
estradiol will be performed at 
Week 28, not Week 20
Correction
Section 9.5.2.1
Section 9.5.2.3
Prior/concomitant medication 
assessment will be performed at 
Week 56
Correction
Section 9.5.2.1
Assessments performed at early 
discontinuation from the study
Correction
Section 9.5.2.1
Summary of blood volumes 
table was updated
Correction
Section 9.5.2.3
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Subject population to include 
children ages 12 to 17 years
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Title Page
Synopsis - Study Protocol Title
Synopsis - Design
Synopsis - Inclusion Criteria
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.7.1.6
Section 9.7.1.8
Protocol Signature Page
Investigator Signature Page
All subjects will be evaluated 
for cardiac valvular disease or 
pulmonary hypertension via 
echocardiographic assessment.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Other Secondary 
Objectives
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.3.2
Section 9.5.1.5.10
Section 9.5.2
Section 9.7.1.8
Section 9.7.1.8.6
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Study drug administration will 
be taken at approximately the 
same time each day.  On the 
days of PK sampling and the 
day before the subjects come to 
the clinic for PK sampling, 
study drug will be taken in the 
morning and doses recorded 2 
days prior to the clinic visit.
This will ensure lower variability 
with regard to PK/PD measurements.
Synopsis - Pharmacokinetic 
Assessments
Section 9.4.1
Section 9.4.4
Section 9.5.1.4.1
Section 9.5.2.1
Screening, diagnosing, 
monitoring, and measuring the 
severity of depression will be 
assessed using the Patient 
Health Questionnaire (PHQ-9), 
and not the Children’s 
Depression Inventory 2 (CDI-
2).
The PHQ-9 was originally proposed 
by the FDA for the population in the 
current study.
Synopsis - Other Secondary 
Objectives
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Primary analysis changed from 
MMRM to using a pattern 
mixture model utilizing 
multiple imputations (MI) to 
impute missing values.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Clarified fasting lipids
Fasting lipid levels provide 
uniformity in lipid measurements for 
definition of dyslipidemia
Synopsis - Other Secondary 
Objectives
Synopsis - Efficacy Assessments
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Removed Appendix 3
The current study will not conduct 
any biomarker or pharmacogenomic
evaluation. PK/PD measurements 
will be done during study.
Appendix 3
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Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Prehypertension was deleted 
from the inclusion criterion.  
Subjects with Stage 1 primary 
hypertension, with an upper 
limit defined as 99% plus 5 
mmHg for age, sex, and height 
are included in the study. 
Prehypertension does not qualify as a 
comorbid condition.  The limitation 
on BP is to further define the proper 
study population.
Synopsis - Inclusion Criteria
Section 9.3.1
Removed the restriction that 
subjects need to have less than 
44 kg/m2 BMI for study entry
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Synopsis - Analysis Sets
Synopsis - Pharmacodynamic 
Analyses
Synopsis -
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study entry 
requirement that the caregiver 
cannot have a history of ADD, 
substance abuse, depression, 
suicidal ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Section 9.3.1
The secondary efficacy 
objective and endpoint were 
revised
To explore the predictability of 12-
week responders for long-term 
sustainable weight loss effect
Synopsis - Secondary Efficacy 
Objectives
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with symptoms or 
signs of cardiac valvular disease 
or pulmonary hypertension are 
not required to have further 
evaluation by centralized 
echocardiogram assessment.  In 
addition, no adjudication will be 
performed.  Local 
echocardiograms can be 
performed if deemed medically 
necessary by the investigator.
This 
change 
allows 
for 
the 
investigator to make the decision to 
perform local echocardiograms on a 
pediatric subject if deemed medically 
indicated rather than burden the 
subject to undergo a mandated, 
unnecessary procedure. 
Synopsis - Safety Assessments
Section 9.5.1.5
Updated study rationale
Clarification 
Section 7.1.1.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will replace the
IR formulation in the United States
market to support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to include 
children ages 9 to 17 years
Expand the age of the population due 
to the change of pediatric development 
strategy
A single dose pharmacokinetic study 
in pediatric obese subjects (APD356-
A001-026) indicated that patients with 
body weight greater than or equal to 
60 kg can be administered a dose 
similar to that given to adults and 
adolescents.  Based on Centers for 
Disease Control and Prevention 
(CDC) growth chart data, almost all 
subjects over 9 years of age are likely 
to be at or over 60 kg body weight.  
Therefore, children age 9 to 11 years 
have been included in the current 
study.
Title Page
Synopsis - Study Protocol Title
Synopsis - Objectives
Synopsis - Study Design
Synopsis - Inclusion Criteria
Synopsis - Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.10
Section 9.7.1.6
Section 9.7.1.8
Additional safety assessments 
including cognitive function, 
serotonin syndrome 
components, bone health and 
endocrine function, priapism, 
and symptoms associated with 
hyperprolactinemia were added.
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Efficacy Assessments
Synopsis - Pharmacokinetic 
Assessments
Synopsis - Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.1
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Change to primary and key 
secondary endpoints
Per FDA request
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary endpoint 
changed
Per FDA request
Synopsis - Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of study-
specific adverse events
To provide clearer guidance for the 
correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and prohibited 
prior and concomitant therapies
For clarification
Synopsis - Exclusion Criteria
Synopsis - Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of adverse 
events
To provide clearer guidance for the 
correct reporting of adverse events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
Update to Introduction and to 
Completion/ Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Belviq XR®
in Conjunction With Lifestyle Modification for Weight Loss in Obese 
Adolescents, Age 12 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
v4.0
03 Nov 2016 (Revision)
v5.0
22 Feb 2017 (Revision)
v6.0
17 May 2017 (per Amendment 01)
v7.0
11 Jul 2017 (per Amendment 02)
V8.0
12 Dec 2017 (per Amendment 03)
V9.0
12 Dec 2017 (per administrative corrections)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference 
on 
Harmonisation 
of 
Technical 
Requirements 
for 
Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information that 
is not authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and 
Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in Obese Adolescents, Age 
12 to 17 Years
Investigators
TBD
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
Approximately 24 months from the 1st subject enrolled to last subject’s last visit or last assessment 
Phase 4
Objectives
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks of treatment 
with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD as compared to 
placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg administered QD compared 
to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of treatment with 
Belviq XR 20 mg administered QD is predictive of sustained change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 52 weeks of 
treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% BMI reduction, 
change in waist circumference) at the end of 52 weeks of treatment
-
Effects on fasting glucose, hemoglobin A1c (HbA1C), insulin levels, and Homeostatic Model 
Assessment of Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) in subjects with 
Type 2 Diabetes at Baseline during 52 weeks of treatment (revised per Amendment 03)
-
Effects on fasting glucose, HbA1c, insulin levels, and HOMA-IR; glucose [mg/dL] × insulin 
[mU/L]/405 in subjects without Type 2 Diabetes at Baseline during 52 weeks of treatment (revised per 
Amendment 03)
-
Effects on body fat and lean mass composition by Dual-enerygy X-ray Absorptiometry (DEXA) in a 
subset of randomized subjects (selected prio to randomization) at selected sites during 52 weeks of 
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treatment (revised per Amendment 03)
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, dyslipidemia)
including fasting lipid changes (total cholesterol, triglycerides, high density lipoprotein [HDL], low 
density lipoprotein [LDL]), systolic and diastolic blood pressure, and heart rate during 52 weeks of 
treatment (revised per Amendment 03)

To assess the safety of Belviq XR, including the effects on cognition with the Leiter-3 International 
Performance Scale (Leiter-3), depression with the Patient Health Questionnaire (PHQ-9), signal of suicidal 
ideation or behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by
Centers for Disease Control and Prevention (CDC) growth chart, sexual maturation (pubescence) measured 
by Tanner Staging scores, and other growth and development parameters by measuring sex hormones, 
thyroid function, adrenal function, bone age, and biochemical markers of bone health, bone mineral density 
and content, total body fat mass, and total body lean mass using DEXA in a subset of randomized subjects 
(selected prior to randomization) at selected sites, valvular function, and pulmonary arterial pressure.  
(revised per Amendments 01 and 03)

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) parameters 
including but not limited to reduction from baseline in BMI and probability of achieving at least a 5% and 
at least a 10% reduction in BMI from baseline at Week 52 using population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese adolescents, 
ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 1:1 ratio to Belviq XR 20 mg QD
(130 subjects) and placebo (130 subjects).  Subjects will be stratified by sex.  Subjects will receive Belviq XR
20 mg or matched placebo QD in a 1:1 ratio for up to 52 weeks. A recruitment plan will be developed to ensure 
at least 20% of younger subjects (12 to 13 years of age) are enrolled in the study.  Throughout the duration of 
the study, subjects will be encouraged to adhere to a lifestyle modification program that includes a 
standardized, age-appropriate diet and exercise counseling. (revised per Amendments 02 and 03)
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization Phase will 
last up to 30 days and consist of 1 visit during which subjects will be screened for eligibility.  The 
Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The Treatment Period will last 
for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52.  The Follow-Up Period will 
extend from the End of Treatment (EOT) visit to the End of Study visit.
Subjects who screen fail can be re-screened only once after 30 days.  All subjects will continue in the study 
until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely will be followed up 
until study completion.  All attempts will be made to capture height and weight in all subjects whether or not 
they are still on study drug at the end of the study.  (revised per Amendment 03)
Study sites will be selected to ensure adequate representation of adolescents of ethnic and racial minorities.  
(revised per Amendment 03)
Data Monitoring Committee (revised per Amendment 03)
A Data Monitoring Committee (DMC) will be established to monitor and conduct periodic safety review of 
unblinded data. DMC members will be chosen based on their expertise in evaluating these clinical events. A 
separate DMC charter will be established.
Number of Subjects
Approximately 500 subjects will be screened to provide 260 randomized subjects.  (revised per Amendment 02)
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years (inclusive) at Screening, with an initial BMI that is 
greater than or equal to the United States (US)-weighted mean of the 95th percentile based on age and sex
with a body weight greater than 60 kg.  Subjects with T2DM may have a pre-existing or new diagnosis of 
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T2DM.
Subjects with pre-existing T2DM should have prior documentation consistent with the diagnosis and/or be 
on active pharmacotherapy for T2DM.  
Subjects with a new diagnosis of T2DM (ie, diagnosed at Screening) should be based on the 2016 
American Diabetes Association (ADA) guidelines.  The diagnostic criteria are met if a subject has 
unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of 
hyperglycemia or hyperglycemic crisis) OR any of the following criteria are observed and confirmed:
◦
HbA1c ≥6.5% 
◦
fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 
◦
2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) by an oral glucose tolerance test (OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being or need to be treated 
with antidiabetic agents, the T2DM treatment regimen must be stable for at least 3 months before 
randomization.  A single rescreen is allowed following stabilization.  Stable control refers to minimal dose 
changes to existing medications for glycemic control and no medications being initiated for glycemic 
control in the 3 months before Randomization.  Minimal changes are defined as a change without any 
change in dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject has not 
been hospitalized due to hypo- or hyperglycemic events. (revised per Amendment 03)
2.
Subjects and their families not planning to move away from the area for the duration of the study
3.
Able and willing to comply with all aspects of the study, including a standardized, reduced-calorie diet and 
an age-appropriate, increased physical activity program
4.
Considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the investigator,
including consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study requirements for the 
caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the subject’s ability 
to fulfill the study requirements or significantly confound the assessments
2.
Who cannot swallow investigational products
3.
With Type 2 diabetes who have hypoglycemia unawareness (revised per Amendment 03)
4.
Any of the following findings on Screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, mean gradient 
>25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean gradient >5 mm Hg and mitral valve 
area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure (SPAP) >40 mmHg (and/or tricuspid regurgitation (TR) jet 
velocity >2.9 m/s)
In cases where an actual SPAP value is not measurable due to lack of adequate TR jet, the pulmonary flow 
acceleration time measured at the right ventricular outflow tract (RVOTAT), will be used to assess 
eligibility. Patients with a RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be determined based on 
combined assessment of the TR jet, septal motion and right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease
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
Clinically significant pericardial effusion (eg, moderate or larger or with hemodynamic compromise)
5.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper limit of 
normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater than 1.5×ULN in 
absence of Gilbert’s syndrome
6.
Any suicidal ideation with intent with or without a plan, at the time of or within 6 months of Screening, as 
indicated by answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS.
7.
Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
8.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit Hyperactivity 
Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th Edition depressive disorder,
suicidal ideation or behavior, bipolar disorder, or schizophrenia
9.
Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi syndrome, Bardet 
Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, Cushing’s syndrome, daily systemic 
corticosteroid exposure for longer than 30 days, history of significant exposure to corticosteroids for 
chronic illness during the past year; inhaled steroids will be allowed) (revised per Amendment 03)
10. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, 
and herbal preparations within 1 month before Screening 
11. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine oxidase inhibitors 
(MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
12. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before Screening, 
including but not limited to pergolide, ergotamine, methysergide, and cabergoline
13. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, gastrointestinal, 
renal, or psychiatric disease) other than prediabetes (impaired fasting glucose or impaired glucose 
tolerance), type 2 diabetes treated with oral anti-diabetic agents (excluding sulfonylurea) or non-insulin 
injectable antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
14. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any of the 
excipients
15. Significant change in diet or level of physical activity within 1 month before dosing or change in weight of 
more than 5 kg within 3 months before Screening
16. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before Screening
17. History of alcohol or drug dependence or abuse
18. Recreational drug use within 2 years before Screening
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19. Known to be human immunodeficiency virus (HIV) positive
20. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
21. Malignancy within 5 years before Screening
22. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or guardian to supervise 
study participation
23. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to profound 
mental retardation [IQ <70], moderate to severe cognitive developmental delay, pervasive development 
disorders, autism)
24. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder within 6 months of 
screening or any time between screening and randomization
25. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate readings recorded 
on 2 separate days.  Those subjects who had hypertension at Screening can be rescreened more than
1 month after initiation or adjustment of antihypertensive therapy 1 time.
26. Currently enrolled in another clinical study or has used any investigational drug or device within 30 days 
before providing informed consent
27. Planned bariatric surgery during the study or prior bariatric surgical procedures (revised per 
Amendment 03)
28. Not suitable to participate in the study in the opinion of the investigator, including consideration of any 
existing physical, medical, or mental condition that prevents compliance with the protocol
29. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
β-human chorionic gonadotropin test).  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.
30. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a 
highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier 
method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire 
study period and for 28 days after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described above) or refrain 
from sexual activity during the study period and for 28 days after study drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during 
the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]).
Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated, biconvex tablets
with one 20-mg tablet administered orally QD.
Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  up to 30 days
Randomization Phase: approximately 56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal preparations, are 
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prohibited as concomitant medications.  OTC cold medicines containing dextromethorphan can be used for up 
to 7 days with study medication temporarily stopped for that time period and resumed the next day after the 
OTC cold medicine is stopped.  Any of the following serotonergic agents or other agents in combination with 
Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
The following concomitant medication guidelines/restrictions will apply:

Medications for the treatment of hypertension, dyslipidemia, or diabetes may be started, discontinued, or 
adjusted during the study according to local standards of care if, in the judgment of the investigator or the 
subject’s physician, such a change is medically indicated.

For diabetic subjects treated with sulfonylureas, insulin (note that subjects should not be enrolled as 
indicated in exclusion criteria), or other antidiabetic agents with hypoglycemic risk, the risk of 
hypoglycemic events may be higher if the subjects experience rapid and significant weight loss (more than 
10% weight reduction than at the previous visit).  It is recommended that the physician advise the subject 
to monitor their blood glucose more frequently and adjust their antidiabetic medications and diet 
accordingly. 

The antihyperglycemic medication dose would be considered for reduction in the event of 1 documented 
and otherwise unexplained hypoglycemic event (blood glucose concentration <65 mg/dL) or 2 
undocumented and otherwise unexplained suspected hypoglycemic events between any 2 scheduled visits. 
For subjects on more than 1 antihyperglycemic medication, it is recommended to reduce insulin first (if 
applicable), then the oral and/or other injectable antidiabetic agents.  If the previous criteria are met again 
following dose reduction, further dose reductions or cessation of 1 or more anti-hyperglycemic agents, are 
suggested.  See Section 9.5.4.2 for the definition and reporting of hypoglycemic events. 
To minimize the risk of cardiac valve toxicity, subjects must not initiate use of agents that have documented 
correlation with increased incidence of valvulopathy and/or pulumonary hypertension (eg, pergolide, 
ergotamine, methysergide, or cabergoline) during the study.  If any of the above agents are clinically warranted, 
and subjects initiate any of these agents, lorcaserin HCl should be discontinued but can be restarted on 
lorcaserin HCl after being off the medications above for 1 month.  Otherwise, the study medication should not 
be restarted, but the subject should continue all study visits.  (revised per Amendment 03)
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Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to calculate the 
proportion (%) of subjects achieving at least a 5% and at least a 10% BMI reduction.

Waist circumference (revised per Amendment 03)

Total body fat mass and total body lean mass will be determined centrally using DEXA in a subset of 
randomized subjects (selected prior to randomization) at selected sites at Baseline and Week 52/EOT
(revised per Amendment 03)

Measurement of systolic and diastolic BP, heart rate (taken after resting for 5 minutes), fasting lipids (total 
cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), fasting plasma glucose, fasting insulin,
HbA1c, and Homeostasis Model Assessment (HOMA) IR to assess cardiovascular and metabolic risk 
profiles from Baseline to Week 52 (revised per Amendment 03)

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents
Every effort will be made to ensure that at least 80% of randomized subjects will have an assessment of the 
primary efficacy endpoint regardless of whether or not the subject remained on study drug or completed other 
study assessments.  (revised per Amendment 03)
Pharmacokinetic Assessments
Blood samples (approximately 4 mL each) for PK assessment will be collected at Weeks 12, 28, 36, and 52 for 
analysis of Population PK. (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at 
home before the visit,but to bring their study drug to the clinic visit, and take their daily dose at the clinic.  
Two blood samples for determination of plasma concentrations of lorcaserin will be taken: 1 predose (within 
30 minutes before dosing), and 1 within 1 to 3 hours after dosing.  Dose times must be recorded for the last 
2 dosing times before the day of clinic visit. Week 52 PK samples should only be collected if the sample can be 
drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at home, and will be 
asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for for PK
assessments will be collected. Dose times must be recorded for the last 2 dosing times prior to the clinic visit.
(revised per Amendment 01)
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their relationships 
with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious adverse events 
(SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, metabolic function (fasting glucose, 
fasting lipids, and thyroid), adrenal function and biochemical blood and urine bone health assessments; blood 
chemistry and urine values; neuropsychiatric events; periodic measurement of vital signs, neuromuscular signs
for screening potential serotonin syndrome, and signs or symptoms of priapism and hyperprolactinemia; and 
performance of physical examinations. In patients with potential prolactin-related AEs, such as galactorrhea, 
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changes in libido, or changes to menstrual cycle, fasting prolactin level will be measured and assessed.
Other Safety Assessments
Effect on growth will be evaluated using the CDC growth chart and bone age determination by x-ray of the 
hand. Sexual maturation will be evaluated by assessing sex hormones and Tanner Staging.   
The C-SSRS will be used to assess all subjects in the study for any signal of depression or suicidal ideation or 
behavior at every visit.  Additionally, screening, diagnosing, monitoring, and measuring the severity of 
depression will be assessed using the PHQ-9 and effects on cognition will be assessed using the Leiter-3.  
(revised per Amendment 01)
Bone mineral density and content, total body fat mass and total body lean mass will be determined using DEXA 
in a subset of randomized subjects (selected prior to randomization) at selected sites.  (revised per Amendment 
03)
Echocardiographic assessments will be used to exclude subjects with FDA-defined valvulopathy, pulmonary 
hypertension, and other major cardiovascular disease (as outlined in Exclusion Criterion No. 3) during the 
Screening Period.  Additionally, cardiac valvular function and pulmonary systolic pressure changes at Weeks
28 and 52 will be assessed only for subjects at selected sites.
Valvular regurgitation as assessed in the 
echocardiogram will be rated absent, trace, mild, moderate, or severe for the aortic, mitral, and tricuspid valves; 
the rating will be absent or present for the pulmonic valve. The evaluations will be based on guidelines from the 
American Society of Echocardiography. Pulmonary artery pressure will be estimated from the TR jet velocity.  
(revised per Amendment 03)
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography coupled with tandem mass 
spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Association between change and percentage change in BMI from Baseline to Week 52 with the outcome of 
achieving at least a 5% BMI reduction at Week 12 (revised per Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI reduction at 
Week 52 with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Change in waist circumference from Baseline to Week 52

Change in total body composition (total fat and lean mass) in a subset of randomized subjects at end of 52 
weeks of treatment (revised per Amendment 03)

Change in HbA1c from Baseline to Week 52 for subjects with Type 2 diabetes as baseline (revised per 
Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for subjects with 
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Type 2 diabetes as baseline (revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for the subjects 
without Type 2 diabetes at baseline (revised per Amendment 03)

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) from 
Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52

Subjects compliance rate at each visit by pill count during 52 week treatment (revised per Amendment 03)
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and had at least 
1 post dose safety assessment.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater compliant 
with study medication, completed the study, have no major protocol deviations, have no violations of 
inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  The determination of subjects 
to be excluded from this population based on the above criteria and a list of major protocol violations will 
be included in the statistical analysis plan (SAP) and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid lorcaserin plasma 
concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who have at least 
1 adequately documented measurement of BMI.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as a 
supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in all efficacy 
analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from baseline in 
BMI will be analyzed using analysis of covariance model (ANCOVA) with factors of treatment,  sex (male and 
female) as fixed effect, and the baseline age and BMI as covariates.  The missing values will be imputed using a 
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are missing not at 
random (MNAR).  The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model and missing value 
imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on the PP.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy analyses described 
above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed and will be
described in the SAP.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI reduction at 
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Week 52. The secondary efficacy endpoint will be analyzed only if the test for the primary efficacy endpoint is 
statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using a logistic 
regression model with factors of treatment, sex (male and female), and baseline BMI as a covariate using FAS.  
Subjects with any missing assessment at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed using 
mixed effect model repeated measurement analysis (MMRM) and categorical variables will be analyzed using
the Cochran Mantel Haenszel test, Chi-square test, or logistic regression as appropriate.  Additional analysis 
may be performed as needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male and female), and 
race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific 
Islander, or White) and age.  Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using nonlinear mixed 
effects modeling. The effect of covariates such as baseline characteristics or demographics on PK will be 
explored. Derived exposure parameters such as the maximum observed concentration and the area under the 
concentration-time curve from time 0 to 24 hours at steady-state will be calculated from the final PK model 
using individual posterior estimates of the PK parameters and from dosing history. The PK analysis set will be 
used for this analysis.
Pharmacodynamic Analyses
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will be used for this 
analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% and ≥10% BMI 
reduction, and change in waist circumference from baseline) will also be assessed as part of the PD analysis.  
The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure and 
response, including but not limited to change in BMI from baseline and the probability of achieving at least a 
5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, exposure-safety relationships 
for select safety parameters may be explored graphically depending on the data at the end of study.  Any 
emergent relationship may be modeled as appropriate.  Any parameters based on the study data may be 
considered for exploratory assessment for its relationship to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the incidence 
of AEs (including changes from baseline in physical examination), growth (CDC growth chart and bone age 
determined by x-ray of the hand), sexual maturation (Tanner Staging), out-of-normal-range laboratory safety 
test values, change from baseline in laboratory safety test values, ECGs, and vital sign measurements will be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
Other Safety Analyses
In addition, cognition will be evaluated by the Leiter-3, depression will be evaluated by the PHQ-9, and suicidal 
ideation and behavior will be evaluated by the C-SSRS, and will also be summarized by treatment group using 
descriptive statistics or frequency count as appropriate. For echocardiographic assessments, the proportion of 
subjects who develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
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hypertension [pulmonary hypertension is defined when the subject’s systolic pulmonary artery pressure 
(SPAP) ≥40 mmHg evaluated by echocardiograph], and change from baseline in SPAP will be summarized by 
treatment group at Week 28 and Week 52 using descriptive statistics or frequency count as appropriate. (revised 
per Amendment 01)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in BMI from 
Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  Assuming a SD of 
2.2 kg/m2 and a 40% dropout rate, a sample size of 260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg 
treatment group; n=130 in the placebo group) will have at least 80% power to detect a treatment difference of 
1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at least a 5% 
BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, this sample of 260 subjects 
(130 subjects for Belviq XR 20 mg and 130 subjects for placebo) will also have greater than 78% power to 
detect an absolute difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 
2-sided Chi-Square test with α=0.05.
The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................20
5.1
Institutional Review Boards/Independent Ethics Committees ..............................20
5.2
Ethical Conduct of the Study.................................................................................21
5.3
Subject Information and Informed Consent...........................................................21
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................23
7
INTRODUCTION ...........................................................................................................24
7.1
Indication ...............................................................................................................24
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................25
7.1.1.1
Mechanism of Action...........................................................................25
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................25
7.1.2
Study Rationale............................................................................................26
8
STUDY OBJECTIVES....................................................................................................28
8.1
Primary Objective..................................................................................................28
8.2
Secondary Objectives.............................................................................................28
9
INVESTIGATIONAL PLAN..........................................................................................30
9.1
Overall Study Design and Plan..............................................................................30
9.1.1
Prerandomization Phase...............................................................................30
9.1.1.1
Screening Period..................................................................................30
9.1.2
Randomization Phase...................................................................................31
9.1.3
Extension Phase ...........................................................................................31
9.2
Discussion of Study Design, Including Choice of Control Groups.......................31
9.3
Selection of Study Population................................................................................32
9.3.1
Inclusion Criteria .........................................................................................32
9.3.2
Exclusion Criteria ........................................................................................33
9.3.3
Removal of Subjects From Therapy or Assessment....................................36
9.4
Treatments..............................................................................................................36
9.4.1
Treatments Administered.............................................................................36
9.4.2
Identity of Investigational Product...............................................................37
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................37
9.4.2.2
Comparator Drug .................................................................................37
9.4.2.3
Labeling for Study Drug......................................................................37
9.4.2.4
Storage Conditions...............................................................................38
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9.4.3
Method of Assigning Subjects to Treatment Groups...................................38
9.4.4
Selection and Timing of Dose for Each Subject..........................................39
9.4.5
Blinding........................................................................................................39
9.4.6
Prior and Concomitant Therapy...................................................................39
9.4.7
Treatment Compliance.................................................................................41
9.4.8
Drug Supplies and Accountability...............................................................41
9.5
Study Assessments.................................................................................................43
9.5.1
Assessments.................................................................................................43
9.5.1.1
Demography.........................................................................................43
9.5.1.2
Baseline Assessments ..........................................................................43
9.5.1.2.1
Medical History .............................................................................43
9.5.1.2.2
Urine Drug Screen .........................................................................43
9.5.1.3
Efficacy Assessments...........................................................................43
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................44
9.5.1.4.1
Pharmacokinetic Assessments .......................................................44
9.5.1.4.2
Pharmacodynamic Assessments ....................................................45
9.5.1.4.3
Pharmacogenomic and Other Biomarker Assessments .................45
9.5.1.5
Safety Assessments..............................................................................45
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...45
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................48
9.5.1.5.3
Laboratory Measurements .............................................................49
9.5.1.5.4
Vital Signs and Weight Measurements..........................................51
9.5.1.5.5
Height Measurements ....................................................................51
9.5.1.5.6
CDC Growth Measurements..........................................................51
9.5.1.5.7
Waist Circumference .....................................................................51
9.5.1.5.8
Physical Examinations...................................................................51
9.5.1.5.9
Electrocardiograms ........................................................................52
9.5.1.5.10
Other Safety Assessments..............................................................52
9.5.1.6
Other Assessments...............................................................................53
9.5.1.6.1
Pregnancy Test...............................................................................53
9.5.2
Schedule of Procedures/Assessments ..........................................................53
9.5.2.1
Schedule of Procedures/Assessments ..................................................53
9.5.2.2
Description of Procedures/Assessments Schedule...............................57
9.5.2.3
Total Volume of Blood Sampling........................................................57
9.5.3
Appropriateness of Measurements...............................................................57
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................58
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9.5.4.1
Reporting of Serious Adverse Events..................................................58
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................58
9.5.4.3
Reporting of Events Association with Special Situations....................59
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................59
9.5.4.3.2
Reporting of Study-Specific Events...............................................60
9.5.4.4
Expedited Reporting ............................................................................61
9.5.4.5
Breaking the Blind...............................................................................61
9.5.4.6
Regulatory Reporting of Adverse Events ............................................61
9.5.5
Completion/Discontinuation of Subjects.....................................................61
9.5.6
Abuse or Diversion of Study Drug ..............................................................62
9.5.7
Confirmation of Medical Care by Another Physician .................................62
9.6
Data Quality Assurance .........................................................................................62
9.6.1
Data Collection ............................................................................................62
9.6.2
Clinical Data Management ..........................................................................63
9.7
Statistical Methods.................................................................................................63
9.7.1
Statistical and Analytical Plans....................................................................63
9.7.1.1
Study Endpoints...................................................................................63
9.7.1.1.1
Primary Efficacy Endpoint ............................................................63
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................63
9.7.1.2
Definitions of Analysis Sets.................................................................64
9.7.1.3
Subject Disposition..............................................................................65
9.7.1.4
Demographic and Other Baseline Characteristics ...............................65
9.7.1.5
Prior and Concomitant Therapy...........................................................65
9.7.1.6
Efficacy Analyses ................................................................................66
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................67
9.7.1.7.1
Pharmacokinetic Analyses.............................................................67
9.7.1.7.2
Pharmacodynamic Analyses..........................................................67
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................67
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................68
9.7.1.8
Safety Analyses....................................................................................68
9.7.1.8.1
Extent of Exposure.........................................................................68
9.7.1.8.2
Adverse Events ..............................................................................68
9.7.1.8.3
Laboratory Values..........................................................................69
9.7.1.8.4
Vital Signs......................................................................................70
9.7.1.8.5
Electrocardiograms ........................................................................70
9.7.1.8.6
Other Safety Analyses....................................................................70
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9.7.2
Determination of Sample Size .....................................................................71
9.7.3
Interim Analysis...........................................................................................71
9.7.4
Other Statistical/Analytical Issues ...............................................................71
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................71
10
REFERENCE LIST .........................................................................................................72
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......74
11.1
Changes to the Protocol .........................................................................................74
11.2
Adherence to the Protocol......................................................................................74
11.3
Monitoring Procedures...........................................................................................74
11.4
Recording of Data..................................................................................................75
11.5
Identification of Source Data.................................................................................75
11.6
Retention of Records..............................................................................................76
11.7
Auditing Procedures and Inspection......................................................................76
11.8
Handling of Study Drug.........................................................................................76
11.9
Publication of Results ............................................................................................77
11.10 Disclosure and Confidentiality ..............................................................................77
11.11 Discontinuation of Study .......................................................................................77
11.12 Subject Insurance and Indemnity...........................................................................78
12
APPENDIX......................................................................................................................79
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests (revised per Amendments 01 and 03) ..............50
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  
(revised per Amendments 01, 02 and 03)..................................................54
Table 3
Summary of Blood Sample Volumes (revised per Amendments 01 
and 03) .......................................................................................................57
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
(revised per Amendments 01 and 03)
Abbreviation
Term
ADA
American Diabetes Association
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
DEXA
Dual-energy X-ray Absorptiometry
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
Leiter-3
Leiter-3 International Performance Scale
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Abbreviation
Term
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
MAR
missing at random
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OGTT
oral glucose tolerance test
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PH
pulmonary hypertension
PHQ-9
Patient Health Questionnaire
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
RVOTAT
right ventricular outflow tract
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SPAP
systolic pulmonary artery pressure  
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TR
tricuspid regurgitation
TSH
thyroid stimulating hormone
ULN
upper limit of normal
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Abbreviation
Term
US
United States
WBC
white blood cell
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity has become a global epidemic, causing a serious public health concern.  In the 
United States, the prevalence of obesity in adolescents ages 12 and 19 years has almost 
doubled over the past 2 decades.  The rate increased from 10.5% between 1988 and 1994 to 
20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, defined in the 
United States as greater than or equal to the 95th percentile in gender- and age-specific body 
mass index (BMI), continues to grow at an alarming rate in the United States and globally.  
Based on data (Wang and Lobstein, 2006) using various criteria for the definition of obesity 
that included more than 30 countries in Europe, North America, Asia, and the West Pacific, 
prevalence of obesity in these countries has also increased significantly, at a rate comparable 
to that in the United States.
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may 
result in a decrease in life expectancy for the 1st time in 200 years (Peeters, et al., 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese adolescents are likely to become 
tomorrow’s obese adults (Whitaker, et al., 1997).
Current approaches to weight management in adults include lifestyle modification, 
pharmacotherapy, and invasive bariatric procedures.  Lifestyle modification involves a 
combination of diet, exercise, and behavioral change, and is the preferred and essential 
strategy for weight management in obese and overweight individuals, including adolescents.  
Although lifestyle modification can be very efficacious in some patients, adherence to the 
prescribed regimens is often poor.  As such, lifestyle modification alone is often not adequate 
and the weight loss is often transient.  On the other hand, bariatric surgery and various other 
invasive procedures are generally reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise, but are rarely used 
for adolescents.
The current standard of care for treatment of obesity in adolescent subjects ranges from
behavioral therapy including lifestyle intervention to the rare use of pharmacotherapy in 
adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
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(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies may be used in 
the present study to help retain participants.  These include a highly trained and competent 
site staff, ample waiting area, readily available parking (at no cost), access to mass transit, 
and reminder and follow-up calls.  In addition, sites may utilize fun and interactive group 
sessions with games and hands-on nutrition and physical activity demonstrations, random 
raffle drawings, social events, birthday and holiday cards, and newsletters to further 
encourage subject retention.  Furthermore, we may make home visits for primary efficacy 
assessments, as needed, to maximize data collection. 
By incorporating some of these 
retention strategies, we hope that we will maximize participant retention, which will help us 
cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:

A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) was 
significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
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studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
used for adolescent subjects with body weight greater than 60 kg.
In adolescent obese populations, it is anticipated that Belviq XR will result in similar effects.
As part of FDA postmarketing requirements, this study is designed to characterize the 
efficacy and safety of Belviq XR in adolescent obese populations in the United States.  It is 
also intended to support an indication for chronic weight management for obese adolescents 
ages 12 to 17 years old. 
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of subjects 
in the placebo-treated group who lose at least 5% of baseline body weight, and the 
difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in obese adolescents, where weight loss will be assessed using BMI
measurements to account for growth. In this study, the objective is to demonstrate that BMI
reduction will be achieved during 52 weeks of treatment with Belviq XR 20 mg administered 
once daily (QD) compared to placebo in obese adolescents.
In the Phase 3 orlistat study in obese adolescents mentioned above, the proportion of subjects 
who lost at least 5% body weight is relatively low. At the end of the study at Week 52, only 
26.5% of the subjects achieved a 5% or greater BMI reduction compared to 15.7% in the 
placebo group. The placebo-corrected BMI reduction was about 0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years
(Peirson, et al, 2015).  Thirty-one studies (29 behavioral, 2 pharmacological and behavioral) 
were included in a meta-analysis of randomized studies conducted in primary care centers in 
overweight and obese children and youth ages 2 to 18 years using behavioral (diet, exercise,
and lifestyle) and pharmacological interventions and providing 6-month postbaseline BMI or 
prevalence of overweight or obesity. Both interventions showed a significant effect on BMI 
in favor of treatment (behavioral: 
standardized mean difference [SMD] -0.54, 
95% confidence interval [CI]
-0.73, -0.36; orlistat plus behavioral: 
SMD -0.43, 
95% CI -0.60, -0.25). The studies reported no significant difference between groups in the 
likelihood of reduced prevalence of overweight or overweight and obese. A great deal of 
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variation was noted across efficacious interventions.
In conclusion, this meta-analysis 
demonstrated low-quality evidence that behavioral treatments alone are associated with a 
smaller effect in terms of reduced BMI compared with the effect shown by combined 
behavioral and pharmacological interventions. This may be because the effect size in the 
randomized, double blind, placebo controlled, phase 3 orlistat study in adolescents was 
relatively low and there was a lack of maintenance effect. These subjects started to regain 
their BMI after 6 months of treatment. At end of the study, only 26.5% of subjects achieved 
a 5% or greater BMI reduction compared to 15.7% in placebo group. In a sibutramine 
Phase 3 study in obese adolescents, a substantially higher proportion of subjects (69%) 
treated with sibutramine achieved at least a 5% BMI reduction compared to 21% of subjects 
in the placebo group. In addition, sibutramine resulted in a substantial reduction in mean 
BMI (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 
8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the weight loss effect of Belviq
in adults and sibutramine in adolescents, subjects in the orlistat study started to increase their 
BMI after 6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of 260 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
sibutramine, and liraglutide 3 mg) (FDA, 2003; Chanoine, et al., 2005; Berkowitz, et al,
2006; CT.gov NCT02918279) and other metabolic or dyslipidemia medication products
(ezetimibe, simvastatin) (FDA, 2007).  (revised per Amendment 02)
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8
STUDY OBJECTIVES
8.1
Primary Objective

To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment with 
Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR
20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of 
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in 
BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo
(revised per Amendment 01)

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% 
BMI reduction, change in waist circumference) at the end of 52 weeks of treatment
-
Effects on fasting glucose, hemoglobin A1c (HbA1c), insulin levels, and Homeostatic 
Model Assessment of Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin 
[mU/L]/405) in subjects with Type 2 diabetes at baseline during 52 weeks of 
treatment (revised per Amendment 03)
-
Effects on fasting glucose, HbA1c, insulin levels, and HOMA-IR; glucose [mg/dL] × 
insulin [mU/L]/405 in subjects without Type 2 Diabetes at Baseline during 52 weeks 
of treatment (revised per Amendment 03)
-
Effects on body fat and lean mass composition by Dual-enerygy X-ray 
Absorptiometry (DEXA) in a subset of randomized subjects (selected prior to 
randomization) at selected sites during 52 weeks of treatment (revised per 
Amendment 03)
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high 
density lipoprotein [HDL], low density lipoprotein [LDL]), systolic and diastolic 
blood pressure, and heart rate) during 52 weeks of treatment (revised per 
Amendment 03)
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•
To assess the safety of Belviq XR, including the effects on cognition by Leiter-3 
International Performance Scale (Leiter-3), depression with the Patient Health 
Questionnaire 
(PHQ-9), 
signal 
of 
suicidal 
ideation 
or 
behavior 
with 
the 
Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by CDC growth 
chart, sexual maturation (pubescence) measured by Tanner Staging scores, and other 
growth and development parameters by measuring sex hormones, thyroid function, 
adrenal function, bone age, and biochemical markers of bone health, bone mineral 
density and content, total body fat mass and total body lean mass by DEXA in a subset of 
randomized subjects (selected prior to randomization) at selected sites, valvular function, 
pulmonary arterial pressure. (revised per Amendments 01 and 03)
•
To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling
•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
probability of achieving at least a 5% and at least a 10% reduction in BMI from baseline 
at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (130 subjects) and placebo (130 subjects).  Subjects will be 
stratified by sex.  Subjects will receive Belviq XR 20 mg or matched placebo QD in a 1:1 
ratio for up to 52 weeks. A recruitment plan will be developled to ensure at least 20% of 
younger subjects (12 to 13 years of age) are enrolled in the study.  Throughout the duration 
of the study, subjects will be encouraged to adhere to a lifestyle modification program that 
includes a standardized, age-appropriate diet and exercise counseling (see Appendix 2).  
(revised per Amendments 02 and 03)
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be rescreened only once after 30 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.  All attempts will be made 
to capture height and weight in all subjects whether or not they are still on study drug at the 
end of the study.  (revised per Amendment 03)
Study sites will be selected to ensure adequate representation of adolescents of ethinic and 
racial minorities.  (revised per Amendment 03)
A Data Monitoring Committee (DMC) will be established to monitor and conduct periodic 
safety review of unblinded data. DMC members will be chosen based on their expertise in 
evaluating these clinical events. A separate DMC charter will be established.  (revised per 
Amendment 03)
9.1.1
Prerandomization Phase
Screening will occur during the Prerandomization Phase at Visit 1.
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
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description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
9.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025.  Overall, the PK parameters of Belviq and its main 
metabolites, M1 and M5, were similar to those in adults.  Following a single, oral 
administration of Belviq 10 mg to a total of 8 healthy adolescent (ages 12 to 17 years old) 
obese subjects, the mean maximum concentration observed and the area under the 
concentration-time curve from time zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 
464 hr×ng/mL, respectively.  The mean Belviq terminal phase half-life was 9.70 hours, 
similar to that observed in adults, thus supporting a similar dosing frequency (QD) in 
adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric or adolescent subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of subjects who are older than 12 years of age 
having a body weight of less than 60 kg is very low; therefore, the current study as designed 
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to enroll subjects between 12 to 17 years of age with body weight at least 60 kg, will cover
majority of the population of interest.  The targeted study population comprises 260 obese 
adolescents 12 to 17 years of age, with a body weight at least 60 kg.  (revised per 
Amendment 02)
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
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, 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 500 subjects will be screened to ensure that 260 subjects will be randomized.  
(revised per Amendment 02)
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug.
Subjects who screen fail can be re-screened immediately 
without repeating the screening echocardiogram for up to 90 days after the previous 
echocardiogram.  All other screening assessments must be repeated when a subject is re-
screened.  Subjects that re-screen more than 90 days after the previous echocardiogram must 
repeat all screening assessments including the screening echocardiogram.  (revised per 
Amendment 03)
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, ages 12 to 17 years old (inclusive) at Screening, with 
an initial BMI that is greater than or equal to the United States (US)-weighted mean of 
the 95th percentile based on age and sex with a body weight greater than 60 kg.  Subjects 
with T2DM may have a pre-existing or new diagnosis of T2DM.  
Subjects with pre-existing T2DM should have prior documentation consistent with the 
diagnosis and/or be on active pharmacotherapy for T2DM.  
Subjects with a new diagnosis of T2DM (ie, diagnosed at Screening) should be based on 
the 2016 American Diabetes Association (ADA) guidelines.  The diagnostic criteria are 
met if a subject has unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL 
(11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis) OR any 
of the following criteria are observed and then confirmed:
o
HbA1c ≥6.5% 
o
fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 
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o
2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) by an oral glucose tolerance 
test (OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being or 
need to be treated with antidiabetic agents, the T2DM treatment regimen must be stable 
for at least 3 months before randomization.  A single rescreen is allowed following 
stabilization.  Stable control refers to minimal dose changes to existing medications for 
glycemic control and no medications being initiated for glycemic control in the 3 months 
before Randomization.  Minimal changes are defined as a change without any change in 
dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject 
has not been hospitalized due to hypo- or hyperglycemic events.  (revised per 
Amendment 03)
2. Subjects and their families are not planning to move away from the area for the duration 
of the study
3. Able and willing to comply with all aspects of the study, including a standardized,
reduced-calorie diet and an age-appropriate, increased physical activity program
4. Considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may affect 
the subject’s ability to fulfill the study requirements or significantly confound the 
assessments
2. Who cannot swallow investigational products
3. With Type 2 diabetes who have hypoglycemia unawareness (revised per Amendment 03)
4. Any of the following findings on screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, 
mean gradient >25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean 
gradient >5 mm Hg and mitral valve area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure
(SPAP) >40 mm Hg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
-
In cases where an actual SPAP value is not measurable due to lack of adequate 
TR jet, the pulmonary flow acceleration time measured at the right ventricular 
outflow tract (RVOTAT), will be used to assess eligibility. Patients with a 
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RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be 
determined based on combined assessment of the TR jet, septal motion and right 
ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with 
hemodynamic compromise)
5. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
6. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, bipolar disorder, or schizophrenia
7. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months 
of Screening, as indicated by answering “Yes” to questions 4 or 5 on the Suicidal 
Ideation section of the C-SSRS.
8. Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
9. Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi 
syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, 
Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 30 days, 
history of significant exposure to corticosteroids for chronic illness during the past year; 
inhaled steroids will be allowed) (revised per Amendment 03)
10. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before Screening
11. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 

bupropion

triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
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b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
12. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and 
cabergoline
13. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), Type 2 diabetes treated with oral anti-diabetic 
agents (excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive 
sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
14. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or 
any of the excipients
15. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
16. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 6 months
before Screening
17. History of alcohol or drug dependence or abuse
18. Recreational drug use within 2 years before Screening
19. Known to be human immunodeficiency virus (HIV) positive
20. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
21. Malignancy within 5 years before Screening
22. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
23. Special needs subjects who are unable to comprehend study-related instructions (eg, mild 
to profound mental retardation [IQ <70], moderate to severe cognitive developmental 
delay, pervasive development disorders, autism)
24. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
25. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate 
readings recorded on 2 separate days.  Those subjects who had uncontrolled hypertension 
at Screening can be rescreened more than 1 month after initiation or adjustment of 
antihypertensive therapy 1 time.
26. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
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27. Planned bariatric surgery during the study or prior bariatic surgical procedures (revised 
per Amendment 03)
28. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
29. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
30. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 
28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after 
study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use 
the same contraceptive during the study and for 28 days after study drug 
discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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.
Investigators should do their best to bring all subject who discontinued early from the study
in for the their primary endpoint collection regardless of the reason for ED. (revised per 
Amendment 01)
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD at 
approximately the same time each day.
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Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled with text that is in full regulatory compliance with each 
participating country. As the study is being conducted in US only, the study drug label will 
be printed in English. 
The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal (US) law to 
investigational use.”
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All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug was 
dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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.
Subjects will be centrally stratified by sex (male and female).  Within each stratum, subjects 
will be randomized to receive either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  
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Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily at approximately the same time of 
every day, and be encouraged to take the study medication with an adequate amount of water 
(8 oz. or 240 mL).  For information on dosing on visits associated with PK sampling, see 
Section 9.5.1.4.1.  (revised per Amendment 03)
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
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Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
The following concomitant medication guidelines/restrictions will apply:

Medications for the treatment of hypertension, dyslipidemia, or diabetes may be 
started, discontinued, or adjusted during the study according to local standards of care 
if, in the judgment of the investigator or the subject’s physician, such a change is 
medically indicated.

For diabetic subjects treated with sulfonylureas, insulin (note that subjects should not 
be enrolled as indicated in exclusion criteria), or other antidiabetic agents with 
hypoglycemic risk, the risk of hypoglycemic events may be higher if the subjects 
experience rapid and significant weight loss (more than 10% weight reduction than at 
the previous visit).  It is recommended that the physician advise the subject to 
monitor their blood glucose more frequently and adjust their antidiabetic medications
and diet accordingly. 
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
The antihyperglycemic medication dose would be considered for reduction in the 
event of 1 documented and otherwise unexplained hypoglycemic event (blood 
glucose concentration <65 mg/dL) or 2 undocumented and otherwise unexplained 
suspected hypoglycemic events between any 2 scheduled visits.   For subjects on 
more than 1 antihyperglycemic medication, it is recommended to reduce insulin first 
(if applicable), then the oral and/or other injectable antidiabetic agents.  If the 
previous criteria are met again following dose reduction, further dose reductions or 
cessation of 1 or more anti-hyperglycemic agents, are suggested.  See Section 9.5.4.2
for the definition and reporting of hypoglycemic events. 
To minimize the risk of cardiac valve toxicity, subjects must not initiate use of agents that 
have documented correlation with increased incidence of valvulopathy and/or PH (eg, 
pergolide, ergotamine, methysergide, or cabergoline) during the study.  (revised per 
Amendment 01)  If any of the above agents are clinically warranted, and subjects initiate any 
of these agents, lorcaserin HCl should be discontinued but can be restarted on lorcaserin HCl 
after being off the medications above for 1 month.  Otherwise, the study medication should 
not be restarted, but the subject should continue all study visits.  (revised per Amendment 03)
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Subjects will 
be asked to bring their study drug bottles to each visit.  The CRAs will review treatment 
compliance during site visits and at the completion of the study.  (revised per 
Amendment 03)
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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
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•
An investigator-signed and dated Form FDA 1572, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 (US 
sites only).  Must be appropriate to handle schedule IV products and not be expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
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at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.2.2
URINE DRUG SCREEN
A 30-mL urine sample will be collected at Screening, as specified in the Schedule of 
Procedures/Assessments (Table 2).  This sample will be tested for common drugs of 
use/abuse (eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, nicotine/cotinine, opioids 
[as a group], benzodiazepines, barbiturates, amphetamines). (revised per Amendment 01)
9.5.1.3
Efficacy Assessments

Body weight and height: will be measured using a standard stadiometer method (Lohman 
T, et al, 1988) to calculate changes in BMI.
Body weight will be measured in the 
morning after at least 8 hours of fasting and voiding using a calibrated scale and 
standardized instructions for clothing (ie, a hospital gown). Weight will be measured to 
the nearest 0.1 kg. Height will be measured in triplicate utilizing a stadiometer with a 
standardized process (eg, subjects should not be wearing shoes). Height must be 
measured to the nearest 0.1 cm.  BMI will then be used to calculate the proportion (%) of 
subjects achieving at least a 5% and at least a 10% BMI reduction.  (revised per 
Amendment 03)
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
Waist circumference: will be determined by measurement taken with a tape measure 
positioned horizontally, parallel to the floor, at one finger width above the iliac crest. The 
subject should be standing erect with relaxed abdominal muscles.  The tape measure 
should be snug but not compress the skin. The waist circumference should be taken to the 
nearest 1.0 cm, at the end of normal expiration. Three measurements will be taken and 
the average will be calculated. (revised per Amendment 03)

Total body fat mass and total body lean mass:  will be determined centrally using DEXA 
in a subset of randomized subjects (selected prior to randomization at selected sites) at 
Baseline and Week 52/EOT.  (revised per Amendment 03)

Measurement of systolic and diastolic BP, heart rate (taken after resting for 5 minutes), 
fasting lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), 
fasting plasma glucose, fasting insulin, HbA1c, and HOMA-IR to assess changes in 
cardiovascular and metabolic risk profiles from Baseline to Week 52 (revised per 
Amendment 03)

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 
(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents, 2011)

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011)
Every effort will be made to ensure that at least 80% of randomized subjects will have an 
assessment of the primary efficacy endpoint regardless of whether or not the subject 
remained on study drug or completed other study assessments.  (revised per Amendment 03)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for Population PK analyses.  (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take 
their study drug at home before the visit, but to bring their study drug to the clinic visit and 
take their daily dose at the clinic.  Two blood samples for determination of plasma 
concentrations of lorcaserin will be taken 1 predose (within 30 minutes before dosing) and 1 
within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times 
before the day of clinic visit. Week 52 PK samples should only be collected if the sample can 
be drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug at home, and will 
be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood 
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sample for PK assessment will be collected.  Dose times must be recorded for the last 2 
dosing times prior to the clinic visit. (revised per Amendment 01)
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
coupled with tandem mass spectrometry method. The collection, handling, and shipping 
procedures for PK samples will be described in a manual to be provided to the study sites.
At Unscheduled Visits, PK samples should only be collected if subject has experienced a 
serious adverse event (SAE) while on study drug and the sample can be drawn within 60 
hours of the initiation of the SAE. (revised per Amendment 01)
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Lorcaserin plasma exposure from PK analysis and population PK/PD modeling will be used 
to explore the relationship between lorcaserin plasma exposure and following response to 
lorcaserin: 

Change from Baseline in BMI 

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC AND OTHER BIOMARKER ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; electrocardiograms 
(ECGs); laboratory evaluations for hematology, metabolic function (fasting glucose, lipids,
and thyroid), adrenal functions, and biochemical blood and urine bone health assessments;
blood chemistry and urine values; neuropsychiatric events; periodic measurements of vital 
signs, neuromuscular signs for screening potential serotonin syndrome, and signs and 
symptoms of priapism and hyperprolactinemia; and performance of physical examinations.  
In subjects with potential prolactin-related AEs, such galactorrhea, changes in libido, or
changes to menstrual cycle, fasting prolactin level will be measured and assessed.  (revised 
per Amendment 03)
Bone mineral density and content, total body fat mass and total body lean mass will be 
determined using DEXA in a subset of randomized subjects (selected prior to randomization)
at selected sites.  (revised per Amendment 03)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
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relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs,
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
At each visit, the investigator should actively assess as to whether any of the following 
adverse events have occurred during the interval since the last visit:
•
Serotonin syndrome and signs or symptoms of serotonergism
•
Signs or symptoms of valvular heart disease or pulmonary hypertension, including 
dyspnea, dependent edema, congestive heart failure, or a new cardiac murmur
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•
Impairments in attention and memory, and confusion, somnolence, and fatigue
•
Psychiatric disorders
•
Hypoglycemia in subjects with diabetes on concomitant anti-diabetes medications (using 
ADA definitions)
•
Priapism and hyperprolactinemia signs and symptoms should be recorded at each visit 
and whenever reported
•
Hypersensitivity reactions
Any such events should be recorded as adverse events.  Serotonin syndrome, valvular heart 
disease, pulmonary hypertension, and priapism should always be reported as serious adverse 
events (SAEs) (See Section 9.5.1.5.2 for a complete list of adverse events that should always 
be considered as Serious).  (revised per Amendment 03)
Events of hypoglycemia in subjects with diabetes on concomitant anti-diabetes medication 
should be captured as per Section 9.5.2.  Severe symptomatic events of hypoglycemia should 
always be reported as an SAE as per Section 9.5.1.5.2.  (revised per Amendment 03)
It is the responsibility of the investigator to review the results of the Leiter-3, C-SSRS, and 
PHQ-9 for all subjects and determine if any result constitutes an AE.  Medical and scientific 
judgment should be exercised in deciding whether an isolated suicidality rating scale 
response should be classified as an AE (see Section 9.5.1.5.10 for a description of the 
C-SSRS).  (revised per Amendment 01)
All AEs must be monitored until symptom resolution, or until the condition stabalizes.  
(revised per Amendment 03)
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
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
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•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of the 
event
•
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious criteria:
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•
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
•
Priapism
•
New onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms (revised per Amendment 03)
•
Fibroadenomas of the breast or ductal carcinoma in situ
•
Severe symptomatic hypoglycemia (revised per Amendment 03)
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
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the study.
Laboratory testing should be conducted on an unscheduled basis if clinically 
indicated.  (revised per Amendment 03)
Table 1
Clinical Laboratory Tests (revised per Amendments 01 and 03)
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium, bicarbonate
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
Thyroid function
T4, TSH
Adrenal function
AM serum Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects)
Bone health assessments
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other (revised per Amendment 01)
Albumin, calcium, globulin, fasting glucose, HbA1c, HDL 
cholesterol, fasting insulin, lactate dehydrogenase, LDL cholesterol,
fasting lipid panel, phosphorus, total protein, total cholesterol,
triglycerides,, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
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9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained in triplicate to the nearest 0.1 cm as designated 
in the Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 03)
9.5.1.5.6
CDC GROWTH MEASUREMENTS
Investigators will calculate the height for age percentile and weight for age percentile 
utilizing the most recent CDC 95th Percentile Growth Chart and the height and weight 
measurements obtained, as designated in the Schedule of Procedures/Assessments (Table 2).  
(revised per Amendment 01)
9.5.1.5.7
WAIST CIRCUMFERENCE
Waist circumference (cm) measurements will be obtained in triplicate to the nearest 1.0 cm 
taken 3 times at each visit as designated in the Schedule of Procedures/Assessments 
(Table 2).  (revised per Amendments 01 and 03)
9.5.1.5.8
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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 eCRF.
As part of the physical examination, a neuromuscular sign assessment for serotonin 
syndrome will be performed for potential serotonergic syndrome components.  Serotonergic 
syndromes that meet the diagnostic criteria will be captured by AE eCRF.
(revised per 
Amendment 01)
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will also be captured in the AE eCRF. (revised per 
Amendment 01)
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9.5.1.5.9
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.10 OTHER SAFETY ASSESSMENTS
Leiter-3
The Leiter International Performance Scale–Third Edition (Leiter-3) is widely used 
non verbal measure of intelligence, memory, and attention in those between the ages of 3 and 
75 years. 
The Attention/Memory Battery consists of 5 subtests: 2 measure nonverbal 
attention; 2 measure memory; and 1 measures cognitive interference (nonverbal Stroop test). 
These subtests are combined to produce a Memory and Processing Speed composite scores, 
normalized to a mean of 100 and standard deviation of 15. The Leiter-3 will be used to 
assess lorcaserin effects on cognition, specifically, attention and memory. In addition, signs 
and symptoms of cognition-related AEs, including impairments in attention, memory, and 
adverse effects on schoolwork will be captured in the eCRF. (revised per Amendment 01)
PHQ-9
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and 
measuring the severity of depression:

The PHQ-9 incorporates Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV) depression diagnostic criteria with other leading major depressive 
symptoms into a brief self-report tool.

The tool rates the frequency of the symptoms which factors into the scoring severity 
index.

Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.

A follow-up, non-scored question on the PHQ-9 assigns weight to the degree to which 
depressive problems have affected the patient's level of function. 
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. Qualified personnel must evaluate positive 
responses on the C-SSRS and take appropriate action as detailed in the training and 
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certification process for administering the C-SSRS.  It will be performed at Screening and at 
study visits as designated in the Schedule of Procedures/Assessments (Table 2). (revised per 
Amendment 01)
DEXA for the Assessment of Bone Mineral Density
Bone mineral density body composition determination by DEXA whole body composition, to 
include bone mineral density and content, total body fat mass and total body lean mass will 
be determined using DEXA in a subset subjects (selected prior to randomization) at selected 
sites.  A contracted vendor will provide all administration and project management services 
for DEXA scanning.  This will include site and image data management services, as well as 
site training and certification.  (revised per Amendment 03)
A miminum of 30 subjects ages 12-18 years (selected prior to randomization) should have 
bone density evaluated with DEXA at BL and week 52/EOT.  (revised per Amendment 03)
Hand X-Ray
A hand x-ray for evaluation of any potential negative effect on bone age will be performed 
on the same hand at each visit as designated in the Schedules/Assessments (Table 2).  
(revised per Amendment 01)
Tanner Staging
The pubic hair growth (both sexes), genital (males only) and breast (females only) 
development of subjects will be using Tanner Staging by a trained clinician (Marshall, 1970).
Subjects will be examined by the investigator as designated in the Schedules/Assessments 
(Table 2). (revised per Amendments 01 and 03)
Echocardiogram
Echocardiograms will be obtained on the Schedule of Procedures/Assessments (Table 2). 
Valvular regurgitation in echocardiogram will be rated absent, trace, mild, moderate, or 
severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve.  The evaluations will be based on guidelines from the American Society of 
Echocardiography. Pulmonary artery systolic pressure will be estimated from the TR
regurgitant jet velocity.  (revised per Amendment 03)
9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at every visit as specified in the 
Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 03)
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01, 02
and 03)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examinationd
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, insulin, and HbA1c sampling
X
X
X
X
X
X
T4 and TSH
X
X
X
X
X
Testosterone, Estradiol
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01, 02
and 03)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Pregnancy test (urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting prolactin
X
X
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Fasting lipid panel
X
X
X
X
Urine NTX
X
X
X
X
PK/PD blood sampling
Xe
Xe
Xe
Xe,f
Xg
Xf
AM serum cortisol
X
X
X
ECG
X
X
X
X
Echocardiograph
Xh
X
X
DEXAi
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
Leiter-3
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01, 02
and 03)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Standardized age-appropriate lifestyle modification 
counselingj
X
X
X
X
X
X
X
X
X
X
AE = adverse event, AM = morning; CDC = Centers for Disease Control and Prevention, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, ED = 
early discontinuation, EOS = End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, IxRS = interactive voice or web response system, NTX = N-telopeptide, OC 
= osteocalcin; PHQ-9 = The Patient Health Questionnaire, PICP = carboxyterminal propeptide of type I procollagen,  PD = pharmacodymanic, PK = pharmacokinetics, SAE = 
serious adverse event; T4 = thyroxine, TSH = thyroid stimulating hormone, US = unscheduled.
a: Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b: Window ±7 days for all visits. (revised per Amendments 01 and 03)
c: Unscheduled visits may be conducted at any time that additional assessments are indicated in the clinical judgment of the investigator.  Note that not all assessments listed 
under Unscheduled Visit need to be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs.  At 
Unscheduled Visits, PK samples should only be collected if subject has experienced a serious adverse event (SAE) while on study drug and the sample can be drawn within 
60 hours of the initiation of the SAE. (revised per Amendments 01 and 03)
d: Includes a neuromuscular assessment for serotonin syndrome, and signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle abnormalities 
or galactorrhea) (revised per Amendments 01 and 03)
e: On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at home before the visit, but to bring their study drug to the clinic 
visit and take their daily dose at the clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken:  1 predose (within 30 minutes before 
dosing) and 1 within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times before the day of clinic visit. Week 52 PK samples should only be 
collected if the sample can be drawn within 60 hours of the last dose of study drug.  On the day of the Week 36 clinic visit, subjects will take the morning dose at home, and 
will be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for PK assessments will be collected  Dose times must be recorded for the 
last 2 dosing times prior to the clinic visit. (revised per Amendment 01)
f: PK samples should only be collected if the sample can be drawn within 60 hours of the last dose of study drug.
g: PK samples should only be collected if subject has experienced an SAE while on study drug and the sample can be drawn within 60 hours of the initiation of the SAE.
h: Echocardiographic assessments will be performed during screening period after subjects have met all other inclusion and exclusion criteria.
i: Only subjects in selected sites will have this assessment done.  (revised per Amendment 03)
j: Lifestyle modification counseling will also be performed at Weeks 3, 16, 24, 32, 40, and 48 in addition to counseling at the scheduled visits in Appendix 2.
.
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes (revised per Amendments 01
and 03)
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
(Chemistry and Hematology)
5
Screening: 1
Visits 2, 3, 4, 6, 8, 11 (EOT),
EOS or ED
58=40
T4, TSH, AM Serum 
Cortisol, Testosterone, 
estradiol 
6
Screening:  1
Visits 2, 8, 11 (EOT), or ED
6×4=24
Serum OC and PICP, 
Hydroxy-proline; Fasting 
lipid panel (HDL cholesterol, 
LDL cholesterol, total 
cholesterol, triglycerides)
8
Visits 2, 8, 11 (EOT), or ED
8×3=24
Fasting Prolactin, FPG, 
fasting insulin, and HbA1c
sampling
5
Screening:  1
Visits 2, 6, 8, 11 (EOT) or ED, 
US
5×6=30
PK/PD blood sampling
4
Visits 6, 8, and 11 (EOT) or ED
(2 samples each); Visit  9 (1 
sample only)
7×4=28
Total
146
ED= early discontinuation from study, EOS = End of Study, EOT = End of Treatment, FPG = fasting plasma glucose, 
HbA1c = hemoglobin A1c, OC = osteocalcin, PD = pharmacodynamic, PICP = carboxyterminal propeptide of type I 
procollagen, PK = pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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.
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
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criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms (revised per Amendment 03)

Fibroadenomas of the breast or ductal carcinoma in situ


Severe symptomatic hypoglycemia (revised per Amendment 03)
Subject-reported episodes of hypoglycemia or decreased blood sugar should be captured on 
the eCRF according to the following guidelines:

Psuedo-hypoglycemia:  An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia 
with a measured plasma glucose concentration >70 mg/dL (>3.9 mmol/L) but 
approaching that level.  (revised per Amendment 03)

Probable symptomatic hypoglycemia:  An event during which symptoms typical of 
hypoglycemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 70 mg/dL (≤ 3.9 mmol/L)
(revised per Amendment 03)

Asymptomatic hypoglycemia: 
An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dL (≤ 
3.9 mmol/L) (revised per Amendment 03)

Documented symptomatic hypoglycemia: An event during which typical hypoglycemia 
symptoms are accompanied by a measured plasma glucose ≤70 mg/dL (≤3.9 mmol/L) 
(revised per Amendment 03)
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
Severe hypoglycemia: 
An event requiring assistance of another person to actively 
administer carbohydrate, glucagon or other resuscitation actions. Plasma glucose 
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration (revised per 
Amendment 03)
See Section 9.4.6 (Prior and Concomitant Therapy) for directions on the recommendations 
for possible adjustment to antihyperglycemic medication doses in response to reported 
episodes of hypoglycemia.  (revised per Amendment 03)
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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue study drug prematurely will continue to be evaluated on for all 
study assessments until study completion.  All attempts will be made to capture height and 
weight in all subjects whether or not they are still on IP at the end of the study.  All subjects 
who discontinue the study are to complete the study’s early discontinuation procedures 
indicated in the Schedule of Procedures/Assessments Table 2). (revised per Amendment 03)
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 contacted by 
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mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of the secondary reasons for discontinuation. Study disposition information will 
be collected on the Subject Disposition CRF. If “lost to follow-up” is recorded in clinical 
data base, appropriate queries will be sent to investigators in order to collect all the relevant 
reasons for missing data.  (revised per Amendment 03)
Every effort, including proper training of all study participants and their parent/guardian, 
should be made in order to achieve optimal subject retention and prevent missing data, 
especially for the Week 52 primary endpoint.  A retention plan to help avoid missing data 
will be developed and included in study manual. (revised per Amendment 03)
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.  The DEA Registrant has 
the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
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guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 
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
Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Association between change and percentage change in BMI from Baseline to Week 52 
with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI 
reduction at Week 52 with the outcome of achieving at least a 5% BMI reduction at 
Week 12 (revised per Amendment 02)

Change in waist circumference from Baseline to Week 52

Change in total body composition (total fat and lean mass) in a subset of randomized 
subjects at end of 52 weeks of treatment (revised per Amendment 03)

Change in HbA1c from Baseline to Week 52 for subjects with Type 2 diabetes at baseline 
(revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for 
subjects with Type 2 diabetes at baseline (revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for 
the subjects without Type 2 diabetes at baseline (revised per Amendment 03)

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52

Subject compliance rate at each visit by pill count during 52 weeks of treatement (per 
Amendment 03)
9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.
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
Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or 
greater compliant with study medication, completed the study, have no major protocol 
deviations, have no violations of inclusion or exclusion criteria, and have BMI data at 
Baseline and Week 52.  The determination of subjects to be excluded from this 
population based on the above criteria and list of major protocol violations will be 
included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 
1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and 
who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
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9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using analysis of covariance model (ANCOVA) with 
factors of treatment, sex (male and female) as fixed effect, and the baseline age and BMI as 
covariates.  The missing values will be imputed using a pattern mixture model utilizing 
multiple imputation (MI) assuming the missing values are missing not at random (MNAR).  
The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model 
and missing value imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated based 
on the PP.

Change from baseline in standardized BMI score (Z-score): The same primary efficacy 
analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed 
and will be described in the SAP.  
Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, and sex (male and 
female), and baseline BMI as a covariate using FAS.  Subjects with any missing assessment 
at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using mixed effect model repeated measurement analysis (MMRM) on the FAS for 
study treatment compared to placebo, as appropriate. The model will include all data and will 
include treatment, time, and the interaction of treatment by time as fixed effects, with 
adjustment for sex (male versus female), BMI and age at baseline, and subject as a random 
effect.  (revised per Amendment 03)
Treatment by time interaction will be used to construct the treatment comparisons at a 
specific time.  The MMRM model assumes that the missing data are missing at random and 
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makes use of all available data even if a subject has missing data at some post-baseline visits.  
An unstructured covariance matrix will be used, and if the model fails to converge, then an 
autoregressive matrix will be used.  (revised per Amendment 03)
Categorical variables will be analyzed using the Cochran Mantel Haenszel test, Chi-square 
test, or logistic regression as appropriate.  Additional analysis may be performed as needed 
using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male 
and female), race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or other Pacific Islander, or White), and age. Additional subgroups may be 
explored, if deemed necessary.  (revised per Amendment 03)
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will 
be used for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also be 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
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9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination, 
neuromuscular sign assessment for serotonin syndrome, and signs and symptoms of priapism 
and hyperprolactinemia), out-of-normal-range laboratory safety test values, change from 
baseline in laboratory safety test values, ECGs, vital sign measurements, bone mineral 
density and content, total body fat mass and total body lean mass will be summarized by 
treatment group using descriptive statistics or frequency count as appropriate.  (revised per 
Amendments 01 and 03)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
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The TEAEs will be summarized by treatment group.  The following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No [not 
related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
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compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, 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
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and greater 
than 60 msec from the baseline visit.
9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including adolescent growth evaluations using 95th percentile CDC 
growth charts and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, study drug effect on cognition assessed by Leiter-3, assessment of suicidality using 
C-SSRS, depression assessment using PHQ-9, bone mineral density and content, total body 
fat mass, and total body lean mass using DEXA will be summarized by treatment group at 
each scheduled visit.  For echocardiographic assessments, the proportion of subjects who 
develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
hypertension (defined as when a subject’s SPAP is
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echocardiograph], and change from baseline in SPAP will also be summarized by treatment 
group at Week 28 and Week 52. (revised per Amendments 01 and 03)
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg treatment group; n=130 in the 
placebo group) will have at least 80% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 260 subjects (130 subjects for Belviq XR 20 mg and 130 subjects for placebo) 
will also have greater than 78% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Chi-Square test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.
Lohman T, Roche AF, Martorell R. Anthropometric Standardization Reference Manual.  
Champaign, IL:  Human Kinetics Books; 1988.
Marshall WA, Tanner JM. Variation in pattern of pubertal changes in boys. Arch. 
Dis.Childhd 1970; 45, 13-23.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.
CT.gov Study NCT02918279. (revised per Amendment 02)
Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L.  
NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
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Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A 
Life-Table Analysis. Ann Intern Med. 2003; 138:24-32.
Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al. A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
Whitaker RC, et al. Predicting obesity in young adulthood from childhood and parental 
obesity. N Engl J Med. 1997 Sep 25;337(13):869-73.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
<LLN – 2.5 mg/dL
<2.5 – 2.0 mg/dL
<2.0 – 1.0 mg/dL
<1.0 mg/dL
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
(hypophosphatemia) 
<LLN – 0.8 mmol/L
<0.8 – 0.6 mmol/L
<0.6 – 0.3 mmol/L
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will be 
encouraged to participate in a standardized weight management program for adolescents 
consisting of multicomponent behavior therapy.  The therapy will focus on healthy eating, 
physical activity, and lifestyle changes that will facilitate weight loss and weight-loss 
maintenance. The role of the caregivers is to support their child or adolescents’ lifestyle 
changes and their taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress but 
caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neurology Business Group
Eisai Inc.
Date
Medicine Development Group
Eisai Inc.
Date
Neurology Business Group
Eisai Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Revised secondary objectives to 
assess effects of glycemia to 
fasting glucose in subjects with 
Type 2 diabetes and those 
without Type 2 diabetes
Per FDA request
Synopsis – Objective
Section 8.2
Section 9.7.1.1.2
Added secondary objective to 
assess the effects on body fat 
and lean mass compostion by 
DEXA in a subset of subjects at 
selected sites
Per FDA request
Synopsis – Objective
Synopsis - Efficacy Assessment
Synopsis – Other Safety 
Assessments
Synopsis – Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.1.2
Table 2
Section 9.7.1.8.6
Revised secondary objective for 
cardiovascular risk factors 
associated with obesity to 
include blood pressure and heart 
rate
Synopsis – Objective
Section 8.2
Revised secondary objective to 
evaluate bone density by DEXA 
in a subset of subjects at 
baseline and Week 52/EOT
Per FDA request
Synopsis – Objective
Synopsis - Other Safety 
Assessment
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.10
Table 2
Section 9.7.1.6
Section 9.7.1.8.6
Added requirement to evaluate 
drug compliance (via pill count)
Per FDA request
Synopsis – Other Secondary 
Efficacy Endpoints
Section 9.4.7
Section 9.7.1.1.2
Revised to specifiy that at least 
20% of all study subjects 
enrolled are younger (12 to 13 
year of age)
Per FDA request
Synopsis - Study Design
Section 9.1
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Added requirement that 80% of 
randomized subject will have 
primary endpoint assessments
Per FDA request
Synopsos – Study Design
Section 9.5.1.3
Revised to specify that study 
sites will be selected to ensure 
adequsate representation of 
adolescents of ethnic and racial 
minorities
Per FDA request
Synopsis - Efficacy Assessments
Section 9.7.1.8.6
Added requirement for Data 
Monitoring Committee
Per FDA request
Synopsis - Study Design
Section 9.1
Added assessment of 
anthropometric measure (waist 
circumfereance)
Per FDA request
Synopsis – Efficacy Assessments
Section 9.5.1.3
Section 9.5.1.5.7
Revised inclusion criteria (#1) 
to define population at baseline 
with regard to Type 2 diabetes
diagnosis
To ensure PPSR requirements are met
Synopsis - Inclusion Criteria
Synopsis – Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.3.1
Added exclusion criteria (#3) 
for subjects with Type 2 
diabetes who are hypoglycemia 
unaware
To ensure PPSR requirements are met
Synopsis - Exclusion Criteria
Section 9.3.2
Revised concomitant 
medication guidelines
To provide futher clarity
Synopsis – Concomitant 
Drug/Therapy
Section 9.4.6
Revised instructions on height 
and body weight measurements
Per FDA request
Synopsis – Study Design
Section 9.1
Section 9.5.1.3
Section 9.5.1.5.5
Added instructions for 
investigator to monitor specific 
list of AEs that have occurred 
since the last visit
Per FDA request
Section 9.5.1.5.1
Added requiirement for report 
hypoglycemic events for the 
subjects with type 2 diabetes
Per PPSR requirements
Section 9.5.1.5.1
Revised requirements for AE 
monitoring
Per PPSR requirements
Section 9.5.1.5.1
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Revision History
Previous Version (Revision): v7.0
Current Version (Revision):  v8.0
Date of Revisions: 12 Dec 2017 (per Amendment 03)
Change
Rationale
Affected Protocol Section(s)
Revised list of events that 
should be considered SAEs and 
reported as important medical 
events
Per PPSR requirements
Section 9.5.1.5.2
Section 9.5.4.3.2
Added requirement for querying 
sites for all relevant information 
for subjects lost to follow-up 
Per FDA request
Section 9.5.5
Added requirement to provide 
proper training to all study 
participants and their 
parent/guardian, in order to 
achieve optimal subject 
retention and prevent missing 
data
Per FDA request
Section 9.5.5
Revised assessment timepoints 
for Tanner Staging, 
Testosterone/Estradiol, TSH, 
fasting prolactic, 
echocardiogram, 
OC/PICP/Hydroxy-proline, 
ECG, and Hand X-rays
Per FDA requeset
Table 2
Revised Other Secondary 
Efficacy Analyses text MMRM
Section 9.7.1.6
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Revision History
Previous Version (Revision): v6.0
Current Version (Revision):  v7.0
Date of Revisions: 11 Jul 2017 (per Amendment 02)
Change
Rationale
Affected Protocol Section(s)
Revised statistical power from 
90% to 80%
80% statistical power would provide 
sufficent sample size to detect weight 
loss effects and evaluate lorcaserin 
safety in the population selected.
Synopsis – Study Design
Synopsis – Number of Subjects
Synopsis – Sample Size Rationale
Section 7.1.2
Section 9.1
Section 9.2
Section 9.3
Section 9.7.2
Revised Other Secondary 
Endpoints
To align with recently submitted 
PPSR
Synopsis – Other Secondary 
Efficacy Endpoints
Section 9.7.1.1.2
Added clarification on timing of 
PK samples taken during an 
early discontinuation visit
Clarification
Table 2
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Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Revised scale for measuring of 
cognition from Wide Range 
Assessment of Memory and 
Learning-2 (WRAML-2) to 
Leiter-3
Leiter-3 is selected to replace 
WRAML-2 for the evaluation of the 
change in cognition for the following 
reasons:Lack of availability of 
WRAML-2 in Spanish, Leiter-3’s 
high scientific validity, non-verbal 
format to offer less biased assessment 
for subjects whose second language is 
English, easier and shorter 
administration and short test time 
reducing investigator burden, as well 
as increase probability of the 
subjects’ retention in the study.
Synopsis – Objectives
Synopsis – Other Safety 
Assessments
Synopsis – Other Safety Analyses
List of Abbreviations
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Added requirement that 
qualified personnel must 
evaluate positive responses on 
the C-SSRS and take 
appropriate action as detailed in 
the training and certification 
process for administering the 
C-SSRS
To provide guidance that qualified 
personnel must evaluate positive 
responses on the C-SSRS and take 
appropriate action as detailed in the 
training and certification process for 
administering the C-SSRS.
Synopsis – Other Safety 
Assessments
Section 9.5.1.5.10
Revised timing of initial C-
SSRS from Baseline to 
Screening
Operational efficiencies
Table 2
Section 9.3.2
Section 9.5.1.5.10
Correct formatting of Synopsis, 
Other Secondary Objectives
Consistency
Synopsis – Objectives
Section 8.2
Revised exclusion criteria for 
viral hepatitis (B or C) (#17) 
whereby active testing will not 
be performed 
To clarify that the subjects will be 
excluded if they are known to have
active hepatitis (B or C). Hepatitis (B 
or C) tests will not be conducted for 
the screening purpose.
Synopsis – Exclusion Criteria
Section 9.3.2
Added footnotes regarding 
collection of PK samples at 
EOT and Early Discontinuation 
visits
To ensure appropriate timing of
sampling relative to administration of 
last dose of study drug
Table 2
Added clarification for
Unscheduled visits, such that 
they may be conducted at any 
time that additional assessments 
are clinically indicated in the 
judgment of the investigator.
Provide additional guidance to 
investigators
Table 2
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Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Added clarification that 
prolactin testing should be 
fasting
Clarification
Table 2
Added requirement for 
pregnancy test and AM serum 
cortisol to Early 
Discontinuation Visit
Correction
Table 2
Table 3
Added requirement for lifestyle 
modification counseling Visit at 
Week 16
To ensure all visits are 4 weeks apart
Table 2
General alignment of text 
throughout
Clarity
Throughout
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Page vii of xii
Revision History
Previous Version (Revision): v4.0
Current Version (Revision):  v5.0
Date of Revisions: 22 Feb 2017
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
A full physical examination will 
be performed at Week 1
Correction
Synopsis - Safety Assessment
Section 9.5.1.5
PHQ-9 questionnaire has been 
added to every scheduled visit.
Per FDA recommendation
Synopsis - Safety Assessment 
Section 9.5.1.5
Section 9.5.2.1
The mixed model repeated 
measures (MMRM) model was 
replaced with the analysis of 
covariance (ANCOVA) model
analyzing Week 52 only.
Per FDA recommendation
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
All postdiscontinuation data 
will be used in the primary 
analysis
Clarification per FDA feedback
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Labeling information for study 
drug was updated
Correction as the study will only be 
conducted in the US
Section 9.4.2.3
The order of assessments was 
reorganized in the Schedule of 
Assessments 
To better align the assessments by 
grouping them
Section 9.5.2.1
Urinalysis will be performed at 
Visit 2 instead of Visit 9
Correction
Section 9.5.2.1
Assessment for testosterone, 
estradiol will be performed at 
Week 28, not Week 20
Correction
Section 9.5.2.1
Section 9.5.2.3
Prior/concomitant medication 
assessment will be performed at 
Week 56
Correction
Section 9.5.2.1
Assessments performed at early 
discontinuation from the study
Correction
Section 9.5.2.1
Summary of blood volumes 
table was updated
Correction
Section 9.5.2.3
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Subject population to include 
children ages 12 to 17 years
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Title Page
Synopsis - Study Protocol Title
Synopsis - Design
Synopsis - Inclusion Criteria
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.7.1.6
Section 9.7.1.8
Protocol Signature Page
Investigator Signature Page
All subjects will be evaluated 
for cardiac valvular disease or 
pulmonary hypertension via 
echocardiographic assessment.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Other Secondary 
Objectives
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.3.2
Section 9.5.1.5.10
Section 9.5.2
Section 9.7.1.8
Section 9.7.1.8.6
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Study drug administration will 
be taken at approximately the 
same time each day.  On the 
days of PK sampling and the 
day before the subjects come to 
the clinic for PK sampling, 
study drug will be taken in the 
morning and doses recorded 2 
days prior to the clinic visit.
This will ensure lower variability 
with regard to PK/PD measurements.
Synopsis - Pharmacokinetic 
Assessments
Section 9.4.1
Section 9.4.4
Section 9.5.1.4.1
Section 9.5.2.1
Screening, diagnosing, 
monitoring, and measuring the 
severity of depression will be 
assessed using the Patient 
Health Questionnaire (PHQ-9), 
and not the Children’s 
Depression Inventory 2 (CDI-
2).
The PHQ-9 was originally proposed 
by the FDA for the population in the 
current study.
Synopsis - Other Secondary 
Objectives
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Primary analysis changed from 
MMRM to using a pattern 
mixture model utilizing 
multiple imputations (MI) to 
impute missing values.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Clarified fasting lipids
Fasting lipid levels provide 
uniformity in lipid measurements for 
definition of dyslipidemia
Synopsis - Other Secondary 
Objectives
Synopsis - Efficacy Assessments
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Removed Appendix 3
The current study will not conduct 
any biomarker or pharmacogenomic
evaluation. PK/PD measurements 
will be done during study.
Appendix 3
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Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Prehypertension was deleted 
from the inclusion criterion.  
Subjects with Stage 1 primary 
hypertension, with an upper 
limit defined as 99% plus 5 
mmHg for age, sex, and height 
are included in the study. 
Prehypertension does not qualify as a 
comorbid condition.  The limitation 
on BP is to further define the proper 
study population.
Synopsis - Inclusion Criteria
Section 9.3.1
Removed the restriction that 
subjects need to have less than 
44 kg/m2 BMI for study entry
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Synopsis - Analysis Sets
Synopsis - Pharmacodynamic 
Analyses
Synopsis -
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study entry 
requirement that the caregiver 
cannot have a history of ADD, 
substance abuse, depression, 
suicidal ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Section 9.3.1
The secondary efficacy 
objective and endpoint were 
revised
To explore the predictability of 12-
week responders for long-term 
sustainable weight loss effect
Synopsis - Secondary Efficacy 
Objectives
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with symptoms or 
signs of cardiac valvular disease 
or pulmonary hypertension are 
not required to have further 
evaluation by centralized 
echocardiogram assessment.  In 
addition, no adjudication will be 
performed.  Local 
echocardiograms can be 
performed if deemed medically 
necessary by the investigator.
This 
change 
allows 
for 
the 
investigator to make the decision to 
perform local echocardiograms on a 
pediatric subject if deemed medically 
indicated rather than burden the 
subject to undergo a mandated, 
unnecessary procedure. 
Synopsis - Safety Assessments
Section 9.5.1.5
Updated study rationale
Clarification 
Section 7.1.1.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will replace the
IR formulation in the United States
market to support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to include 
children ages 9 to 17 years
Expand the age of the population due 
to the change of pediatric development 
strategy
A single dose pharmacokinetic study 
in pediatric obese subjects (APD356-
A001-026) indicated that patients with 
body weight greater than or equal to 
60 kg can be administered a dose 
similar to that given to adults and 
adolescents.  Based on Centers for 
Disease Control and Prevention 
(CDC) growth chart data, almost all 
subjects over 9 years of age are likely 
to be at or over 60 kg body weight.  
Therefore, children age 9 to 11 years 
have been included in the current 
study.
Title Page
Synopsis - Study Protocol Title
Synopsis - Objectives
Synopsis - Study Design
Synopsis - Inclusion Criteria
Synopsis - Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.10
Section 9.7.1.6
Section 9.7.1.8
Additional safety assessments 
including cognitive function, 
serotonin syndrome 
components, bone health and 
endocrine function, priapism, 
and symptoms associated with 
hyperprolactinemia were added.
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Efficacy Assessments
Synopsis - Pharmacokinetic 
Assessments
Synopsis - Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.1
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Change to primary and key 
secondary endpoints
Per FDA request
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary endpoint 
changed
Per FDA request
Synopsis - Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of study-
specific adverse events
To provide clearer guidance for the 
correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and prohibited 
prior and concomitant therapies
For clarification
Synopsis - Exclusion Criteria
Synopsis - Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of adverse 
events
To provide clearer guidance for the 
correct reporting of adverse events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
Update to Introduction and to 
Completion/ Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Belviq XR®
in Conjunction With Lifestyle Modification for Weight Loss in Obese 
Adolescents, Age 12 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
v4.0
03 Nov 2016 (Revision)
v5.0
22 Feb 2017 (Revision)
v6.0
17 May 2017 (per Amendment 01)
v7.0
11 Jul 2017 (per Amendment 02)
V8.0
12 Dec 2017 (per Amendment 03)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference 
on 
Harmonisation
of 
Technical 
Requirements 
for 
Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information that 
is not authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and 
Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in Obese Adolescents, Age 
12 to 17 Years
Investigators
TBD
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
Approximately 24 months from the 1st subject enrolled to last subject’s last visit or last assessment 
Phase 4
Objectives
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks of treatment 
with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD as compared to 
placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg administered QD compared 
to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of treatment with 
Belviq XR 20 mg administered QD is predictive of sustained change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 52 weeks of 
treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% BMI reduction, 
change in waist circumference) at the end of 52 weeks of treatment
-
Effects on fasting glucose, hemoglobin A1c (HbA1C), insulin levels, and Homeostatic Model 
Assessment of Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) in subjects with 
Type 2 Diabetes at Baseline during 52 weeks of treatment (revised per Amendment 03)
-
Effects on fasting glucose, HbA1c, insulin levels, and HOMA-IR; glucose [mg/dL] × insulin 
[mU/L]/405 in subjects without Type 2 Diabetes at Baseline during 52 weeks of treatment (revised per 
Amendment 03)
-
Effects on body fat and lean mass composition by Dual-enerygy X-ray Absorptiometry (DEXA) in a 
subset of randomized subjects (selected prio to randomization) at selected sites during 52 weeks of 
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treatment (revised per Amendment 03)
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, dyslipidemia)
including fasting lipid changes (total cholesterol, triglycerides, high density lipoprotein [HDL], low 
density lipoprotein [LDL]), systolic and diastolic blood pressure, and heart rate during 52 weeks of 
treatment (revised per Amendment 03)

To assess the safety of Belviq XR, including the effects on cognition with the Leiter-3 International 
Performance Scale (Leiter-3), depression with the Patient Health Questionnaire (PHQ-9), signal of suicidal 
ideation or behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by
Centers for Disease Control and Prevention (CDC) growth chart, sexual maturation (pubescence) measured 
by Tanner Staging scores, and other growth and development parameters by measuring sex hormones, 
thyroid function, adrenal function, bone age, and biochemical markers of bone health, bone mineral density 
and content, total body fat mass, and total body lean mass using DEXA in a subset of randomized subjects 
(selected prior to randomization) at selected sites, valvular function, and pulmonary arterial pressure.  
(revised per Amendments 01 and 03)

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) parameters 
including but not limited to reduction from baseline in BMI and probability of achieving at least a 5% and 
at least a 10% reduction in BMI from baseline at Week 52 using population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese adolescents, 
ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 1:1 ratio to Belviq XR 20 mg QD
(130 subjects) and placebo (130 subjects).  Subjects will be stratified by sex.  Subjects will receive Belviq XR
20 mg or matched placebo QD in a 1:1 ratio for up to 52 weeks. A recruitment plan will be developed to ensure 
at least 20% of younger subjects (12 to 13 years of age) are enrolled in the study.  Throughout the duration of 
the study, subjects will be encouraged to adhere to a lifestyle modification program that includes a 
standardized, age-appropriate diet and exercise counseling. (revised per Amendments 02 and 03)
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization Phase will 
last up to 30 days and consist of 1 visit during which subjects will be screened for eligibility.  The 
Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The Treatment Period will last 
for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52.  The Follow-Up Period will 
extend from the End of Treatment (EOT) visit to the End of Study visit.
Subjects who screen fail can be re-screened only once after 30 days.  All subjects will continue in the study 
until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely will be followed up 
until study completion.  All attempts will be made to capture height and weight in all subjects whether or not 
they are still on study drug at the end of the study.  (revised per Amendment 03)
Study sites will be selected to ensure adequate representation of adolescents of ethnic and racial minorities.  
(revised per Amendment 03)
Data Monitoring Committee (revised per Amendment 03)
A Data Monitoring Committee (DMC) will be established to monitor and conduct periodic safety review of 
unblinded data. DMC members will be chosen based on their expertise in evaluating these clinical events. A 
separate DMC charter will be established.
Number of Subjects
Approximately 500 subjects will be screened to provide 260 randomized subjects.  (revised per Amendment 02)
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years (inclusive) at Screening, with an initial BMI that is 
greater than or equal to the United States (US)-weighted mean of the 95th percentile based on age and sex
with a body weight greater than 60 kg.  Subjects with T2DM may have a pre-existing or new diagnosis of 
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T2DM.
Subjects with pre-existing T2DM should have prior documentation consistent with the diagnosis and/or be 
on active pharmacotherapy for T2DM.  
Subjects with a new diagnosis of T2DM (ie, diagnosed at Screening) should be based on the 2016 
American Diabetes Association (ADA) guidelines.  The diagnostic criteria are met if a subject has 
unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of 
hyperglycemia or hyperglycemic crisis) OR any of the following criteria are observed and confirmed:
◦
HbA1c ≥6.5% 
◦
fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 
◦
2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) by an oral glucose tolerance test (OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being or need to be treated 
with antidiabetic agents, the T2DM treatment regimen must be stable for at least 3 months before 
randomization.  A single rescreen is allowed following stabilization.  Stable control refers to minimal dose 
changes to existing medications for glycemic control and no medications being initiated for glycemic 
control in the 3 months before Randomization.  Minimal changes are defined as a change without any 
change in dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject has not 
been hospitalized due to hypo- or hyperglycemic events. (revised per Amendment 03)
2.
Subjects and their families not planning to move away from the area for the duration of the study
3.
Able and willing to comply with all aspects of the study, including a standardized, reduced-calorie diet and 
an age-appropriate, increased physical activity program
4.
Considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the investigator,
including consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study requirements for the 
caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the subject’s ability 
to fulfill the study requirements or significantly confound the assessments
2.
Who cannot swallow investigational products
3.
With Type 2 diabetes who have hypoglycemia unawareness (revised per Amendment 03)
4.
Any of the following findings on Screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, mean gradient 
>25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean gradient >5 mm Hg and mitral valve 
area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure (SPAP) >40 mmHg (and/or tricuspid regurgitation (TR) jet 
velocity >2.9 m/s)
In cases where an actual SPAP value is not measurable due to lack of adequate TR jet, the pulmonary flow 
acceleration time measured at the right ventricular outflow tract (RVOTAT), will be used to assess 
eligibility. Patients with a RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be determined based on 
combined assessment of the TR jet, septal motion and right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease
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
Clinically significant pericardial effusion (eg, moderate or larger or with hemodynamic compromise)
5.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper limit of 
normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater than 1.5×ULN in 
absence of Gilbert’s syndrome
6.
Any suicidal ideation with intent with or without a plan, at the time of or within 6 months of Screening, as 
indicated by answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS.
7.
Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
8.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit Hyperactivity 
Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th Edition depressive disorder,
suicidal ideation or behavior, bipolar disorder, or schizophrenia
9.
Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi syndrome, Bardet 
Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, Cushing’s syndrome, daily systemic 
corticosteroid exposure for longer than 30 days, history of significant exposure to corticosteroids for 
chronic illness during the past year; inhaled steroids will be allowed) (revised per Amendment 03)
10. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, 
and herbal preparations within 1 month before Screening 
11. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine oxidase inhibitors 
(MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
12. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before Screening, 
including but not limited to pergolide, ergotamine, methysergide, and cabergoline
13. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, gastrointestinal, 
renal, or psychiatric disease) other than prediabetes (impaired fasting glucose or impaired glucose 
tolerance), type 2 diabetes treated with oral anti-diabetic agents (excluding sulfonylurea) or non-insulin 
injectable antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
14. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any of the 
excipients
15. Significant change in diet or level of physical activity within 1 month before dosing or change in weight of 
more than 5 kg within 3 months before Screening
16. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before Screening
17. History of alcohol or drug dependence or abuse
18. Recreational drug use within 2 years before Screening
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19. Known to be human immunodeficiency virus (HIV) positive
20. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
21. Malignancy within 5 years before Screening
22. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or guardian to supervise 
study participation
23. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to profound 
mental retardation [IQ <70], moderate to severe cognitive developmental delay, pervasive development 
disorders, autism)
24. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder within 6 months of 
screening or any time between screening and randomization
25. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate readings recorded 
on 2 separate days.  Those subjects who had hypertension at Screening can be rescreened more than
1 month after initiation or adjustment of antihypertensive therapy 1 time.
26. Currently enrolled in another clinical study or has used any investigational drug or device within 30 days 
before providing informed consent
27. Planned bariatric surgery during the study or prior bariatric surgical procedures (revised per 
Amendment 03)
28. Not suitable to participate in the study in the opinion of the investigator, including consideration of any 
existing physical, medical, or mental condition that prevents compliance with the protocol
29. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
β-human chorionic gonadotropin test).  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.
30. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a 
highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier 
method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire 
study period and for 28 days after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described above) or refrain 
from sexual activity during the study period and for 28 days after study drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during 
the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]).
Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated, biconvex tablets
with one 20-mg tablet administered orally QD.
Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  up to 30 days
Randomization Phase: approximately 56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal preparations, are 
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prohibited as concomitant medications.  OTC cold medicines containing dextromethorphan can be used for up 
to 7 days with study medication temporarily stopped for that time period and resumed the next day after the 
OTC cold medicine is stopped.  Any of the following serotonergic agents or other agents in combination with 
Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
The following concomitant medication guidelines/restrictions will apply:

Medications for the treatment of hypertension, dyslipidemia, or diabetes may be started, discontinued, or 
adjusted during the study according to local standards of care if, in the judgment of the investigator or the 
subject’s physician, such a change is medically indicated.

For diabetic subjects treated with sulfonylureas, insulin (note that subjects should not be enrolled as 
indicated in exclusion criteria), or other antidiabetic agents with hypoglycemic risk, the risk of 
hypoglycemic events may be higher if the subjects experience rapid and significant weight loss (more than 
10% weight reduction than at the previous visit).  It is recommended that the physician advise the subject 
to monitor their blood glucose more frequently and adjust their antidiabetic medications and diet 
accordingly. 

The antihyperglycemic medication dose would be considered for reduction in the event of 1 documented 
and otherwise unexplained hypoglycemic event (blood glucose concentration <65 mg/dL) or 2 
undocumented and otherwise unexplained suspected hypoglycemic events between any 2 scheduled visits. 
For subjects on more than 1 antihyperglycemic medication, it is recommended to reduce insulin first (if 
applicable), then the oral and/or other injectable antidiabetic agents.  If the previous criteria are met again 
following dose reduction, further dose reductions or cessation of 1 or more anti-hyperglycemic agents, are 
suggested.  See Section 9.5.4.2 for the definition and reporting of hypoglycemic events. 
To minimize the risk of cardiac valve toxicity, subjects must not initiate use of agents that have documented 
correlation with increased incidence of valvulopathy and/or pulumonary hypertension (eg, pergolide, 
ergotamine, methysergide, or cabergoline) during the study.  If any of the above agents are clinically warranted, 
and subjects initiate any of these agents, lorcaserin HCl should be discontinued but can be restarted on 
lorcaserin HCl after being off the medications above for 1 month.  Otherwise, the study medication should not 
be restarted, but the subject should continue all study visits.  (revised per Amendment 03)
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Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to calculate the 
proportion (%) of subjects achieving at least a 5% and at least a 10% BMI reduction.

Waist circumference (revised per Amendment 03)

Total body fat mass and total body lean mass will be determined centrally using DEXA in a subset of 
randomized subjects (selected prior to randomization) at selected sites at Baseline and Week 52/EOT
(revised per Amendment 03)

Measurement of systolic and diastolic BP, heart rate (taken after resting for 5 minutes), fasting lipids (total 
cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), fasting plasma glucose, fasting insulin,
HbA1c, and Homeostasis Model Assessment (HOMA) IR to assess cardiovascular and metabolic risk 
profiles from Baseline to Week 52 (revised per Amendment 03)

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents
Every effort will be made to ensure that at least 80% of randomized subjects will have an assessment of the 
primary efficacy endpoint regardless of whether or not the subject remained on study drug or completed other 
study assessments.  (revised per Amendment 03)
Pharmacokinetic Assessments
Blood samples (approximately 4 mL each) for PK assessment will be collected at Weeks 12, 28, 36, and 52 for 
analysis of Population PK. (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at 
home before the visit,but to bring their study drug to the clinic visit, and take their daily dose at the clinic.  
Two blood samples for determination of plasma concentrations of lorcaserin will be taken: 1 predose (within 
30 minutes before dosing), and 1 within 1 to 3 hours after dosing.  Dose times must be recorded for the last 
2 dosing times before the day of clinic visit. Week 52 PK samples should only be collected if the sample can be 
drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at home, and will be 
asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for for PK 
assessments will be collected. Dose times must be recorded for the last 2 dosing times prior to the clinic visit.
(revised per Amendment 01)
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their relationships 
with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious adverse events 
(SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, metabolic function (fasting glucose, 
fasting lipids, and thyroid), adrenal function and biochemical blood and urine bone health assessments; blood 
chemistry and urine values; neuropsychiatric events; periodic measurement of vital signs, neuromuscular signs
for screening potential serotonin syndrome, and signs or symptoms of priapism and hyperprolactinemia; and 
performance of physical examinations. In patients with potential prolactin-related AEs, such as galactorrhea, 
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changes in libido, or changes to menstrual cycle, fasting prolactin level will be measured and assessed.
Other Safety Assessments
Effect on growth will be evaluated using the CDC growth chart and bone age determination by x-ray of the 
hand. Sexual maturation will be evaluated by assessing sex hormones and Tanner Staging.   
The C-SSRS will be used to assess all subjects in the study for any signal of depression or suicidal ideation or 
behavior at every visit.  Additionally, screening, diagnosing, monitoring, and measuring the severity of 
depression will be assessed using the PHQ-9 and effects on cognition will be assessed using the Leiter-3.  
(revised per Amendment 01)
Bone mineral density and content, total body fat mass and total body lean mass will be determined using DEXA 
in a subset of randomized subjects (selected prior to randomization) at selected sites.  (revised per Amendment 
03)
Echocardiographic assessments will be used to exclude subjects with FDA-defined valvulopathy, pulmonary 
hypertension, and other major cardiovascular disease (as outlined in Exclusion Criterion No. 3) during the 
Screening Period.  Additionally, cardiac valvular function and pulmonary systolic pressure changes at Weeks
28 and 52 will be assessed only for subjects at selected sites.
Valvular regurgitation as assessed in the 
echocardiogram will be rated absent, trace, mild, moderate, or severe for the aortic, mitral, and tricuspid valves; 
the rating will be absent or present for the pulmonic valve. The evaluations will be based on guidelines from the 
American Society of Echocardiography. Pulmonary artery pressure will be estimated from the TR jet velocity.  
(revised per Amendment 03)
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography coupled with tandem mass 
spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Association between change and percentage change in BMI from Baseline to Week 52 with the outcome of 
achieving at least a 5% BMI reduction at Week 12 (revised per Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI reduction at 
Week 52 with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Change in waist circumference from Baseline to Week 52

Change in total body composition (total fat and lean mass) in a subset of randomized subjects at end of 52 
weeks of treatment (revised per Amendment 03)

Change in HbA1c from Baseline to Week 52 for subjects with Type 2 diabetes as baseline (revised per 
Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for subjects with 
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Type 2 diabetes as baseline (revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for the subjects 
without Type 2 diabetes at baseline (revised per Amendment 03)

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) from 
Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52

Subjects compliance rate at each visit by pill count during 52 week treatment (revised per Amendment 03)
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and had at least 
1 post dose safety assessment.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater compliant 
with study medication, completed the study, have no major protocol deviations, have no violations of 
inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  The determination of subjects 
to be excluded from this population based on the above criteria and a list of major protocol violations will 
be included in the statistical analysis plan (SAP) and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid lorcaserin plasma 
concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who have at least 
1 adequately documented measurement of BMI.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as a 
supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in all efficacy 
analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from baseline in 
BMI will be analyzed using analysis of covariance model (ANCOVA) with factors of treatment,  sex (male and 
female) as fixed effect, and the baseline age and BMI as covariates.  The missing values will be imputed using a 
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are missing not at 
random (MNAR).  The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model and missing value 
imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on the PP.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy analyses described 
above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed and will be
described in the SAP.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI reduction at 
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Week 52. The secondary efficacy endpoint will be analyzed only if the test for the primary efficacy endpoint is 
statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using a logistic 
regression model with factors of treatment, sex (male and female), and baseline BMI as a covariate using FAS.  
Subjects with any missing assessment at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed using 
mixed effect model repeated measurement analysis (MMRM) and categorical variables will be analyzed using
the Cochran Mantel Haenszel test, Chi-square test, or logistic regression as appropriate.  Additional analysis 
may be performed as needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male and female), and 
race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific 
Islander, or White) and age.  Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using nonlinear mixed 
effects modeling. The effect of covariates such as baseline characteristics or demographics on PK will be 
explored. Derived exposure parameters such as the maximum observed concentration and the area under the 
concentration-time curve from time 0 to 24 hours at steady-state will be calculated from the final PK model 
using individual posterior estimates of the PK parameters and from dosing history. The PK analysis set will be 
used for this analysis.
Pharmacodynamic Analyses
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will be used for this 
analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% and ≥10% BMI 
reduction, and change in waist circumference from baseline) will also be assessed as part of the PD analysis.  
The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure and 
response, including but not limited to change in BMI from baseline and the probability of achieving at least a 
5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, exposure-safety relationships 
for select safety parameters may be explored graphically depending on the data at the end of study.  Any 
emergent relationship may be modeled as appropriate.  Any parameters based on the study data may be 
considered for exploratory assessment for its relationship to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the incidence 
of AEs (including changes from baseline in physical examination), growth (CDC growth chart and bone age 
determined by x-ray of the hand), sexual maturation (Tanner Staging), out-of-normal-range laboratory safety 
test values, change from baseline in laboratory safety test values, ECGs, and vital sign measurements will be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
Other Safety Analyses
In addition, cognition will be evaluated by the Leiter-3, depression will be evaluated by the PHQ-9, and suicidal 
ideation and behavior will be evaluated by the C-SSRS, and will also be summarized by treatment group using 
descriptive statistics or frequency count as appropriate. For echocardiographic assessments, the proportion of 
subjects who develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
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hypertension [pulmonary hypertension is defined when the subject’s systolic pulmonary artery pressure 
(SPAP) ≥40 mmHg evaluated by echocardiograph], and change from baseline in SPAP will be summarized by 
treatment group at Week 28 and Week 52 using descriptive statistics or frequency count as appropriate. (revised 
per Amendment 01)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in BMI from 
Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  Assuming a SD of 
2.2 kg/m2 and a 40% dropout rate, a sample size of 260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg 
treatment group; n=130 in the placebo group) will have at least 80% power to detect a treatment difference of 
1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at least a 5% 
BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, this sample of 260 subjects 
(130 subjects for Belviq XR 20 mg and 130 subjects for placebo) will also have greater than 78% power to 
detect an absolute difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 
2-sided Chi-Square test with α=0.05.
The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................20
5.1
Institutional Review Boards/Independent Ethics Committees ..............................20
5.2
Ethical Conduct of the Study.................................................................................21
5.3
Subject Information and Informed Consent...........................................................21
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................23
7
INTRODUCTION ...........................................................................................................24
7.1
Indication ...............................................................................................................24
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................25
7.1.1.1
Mechanism of Action...........................................................................25
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................25
7.1.2
Study Rationale............................................................................................26
8
STUDY OBJECTIVES....................................................................................................28
8.1
Primary Objective..................................................................................................28
8.2
Secondary Objectives.............................................................................................28
9
INVESTIGATIONAL PLAN..........................................................................................30
9.1
Overall Study Design and Plan..............................................................................30
9.1.1
Prerandomization Phase...............................................................................30
9.1.1.1
Screening Period..................................................................................30
9.1.2
Randomization Phase...................................................................................31
9.1.3
Extension Phase ...........................................................................................31
9.2
Discussion of Study Design, Including Choice of Control Groups.......................31
9.3
Selection of Study Population................................................................................32
9.3.1
Inclusion Criteria .........................................................................................32
9.3.2
Exclusion Criteria ........................................................................................33
9.3.3
Removal of Subjects From Therapy or Assessment....................................36
9.4
Treatments..............................................................................................................36
9.4.1
Treatments Administered.............................................................................36
9.4.2
Identity of Investigational Product...............................................................37
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................37
9.4.2.2
Comparator Drug .................................................................................37
9.4.2.3
Labeling for Study Drug......................................................................37
9.4.2.4
Storage Conditions...............................................................................38
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9.4.3
Method of Assigning Subjects to Treatment Groups...................................38
9.4.4
Selection and Timing of Dose for Each Subject..........................................39
9.4.5
Blinding........................................................................................................39
9.4.6
Prior and Concomitant Therapy...................................................................39
9.4.7
Treatment Compliance.................................................................................41
9.4.8
Drug Supplies and Accountability...............................................................41
9.5
Study Assessments.................................................................................................43
9.5.1
Assessments.................................................................................................43
9.5.1.1
Demography.........................................................................................43
9.5.1.2
Baseline Assessments ..........................................................................43
9.5.1.2.1
Medical History .............................................................................43
9.5.1.2.2
Urine Drug Screen .........................................................................43
9.5.1.3
Efficacy Assessments...........................................................................43
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................44
9.5.1.4.1
Pharmacokinetic Assessments .......................................................44
9.5.1.4.2
Pharmacodynamic Assessments ....................................................45
9.5.1.4.3
Pharmacogenomic and Other Biomarker Assessments .................45
9.5.1.5
Safety Assessments..............................................................................45
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...45
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................48
9.5.1.5.3
Laboratory Measurements .............................................................49
9.5.1.5.4
Vital Signs and Weight Measurements..........................................51
9.5.1.5.5
Height Measurements ....................................................................51
9.5.1.5.6
CDC Growth Measurements..........................................................51
9.5.1.5.7
Waist Circumference .....................................................................51
9.5.1.5.8
Physical Examinations...................................................................51
9.5.1.5.9
Electrocardiograms ........................................................................52
9.5.1.5.10
Other Safety Assessments..............................................................52
9.5.1.6
Other Assessments...............................................................................53
9.5.1.6.1
Pregnancy Test...............................................................................53
9.5.2
Schedule of Procedures/Assessments ..........................................................53
9.5.2.1
Schedule of Procedures/Assessments ..................................................53
9.5.2.2
Description of Procedures/Assessments Schedule...............................57
9.5.2.3
Total Volume of Blood Sampling........................................................57
9.5.3
Appropriateness of Measurements...............................................................57
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................58
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9.5.4.1
Reporting of Serious Adverse Events..................................................58
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................58
9.5.4.3
Reporting of Events Association with Special Situations....................59
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................59
9.5.4.3.2
Reporting of Study-Specific Events...............................................60
9.5.4.4
Expedited Reporting ............................................................................61
9.5.4.5
Breaking the Blind...............................................................................61
9.5.4.6
Regulatory Reporting of Adverse Events ............................................61
9.5.5
Completion/Discontinuation of Subjects.....................................................61
9.5.6
Abuse or Diversion of Study Drug ..............................................................62
9.5.7
Confirmation of Medical Care by Another Physician .................................62
9.6
Data Quality Assurance .........................................................................................62
9.6.1
Data Collection ............................................................................................62
9.6.2
Clinical Data Management ..........................................................................63
9.7
Statistical Methods.................................................................................................63
9.7.1
Statistical and Analytical Plans....................................................................63
9.7.1.1
Study Endpoints...................................................................................63
9.7.1.1.1
Primary Efficacy Endpoint ............................................................63
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................63
9.7.1.2
Definitions of Analysis Sets.................................................................64
9.7.1.3
Subject Disposition..............................................................................65
9.7.1.4
Demographic and Other Baseline Characteristics ...............................65
9.7.1.5
Prior and Concomitant Therapy...........................................................65
9.7.1.6
Efficacy Analyses ................................................................................66
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................67
9.7.1.7.1
Pharmacokinetic Analyses.............................................................67
9.7.1.7.2
Pharmacodynamic Analyses..........................................................67
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................67
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................68
9.7.1.8
Safety Analyses....................................................................................68
9.7.1.8.1
Extent of Exposure.........................................................................68
9.7.1.8.2
Adverse Events ..............................................................................68
9.7.1.8.3
Laboratory Values..........................................................................69
9.7.1.8.4
Vital Signs......................................................................................70
9.7.1.8.5
Electrocardiograms ........................................................................70
9.7.1.8.6
Other Safety Analyses....................................................................70
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9.7.2
Determination of Sample Size .....................................................................71
9.7.3
Interim Analysis...........................................................................................71
9.7.4
Other Statistical/Analytical Issues ...............................................................71
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................71
10
REFERENCE LIST .........................................................................................................72
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......74
11.1
Changes to the Protocol .........................................................................................74
11.2
Adherence to the Protocol......................................................................................74
11.3
Monitoring Procedures...........................................................................................74
11.4
Recording of Data..................................................................................................75
11.5
Identification of Source Data.................................................................................75
11.6
Retention of Records..............................................................................................76
11.7
Auditing Procedures and Inspection......................................................................76
11.8
Handling of Study Drug.........................................................................................76
11.9
Publication of Results ............................................................................................77
11.10 Disclosure and Confidentiality ..............................................................................77
11.11 Discontinuation of Study .......................................................................................77
11.12 Subject Insurance and Indemnity...........................................................................78
12
APPENDIX......................................................................................................................79
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests (revised per Amendments 01 and 03) ..............50
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  
(revised per Amendments 01 02 and 03)...................................................54
Table 3
Summary of Blood Sample Volumes (revised per Amendments 01 
and 03) .......................................................................................................57
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
(revised per Amendments 01 and 03)
Abbreviation
Term
ADA
American Diabetes Association
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
DEXA
Dual-energy X-ray Absorptiometry
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
Leiter-3
Leiter-3 International Performance Scale
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Abbreviation
Term
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
MAR
missing at random
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OGTT
oral glucose tolerance test
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PH
pulmonary hypertension
PHQ-9
Patient Health Questionnaire
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
RVOTAT
right ventricular outflow tract
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SPAP
systolic pulmonary artery pressure  
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TR
tricuspid regurgitation
TSH
thyroid stimulating hormone
ULN
upper limit of normal
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Abbreviation
Term
US
United States
WBC
white blood cell
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity has become a global epidemic, causing a serious public health concern.  In the 
United States, the prevalence of obesity in adolescents ages 12 and 19 years has almost 
doubled over the past 2 decades.  The rate increased from 10.5% between 1988 and 1994 to 
20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, defined in the 
United States as greater than or equal to the 95th percentile in gender- and age-specific body 
mass index (BMI), continues to grow at an alarming rate in the United States and globally.  
Based on data (Wang and Lobstein, 2006) using various criteria for the definition of obesity 
that included more than 30 countries in Europe, North America, Asia, and the West Pacific, 
prevalence of obesity in these countries has also increased significantly, at a rate comparable 
to that in the United States.
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may 
result in a decrease in life expectancy for the 1st time in 200 years (Peeters, et al., 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese adolescents are likely to become 
tomorrow’s obese adults (Whitaker, et al., 1997).
Current approaches to weight management in adults include lifestyle modification, 
pharmacotherapy, and invasive bariatric procedures.  Lifestyle modification involves a 
combination of diet, exercise, and behavioral change, and is the preferred and essential 
strategy for weight management in obese and overweight individuals, including adolescents.  
Although lifestyle modification can be very efficacious in some patients, adherence to the 
prescribed regimens is often poor.  As such, lifestyle modification alone is often not adequate 
and the weight loss is often transient.  On the other hand, bariatric surgery and various other 
invasive procedures are generally reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise, but are rarely used 
for adolescents.
The current standard of care for treatment of obesity in adolescent subjects ranges from
behavioral therapy including lifestyle intervention to the rare use of pharmacotherapy in 
adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
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(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies may be used in 
the present study to help retain participants.  These include a highly trained and competent 
site staff, ample waiting area, readily available parking (at no cost), access to mass transit, 
and reminder and follow-up calls.  In addition, sites may utilize fun and interactive group 
sessions with games and hands-on nutrition and physical activity demonstrations, random 
raffle drawings, social events, birthday and holiday cards, and newsletters to further 
encourage subject retention.  Furthermore, we may make home visits for primary efficacy 
assessments of, as needed, to maximize data collection. By incorporating some of these 
retention strategies, we hope that we will maximize participant retention, which will help us 
cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:

A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) was 
significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
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studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
used for adolescent subjects with body weight greater than 60 kg.
In adolescent obese populations, it is anticipated that Belviq XR will result in similar effects.
As part of FDA postmarketing requirements, this study is designed to characterize the 
efficacy and safety of Belviq XR in adolescent obese populations in the United States.  It is 
also intended to support an indication for chronic weight management for obese adolescents 
ages 12 to 17 years old. 
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of subjects 
in the placebo-treated group who lose at least 5% of baseline body weight, and the 
difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in obese adolescents, where weight loss will be assessed using BMI
measurements to account for growth. In this study, the objective is to demonstrate that BMI
reduction will be achieved during 52 weeks of treatment with Belviq XR 20 mg administered 
once daily (QD) compared to placebo in obese adolescents.
In the Phase 3 orlistat study in obese adolescents mentioned above, the proportion of subjects 
who lost at least 5% body weight is relatively low. At the end of the study at Week 52, only 
26.5% of the subjects achieved a 5% or greater BMI reduction compared to 15.7% in the 
placebo group. The placebo-corrected BMI reduction was about 0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years
(Peirson, et al, 2015).  Thirty-one studies (29 behavioral, 2 pharmacological and behavioral) 
were included in a meta-analysis of randomized studies conducted in primary care centers in 
overweight and obese children and youth ages 2 to 18 years using behavioral (diet, exercise,
and lifestyle) and pharmacological interventions and providing 6-month postbaseline BMI or 
prevalence of overweight or obesity. Both interventions showed a significant effect on BMI 
in favor of treatment (behavioral: 
standardized mean difference [SMD] -0.54, 
95% confidence interval [CI]
-0.73, -0.36; orlistat plus behavioral: 
SMD -0.43, 
95% CI -0.60, -0.25). The studies reported no significant difference between groups in the 
likelihood of reduced prevalence of overweight or overweight and obese. A great deal of 
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variation was noted across efficacious interventions.
In conclusion, this meta-analysis 
demonstrated low-quality evidence that behavioral treatments alone are associated with a 
smaller effect in terms of reduced BMI compared with the effect shown by combined 
behavioral and pharmacological interventions. This may be because the effect size in the 
randomized, double blind, placebo controlled, phase 3 orlistat study in adolescents was 
relatively low and there was a lack of maintenance effect. These subjects started to regain 
their BMI after 6 months of treatment. At end of the study, only 26.5% of subjects achieved 
a 5% or greater BMI reduction compared to 15.7% in placebo group. In a sibutramine 
Phase 3 study in obese adolescents, a substantially higher proportion of subjects (69%) 
treated with sibutramine achieved at least a 5% BMI reduction compared to 21% of subjects 
in the placebo group. In addition, sibutramine resulted in a substantial reduction in mean 
BMI (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 
8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the weight loss effect of Belviq
in adults and sibutramine in adolescents, subjects in the orlistat study started to increase their 
BMI after 6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of 260 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
sibutramine, and liraglutide 3 mg) (FDA, 2003; Chanoine, et al., 2005; Berkowitz, et al,
2006; CT.gov NCT02918279) and other metabolic or dyslipidemia medication products
(ezetimibe, simvastatin) (FDA, 2007).  (revised per Amendment 02)
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8
STUDY OBJECTIVES
8.1
Primary Objective

To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment with 
Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR
20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of 
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in 
BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo
(revised per Amendment 01)

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% 
BMI reduction, change in waist circumference) at the end of 52 weeks of treatment
-
Effects on fasting glucose, hemoglobin A1c (HbA1c), insulin levels, and Homeostatic 
Model Assessment of Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin 
[mU/L]/405) in subjects with Type 2 diabetes at baseline during 52 weeks of 
treatment (revised per Amendment 03)
-
Effects on fasting glucose, HbA1c, insulin levels, and HOMA-IR; glucose [mg/dL] × 
insulin [mU/L]/405 in subjects without Type 2 Diabetes at Baseline during 52 weeks 
of treatment (revised per Amendment 03)
-
Effects on body fat and lean mass composition by Dual-enerygy X-ray 
Absorptiometry (DEXA) in a subset of randomized subjects (selected prior to 
randomization) at selected sites during 52 weeks of treatment (revised per 
Amendment 03)
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high 
density lipoprotein [HDL], low density lipoprotein [LDL]), systolic and diastolic 
blood pressure, and heart rate) during 52 weeks of treatment (revised per 
Amendment 03)
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•
To assess the safety of Belviq XR, including the effects on cognition by Leiter-3 
International Performance Scale (Leiter-3), depression with the Patient Health 
Questionnaire 
(PHQ-9), 
signal 
of 
suicidal 
ideation 
or 
behavior 
with 
the 
Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by CDC growth 
chart, sexual maturation (pubescence) measured by Tanner Staging scores, and other 
growth and development parameters by measuring sex hormones, thyroid function, 
adrenal function, bone age, and biochemical markers of bone health, bone mineral 
density and content, total body fat mass and total body lean mass by DEXA in a subset of 
randomized subjects (selected prior to randomization) at selected sites, valvular function, 
pulmonary arterial pressure. (revised per Amendments 01 and 03)
•
To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling
•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
probability of achieving at least a 5% and at least a 10% reduction in BMI from baseline 
at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (130 subjects) and placebo (130 subjects).  Subjects will be 
stratified by sex.  Subjects will receive Belviq XR 20 mg or matched placebo QD in a 1:1 
ratio for up to 52 weeks. A recruitment plan will be developled to ensure at least 20% of 
younger subjects (12 to 13 years of age) are enrolled in the study.  Throughout the duration 
of the study, subjects will be encouraged to adhere to a lifestyle modification program that 
includes a standardized, age-appropriate diet and exercise counseling (see Appendix 2).  
(revised per Amendments 02 and 03)
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be rescreened only once after 30 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.  All attempts will be made 
to capture height and weight in all subjects whether or not they are still on study drug at the 
end of the study.  (revised per Amendment 03)
Study sites will be selected to ensure adequate representation of adolescents of ethinic and 
racial minorities.  (revised per Amendment 03)
A Data Monitoring Committee (DMC) will be established to monitor and conduct periodic 
safety review of unblinded data. DMC members will be chosen based on their expertise in 
evaluating these clinical events. A separate DMC charter will be established.  (revised per 
Amendment 03)
9.1.1
Prerandomization Phase
Screening will occur during the Prerandomization Phase at Visit 1.
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
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description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
9.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025.  Overall, the PK parameters of Belviq and its main 
metabolites, M1 and M5, were similar to those in adults.  Following a single, oral 
administration of Belviq 10 mg to a total of 8 healthy adolescent (ages 12 to 17 years old) 
obese subjects, the mean maximum concentration observed and the area under the 
concentration-time curve from time zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 
464 hr×ng/mL, respectively.  The mean Belviq terminal phase half-life was 9.70 hours, 
similar to that observed in adults, thus supporting a similar dosing frequency (QD) in 
adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric or adolescent subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of subjects who are older than 12 years of age 
having a body weight of less than 60 kg is very low; therefore, the current study as designed 
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to enroll subjects between 12 to 17 years of age with body weight at least 60 kg, will cover
majority of the population of interest.  The targeted study population comprises 260 obese 
adolescents 12 to 17 years of age, with a body weight at least 60 kg.  (revised per 
Amendment 02)
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
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, 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 500 subjects will be screened to ensure that 260 subjects will be randomized.  
(revised per Amendment 02)
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug.
Subjects who screen fail can be re-screened immediately 
without repeating the screening echocardiogram for up to 90 days after the previous 
echocardiogram.  All other screening assessments must be repeated when a subject is re-
screened.  Subjects that re-screen more than 90 days after the previous echocardiogram must 
repeat all screening assessments including the screening echocardiogram.  (revised per 
Amendment 03)
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, ages 12 to 17 years old (inclusive) at Screening, with 
an initial BMI that is greater than or equal to the United States (US)-weighted mean of 
the 95th percentile based on age and sex with a body weight greater than 60 kg.  Subjects 
with T2DM may have a pre-existing or new diagnosis of T2DM.  
Subjects with pre-existing T2DM should have prior documentation consistent with the 
diagnosis and/or be on active pharmacotherapy for T2DM.  
Subjects with a new diagnosis of T2DM (ie, diagnosed at Screening) should be based on 
the 2016 American Diabetes Association (ADA) guidelines.  The diagnostic criteria are 
met if a subject has unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL 
(11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis) OR any 
of the following criteria are observed and then confirmed:
o
HbA1c ≥6.5% 
o
fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 
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o
2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) by an oral glucose tolerance 
test (OGTT)
All T2DM subjects must have an HbA1c <10% at Screening.  If subjects are being or 
need to be treated with antidiabetic agents, the T2DM treatment regimen must be stable 
for at least 3 months before randomization.  A single rescreen is allowed following 
stabilization.  Stable control refers to minimal dose changes to existing medications for 
glycemic control and no medications being initiated for glycemic control in the 3 months 
before Randomization.  Minimal changes are defined as a change without any change in 
dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject 
has not been hospitalized due to hypo- or hyperglycemic events.  (revised per 
Amendment 03)
2. Subjects and their families are not planning to move away from the area for the duration 
of the study
3. Able and willing to comply with all aspects of the study, including a standardized,
reduced-calorie diet and an age-appropriate, increased physical activity program
4. Considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may affect 
the subject’s ability to fulfill the study requirements or significantly confound the 
assessments
2. Who cannot swallow investigational products
3. With Type 2 diabetes who have hypoglycemia unawareness (revised per Amendment 03)
4. Any of the following findings on screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, 
mean gradient >25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean 
gradient >5 mm Hg and mitral valve area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure
(SPAP) >40 mm Hg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
-
In cases where an actual SPAP value is not measurable due to lack of adequate 
TR jet, the pulmonary flow acceleration time measured at the right ventricular 
outflow tract (RVOTAT), will be used to assess eligibility. Patients with a 
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RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be 
determined based on combined assessment of the TR jet, septal motion and right 
ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with 
hemodynamic compromise)
5. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
6. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, bipolar disorder, or schizophrenia
7. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months 
of Screening, as indicated by answering “Yes” to questions 4 or 5 on the Suicidal 
Ideation section of the C-SSRS.
8. Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
9. Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi 
syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, 
Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 30 days, 
history of significant exposure to corticosteroids for chronic illness during the past year; 
inhaled steroids will be allowed) (revised per Amendment 03)
10. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before Screening
11. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 

bupropion

triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
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b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
12. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and 
cabergoline
13. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), Type 2 diabetes treated with oral anti-diabetic 
agents (excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive 
sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
14. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or 
any of the excipients
15. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
16. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 6 months
before Screening
17. History of alcohol or drug dependence or abuse
18. Recreational drug use within 2 years before Screening
19. Known to be human immunodeficiency virus (HIV) positive
20. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
21. Malignancy within 5 years before Screening
22. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
23. Special needs subjects who are unable to comprehend study-related instructions (eg, mild 
to profound mental retardation [IQ <70], moderate to severe cognitive developmental 
delay, pervasive development disorders, autism)
24. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
25. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate 
readings recorded on 2 separate days.  Those subjects who had uncontrolled hypertension 
at Screening can be rescreened more than 1 month after initiation or adjustment of 
antihypertensive therapy 1 time.
26. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
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27. Planned bariatric surgery during the study or prior bariatic surgical procedures (revised 
per Amendment 03)
28. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
29. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
30. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 
28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after 
study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use 
the same contraceptive during the study and for 28 days after study drug 
discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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.
Investigators should do their best to bring all subject who discontinued early from the study
in for the their primary endpoint collection regardless of the reason for ED. (revised per 
Amendment 01)
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD at 
approximately the same time each day.
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Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled with text that is in full regulatory compliance with each 
participating country. As the study is being conducted in US only, the study drug label will 
be printed in English. 
The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal (US) law to 
investigational use.”
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All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug was 
dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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.
Subjects will be centrally stratified by sex (male and female).  Within each stratum, subjects 
will be randomized to receive either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  
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Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily at approximately the same time of 
every day, and be encouraged to take the study medication with an adequate amount of water 
(8 oz. or 240 mL).  For information on dosing on visits associated with PK sampling, see 
Section 9.5.1.4.1.  (revised per Amendment 03)
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
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Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
The following concomitant medication guidelines/restrictions will apply:

Medications for the treatment of hypertension, dyslipidemia, or diabetes may be 
started, discontinued, or adjusted during the study according to local standards of care 
if, in the judgment of the investigator or the subject’s physician, such a change is 
medically indicated.

For diabetic subjects treated with sulfonylureas, insulin (note that subjects should not 
be enrolled as indicated in exclusion criteria), or other antidiabetic agents with 
hypoglycemic risk, the risk of hypoglycemic events may be higher if the subjects 
experience rapid and significant weight loss (more than 10% weight reduction than at 
the previous visit).  It is recommended that the physician advise the subject to 
monitor their blood glucose more frequently and adjust their antidiabetic medications 
and diet accordingly. 
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
The antihyperglycemic medication dose would be considered for reduction in the 
event of 1 documented and otherwise unexplained hypoglycemic event (blood 
glucose concentration <65 mg/dL) or 2 undocumented and otherwise unexplained 
suspected hypoglycemic events between any 2 scheduled visits.   For subjects on 
more than 1 antihyperglycemic medication, it is recommended to reduce insulin first 
(if applicable), then the oral and/or other injectable antidiabetic agents.  If the 
previous criteria are met again following dose reduction, further dose reductions or 
cessation of 1 or more anti-hyperglycemic agents, are suggested.  See Section 9.5.4.2
for the definition and reporting of hypoglycemic events. 
To minimize the risk of cardiac valve toxicity, subjects must not initiate use of agents that 
have documented correlation with increased incidence of valvulopathy and/or PH (eg, 
pergolide, ergotamine, methysergide, or cabergoline) during the study.  (revised per 
Amendment 01)  If any of the above agents are clinically warranted, and subjects initiate any 
of these agents, lorcaserin HCl should be discontinued but can be restarted on lorcaserin HCl 
after being off the medications above for 1 month.  Otherwise, the study medication should 
not be restarted, but the subject should continue all study visits.  (revised per Amendment 03)
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Subjects will 
be asked to bring their study drug bottles to each visit.  The CRAs will review treatment 
compliance during site visits and at the completion of the study.  (revised per 
Amendment 03)
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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
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•
An investigator-signed and dated Form FDA 1572, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 (US 
sites only).  Must be appropriate to handle schedule IV products and not be expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
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at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.2.2
URINE DRUG SCREEN
A 30-mL urine sample will be collected at Screening, as specified in the Schedule of 
Procedures/Assessments (Table 2).  This sample will be tested for common drugs of 
use/abuse (eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, nicotine/cotinine, opioids 
[as a group], benzodiazepines, barbiturates, amphetamines). (revised per Amendment 01)
9.5.1.3
Efficacy Assessments

Body weight and height: will be measured using a standard stadiometer method (Lohman 
T, et al, 1988) to calculate changes in BMI.
Body weight will be measured in the 
morning after at least 8 hours of fasting and voiding using a calibrated scale and 
standardized instructions for clothing (ie, a hospital gown). Weight will be measured to 
the nearest 0.1 kg. Height will be measured in triplicate utilizing a stadiometer with a 
standardized process (eg, subjects should not be wearing shoes). Height must be 
measured to the nearest 0.1 cm.  BMI will then be used to calculate the proportion (%) of 
subjects achieving at least a 5% and at least a 10% BMI reduction.  (revised per 
Amendment 03)
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
Waist circumference: will be determined by measurement taken with a tape measure 
positioned horizontally, parallel to the floor, at one finger width above the iliac crest. The 
subject should be standing erect with relaxed abdominal muscles.  The tape measure 
should be snug but not compress the skin. The waist circumference should be taken to the 
nearest 1.0 cm, at the end of normal expiration. Three measurements will be taken and 
the average will be calculated. (revised per Amendment 03)

Total body fat mass and total body lean mass:  will be determined centrally using DEXA 
in a subset of randomized subjects (selected prior to randomization at selected sites) at 
Baseline and Week 52/EOT  (revised per Amendment 03)

Measurement of systolic and diastolic BP, heart rate (taken after resting for 5 minutes), 
fasting lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), 
fasting plasma glucose, fasting insulin, HbA1c, and HOMA-IR to assess changes in 
cardiovascular and metabolic risk profiles from Baseline to Week 52 (revised per 
Amendment 03)

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 
(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents, 2011)

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011)
Every effort will be made to ensure that at least 80% of randomized subjects will have an 
assessment of the primary efficacy endpoint regardless of whether or not the subject 
remained on study drug or completed other study assessments.  (revised per Amendment 03)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for Population PK analyses.  (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take 
their study drug at home before the visit, but to bring their study drug to the clinic visit and 
take their daily dose at the clinic.  Two blood samples for determination of plasma 
concentrations of lorcaserin will be taken 1 predose (within 30 minutes before dosing) and 1 
within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times 
before the day of clinic visit. Week 52 PK samples should only be collected if the sample can 
be drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug at home, and will 
be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood 
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sample for PK assessment will be collected.  Dose times must be recorded for the last 2 
dosing times prior to the clinic visit. (revised per Amendment 01)
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
coupled with tandem mass spectrometry method. The collection, handling, and shipping 
procedures for PK samples will be described in a manual to be provided to the study sites.
At Unscheduled Visits, PK samples should only be collected if subject has experienced a 
serious adverse event (SAE) while on study drug and the sample can be drawn within 60 
hours of the initiation of the SAE. (revised per Amendment 01)
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Lorcaserin plasma exposure from PK analysis and population PK/PD modeling will be used 
to explore the relationship between lorcaserin plasma exposure and following response to 
lorcaserin: 

Change from Baseline in BMI 

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC AND OTHER BIOMARKER ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; electrocardiograms 
(ECGs); laboratory evaluations for hematology, metabolic function (fasting glucose, lipids,
and thyroid), adrenal functions, and biochemical blood and urine bone health assessments;
blood chemistry and urine values; neuropsychiatric events; periodic measurements of vital 
signs, neuromuscular signs for screening potential serotonin syndrome, and signs and 
symptoms of priapism and hyperprolactinemia; and performance of physical examinations.  
In subjects with potential prolactin-related AEs, such galactorrhea, changes in libido, or
changes to menstrual cycle, fasting prolactin level will be measured and assessed.  (revised 
per Amendment 03)
Bone mineral density and content, total body fat mass and total body lean mass will be 
determined using DEXA in a subset of randomized subjects (selected prior to randomization)
at selected sites.  (revised per Amendment 03)
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
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relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
At each visit, the investigator should actively assess as to whether any of the following 
adverse events have occurred during the interval since the last visit:
•
Serotonin syndrome and signs or symptoms of serotonergism
•
Signs or symptoms of valvular heart disease or pulmonary hypertension, including 
dyspnea, dependent edema, congestive heart failure, or a new cardiac murmur
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•
Impairments in attention and memory, and confusion, somnolence, and fatigue
•
Psychiatric disorders
•
Hypoglycemia in subjects with diabetes on concomitant anti-diabetes medications (using 
ADA definitions)
•
Priapism and hyperprolactinemia signs and symptoms should be recorded at each visit 
and whenever reported
•
Hypersensitivity reactions
Any such events should be recorded as adverse events.  Serotonin syndrome, valvular heart 
disease, pulmonary hypertension, and priapism should always be reported as serious adverse 
events (SAEs) (See Section 9.5.1.5.2 for a complete list of adverse events that should always 
be considered as Serious).  (revised per Amendment 03)
Events of hypoglycemia in subjects with diabetes on concomitant anti-diabetes medication 
should be captured as per Section 9.5.2.  Severe symptomatic events of hypoglycemia should 
always be reported as an SAE as per Section 9.5.1.5.2.  (revised per Amendment 03)
It is the responsibility of the investigator to review the results of the Leiter-3, C-SSRS, and 
PHQ-9 for all subjects and determine if any result constitutes an AE.  Medical and scientific 
judgment should be exercised in deciding whether an isolated suicidality rating scale 
response should be classified as an AE (see Section 9.5.1.5.10 for a description of the 
C-SSRS).  (revised per Amendment 01)
All AEs must be monitored until symptom resolution, or until the condition stabalizes.  
(revised per Amendment 03)
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
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
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•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of the 
event
•
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious criteria:
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•
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
•
Priapism
•
New onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms (revised per Amendment 03)
•
Fibroadenomas of the breast or ductal carcinoma in situ
•
Severe symptomatic hypoglycemia (revised per Amendment 03)
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
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the study.
Laboratory testing should be conducted on an unscheduled basis if clinically 
indicated.  (revised per Amendment 03)
Table 1
Clinical Laboratory Tests (revised per Amendments 01 and 03)
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium, bicarbonate
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
Thyroid function
T4, TSH
Adrenal function
AM serum Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects)
Bone health assessments
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other (revised per Amendment 01)
Albumin, calcium, globulin, fasting glucose, HbA1c, HDL 
cholesterol, fasting insulin, lactate dehydrogenase, LDL cholesterol,
fasting lipid panel, phosphorus, total protein, total cholesterol,
triglycerides,, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
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9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained in triplicate to the nearest 0.1 cm as designated 
in the Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 03)
9.5.1.5.6
CDC GROWTH MEASUREMENTS
Investigators will calculate the height for age percentile and weight for age percentile 
utilizing the most recent CDC 95th Percentile Growth Chart and the height and weight 
measurements obtained, as designated in the Schedule of Procedures/Assessments (Table 2).  
(revised per Amendment 01)
9.5.1.5.7
WAIST CIRCUMFERENCE
Waist circumference (cm) measurements will be obtained in triplicate to the nearest 1.0 cm 
taken 3 times at each visit as designated in the Schedule of Procedures/Assessments 
(Table 2).  (revised per Amendments 01 and 03)
9.5.1.5.8
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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 eCRF.
As part of the physical examination, a neuromuscular sign assessment for serotonin 
syndrome will be performed for potential serotonergic syndrome components.  Serotonergic 
syndromes that meet the diagnostic criteria will be captured by AE eCRF.
(revised per 
Amendment 01)
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will also be captured in the AE eCRF. (revised per 
Amendment 01)
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9.5.1.5.9
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.10 OTHER SAFETY ASSESSMENTS
Leiter-3
The Leiter International Performance Scale–Third Edition (Leiter-3) is widely used 
non verbal measure of intelligence, memory, and attention in those between the ages of 3 and 
75 years. 
The Attention/Memory Battery consists of 5 subtests: 2 measure nonverbal 
attention; 2 measure memory; and 1 measures cognitive interference (nonverbal Stroop test). 
These subtests are combined to produce a Memory and Processing Speed composite scores, 
normalized to a mean of 100 and standard deviation of 15. The Leiter-3 will be used to 
assess lorcaserin effects on cognition, specifically, attention and memory. In addition, signs 
and symptoms of cognition-related AEs, including impairments in attention, memory, and 
adverse effects on schoolwork will be captured in the eCRF. (revised per Amendment 01)
PHQ-9
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and 
measuring the severity of depression:

The PHQ-9 incorporates Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV) depression diagnostic criteria with other leading major depressive 
symptoms into a brief self-report tool.

The tool rates the frequency of the symptoms which factors into the scoring severity 
index.

Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.

A follow-up, non-scored question on the PHQ-9 assigns weight to the degree to which 
depressive problems have affected the patient's level of function. 
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. Qualified personnel must evaluate positive 
responses on the C-SSRS and take appropriate action as detailed in the training and 
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certification process for administering the C-SSRS.  It will be performed at Screening and at 
study visits as designated in the Schedule of Procedures/Assessments (Table 2). (revised per 
Amendment 01)
DEXA for the Assessment of Bone Mineral Density
Bone mineral density body composition determination by DEXA whole body composition, to 
include bone mineral density and content, total body fat mass and total body lean mass will 
be determined using DEXA in a subset subjects (selected prior to randomization) at selected 
sites.  A contracted vendor will provide all administration and project management services 
for DEXA scanning.  This will include site and image data management services, as well as 
site training and certification.  (revised per Amendment 03)
A miminum of 30 subjects ages 12-18 years (selected prior to randomization) should have 
bone density evaluated with DEXA at BL and week 52/EOT.  (revised per Amendment 03)
Hand X-Ray
A hand x-ray for evaluation of any potential negative effect on bone age will be performed 
on the same hand at each visit as designated in the Schedules/Assessments (Table 2).  
(revised per Amendment 01)
Tanner Staging
The pubic hair growth (both sexes), genital (males only) and breast (females only) 
development of subjects will be using Tanner Staging by a trained clinician (Marshall, 1970).
Subjects will be examined by the investigator as designated in the Schedules/Assessments 
(Table 2). (revised per Amendments 01 and 03)
Echocardiogram
Echocardiograms will be obtained on the Schedule of Procedures/Assessments (Table 2). 
Valvular regurgitation in echocardiogram will be rated absent, trace, mild, moderate, or 
severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve.  The evaluations will be based on guidelines from the American Society of 
Echocardiography. Pulmonary artery systolic pressure will be estimated from the TR
regurgitant jet velocity.  (revised per Amendment 03)
9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at every visit as specified in the 
Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 03)
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01, 02
and 03)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examinatione
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, insulin, and HbA1c sampling
X
X
X
X
X
X
T4 and TSH
X
X
X
X
X
Testosterone, Estradiol
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01, 02
and 03)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Pregnancy test (urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting prolactin
X
X
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Fasting lipid panel
X
X
X
X
Urine NTX
X
X
X
X
PK/PD blood sampling
X
X
X
Xf
Xg
Xf
AM serum cortisol
X
X
X
ECG
X
X
X
X
Echocardiograph
Xh
X
X
DEXAi
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
Leiter-3
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01, 02
and 03)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatmentb
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USc
ED
Day:
-30 to -1
1
Weeks,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Standardized age-appropriate lifestyle modification 
counselingj
X
X
X
X
X
X
X
X
X
X
AE = adverse event, AM = morning; CDC = Centers for Disease Control and Prevention, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, ED = 
early discontinuation, EOS = End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, IxRS = interactive voice or web response system, NTX = N-telopeptide, OC 
= osteocalcin; PHQ-9 = The Patient Health Questionnaire, PICP = carboxyterminal propeptide of type I procollagen,  PD = pharmacodymanic, PK = pharmacokinetics, SAE = 
serious adverse event; T4 = thyroxine, TSH = thyroid stimulating hormone, US = unscheduled.
a: Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b: Window ±7 days for all visits. (revised per Amendments 01 and 03)
Unscheduled visits may be conducted at any time that additional assessments are indicated in the clinical judgment of the investigator.  Note that not all assessments listed 
under Unscheduled Visit need to be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs.  At 
Unscheduled Visits, PK samples should only be collected if subject has experienced a serious adverse event (SAE) while on study drug and the sample can be drawn within 
60 hours of the initiation of the SAE. (revised per Amendments 01 and 03)
c: On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at home before the visit, but to bring their study drug to the clinic 
visit and take their daily dose at the clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken:  1 predose (within 30 minutes before 
dosing) and 1 within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times before the day of clinic visit. Week 52 PK samples should only be 
collected if the sample can be drawn within 60 hours of the last dose of study drug.  On the day of the Week 36 clinic visit, subjects will take the morning dose at home, and 
will be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for PK assessments will be collected  Dose times must be recorded for the 
last 2 dosing times prior to the clinic visit. (revised per Amendment 01)
d: Includes a neuromuscular assessment for serotonin syndrome, and signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle abnormalities 
or galactorrhea) (revised per Amendments 01 and 03)
e: PK samples should only be collected if the sample can be drawn within 60 hours of the last dose of study drug.
f: PK samples should only be collected if subject has experienced an SAE while on study drug and the sample can be drawn within 60 hours of the initiation of the SAE.
g: Echocardiographic assessments will be performed during screening period after subjects have met all other inclusion and exclusion criteria.
h: Only subjects in selected sites will have this assessment done.  (revised per Amendment 03)
i: Lifestyle modification counseling will also be performed at Weeks 3, 16, 24, 32, 40, and 48 in addition to counseling at the scheduled visits in Appendix 2.
.
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes (revised per Amendments 01
and 03)
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
(Chemistry and Hematology)
5
Screening: 1
Visits 2, 3, 4, 6, 8, 11 (EOT),
EOS or ED
58=40
T4, TSH, AM Serum 
Cortisol, Testosterone, 
estradiol 
6
Screening:  1
Visits 2, 8, 11 (EOT), or ED
6×4=24
Serum OC and PICP, 
Hydroxy-proline; Fasting 
lipid panel (HDL cholesterol, 
LDL cholesterol, total 
cholesterol, triglycerides)
8
Visits 2, 8, 11 (EOT), or ED
8×3=24
Fasting Prolactin, FPG, 
fasting insulin, and HbA1c
sampling
5
Screening:  1
Visits 2, 6, 8, 11 (EOT) or ED, 
US
5×6=30
PK/PD blood sampling
4
Visits 6, 8, and 11 (EOT) or ED
(2 samples each); Visit  9 (1 
sample only)
7×4=28
Total
146
ED= early discontinuation from study, EOS = End of Study, EOT = End of Treatment, FPG = fasting plasma glucose, 
HbA1c = hemoglobin A1c, OC = osteocalcin, PD = pharmacodynamic, PICP = carboxyterminal propeptide of type I 
procollagen, PK = pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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.
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
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criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms (revised per Amendment 03)

Fibroadenomas of the breast or ductal carcinoma in situ


Severe symptomatic hypoglycemia (revised per Amendment 03)
Subject-reported episodes of hypoglycemia or decreased blood sugar should be captured on 
the eCRF according to the following guidelines:

Psuedo-hypoglycemia:  An event during which the person with diabetes reports any of 
the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia 
with a measured plasma glucose concentration >70 mg/dL (>3.9 mmol/L) but 
approaching that level.  (revised per Amendment 03)

Probable symptomatic hypoglycemia:  An event during which symptoms typical of 
hypoglycemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration ≤ 70 mg/dL (≤ 3.9 mmol/L)
(revised per Amendment 03)

Asymptomatic hypoglycemia: 
An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dL (≤ 
3.9 mmol/L) (revised per Amendment 03)

Documented symptomatic hypoglycemia: An event during which typical hypoglycemia 
symptoms are accompanied by a measured plasma glucose ≤70 mg/dL (≤3.9 mmol/L) 
(revised per Amendment 03)
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
Severe hypoglycemia: 
An event requiring assistance of another person to actively 
administer carbohydrate, glucagon or other resuscitation actions. Plasma glucose
measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration (revised per 
Amendment 03)
See Section 9.4.6 (Prior and Concomitant Therapy) for directions on the recommendations 
for possible adjustment to antihyperglycemic medication doses in response to reported 
episodes of hypoglycemia.  (revised per Amendment 03)
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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue study drug prematurely will continue to be evaluated on for all 
study assessments until study completion.  All attempts will be made to capture height and 
weight in all subjects whether or not they are still on IP at the end of the study.  All subjects 
who discontinue the study are to complete the study’s early discontinuation procedures 
indicated in the Schedule of Procedures/Assessments Table 2). (revised per Amendment 03)
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 contacted by 
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mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of the secondary reasons for discontinuation.  Study disposition information will 
be collected on the Subject Disposition CRF. If “lost to follow-up” is recorded in clinical 
data base, appropriate queries will be sent to investigators in order to collect all the relevant 
reasons for missing data.  (revised per Amendment 03)
Every effort, including proper training of all study participants and their parent/guardian, 
should be made in order to achieve optimal subject retention and prevent missing data, 
especially for the Week 52 primary endpoint.  A retention plan to help avoid missing data 
will be developed and included in study manual. (revised per Amendment 03)
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.  The DEA Registrant has 
the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
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guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 
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
Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Association between change and percentage change in BMI from Baseline to Week 52 
with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI 
reduction at Week 52 with the outcome of achieving at least a 5% BMI reduction at 
Week 12 (revised per Amendment 02)

Change in waist circumference from Baseline to Week 52

Change in total body composition (total fat and lean mass) in a subset of randomized 
subjects at end of 52 weeks of treatment (revised per Amendment 03)

Change in HbA1c from Baseline to Week 52 for subjects with Type 2 diabetes at baseline 
(revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for 
subjects with Type 2 diabetes at baseline (revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 for 
the subjects without Type 2 diabetes at baseline (revised per Amendment 03)

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52

Subject compliance rate at each visit by pill count during 52 weeks of treatement (per 
Amendment 03)
9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.
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
Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or 
greater compliant with study medication, completed the study, have no major protocol 
deviations, have no violations of inclusion or exclusion criteria, and have BMI data at 
Baseline and Week 52.  The determination of subjects to be excluded from this 
population based on the above criteria and list of major protocol violations will be 
included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 
1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and 
who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
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9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using analysis of covariance model (ANCOVA) with 
factors of treatment, sex (male and female) as fixed effect, and the baseline age and BMI as 
covariates.  The missing values will be imputed using a pattern mixture model utilizing 
multiple imputation (MI) assuming the missing values are missing not at random (MNAR).  
The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model 
and missing value imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated based 
on the PP.

Change from baseline in standardized BMI score (Z-score): The same primary efficacy 
analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed 
and will be described in the SAP.  
Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, and sex (male and 
female), and baseline BMI as a covariate using FAS.  Subjects with any missing assessment 
at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using mixed effect model repeated measurement analysis (MMRM) on the FAS for 
study treatment compared to placebo, as appropriate. The model will include all data and will 
include treatment, time, and the interaction of treatment by time as fixed effects, with 
adjustment for sex (male versus female), BMI and age at baseline, and subject as a random 
effect.  (revised per Amendment 03)
Treatment by time interaction will be used to construct the treatment comparisons at a 
specific time.  The MMRM model assumes that the missing data are missing at random and 
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makes use of all available data even if a subject has missing data at some post-baseline visits.  
An unstructured covariance matrix will be used, and if the model fails to converge, then an 
autoregressive matrix will be used.  (revised per Amendment 03)
Categorical variables will be analyzed using the Cochran Mantel Haenszel test, Chi-square 
test, or logistic regression as appropriate.  Additional analysis may be performed as needed 
using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male 
and female), race (American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or other Pacific Islander, or White), and age. Additional subgroups may be 
explored, if deemed necessary.  (revised per Amendment 03)
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will 
be used for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also be 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
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9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination, 
neuromuscular sign assessment for serotonin syndrome, and signs and symptoms of priapism 
and hyperprolactinemia), out-of-normal-range laboratory safety test values, change from 
baseline in laboratory safety test values, ECGs, vital sign measurements, bone mineral 
density and content, total body fat mass and total body lean mass will be summarized by 
treatment group using descriptive statistics or frequency count as appropriate.  (revised per 
Amendments 01 and 03)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
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The TEAEs will be summarized by treatment group.  The following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No [not 
related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
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compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, 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
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and greater 
than 60 msec from the baseline visit.
9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including adolescent growth evaluations using 95th percentile CDC 
growth charts and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, study drug effect on cognition assessed by Leiter-3, assessment of suicidality using 
C-SSRS, depression assessment using PHQ-9, bone mineral density and content, total body 
fat mass, and total body lean mass using DEXA will be summarized by treatment group at 
each scheduled visit.  For echocardiographic assessments, the proportion of subjects who 
develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
hypertension (defined as when a subject’s SPAP is
≥40 mmHg evaluated by 
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echocardiograph], and change from baseline in SPAP will also be summarized by treatment 
group at Week 28 and Week 52. (revised per Amendments 01 and 03)
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg treatment group; n=130 in the 
placebo group) will have at least 80% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 260 subjects (130 subjects for Belviq XR 20 mg and 130 subjects for placebo) 
will also have greater than 78% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Chi-Square test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.
Lohman T, Roche AF, Martorell R. Anthropometric Standardization Reference Manual.  
Champaign, IL:  Human Kinetics Books; 1988.
Marshall WA, Tanner JM. Variation in pattern of pubertal changes in boys. Arch. 
Dis.Childhd 1970; 45, 13-23.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.
CT.gov Study NCT02918279. (revised per Amendment 02)
Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L.  
NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
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Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A 
Life-Table Analysis. Ann Intern Med. 2003; 138:24-32.
Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al. A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
Whitaker RC, et al. Predicting obesity in young adulthood from childhood and parental 
obesity. N Engl J Med. 1997 Sep 25;337(13):869-73.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
<LLN – 2.5 mg/dL
<2.5 – 2.0 mg/dL
<2.0 – 1.0 mg/dL
<1.0 mg/dL
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Page 81 of 84
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
(hypophosphatemia) 
<LLN – 0.8 mmol/L
<0.8 – 0.6 mmol/L
<0.6 – 0.3 mmol/L
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will be 
encouraged to participate in a standardized weight management program for adolescents 
consisting of multicomponent behavior therapy.  The therapy will focus on healthy eating, 
physical activity, and lifestyle changes that will facilitate weight loss and weight-loss 
maintenance. The role of the caregivers is to support their child or adolescents’ lifestyle 
changes and their taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress but 
caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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FINAL:  v8.0, 12Dec2017
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Page 83 of 84
PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neurology Business Group
Eisai Inc.
Date
 Medicine Development Group
Eisai Inc.
Date
Neurology Business Group
Eisai Inc.
Date
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PPD
PPD
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Eisai
FINAL:  v8.0, 12Dec2017
Confidential
Page 84 of 84
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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FINAL:  v7.0, 11 Jul 2017
Confidential
Page i of ix
Revision History
Previous Version (Revision): v6.0
Current Version (Revision):  v7.0
Date of Revisions: 11 Jul 2017 (per Amendment 02)
Change
Rationale
Affected Protocol Section(s)
Revised statistical power from 
90% to 80%
80% statistical power would provide 
sufficent sample size to detect weight 
loss effects and evaluate lorcaserin 
safety in the population selected.
Synopsis – Study Design
Synopsis – Number of Subjects
Synopsis – Sample Size Rationale
Section 7.1.2
Section 9.1
Section 9.2
Section 9.3
Section 9.7.2
Revised Other Secondary 
Endpoints
To align with recently submitted 
PPSR
Synopsis – Other Secondary 
Efficacy Endpoints
Section 9.7.1.1.2
Added clarification on timing of 
PK samples taken during an 
early discontinuation visit
Clarification
Table 2
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FINAL:  v7.0, 11 Jul 2017
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Page ii of ix
Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Revised scale for measuring of 
cognition from Wide Range 
Assessment of Memory and 
Learning-2 (WRAML-2) to 
Leiter-3
Leiter-3 is selected to replace 
WRAML-2 for the evaluation of the 
change in cognition for the following 
reasons:Lack of availability of 
WRAML-2 in Spanish, Leiter-3’s 
high scientific validity, non-verbal 
format to offer less biased assessment 
for subjects whose second language is 
English, easier and shorter 
administration and short test time 
reducing investigator burden, as well 
as increase probability of the 
subjects’ retention in the study.
Synopsis – Objectives
Synopsis – Other Safety 
Assessments
Synopsis – Other Safety Analyses
List of Abbreviations
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Added requirement that 
qualified personnel must 
evaluate positive responses on 
the C-SSRS and take 
appropriate action as detailed in 
the training and certification 
process for administering the 
C-SSRS
To provide guidance that qualified 
personnel must evaluate positive 
responses on the C-SSRS and take 
appropriate action as detailed in the 
training and certification process for 
administering the C-SSRS.
Synopsis – Other Safety 
Assessments
Section 9.5.1.5.10
Revised timing of initial C-
SSRS from Baseline to 
Screening
Operational efficiencies
Table 2
Section 9.3.2
Section 9.5.1.5.10
Correct formatting of Synopsis, 
Other Secondary Objectives
Consistency
Synopsis – Objectives
Section 8.2
Revised exclusion criteria for 
viral hepatitis (B or C) (#17) 
whereby active testing will not 
be performed 
To clarify that the subjects will be 
excluded if they are known to have
active hepatitis (B or C). Hepatitis (B 
or C) tests will not be conducted for 
the screening purpose.
Synopsis – Exclusion Criteria
Section 9.3.2
Added footnotes regarding 
collection of PK samples at 
EOT and Early Discontinuation 
visits
To ensure appropriate timing of
sampling relative to administration of 
last dose of study drug
Table 2
Added clarification for
Unscheduled visits, such that 
they may be conducted at any 
time that additional assessments 
are clinically indicated in the 
judgment of the investigator.
Provide additional guidance to 
investigators
Table 2
Added clarification that 
prolactin testing should be 
fasting
Clarification
Table 2
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Eisai
FINAL:  v7.0, 11 Jul 2017
Confidential
Page iii of ix
Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Added requirement for 
pregnancy test and AM serum 
cortisol to Early 
Discontinuation Visit
Correction
Table 2
Table 3
Added requirement for lifestyle 
modification counseling Visit at 
Week 16
To ensure all visits are 4 weeks apart
Table 2
General alignment of text 
throughout
Clarity
Throughout
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Eisai
FINAL:  v7.0, 11 Jul 2017
Confidential
Page iv of ix
Revision History
Previous Version (Revision): v4.0
Current Version (Revision):  v5.0
Date of Revisions: 22 Feb 2017
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
A full physical examination will 
be performed at Week 1
Correction
Synopsis - Safety Assessment
Section 9.5.1.5
PHQ-9 questionnaire has been 
added to every scheduled visit.
Per FDA recommendation
Synopsis - Safety Assessment 
Section 9.5.1.5
Section 9.5.2.1
The mixed model repeated 
measures (MMRM) model was 
replaced with the analysis of 
covariance (ANCOVA) model
analyzing Week 52 only.
Per FDA recommendation
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
All postdiscontinuation data 
will be used in the primary 
analysis
Clarification per FDA feedback
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Labeling information for study 
drug was updated
Correction as the study will only be 
conducted in the US
Section 9.4.2.3
The order of assessments was 
reorganized in the Schedule of 
Assessments 
To better align the assessments by 
grouping them
Section 9.5.2.1
Urinalysis will be performed at 
Visit 2 instead of Visit 9
Correction
Section 9.5.2.1
Assessment for testosterone, 
estradiol will be performed at 
Week 28, not Week 20
Correction
Section 9.5.2.1
Section 9.5.2.3
Prior/concomitant medication 
assessment will be performed at 
Week 56
Correction
Section 9.5.2.1
Assessments performed at early 
discontinuation from the study
Correction
Section 9.5.2.1
Summary of blood volumes 
table was updated
Correction
Section 9.5.2.3
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Eisai
FINAL:  v7.0, 11 Jul 2017
Confidential
Page v of ix
Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Subject population to include 
children ages 12 to 17 years
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Title Page
Synopsis - Study Protocol Title
Synopsis - Design
Synopsis - Inclusion Criteria
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.7.1.6
Section 9.7.1.8
Protocol Signature Page
Investigator Signature Page
All subjects will be evaluated 
for cardiac valvular disease or 
pulmonary hypertension via 
echocardiographic assessment.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Other Secondary 
Objectives
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.3.2
Section 9.5.1.5.10
Section 9.5.2
Section 9.7.1.8
Section 9.7.1.8.6
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Eisai
FINAL:  v7.0, 11 Jul 2017
Confidential
Page vi of ix
Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Study drug administration will 
be taken at approximately the 
same time each day.  On the 
days of PK sampling and the 
day before the subjects come to 
the clinic for PK sampling, 
study drug will be taken in the 
morning and doses recorded 2 
days prior to the clinic visit.
This will ensure lower variability 
with regard to PK/PD measurements.
Synopsis - Pharmacokinetic 
Assessments
Section 9.4.1
Section 9.4.4
Section 9.5.1.4.1
Section 9.5.2.1
Screening, diagnosing, 
monitoring, and measuring the 
severity of depression will be 
assessed using the Patient 
Health Questionnaire (PHQ-9), 
and not the Children’s 
Depression Inventory 2 (CDI-
2).
The PHQ-9 was originally proposed 
by the FDA for the population in the 
current study.
Synopsis - Other Secondary 
Objectives
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Primary analysis changed from 
MMRM to using a pattern 
mixture model utilizing 
multiple imputations (MI) to 
impute missing values.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Clarified fasting lipids
Fasting lipid levels provide 
uniformity in lipid measurements for 
definition of dyslipidemia
Synopsis - Other Secondary 
Objectives
Synopsis - Efficacy Assessments
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Removed Appendix 3
The current study will not conduct 
any biomarker or pharmacogenomic
evaluation. PK/PD measurements 
will be done during study.
Appendix 3
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FINAL:  v7.0, 11 Jul 2017
Confidential
Page vii of ix
Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Prehypertension was deleted 
from the inclusion criterion.  
Subjects with Stage 1 primary 
hypertension, with an upper 
limit defined as 99% plus 5 
mmHg for age, sex, and height 
are included in the study. 
Prehypertension does not qualify as a 
comorbid condition.  The limitation 
on BP is to further define the proper 
study population.
Synopsis - Inclusion Criteria
Section 9.3.1
Removed the restriction that 
subjects need to have less than 
44 kg/m2 BMI for study entry
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Synopsis - Analysis Sets
Synopsis - Pharmacodynamic 
Analyses
Synopsis -
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study entry 
requirement that the caregiver 
cannot have a history of ADD, 
substance abuse, depression, 
suicidal ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Section 9.3.1
The secondary efficacy 
objective and endpoint were 
revised
To explore the predictability of 12-
week responders for long-term 
sustainable weight loss effect
Synopsis - Secondary Efficacy 
Objectives
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with symptoms or 
signs of cardiac valvular disease 
or pulmonary hypertension are 
not required to have further 
evaluation by centralized 
echocardiogram assessment.  In 
addition, no adjudication will be 
performed.  Local 
echocardiograms can be 
performed if deemed medically 
necessary by the investigator.
This 
change 
allows 
for 
the 
investigator to make the decision to 
perform local echocardiograms on a 
pediatric subject if deemed medically 
indicated rather than burden the 
subject to undergo a mandated, 
unnecessary procedure. 
Synopsis - Safety Assessments
Section 9.5.1.5
Updated study rationale
Clarification 
Section 7.1.1.2
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FINAL:  v7.0, 11 Jul 2017
Confidential
Page viii of ix
Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will replace the
IR formulation in the United States
market to support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to include 
children ages 9 to 17 years
Expand the age of the population due 
to the change of pediatric development 
strategy
A single dose pharmacokinetic study 
in pediatric obese subjects (APD356-
A001-026) indicated that patients with 
body weight greater than or equal to 
60 kg can be administered a dose 
similar to that given to adults and 
adolescents.  Based on Centers for 
Disease Control and Prevention 
(CDC) growth chart data, almost all 
subjects over 9 years of age are likely 
to be at or over 60 kg body weight.  
Therefore, children age 9 to 11 years 
have been included in the current 
study.
Title Page
Synopsis - Study Protocol Title
Synopsis - Objectives
Synopsis - Study Design
Synopsis - Inclusion Criteria
Synopsis - Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.10
Section 9.7.1.6
Section 9.7.1.8
Additional safety assessments 
including cognitive function, 
serotonin syndrome 
components, bone health and 
endocrine function, priapism, 
and symptoms associated with 
hyperprolactinemia were added.
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Efficacy Assessments
Synopsis - Pharmacokinetic 
Assessments
Synopsis - Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.1
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FINAL:  v7.0, 11 Jul 2017
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Page ix of ix
Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Change to primary and key 
secondary endpoints
Per FDA request
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary endpoint 
changed
Per FDA request
Synopsis - Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of study-
specific adverse events
To provide clearer guidance for the 
correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and prohibited 
prior and concomitant therapies
For clarification
Synopsis - Exclusion Criteria
Synopsis - Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of adverse 
events
To provide clearer guidance for the 
correct reporting of adverse events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
Update to Introduction and to 
Completion/ Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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Confidential
Page 1 of 78
1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction With Lifestyle Modification for Weight 
Loss in Obese Adolescents, Age 12 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
v4.0
03 Nov 2016 (Revision)
v5.0
22 Feb 2017 (Revision)
v6.0
17 May 2017 (per Amendment 01)
v7.0
11 Jul 2017 (per Amendment 02)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation
of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 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.
Page 303 of 897


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Eisai
FINAL:  v7.0, 11 Jul 2017
Confidential
Page 2 of 78
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and 
Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in Obese Adolescents, Age 
12 to 17 Years
Investigators
Unknown
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
Approximately 24 months from the 1st subject enrolled to last subject’s last visit or last assessment 
Phase 4
Objectives
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks of treatment 
with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD as compared to 
placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg administered QD compared 
to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of treatment with 
Belviq XR 20 mg administered QD is predictive of sustained change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 52 weeks of 
treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% BMI reduction, 
change in waist circumference) at the end of 52 weeks of treatment
-
Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin Resistance
(HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) during 52 weeks of treatment
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, dyslipidemia)
including fasting lipid changes (total cholesterol, triglycerides, high density lipoprotein [HDL], and 
low density lipoprotein [LDL]) during 52 weeks of treatment.

To assess the safety of Belviq XR, including the effects on cognition with the Leiter-3 International 
Performance Scale (Leiter-3), depression with the Patient Health Questionnaire (PHQ-9), signal of suicidal 
ideation or behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by
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Centers for Disease Control and Prevention (CDC) growth chart, sexual maturation (pubescence) measured 
by Tanner Staging scores, and other growth and development parameters by measuring sex hormones, 
thyroid function, adrenal function, bone age, and biochemical markers of bone health, valvular function,
and pulmonary arterial pressure.(revised per Amendment 01)

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) parameters 
including but not limited to reduction from baseline in BMI and probability of achieving at least a 5% and 
at least a 10% reduction in BMI from baseline at Week 52 using population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese adolescents, 
ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 1:1 ratio to Belviq XR 20 mg QD
(130 subjects) and placebo (130 subjects).  Subjects will be stratified by sex.  Subjects will receive Belviq XR
20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout the duration of the study, subjects will be 
encouraged to adhere to a lifestyle modification program that includes a standardized, age-appropriate diet and 
exercise counseling. (revised per Amendment 02)
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization Phase will 
last up to 30 days and consist of 1 visit during which subjects will be screened for eligibility.  The 
Randomization Phase consists of a Treatment Period and a Follow-Up Period. The Treatment Period will last 
for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52.  The Follow-Up Period will 
extend from the End of Treatment visit to the End of Study visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will continue in the study 
until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely will be followed up 
until study completion.  
Number of Subjects
Approximately500 subjects will be screened to provide260 randomized subjects.  (revised per Amendment 02)
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that is greater than or 
equal to the United States (US)-weighted mean of the 95th percentile based on age and sex with a body 
weight greater than 60 kg
2.
Subjects and their families not planning to move away from the area for the duration of the study
3.
Subjects able and willing to comply with all aspects of the study, including a standardized, reduced-calorie 
diet and an age-appropriate, increased physical activity program
4.
Subjects considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the investigator,
including consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study requirements for the 
caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the subject’s ability 
to fulfill the study requirements or significantly confound the assessments
2.
Subjects who cannot swallow investigational products
3.
Any of the following findings on Screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, mean gradient 
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>25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean gradient >5 mm Hg and mitral valve 
area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure (SPAP) >40 mmHg (and/or tricuspid regurgitation (TR) jet 
velocity >2.9 m/s)
In cases where an actual SPAP value is not measurable due to lack of adequate TR jet, the pulmonary flow 
acceleration time measured at the right ventricular outflow tract (RVOTAT), will be used to assess 
eligibility. Patients with a RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be determined based on 
combined assessment of the TR jet, septal motion and right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with hemodynamic compromise)
4.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper limit of 
normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater than 1.5×ULN in 
absence of Gilbert’s syndrome
5.
Any suicidal ideation with intent with or without a plan, at the time of or within 6 months of Screening, as 
indicated by answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS.
6.
Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
7.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit Hyperactivity 
Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th Edition depressive disorder,
suicidal ideation or behavior, bipolar disorder, or schizophrenia
8.
Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi syndrome, Bardet 
Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, Cushing’s syndrome, daily systemic 
corticosteroid exposure for longer than 30 days, history of significant exposure to corticosteroids for 
chronic illness during the past year)
9.
Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, 
and herbal preparations within 1 month before Screening 
10. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine oxidase inhibitors 
(MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
11. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before Screening, 
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including but not limited to pergolide, ergotamine, methysergide, and cabergoline
12. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, gastrointestinal, 
renal, or psychiatric disease) other than prediabetes (impaired fasting glucose or impaired glucose 
tolerance), type 2 diabetes treated with oral anti-diabetic agents (excluding sulfonylurea) or non-insulin 
injectable antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
13. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any of the 
excipients
14. Significant change in diet or level of physical activity within 1 month before dosing or change in weight of 
more than 5 kg within 3 months before Screening
15. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before Screening
16. History of alcohol or drug dependence or abuse
17. Recreational drug use within 2 years before Screening
18. Known to be human immunodeficiency virus positive
19. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
20. Malignancy within 5 years before Screening
21. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or guardian to supervise 
study participation
22. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to profound 
mental retardation [IQ <70], moderate to severe cognitive developmental delay, pervasive development 
disorders, autism)
23. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder within 6 months of 
screening or any time between screening and randomization
24. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate readings recorded 
on 2 separate days.  Those subjects who had hypertension at Screening can be rescreened more than
1 month after initiation or adjustment of antihypertensive therapy 1 time.
25. Currently enrolled in another clinical study or has used any investigational drug or device within 30 days 
before providing informed consent
26. Planned bariatric surgery during the study
27. Not suitable to participate in the study in the opinion of the investigator, including consideration of any 
existing physical, medical, or mental condition that prevents compliance with the protocol
28. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
β-human chorionic gonadotropin test).  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.
29. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a 
highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier 
method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire 
study period and for 28 days after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described above) or refrain 
from sexual activity during the study period and for 28 days after study drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during 
the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]).
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Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated, biconvex tablets
with one 20-mg tablet administered orally QD.
Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  up to 30 days
Randomization Phase: approximately 56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal preparations, are 
prohibited as concomitant medications.  OTC cold medicines containing dextromethorphan can be used for up 
to 7 days with study medication temporarily stopped for that time period and resumed the next day after the 
OTC cold medicine is stopped.  Any of the following serotonergic agents or other agents in combination with 
Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to calculate the 
proportion (%) of patients achieving at least a 5% and at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total cholesterol, HDL cholesterol, 
LDL cholesterol, and triglycerides), fasting plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and 
Homeostasis Model Assessment (HOMA) IR to assess cardiovascular and metabolic risk profiles from 
Baseline to Week 52
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
Prehypertension and primary hypertension as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents
Pharmacokinetic Assessments
Blood samples (approximately 4 mL each) for PK assessment will be collected at Weeks 12, 28, 36, and 52 for 
analysis of Population PK. (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at 
home before the visit,but to bring their study drug to the clinic visit, and take their daily dose at the clinic.  
Two blood samples for determination of plasma concentrations of lorcaserin will be taken: 1 predose (within 
30 minutes before dosing), and 1 within 1 to 3 hours after dosing.  Dose times must be recorded for the last 
2 dosing times before the day of clinic visit. Week 52 PK samples should only be collected if the sample can be 
drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at home, and will be 
asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for for PK 
assessments will be collected. Dose times must be recorded for the last 2 dosing times prior to the clinic visit.
(revised per Amendment 01)
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their relationships 
with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious adverse events 
(SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, metabolic function (fasting glucose, 
fasting lipids, and thyroid), adrenal function and biochemical blood and urine bone health assessments; blood 
chemistry and urine values; neuropsychiatric events; periodic measurement of vital signs, neuromuscular signs
for screening potential serotonin syndrome, and signs or symptoms of priapism and hyperprolactinemia; and 
performance of physical examinations. In patients with potential prolactin-related AEs, such as galactorrhea, 
changes in libido, or changes to menstrual cycle, prolactin level will be measured and assessed.
Other Safety Assessments
Effect on growth will be evaluated using the CDC growth chart and bone age determination by x-ray of the 
hand. Sexual maturation will be evaluated by assessing sex hormones and Tanner Staging.   
The C-SSRS will be used to assess all subjects in the study for any signal of depression or suicidal ideation or 
behavior at every visit.  Additionally, screening, diagnosing, monitoring, and measuring the severity of 
depression will be assessed using the PHQ-9 and effects on cognition will be assessed using the Leiter-3.  
(revised per Amendment 01)
Echocardiographic assessments will be used to exclude subjects with FDA-defined valvulopathy, pulmonary 
hypertension, and other major cardiovascular disease (as outlined in Exclusion Criterion No. 3) during the 
Screening Period.  Additionally, cardiac valvular function and pulmonary systolic pressure changes at Weeks
28 and 52 will be assessed. Valvular regurgitation as assessed in the echocardiogram will be rated absent, trace, 
mild, moderate, or severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve. The evaluations will be based on guidelines from the American Society of Echocardiography. 
Pulmonary artery pressure will be estimated from the TR jet velocity.
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Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography coupled with tandem mass 
spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Association between change and percentage change in BMI from Baseline to Week 52 with the outcome of 
achieving at least a 5% BMI reduction at Week 12 (revised per Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI reduction at 
Week 52 with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) from 
Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and had at least 
1 post dose safety assessment.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater compliant 
with study medication, completed the study, have no major protocol deviations, have no violations of 
inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  The determination of subjects 
to be excluded from this population based on the above criteria and a list of major protocol violations will 
be included in the statistical analysis plan (SAP) and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid lorcaserin plasma 
concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who have at least 
1 adequately documented measurement of BMI.
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Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as a 
supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in all efficacy 
analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from baseline in 
BMI will be analyzed using analysis of covariance model (ANCOVA) with factors of treatment,  sex (male and 
female) as fixed effect, and the baseline age and BMI as covariates.  The missing values will be imputed using a 
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are missing not at 
random (MNAR).  The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model and missing value 
imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on the PP.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy analyses described 
above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed and will be
described in the SAP.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI reduction at 
Week 52. The secondary efficacy endpoint will be analyzed only if the test for the primary efficacy endpoint is 
statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using a logistic 
regression model with factors of treatment, sex (male and female), and baseline BMI as a covariate using FAS.  
Subjects with any missing assessment at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed using 
mixed effect model repeated measurement analysis (MMRM) and categorical variables will be analyzed using
the Cochran Mantel Haenszel test, Chi-square test, or logistic regression as appropriate.  Additional analysis 
may be performed as needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male and female), and 
race (white, black, Asian, and other).  Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using nonlinear mixed 
effects modeling. The effect of covariates such as baseline characteristics or demographics on PK will be 
explored. Derived exposure parameters such as the maximum observed concentration and the area under the 
concentration-time curve from time 0 to 24 hours at steady-state will be calculated from the final PK model 
using individual posterior estimates of the PK parameters and from dosing history. The PK analysis set will be 
used for this analysis.
Pharmacodynamic Analyses
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will be used for this 
analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% and ≥10% BMI 
reduction, and change in waist circumference from baseline) will also be assessed as part of the PD analysis.  
The PK/PD analysis set will be used for this analysis.
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Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure and 
response, including but not limited to change in BMI from baseline and the probability of achieving at least a 
5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, exposure-safety relationships 
for select safety parameters may be explored graphically depending on the data at the end of study.  Any 
emergent relationship may be modeled as appropriate.  Any parameters based on the study data may be 
considered for exploratory assessment for its relationship to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the incidence 
of AEs (including changes from baseline in physical examination), growth (CDC growth chart and bone age 
determined by x-ray of the hand), sexual maturation (Tanner Staging), out-of-normal-range laboratory safety 
test values, change from baseline in laboratory safety test values, ECGs, and vital sign measurements will be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
Other Safety Analyses
In addition, cognition will be evaluated by the Leiter-3, depression will be evaluated by the PHQ-9, and suicidal 
ideation and behavior will be evaluated by the C-SSRS, and will also be summarized by treatment group using 
descriptive statistics or frequency count as appropriate. For echocardiographic assessments, the proportion of 
subjects who develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
hypertension [pulmonary hypertension is defined when the subject’s systolic pulmonary artery pressure 
(SPAP) ≥40 mmHg evaluated by echocardiograph], and change from baseline in SPAP will be summarized by 
treatment group at Week 28 and Week 52 using descriptive statistics or frequency count as appropriate. (revised 
per Amendment 01)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in BMI from 
Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  Assuming a SD of 
2.2 kg/m2 and a 40% dropout rate, a sample size of 260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg 
treatment group; n=130 in the placebo group) will have at least 80% power to detect a treatment difference of 
1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at least a 5% 
BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, this sample of 260 subjects 
(130 subjects for Belviq XR 20 mg and 130 subjects for placebo) will also have greater than 78% power to 
detect an absolute difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 
2-sided Chi-Square test with α=0.05.
The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................11
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................15
5
ETHICS............................................................................................................................17
5.1
Institutional Review Boards/Independent Ethics Committees ..............................17
5.2
Ethical Conduct of the Study.................................................................................18
5.3
Subject Information and Informed Consent...........................................................18
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................20
7
INTRODUCTION ...........................................................................................................21
7.1
Indication ...............................................................................................................21
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................22
7.1.1.1
Mechanism of Action...........................................................................22
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................22
7.1.2
Study Rationale............................................................................................23
8
STUDY OBJECTIVES....................................................................................................25
8.1
Primary Objective..................................................................................................25
8.2
Secondary Objectives.............................................................................................25
9
INVESTIGATIONAL PLAN..........................................................................................27
9.1
Overall Study Design and Plan..............................................................................27
9.1.1
Prerandomization Phase...............................................................................27
9.1.1.1
Screening Period..................................................................................27
9.1.2
Randomization Phase...................................................................................28
9.1.3
Extension Phase ...........................................................................................28
9.2
Discussion of Study Design, Including Choice of Control Groups.......................28
9.3
Selection of Study Population................................................................................29
9.3.1
Inclusion Criteria .........................................................................................29
9.3.2
Exclusion Criteria ........................................................................................29
9.3.3
Removal of Subjects From Therapy or Assessment....................................32
9.4
Treatments..............................................................................................................33
9.4.1
Treatments Administered.............................................................................33
9.4.2
Identity of Investigational Product...............................................................33
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................33
9.4.2.2
Comparator Drug .................................................................................33
9.4.2.3
Labeling for Study Drug......................................................................33
9.4.2.4
Storage Conditions...............................................................................34
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9.4.3
Method of Assigning Subjects to Treatment Groups...................................35
9.4.4
Selection and Timing of Dose for Each Subject..........................................35
9.4.5
Blinding........................................................................................................35
9.4.6
Prior and Concomitant Therapy...................................................................35
9.4.7
Treatment Compliance.................................................................................36
9.4.8
Drug Supplies and Accountability...............................................................37
9.5
Study Assessments.................................................................................................38
9.5.1
Assessments.................................................................................................38
9.5.1.1
Demography.........................................................................................38
9.5.1.2
Baseline Assessments ..........................................................................38
9.5.1.2.1
Medical History .............................................................................38
9.5.1.2.2
Urine Drug Screen .........................................................................39
9.5.1.3
Efficacy Assessments...........................................................................39
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................39
9.5.1.4.1
Pharmacokinetic Assessments .......................................................39
9.5.1.4.2
Pharmacodynamic Assessments ....................................................40
9.5.1.4.3
Pharmacogenomic and Other Biomarker Assessments .................40
9.5.1.5
Safety Assessments..............................................................................40
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...40
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................42
9.5.1.5.3
Laboratory Measurements .............................................................44
9.5.1.5.4
Vital Signs and Weight Measurements..........................................45
9.5.1.5.5
Height Measurements ....................................................................46
9.5.1.5.6
CDC Growth Measurements..........................................................46
9.5.1.5.7
Waist Circumference .....................................................................46
9.5.1.5.8
Physical Examinations...................................................................46
9.5.1.5.9
Electrocardiograms ........................................................................46
9.5.1.5.10
Other Safety Assessments..............................................................47
9.5.1.6
Other Assessments...............................................................................48
9.5.1.6.1
Pregnancy Test...............................................................................48
9.5.2
Schedule of Procedures/Assessments ..........................................................48
9.5.2.1
Schedule of Procedures/Assessments ..................................................48
9.5.2.2
Description of Procedures/Assessments Schedule...............................52
9.5.2.3
Total Volume of Blood Sampling........................................................52
9.5.3
Appropriateness of Measurements...............................................................52
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................53
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9.5.4.1
Reporting of Serious Adverse Events..................................................53
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................53
9.5.4.3
Reporting of Events Association with Special Situations....................54
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................54
9.5.4.3.2
Reporting of Study-Specific Events...............................................55
9.5.4.4
Expedited Reporting ............................................................................55
9.5.4.5
Breaking the Blind...............................................................................55
9.5.4.6
Regulatory Reporting of Adverse Events ............................................56
9.5.5
Completion/Discontinuation of Subjects.....................................................56
9.5.6
Abuse or Diversion of Study Drug ..............................................................56
9.5.7
Confirmation of Medical Care by Another Physician .................................57
9.6
Data Quality Assurance .........................................................................................57
9.6.1
Data Collection ............................................................................................57
9.6.2
Clinical Data Management ..........................................................................57
9.7
Statistical Methods.................................................................................................57
9.7.1
Statistical and Analytical Plans....................................................................58
9.7.1.1
Study Endpoints...................................................................................58
9.7.1.1.1
Primary Efficacy Endpoint ............................................................58
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................58
9.7.1.2
Definitions of Analysis Sets.................................................................59
9.7.1.3
Subject Disposition..............................................................................59
9.7.1.4
Demographic and Other Baseline Characteristics ...............................59
9.7.1.5
Prior and Concomitant Therapy...........................................................60
9.7.1.6
Efficacy Analyses ................................................................................60
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................61
9.7.1.7.1
Pharmacokinetic Analyses.............................................................61
9.7.1.7.2
Pharmacodynamic Analyses..........................................................61
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................62
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................62
9.7.1.8
Safety Analyses....................................................................................62
9.7.1.8.1
Extent of Exposure.........................................................................62
9.7.1.8.2
Adverse Events ..............................................................................62
9.7.1.8.3
Laboratory Values..........................................................................63
9.7.1.8.4
Vital Signs......................................................................................64
9.7.1.8.5
Electrocardiograms ........................................................................64
9.7.1.8.6
Other Safety Analyses....................................................................65
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9.7.2
Determination of Sample Size .....................................................................65
9.7.3
Interim Analysis...........................................................................................65
9.7.4
Other Statistical/Analytical Issues ...............................................................65
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................65
10
REFERENCE LIST .........................................................................................................66
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......68
11.1
Changes to the Protocol .........................................................................................68
11.2
Adherence to the Protocol......................................................................................68
11.3
Monitoring Procedures...........................................................................................68
11.4
Recording of Data..................................................................................................69
11.5
Identification of Source Data.................................................................................69
11.6
Retention of Records..............................................................................................70
11.7
Auditing Procedures and Inspection......................................................................70
11.8
Handling of Study Drug.........................................................................................70
11.9
Publication of Results ............................................................................................71
11.10 Disclosure and Confidentiality ..............................................................................71
11.11 Discontinuation of Study .......................................................................................71
11.12 Subject Insurance and Indemnity...........................................................................72
12
APPENDIX......................................................................................................................73
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests (revised per Amendment 01)...........................45
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  
(revised per Amendments 01 and 02)........................................................49
Table 3
Summary of Blood Sample Volumes (revised per Amendment 01) ........52
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
(revised per Amendment 01)
Abbreviation
Term
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
Leiter-3
Leiter-3 International Performance Scale
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Term
MAR
missing at random
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PHQ-9
The Patient Health Questionnaire
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
RVOTAT
right ventricular outflow tract
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SPAP
systolic pulmonary artery pressure  
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TR
tricuspid regurgitation
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity has become a global epidemic, causing a serious public health concern.  In the 
United States, the prevalence of obesity in adolescents ages 12 and 19 years has almost 
doubled over the past 2 decades.  The rate increased from 10.5% between 1988 and 1994 to 
20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, defined in the 
United States as greater than or equal to the 95th percentile in gender- and age-specific body 
mass index (BMI), continues to grow at an alarming rate in the United States and globally.  
Based on data (Wang and Lobstein, 2006) using various criteria for the definition of obesity 
that included more than 30 countries in Europe, North America, Asia, and the West Pacific, 
prevalence of obesity in these countries has also increased significantly, at a rate comparable 
to that in the United States.
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may
result in a decrease in life expectancy for the 1st time in 200 years (Peeters, et al., 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese adolescents are likely to become 
tomorrow’s obese adults (Whitaker, et al., 1997).
Current approaches to weight management in adults include lifestyle modification, 
pharmacotherapy, and invasive bariatric procedures.  Lifestyle modification involves a 
combination of diet, exercise, and behavioral change, and is the preferred and essential 
strategy for weight management in obese and overweight individuals, including adolescents.  
Although lifestyle modification can be very efficacious in some patients, adherence to the 
prescribed regimens is often poor.  As such, lifestyle modification alone is often not adequate 
and the weight loss is often transient.  On the other hand, bariatric surgery and various other 
invasive procedures are generally reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise, but are rarely used 
for adolescents.
The current standard of care for treatment of obesity in adolescent subjects ranges from
behavioral therapy including lifestyle intervention to the rare use of pharmacotherapy in 
adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
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(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies that will be 
used in the present study to help retain participants.  These include a highly trained and 
competent staff, ample waiting area, readily available parking (at no cost), access to mass 
transit, and reminder and follow-up calls.  In addition, we will provide fun and interactive 
group sessions with games and hands-on nutrition and physical activity demonstrations, 
random raffle drawings, social events, birthday and holiday cards, and newsletters.  
Furthermore, we will make home visits for assessments of families, as needed, to maximize 
data collection. 
By using these retention strategies, we hope that we will maximize 
participant retention, which will help us cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:

A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) was 
significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
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used for adolescent subjects with body weight greater than 60 kg.
In adolescent obese populations, it is anticipated that Belviq XR will result in similar effects.
As part of FDA postmarketing requirements, this study is designed to characterize the 
efficacy and safety of Belviq XR in adolescent obese populations in the United States.  It is 
also intended to support an indication for chronic weight management for obese adolescents 
ages 12 to 17 years old. 
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of subjects 
in the placebo-treated group who lose at least 5% of baseline body weight, and the 
difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in obese adolescents, where weight loss will be assessed using BMI
measurements to account for growth. In this study, the objective is to demonstrate that BMI
reduction will be achieved during 52 weeks of treatment with Belviq XR 20 mg administered 
once daily (QD) compared to placebo in obese adolescents.
In the Phase 3 orlistat study in obese adolescents mentioned above, the proportion of subjects 
who lost at least 5% body weight is relatively low. At the end of the study at Week 52, only 
26.5% of the subjects achieved a 5% or greater BMI reduction compared to 15.7% in the 
placebo group. The placebo-corrected BMI reduction was about 0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years
(Peirson, et al, 2015).  Thirty-one studies (29 behavioral, 2 pharmacological and behavioral) 
were included in a meta-analysis of randomized studies conducted in primary care centers in 
overweight and obese children and youth ages 2 to 18 years using behavioral (diet, exercise,
and lifestyle) and pharmacological interventions and providing 6-month postbaseline BMI or 
prevalence of overweight or obesity. Both interventions showed a significant effect on BMI 
in favor of treatment (behavioral: 
standardized mean difference [SMD] -0.54, 
95% confidence interval [CI]
-0.73, -0.36; orlistat plus behavioral: 
SMD -0.43, 
95% CI -0.60, -0.25). The studies reported no significant difference between groups in the 
likelihood of reduced prevalence of overweight or overweight and obese. A great deal of 
variation was noted across efficacious interventions.
In conclusion, this meta-analysis 
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demonstrated low-quality evidence that behavioral treatments alone are associated with a 
smaller effect in terms of reduced BMI compared with the effect shown by combined 
behavioral and pharmacological interventions. This may be because the effect size in the 
randomized, double blind, placebo controlled, phase 3 orlistat study in adolescents was 
relatively low and there was a lack of maintenance effect. These subjects started to regain 
their BMI after 6 months of treatment. At end of the study, only 26.5% of subjects achieved 
a 5% or greater BMI reduction compared to 15.7% in placebo group. In a sibutramine 
Phase 3 study in obese adolescents, a substantially higher proportion of subjects (69%) 
treated with sibutramine achieved at least a 5% BMI reduction compared to 21% of subjects 
in the placebo group. In addition, sibutramine resulted in a substantial reduction in mean 
BMI (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 
8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the weight loss effect of Belviq
in adults and sibutramine in adolescents, subjects in the orlistat study started to increase their 
BMI after 6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of260 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
sibutramine, and liraglutide 3 mg) (FDA, 2003; Chanoine, et al., 2005; Berkowitz, et al,
2006; CT.gov NCT02918279) and other metabolic or dyslipidemia medication products
(ezetimibe, simvastatin) (FDA, 2007).  (revised per Amendment 02)
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8
STUDY OBJECTIVES
8.1
Primary Objective

To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment with 
Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR
20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of 
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in 
BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo
(revised per Amendment 01)

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% 
BMI reduction, change in waist circumference) at the end of 52 weeks of treatment
-
Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin 
Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) during 52 weeks of 
treatment
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high 
density lipoprotein [HDL], and low density lipoprotein [LDL]) during 52 weeks of 
treatment
•
To assess the safety of Belviq XR, including the effects on cognition by Leiter-3 
International Performance Scale (Leiter-3), depression with the Patient Health 
Questionnaire 
(PHQ-9), 
signal 
of 
suicidal 
ideation 
or 
behavior 
with 
the 
Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by CDC growth 
chart, sexual maturation (pubescence) measured by Tanner Staging scores, and other 
growth and development parameters by measuring sex hormones, thyroid function, 
adrenal function, bone age, and biochemical markers of bone health assessments valvular 
function, pulmonary arterial pressure. (revised per Amendment 01)
•
To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling
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•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
probability of achieving at least a 5% and at least a 10% reduction in BMI from baseline 
at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents ages 12 to 17 years.  Approximately 260 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (130 subjects) and placebo (130 subjects).  Subjects will be 
stratified by sex.  Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up 
to 52 weeks. Throughout the duration of the study, subjects will be encouraged to adhere to 
a lifestyle modification program that includes a standardized, age-appropriate diet and 
exercise counseling (see Appendix 2).  (revised per Amendment 02)
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be rescreened only once after 60 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.
9.1.1
Prerandomization Phase
Screening will occur during the Prerandomization Phase at Visit 1.
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
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9.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025.  Overall, the PK parameters of Belviq and its main 
metabolites, M1 and M5, were similar to those in adults.  Following a single, oral 
administration of Belviq 10 mg to a total of 8 healthy adolescent (ages 12 to 17 years old) 
obese subjects, the mean maximum concentration observed and the area under the 
concentration-time curve from time zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 
464 hr×ng/mL, respectively.  The mean Belviq terminal phase half-life was 9.70 hours, 
similar to that observed in adults, thus supporting a similar dosing frequency (QD) in 
adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric or adolescent subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of subjects who are older than 12 years of age 
having a body weight of less than 60 kg is very low; therefore, the current study as designed 
to enroll subjects between 12 to 17 years of age with body weight at least 60 kg, will cover
majority of the population of interest.  The targeted study population comprises 260 obese 
adolescents 12 to 17 years of age, with a body weight at least 60 kg.  (revised per 
Amendment 02)
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
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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, 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 500 subjects will be screened to ensure that 260 subjects will be randomized.  
(revised per Amendment 02)
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug. Subjects who screen fail can be re-screened only once after 
60 days.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, ages 12 to 17 years old at Screening, with a BMI 
that is greater than or equal to the United States (US)-weighted mean of the 
95th percentile based on age and sex with a body weight greater than 60 kg
2. Subjects and their families are not planning to move away from the area for the duration 
of the study
3. Subjects able and willing to comply with all aspects of the study, including a 
standardized, reduced-calorie diet and an age-appropriate, increased physical activity 
program
4. Subjects considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may affect 
the subject’s ability to fulfill the study requirements or significantly confound the 
assessments
2. Subjects who cannot swallow investigational products
3. Any of the following findings on screening echocardiography:

Aortic regurgitation mild or greater
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
Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, 
mean gradient >25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean 
gradient >5 mm Hg and mitral valve area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure
(SPAP) >40 mm Hg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
-
In cases where an actual SPAP value is not measurable due to lack of adequate 
TR jet, the pulmonary flow acceleration time measured at the right ventricular 
outflow tract (RVOTAT), will be used to assess eligibility. Patients with a 
RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be 
determined based on combined assessment of the TR jet, septal motion and right 
ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with 
hemodynamic compromise)
4. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
5. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, bipolar disorder, or schizophrenia
6. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months 
of Screening, as indicated by answering “Yes” to questions 4 or 5 on the Suicidal 
Ideation section of the C-SSRS.
7. Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
8. Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi 
syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, 
Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 30 days, 
history of significant exposure to corticosteroids for chronic illness during the past year)
9. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before Screening
10. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion
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
triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
11. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and 
cabergoline
12. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), Type 2 diabetes treated with oral anti-diabetic 
agents (excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive 
sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
13. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or 
any of the excipients
14. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
15. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 6 months
before Screening
16. History of alcohol or drug dependence or abuse
17. Recreational drug use within 2 years before Screening
18. Known to be human immunodeficiency virus positive
19. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
20. Malignancy within 5 years before Screening
21. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
22. Special needs subjects who are unable to comprehend study-related instructions (eg, mild 
to profound mental retardation [IQ <70], moderate to severe cognitive developmental 
delay, pervasive development disorders, autism)
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23. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
24. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate 
readings recorded on 2 separate days.  Those subjects who had uncontrolled hypertension 
at Screening can be rescreened more than 1 month after initiation or adjustment of 
antihypertensive therapy 1 time.
25. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
26. Planned bariatric surgery during the study
27. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
28. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
29. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 
28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after 
study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use 
the same contraceptive during the study and for 28 days after study drug 
discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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.
Investigators should do their best to bring all subject who discontinued early from the study
in for the their primary endpoint collection regardless of the reason for ED. (revised per 
Amendment 01)
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9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD at 
approximately the same time each day.
Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled with text that is in full regulatory compliance with each 
participating country. As the study is being conducted in US only, the study drug label will 
be printed in English. 
The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
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5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal (US) law to 
investigational use.”
All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug was 
dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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.
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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.
Subjects will be centrally stratified by sex (male and female).  Within each stratum, subjects 
will be randomized to receive either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  
Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily at approximately the same time of 
every day, and be encouraged to take the study medication with an adequate amount of water 
(8 oz. or 240 mL).
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
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being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs
will review treatment compliance during site visits and at the completion of the study.
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
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9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 (US 
sites only).  Must be appropriate to handle schedule IV products and not be expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
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supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
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9.5.1.2.2
URINE DRUG SCREEN
A 30-mL urine sample will be collected at Screening, as specified in the Schedule of 
Procedures/Assessments (Table 2).  This sample will be tested for common drugs of 
use/abuse (eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, nicotine/cotinine, opioids 
[as a group], benzodiazepines, barbiturates, amphetamines). (revised per Amendment 01)
9.5.1.3
Efficacy Assessments

Body weight and height will be measured using a standard stadiometer method (Lohman 
T, et al, 1988) to calculate changes in BMI; BMI will then be used to calculate the 
proportion (%) of patients achieving at least a 5% and at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total cholesterol, 
HDL cholesterol, LDL cholesterol, and triglycerides), fasting plasma glucose, fasting 
insulin, hemoglobin A1c (HbA1c), and HOMA-IR to assess changes in cardiovascular and 
metabolic risk profiles from Baseline to Week 52

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 
(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents, 2011)

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for Population PK analyses.    (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take 
their study drug at home before the visit, but to bring their study drug to the clinic visit and 
take their daily dose at the clinic.  Two blood samples for determination of plasma 
concentrations of lorcaserin will be taken 1 predose (within 30 minutes before dosing) and 1 
within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times 
before the day of clinic visit. Week 52 PK samples should only be collected if the sample can 
be drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug at home, and will 
be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood 
sample for PK assessment will be collected.  Dose times must be recorded for the last 2 
dosing times prior to the clinic visit. (revised per Amendment 01)
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Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
coupled with tandem mass spectrometry method. The collection, handling, and shipping 
procedures for PK samples will be described in a manual to be provided to the study sites.
At Unscheduled Visits, PK samples should only be collected if subject has experienced a 
serious adverse event (SAE) while on study drug and the sample can be drawn within 60 
hours of the initiation of the SAE. (revised per Amendment 01)
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Lorcaserin plasma exposure from PK analysis and population PK/PD modeling will be used 
to explore the relationship between lorcaserin plasma exposure and following response to 
lorcaserin: 

Change from Baseline in BMI 

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC AND OTHER BIOMARKER ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; electrocardiograms 
(ECGs); laboratory evaluations for hematology, metabolic function (fasting glucose, lipids,
and thyroid), adrenal functions, and biochemical blood and urine bone health assessments;
blood chemistry and urine values; neuropsychiatric events; periodic measurements of vital 
signs, neuromuscular signs for screening potential serotonin syndrome, and signs and 
symptoms of priapism and hyperprolactinemia; and performance of physical examinations.  
In subjects with potential prolactin-related AEs, such galactorrhea, changes in libido, or
changes to menstrual cycle, prolactin level will be measured and assessed.  
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
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symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
It is the responsibility of the investigator to review the results of the Leiter-3, C-SSRS, and 
PHQ-9 for all subjects and determine if any result constitutes an AE.  Medical and scientific 
judgment should be exercised in deciding whether an isolated suicidality rating scale 
response should be classified as an AE (see Section 9.5.1.5.10 for a description of the 
C-SSRS).  (revised per Amendment 01)
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.
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Assessing Severity of Adverse Events
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of the 
event
•
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
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•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious 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
•
Priapism
•
New onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas of 
the skin
•
Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study specific event 
does not meet serious criteria.  If the event meets seriousness criteria, it should be reported as 
an SAE as above.  However, if the event listed below does not meet serious criteria, it should 
be noted as nonserious on the Adverse Event CRF:  
•
Suicidal ideation   
•
Euphoria 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
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misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
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Table 1
Clinical Laboratory Tests (revised per Amendment 01)
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function
T4, TSH
Adrenal function
AM serum Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects)
Bone health assessments
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other (revised per Amendment 01)
Albumin, calcium, globulin, fasting glucose, HbA1c, HDL 
cholesterol, fasting insulin, lactate dehydrogenase, LDL cholesterol,
fasting lipid panel, phosphorus, total protein, total cholesterol,
triglycerides,, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
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method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2).  
9.5.1.5.6
CDC GROWTH MEASUREMENTS
Investigators will calculate the height for age percentile and weight for age percentile 
utilizing the most recent CDC 95th Percentile Growth Chart and the height and weight 
measurements obtained, as designated in the Schedule of Procedures/Assessments (Table 2).  
(revised per Amendment 01)
9.5.1.5.7
WAIST CIRCUMFERENCE
Waist circumference (cm) measurements will be taken 3 times at each visit as designated in 
the Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 01)
9.5.1.5.8
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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 eCRF.
As part of the physical examination, a neuromuscular sign assessment for serotonin 
syndrome will be performed for potential serotonergic syndrome components.  Serotonergic 
syndromes that meet the diagnostic criteria will be captured by AE eCRF.
(revised per 
Amendment 01)
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will also be captured in the AE eCRF. (revised per 
Amendment 01)
9.5.1.5.9
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
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An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.10 OTHER SAFETY ASSESSMENTS
Leiter-3
The Leiter International Performance Scale–Third Edition (Leiter-3) is widely used 
non verbal measure of intelligence, memory, and attention in those between the ages of 3 and 
75 years. 
The Attention/Memory Battery consists of 5 subtests: 2 measure nonverbal 
attention; 2 measure memory; and 1 measures cognitive interference (nonverbal Stroop test). 
These subtests are combined to produce a Memory and Processing Speed composite scores, 
normalized to a mean of 100 and standard deviation of 15. The Leiter-3 will be used to 
assess lorcaserin effects on cognition, specifically, attention and memory. In addition, signs 
and symptoms of cognition-related AEs, including impairments in attention, memory, and 
adverse effects on schoolwork will be captured in the eCRF. (revised per Amendment 01)
PHQ-9
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and 
measuring the severity of depression:

The PHQ-9 incorporates Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV) depression diagnostic criteria with other leading major depressive 
symptoms into a brief self-report tool.

The tool rates the frequency of the symptoms which factors into the scoring severity 
index.

Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.

A follow-up, non-scored question on the PHQ-9 assigns weight to the degree to which 
depressive problems have affected the patient's level of function. 
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. Qualified personnel must evaluate positive 
responses on the C-SSRS and take appropriate action as detailed in the training and 
certification process for administering the C-SSRS.  It will be performed at Screening and at 
study visits as designated in the Schedule of Procedures/Assessments (Table 2). (revised per 
Amendment 01)
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Hand X-Ray
A hand x-ray for evaluation of any potential negative effect on bone age will be performed 
on the same hand at each visit as designated in the Schedules/Assessments (Table 2).  
(revised per Amendment 01)
Tanner Staging
The pubic hair growth (both sexes), genital (males only) and breast (females only) 
development of subjects will be using Tanner Staging (Marshall, 1970). Subjects will be 
examined by the investigator as designated in the Schedules/Assessments (Table 2). (revised 
per Amendment 01)
Echocardiogram
Echocardiograms will be obtained on the Schedule of Procedures/Assessments (Table 2). 
Valvular regurgitation in echocardiogram will be rated absent, trace, mild, moderate, or 
severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve.  The evaluations will be based on guidelines from the American Society of 
Echocardiography. Pulmonary artery pressure will be estimated from the TR regurgitant jet 
velocity.
9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at designated time points as 
specified in the Schedule of Procedures/Assessments (Table 2).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01
and 02)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatment
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USb
ED
Day:
-30 to -1
1
Weeksc,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examinatione
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, insulin, and HbA1c sampling
X
X
X
X
X
X
T4 and TSH
X
X
X
X
Testosterone, Estradiol
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01
and 02)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatment
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USb
ED
Day:
-30 to -1
1
Weeksc,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Pregnancy test (urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting prolactin
X
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Fasting lipid panel
X
X
X
X
Urine NTX
X
X
X
X
PK/PD blood sampling
X
X
X
Xf
Xg
Xf
AM serum cortisol
X
X
X
ECG
X
X
X
X
X
Echocardiograph
Xh
X
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
Leiter-3
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
X
Standardized age-appropriate lifestyle modification 
counselingi
X
X
X
X
X
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendments 01
and 02)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatment
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USb
ED
Day:
-30 to -1
1
Weeksc,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
AE = adverse event, AM = morning; CDC = Centers for Disease Control and Prevention, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, ED = 
early discontinuation, EOS = End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, IxRS = interactive voice or web response system, NTX = N-telopeptide, OC 
= osteocalcin; PHQ-9 = The Patient Health Questionnaire, PICP = carboxyterminal propeptide of type I procollagen,  PD = pharmacodymanic, PK = pharmacokinetics, SAE = 
serious adverse event; T4 = thyroxine, TSH = thyroid stimulating hormone, US = unscheduled.
a: Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b: Unscheduled visits may be conducted at any time that additional assessments are indicated in the clinical judgment of the investigator.  Note that not all assessments listed 
under Unscheduled Visit need to be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs.  At 
Unscheduled Visits, PK samples should only be collected if subject has experienced a serious adverse event (SAE) while on study drug and the sample can be drawn within 
60 hours of the initiation of the SAE. (revised per Amendment 01)
c: Window ±7 days for all visits. (revised per Amendment 01)
d: On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at home before the visit, but to bring their study drug to the clinic 
visit and take their daily dose at the clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken:  1 predose (within 30 minutes before 
dosing) and 1 within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times before the day of clinic visit. Week 52 PK samples should only be 
collected if the sample can be drawn within 60 hours of the last dose of study drug.  On the day of the Week 36 clinic visit, subjects will take the morning dose at home, and 
will be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for PK assessments will be collected  Dose times must be recorded for the 
last 2 dosing times prior to the clinic visit. (revised per Amendment 01)
e: Includes a neuromuscular assessment and signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle abnormalities or galactorrhea) (revised
per Amendment 01)
f: PK samples should only be collected if the sample can be drawn within 60 hours of the last dose of study drug.
g: PK samples should only be collected if subject has experienced an SAE while on study drug and the sample can be drawn within 60 hours of the initiation of the SAE.
h: Echocardiographic assessments will be performed during screening period after subjects have met all other inclusion and exclusion criteria.
i: Lifestyle modification counseling will also be performed at Weeks 3, 16, 24, 32, 40, and 48 in addition to counseling at the scheduled visits in Appendix 2.
.
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes (revised per Amendment 01)
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
(Chemistry and Hematology)
5
Screening: 1
Visits 2, 3, 4, 6, 8, 11 (EOT),
EOS or ED
58=40
T4, TSH, AM Serum 
Cortisol, Testosterone, 
estradiol 
6
Screening:  1
Visits 8, 11 (EOT), or ED
6×3=18
Serum OC and PICP, 
Hydroxy-proline; Fasting 
lipid panel (HDL cholesterol, 
LDL cholesterol, total 
cholesterol, triglycerides)
8
Visits 2, 8, 11 (EOT), or ED
8×3=24
Fasting Prolactin, FPG, 
fasting insulin, and HbA1c
sampling
5
Screening:  1
Visits 2, 6, 8, 11 (EOT) or ED
5×5=25
PK/PD blood sampling
4
Visits 6, 8, and 11 (EOT) or ED
(2 samples each); Visit  9 (1 
sample only)
7×4=28
Total
135
ED= early discontinuation from study, EOS = End of Study, EOT = End of Treatment, FPG = fasting plasma glucose, 
HbA1c = hemoglobin A1c, OC = osteocalcin, PD = pharmacodynamic, PICP = carboxyterminal propeptide of type I 
procollagen, PK = pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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.
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
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criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas of 
the skin

Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study-specific 
event does not meet serious criteria.  If the event meets seriousness criteria, it should be 
reported as an SAE as above.  However, if the event listed below does not meet serious 
criteria, it should be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation

Euphoria 
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 
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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
Adverse events will be reported by the sponsor or a third party acting on behalf of the
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue treatment prematurely will be followed up until study completion.  
All subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments Table 2).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
Detailed retention strategies will be developed and included in study manual. These include 
a highly trained and competent staff, easy access to the clinic, reminder and follow-up calls, 
interactive group sessions with games and hands-on nutrition and physical activity 
demonstrations, random raffle drawings, social events, birthday and holiday cards, and
newsletters. In addition, home visits for assessments of families will be an option, as needed, 
to maximize data collection. This detailed retention plan will help prevent missing data.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.  The DEA Registrant has 
the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
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9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Association between change and percentage change in BMI from Baseline to Week 52 
with the outcome of achieving at least a 5% BMI reduction at Week 12 (revised per 
Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% BMI 
reduction at Week 52 with the outcome of achieving at least a 5% BMI reduction at 
Week 12 (revised per Amendment 02)

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
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9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or 
greater compliant with study medication, completed the study, have no major protocol 
deviations, have no violations of inclusion or exclusion criteria, and have BMI data at 
Baseline and Week 52.  The determination of subjects to be excluded from this 
population based on the above criteria and list of major protocol violations will be 
included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 
1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and 
who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
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9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using analysis of covariance model (ANCOVA) with 
factors of treatment, sex (male and female) as fixed effect, and the baseline age and BMI as 
covariates.  The missing values will be imputed using a pattern mixture model utilizing 
multiple imputation (MI) assuming the missing values are missing not at random (MNAR).  
The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model 
and missing value imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated based 
on the PP.

Change from baseline in standardized BMI score (Z-score): The same primary efficacy 
analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed 
and will be described in the SAP.  
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Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, and sex (male and 
female), and baseline BMI as a covariate using FAS.  Subjects with any missing assessment 
at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using mixed effect model repeated measurement analysis (MMRM) and categorical
variables will be analyzed using the Cochran Mantel Haenszel test, Chi-square test, or 
logistic regression as appropriate.  Additional analysis may be performed as needed using 
appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male 
and female), race (white, black, Asian, and other). Additional subgroups may be explored, if 
deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will 
be used for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also be 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
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9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination, 
neuromuscular 
sign 
assessment, 
and 
signs 
and 
symptoms 
of 
priapism 
and 
hyperprolactinemia), out-of-normal-range laboratory safety test values, change from baseline 
in laboratory safety test values, ECGs, and vital sign measurements will be summarized by 
treatment group using descriptive statistics or frequency count as appropriate.  (revised per 
Amendment 01)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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.
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A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No [not 
related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
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baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, 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
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and greater 
than 60 msec from the baseline visit.
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9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including adolescent growth evaluations using 95th percentile CDC 
growth charts and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, study drug effect on cognition assessed by Leiter-3, assessment of suicidality using 
C-SSRS, and depression assessment using PHQ-9 will be summarized by treatment group at 
each scheduled visit.  For echocardiographic assessments, the proportion of subjects who 
develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
hypertension (defined as when a subject’s SPAP is
≥40 mmHg evaluated by 
echocardiograph], and change from baseline in SPAP will also be summarized by treatment 
group at Week 28 and Week 52. (revised per Amendment 01)
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
260 subjects in a 1:1 ratio (n=130 in the Belviq XR 20-mg treatment group; n=130 in the 
placebo group) will have at least 80% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 260 subjects (130 subjects for Belviq XR 20 mg and 130 subjects for placebo) 
will also have greater than 78% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Chi-Square test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.  
(revised per Amendment 02)
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.
Lohman T, Roche AF, Martorell R. Anthropometric Standardization Reference Manual.  
Champaign, IL:  Human Kinetics Books; 1988.
Marshall WA, Tanner JM. Variation in pattern of pubertal changes in boys. Arch. 
Dis.Childhd 1970; 45, 13-23.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.
CT.gov Study NCT02918279. (revised per Amendment 02)
Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L.  
NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
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Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A 
Life-Table Analysis. Ann Intern Med. 2003; 138:24-32.
Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al. A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
Whitaker RC, et al. Predicting obesity in young adulthood from childhood and parental 
obesity. N Engl J Med. 1997 Sep 25;337(13):869-73.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
<LLN – 2.5 mg/dL
<2.5 – 2.0 mg/dL
<2.0 – 1.0 mg/dL
<1.0 mg/dL
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
(hypophosphatemia) 
<LLN – 0.8 mmol/L
<0.8 – 0.6 mmol/L
<0.6 – 0.3 mmol/L
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will be 
encouraged to participate in a standardized weight management program for adolescents 
consisting of multicomponent behavior therapy.  The therapy will focus on healthy eating, 
physical activity, and lifestyle changes that will facilitate weight loss and weight-loss 
maintenance. The role of the caregivers is to support their child or adolescents’ lifestyle 
changes and their taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress but 
caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neurology Business Group
Eisai Inc.
Date
Medicine Development Group
Eisai Inc.
Date
Neurology Business Group
Eisai Inc.
Date
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PPD
PPD
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APD356-A001-403
Eisai
FINAL:  v7.0, 11 Jul 2017
Confidential
Page 78 of 78
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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FINAL:  v6.0, 17 May  2017
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Page i of viii
Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Revised scale for measuring of 
cognition from Wide Range 
Assessment of Memory and 
Learning-2 (WRAML-2) to 
Leiter-3
Leiter-3 is selected to replace 
WRAML-2 for the evaluation of the 
change in cognition for the following 
reasons:Lack of availability of 
WRAML-2 in Spanish, Leiter-3’s 
high scientific validity, non-verbal 
format to offer less biased assessment 
for subjects whose second language is 
English, easier and shorter 
administration and short test time 
reducing investigator burden, as well 
as increase probability of the 
subjects’ retention in the study.
Synopsis – Objectives
Synopsis – Other Safety 
Assessments
Synopsis – Other Safety Analyses
List of Abbreviations
Section 8.2
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Added requirement that 
qualified personnel must 
evaluate positive responses on 
the C-SSRS and take 
appropriate action as detailed in 
the training and certification 
process for administering the 
C-SSRS
To provide guidance that qualified 
personnel must evaluate positive 
responses on the C-SSRS and take 
appropriate action as detailed in the 
training and certification process for 
administering the C-SSRS.
Synopsis – Other Safety 
Assessments
Section 9.5.1.5.10
Revised timing of initial C-
SSRS from Baseline to 
Screening
Operational efficiencies
Table 2
Section 9.3.2
Section 9.5.1.5.10
Correct formatting of Synopsis, 
Other Secondary Objectives
Consistency
Synopsis – Objectives
Section 8.2
Revised exclusion criteria for 
viral hepatitis (B or C) (#17) 
whereby active testing will not 
be performed 
To clarify that the subjects will be 
excluded if they are known to have
active hepatitis (B or C). Hepatitis (B 
or C) tests will not be conducted for 
the screening purpose.
Synopsis – Exclusion Criteria
Section 9.3.2
Added footnotes regarding 
collection of PK samples at 
EOT and Early Discontinuation 
visits
To ensure appropriate timing of
sampling relative to administration of 
last dose of study drug
Table 2
Added clarification for
Unscheduled visits, such that 
they may be conducted at any 
time that additional assessments 
are clinically indicated in the 
judgment of the investigator.
Provide additional guidance to 
investigators
Table 2
Added clarification that 
prolactin testing should be 
fasting
Clarification
Table 2
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Eisai
FINAL:  v6.0, 17 May  2017
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Page ii of viii
Revision History
Previous Version (Revision): v5.0
Current Version (Revision):  v6.0
Date of Revisions: 17 May 2017 (per Amendment 01)
Change
Rationale
Affected Protocol Section(s)
Added requirement for 
pregnancy test and AM serum 
cortisol to Early 
Discontinuation Visit
Correction
Table 2
Table 3
Added requirement for lifestyle 
modification counseling Visit at 
Week 16
To ensure all visits are 4 weeks apart
Table 2
General alignment of text 
throughout
Clarity
Throughout
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Eisai
FINAL:  v6.0, 17 May  2017
Confidential
Page iii of viii
Revision History
Previous Version (Revision): v4.0
Current Version (Revision):  v5.0
Date of Revisions: 22 Feb 2017
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
A full physical examination will 
be performed at Week 1
Correction
Synopsis - Safety Assessment
Section 9.5.1.5
PHQ-9 questionnaire has been 
added to every scheduled visit.
Per FDA recommendation
Synopsis - Safety Assessment 
Section 9.5.1.5
Section 9.5.2.1
The mixed model repeated 
measures (MMRM) model was 
replaced with the analysis of 
covariance (ANCOVA) model
analyzing Week 52 only.
Per FDA recommendation
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
All postdiscontinuation data 
will be used in the primary 
analysis
Clarification per FDA feedback
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Labeling information for study 
drug was updated
Correction as the study will only be 
conducted in the US
Section 9.4.2.3
The order of assessments was 
reorganized in the Schedule of 
Assessments 
To better align the assessments by 
grouping them
Section 9.5.2.1
Urinalysis will be performed at 
Visit 2 instead of Visit 9
Correction
Section 9.5.2.1
Assessment for testosterone, 
estradiol will be performed at 
Week 28, not Week 20
Correction
Section 9.5.2.1
Section 9.5.2.3
Prior/concomitant medication 
assessment will be performed at 
Week 56
Correction
Section 9.5.2.1
Assessments performed at early 
discontinuation from the study
Correction
Section 9.5.2.1
Summary of blood volumes 
table was updated
Correction
Section 9.5.2.3
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Eisai
FINAL:  v6.0, 17 May  2017
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Page iv of viii
Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Subject population to include 
children ages 12 to 17 years
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Title Page
Synopsis - Study Protocol Title
Synopsis - Design
Synopsis - Inclusion Criteria
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.7.1.6
Section 9.7.1.8
Protocol Signature Page
Investigator Signature Page
All subjects will be evaluated 
for cardiac valvular disease or 
pulmonary hypertension via 
echocardiographic assessment.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Other Secondary 
Objectives
Synopsis - Exclusion Criteria
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.3.2
Section 9.5.1.5.10
Section 9.5.2
Section 9.7.1.8
Section 9.7.1.8.6
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FINAL:  v6.0, 17 May  2017
Confidential
Page v of viii
Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Study drug administration will 
be taken at approximately the 
same time each day.  On the 
days of PK sampling and the 
day before the subjects come to 
the clinic for PK sampling, 
study drug will be taken in the 
morning and doses recorded 2 
days prior to the clinic visit.
This will ensure lower variability 
with regard to PK/PD measurements.
Synopsis - Pharmacokinetic 
Assessments
Section 9.4.1
Section 9.4.4
Section 9.5.1.4.1
Section 9.5.2.1
Screening, diagnosing, 
monitoring, and measuring the 
severity of depression will be 
assessed using the Patient 
Health Questionnaire (PHQ-9), 
and not the Children’s 
Depression Inventory 2 (CDI-
2).
The PHQ-9 was originally proposed 
by the FDA for the population in the 
current study.
Synopsis - Other Secondary 
Objectives
Synopsis - Safety Assessments
Synopsis - Safety Analyses
Section 8.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.1.5.1
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.6
Primary analysis changed from 
MMRM to using a pattern 
mixture model utilizing 
multiple imputations (MI) to 
impute missing values.
Changes were made upon regulatory 
advice received at the Type C 
meeting.
Synopsis - Primary Efficacy 
Analysis
Section 9.7.1.6
Clarified fasting lipids
Fasting lipid levels provide 
uniformity in lipid measurements for 
definition of dyslipidemia
Synopsis - Other Secondary 
Objectives
Synopsis - Efficacy Assessments
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.5.1.3
Removed Appendix 3
The current study will not conduct 
any biomarker or pharmacogenomic
evaluation. PK/PD measurements 
will be done during study.
Appendix 3
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FINAL:  v6.0, 17 May  2017
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Page vi of viii
Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Prehypertension was deleted 
from the inclusion criterion.  
Subjects with Stage 1 primary 
hypertension, with an upper 
limit defined as 99% plus 5 
mmHg for age, sex, and height 
are included in the study. 
Prehypertension does not qualify as a 
comorbid condition.  The limitation 
on BP is to further define the proper 
study population.
Synopsis - Inclusion Criteria
Section 9.3.1
Removed the restriction that 
subjects need to have less than 
44 kg/m2 BMI for study entry
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Synopsis - Analysis Sets
Synopsis - Pharmacodynamic 
Analyses
Synopsis -
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study entry 
requirement that the caregiver 
cannot have a history of ADD, 
substance abuse, depression, 
suicidal ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Inclusion Criteria
Section 9.3.1
The secondary efficacy 
objective and endpoint were 
revised
To explore the predictability of 12-
week responders for long-term 
sustainable weight loss effect
Synopsis - Secondary Efficacy 
Objectives
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with symptoms or 
signs of cardiac valvular disease 
or pulmonary hypertension are 
not required to have further 
evaluation by centralized 
echocardiogram assessment.  In 
addition, no adjudication will be 
performed.  Local 
echocardiograms can be 
performed if deemed medically 
necessary by the investigator.
This 
change 
allows 
for 
the 
investigator to make the decision to 
perform local echocardiograms on a 
pediatric subject if deemed medically 
indicated rather than burden the 
subject to undergo a mandated, 
unnecessary procedure. 
Synopsis - Safety Assessments
Section 9.5.1.5
Updated study rationale
Clarification 
Section 7.1.1.2
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FINAL:  v6.0, 17 May  2017
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Page vii of viii
Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will replace the
IR formulation in the United States
market to support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to include 
children ages 9 to 17 years
Expand the age of the population due 
to the change of pediatric development 
strategy
A single dose pharmacokinetic study 
in pediatric obese subjects (APD356-
A001-026) indicated that patients with 
body weight greater than or equal to 
60 kg can be administered a dose 
similar to that given to adults and 
adolescents.  Based on Centers for 
Disease Control and Prevention 
(CDC) growth chart data, almost all 
subjects over 9 years of age are likely 
to be at or over 60 kg body weight.  
Therefore, children age 9 to 11 years 
have been included in the current 
study.
Title Page
Synopsis - Study Protocol Title
Synopsis - Objectives
Synopsis - Study Design
Synopsis - Inclusion Criteria
Synopsis - Assessments
Synopsis - Efficacy Analyses
Synopsis - Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.10
Section 9.7.1.6
Section 9.7.1.8
Additional safety assessments 
including cognitive function, 
serotonin syndrome 
components, bone health and 
endocrine function, priapism, 
and symptoms associated with 
hyperprolactinemia were added.
Per United States Food and Drug 
Administration (FDA) request
Synopsis - Efficacy Assessments
Synopsis - Pharmacokinetic 
Assessments
Synopsis - Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.10
Section 9.7.1.8
Section 9.7.1.8.1
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FINAL:  v6.0, 17 May  2017
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Page viii of viii
Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Change to primary and key 
secondary endpoints
Per FDA request
Synopsis - Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary endpoint 
changed
Per FDA request
Synopsis - Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of study-
specific adverse events
To provide clearer guidance for the 
correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and prohibited 
prior and concomitant therapies
For clarification
Synopsis - Exclusion Criteria
Synopsis - Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of adverse 
events
To provide clearer guidance for the 
correct reporting of adverse events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
Update to Introduction and to 
Completion/ Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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FINAL:  v6.0, 17 May  2017
Confidential
Page 1 of 78
1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction With Lifestyle Modification for Weight 
Loss in Obese Adolescents, Age 12 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
v4.0
03 Nov 2016 (Revision)
v5.0
22 Feb 2017 (Revision)
v6.0
17 May 2017 (per Amendment 01)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation
of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 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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FINAL:  v6.0, 17 May  2017
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Page 2 of 78
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and 
Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in Obese Adolescents, Age 
12 to 17 Years
Investigators
Unknown
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
Approximately 24 months from the 1st subject enrolled to last subject’s last visit or last assessment 
Phase 4
Objectives
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks of treatment 
with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD as compared to 
placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at least a 5% 
reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg administered QD compared 
to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of treatment with 
Belviq XR 20 mg administered QD is predictive of sustained change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 52 weeks of 
treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% BMI reduction, 
change in waist circumference) at the end of 52 weeks of treatment
-
Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin Resistance
(HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) during 52 weeks of treatment
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, dyslipidemia)
including fasting lipid changes (total cholesterol, triglycerides, high density lipoprotein [HDL], and 
low density lipoprotein [LDL]) during 52 weeks of treatment.

To assess the safety of Belviq XR, including the effects on cognition with the Leiter-3 International 
Performance Scale (Leiter-3), depression with the Patient Health Questionnaire (PHQ-9), signal of suicidal 
ideation or behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by
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Page 3 of 78
Centers for Disease Control and Prevention (CDC) growth chart, sexual maturation (pubescence) measured 
by Tanner Staging scores, and other growth and development parameters by measuring sex hormones, 
thyroid function, adrenal function, bone age, and biochemical markers of bone health, valvular function,
and pulmonary arterial pressure.(revised per Amendment 01)

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) parameters 
including but not limited to reduction from baseline in BMI and probability of achieving at least a 5% and 
at least a 10% reduction in BMI from baseline at Week 52 using population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese adolescents, 
ages 12 to 17 years.  Approximately 360 subjects will be randomized in a 1:1 ratio to Belviq XR 20 mg QD
(180 subjects) and placebo (180 subjects).  Subjects will be stratified by sex.  Subjects will receive Belviq XR
20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout the duration of the study, subjects will be 
encouraged to adhere to a lifestyle modification program that includes a standardized, age-appropriate diet and 
exercise counseling.
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization Phase will 
last up to 30 days and consist of 1 visit during which subjects will be screened for eligibility.  The 
Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The Treatment Period will last 
for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52.  The Follow-Up Period will 
extend from the End of Treatment visit to the End of Study visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will continue in the study 
until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely will be followed up 
until study completion.  
Number of Subjects
Approximately 700 subjects will be screened to provide 360 randomized subjects.
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that is greater than or 
equal to the United States (US)-weighted mean of the 95th percentile based on age and sex with a body 
weight greater than 60 kg
2.
Subjects and their families not planning to move away from the area for the duration of the study
3.
Subjects able and willing to comply with all aspects of the study, including a standardized, reduced-calorie 
diet and an age-appropriate, increased physical activity program
4.
Subjects considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the investigator,
including consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study requirements for the 
caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the subject’s ability 
to fulfill the study requirements or significantly confound the assessments
2.
Subjects who cannot swallow investigational products
3.
Any of the following findings on Screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater
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
Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, mean gradient 
>25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean gradient >5 mm Hg and mitral valve 
area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure (SPAP) >40 mmHg (and/or tricuspid regurgitation (TR) jet 
velocity >2.9 m/s)
In cases where an actual SPAP value is not measurable due to lack of adequate TR jet, the pulmonary flow 
acceleration time measured at the right ventricular outflow tract (RVOTAT), will be used to assess 
eligibility. Patients with a RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be determined based on 
combined assessment of the TR jet, septal motion and right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with hemodynamic compromise)
4.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper limit of
normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater than 1.5×ULN in 
absence of Gilbert’s syndrome
5.
Any suicidal ideation with intent with or without a plan, at the time of or within 6 months of Screening, as 
indicated by answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the C-SSRS.
6.
Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
7.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit Hyperactivity 
Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th Edition depressive disorder,
suicidal ideation or behavior, bipolar disorder, or schizophrenia
8.
Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi syndrome, Bardet 
Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, Cushing’s syndrome, daily systemic 
corticosteroid exposure for longer than 30 days, history of significant exposure to corticosteroids for 
chronic illness during the past year)
9.
Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, 
and herbal preparations within 1 month before Screening 
10. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine oxidase inhibitors 
(MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
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11. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before Screening, 
including but not limited to pergolide, ergotamine, methysergide, and cabergoline
12. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, gastrointestinal, 
renal, or psychiatric disease) other than prediabetes (impaired fasting glucose or impaired glucose 
tolerance), type 2 diabetes treated with oral anti-diabetic agents (excluding sulfonylurea) or non-insulin 
injectable antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
13. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any of the 
excipients
14. Significant change in diet or level of physical activity within 1 month before dosing or change in weight of 
more than 5 kg within 3 months before Screening
15. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before Screening
16. History of alcohol or drug dependence or abuse
17. Recreational drug use within 2 years before Screening
18. Known to be human immunodeficiency virus positive
19. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
20. Malignancy within 5 years before Screening
21. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or guardian to supervise 
study participation
22. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to profound 
mental retardation [IQ <70], moderate to severe cognitive developmental delay, pervasive development 
disorders, autism)
23. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder within 6 months of 
screening or any time between screening and randomization
24. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate readings recorded 
on 2 separate days.  Those subjects who had hypertension at Screening can be rescreened more than
1 month after initiation or adjustment of antihypertensive therapy 1 time.
25. Currently enrolled in another clinical study or has used any investigational drug or device within 30 days 
before providing informed consent
26. Planned bariatric surgery during the study
27. Not suitable to participate in the study in the opinion of the investigator, including consideration of any 
existing physical, medical, or mental condition that prevents compliance with the protocol
28. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
β-human chorionic gonadotropin test).  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.
29. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a 
highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier 
method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire 
study period and for 28 days after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described above) or refrain 
from sexual activity during the study period and for 28 days after study drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during 
the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]).
Study Treatment(s)
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Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated, biconvex tablets
with one 20-mg tablet administered orally QD.
Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  up to 30 days
Randomization Phase: approximately 56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal preparations, are 
prohibited as concomitant medications.  OTC cold medicines containing dextromethorphan can be used for up 
to 7 days with study medication temporarily stopped for that time period and resumed the next day after the 
OTC cold medicine is stopped.  Any of the following serotonergic agents or other agents in combination with 
Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to calculate the 
proportion (%) of patients achieving at least a 5% and at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total cholesterol, HDL cholesterol, 
LDL cholesterol, and triglycerides), fasting plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and 
Homeostasis Model Assessment (HOMA) IR to assess cardiovascular and metabolic risk profiles from 
Baseline to Week 52

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents
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
Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents
Pharmacokinetic Assessments
Blood samples (approximately 4 mL each) for PK assessment will be collected at Weeks 12, 28, 36, and 52 for 
analysis of Population PK. (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at 
home before the visit,but to bring their study drug to the clinic visit, and take their daily dose at the clinic.  
Two blood samples for determination of plasma concentrations of lorcaserin will be taken: 1 predose (within 
30 minutes before dosing), and 1 within 1 to 3 hours after dosing.  Dose times must be recorded for the last 
2 dosing times before the day of clinic visit. Week 52 PK samples should only be collected if the sample can be 
drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at home, and will be 
asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for for PK 
assessments will be collected. Dose times must be recorded for the last 2 dosing times prior to the clinic visit.
(revised per Amendment 01)
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their relationships 
with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious adverse events 
(SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, metabolic function (fasting glucose, 
fasting lipids, and thyroid), adrenal function and biochemical blood and urine bone health assessments; blood 
chemistry and urine values; neuropsychiatric events; periodic measurement of vital signs, neuromuscular signs
for screening potential serotonin syndrome, and signs or symptoms of priapism and hyperprolactinemia; and 
performance of physical examinations. In patients with potential prolactin-related AEs, such as galactorrhea, 
changes in libido, or changes to menstrual cycle, prolactin level will be measured and assessed.
Other Safety Assessments
Effect on growth will be evaluated using the CDC growth chart and bone age determination by x-ray of the 
hand. Sexual maturation will be evaluated by assessing sex hormones and Tanner Staging.   
The C-SSRS will be used to assess all subjects in the study for any signal of depression or suicidal ideation or 
behavior at every visit.  Additionally, screening, diagnosing, monitoring, and measuring the severity of 
depression will be assessed using the PHQ-9 and effects on cognition will be assessed using the Leiter-3.  
(revised per Amendment 01)
Echocardiographic assessments will be used to exclude subjects with FDA-defined valvulopathy, pulmonary 
hypertension, and other major cardiovascular disease (as outlined in Exclusion Criterion No. 3) during the 
Screening Period.  Additionally, cardiac valvular function and pulmonary systolic pressure changes at Weeks
28 and 52 will be assessed. Valvular regurgitation as assessed in the echocardiogram will be rated absent, trace, 
mild, moderate, or severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve. The evaluations will be based on guidelines from the American Society of Echocardiography. 
Pulmonary artery pressure will be estimated from the TR jet velocity.
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography coupled with tandem mass 
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spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from baseline to Week 52 and proportion (%) of subjects achieving 
at least a 5% or 10% BMI reduction at Week 52 by the outcome of achieving at least a 5% BMI reduction 
at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) from 
Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and had at least 
1 post dose safety assessment.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater compliant 
with study medication, completed the study, have no major protocol deviations, have no violations of 
inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  The determination of subjects 
to be excluded from this population based on the above criteria and a list of major protocol violations will 
be included in the statistical analysis plan (SAP) and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid lorcaserin plasma 
concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who have at least 
1 adequately documented measurement of BMI.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as a 
supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in all efficacy 
analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from baseline in 
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BMI will be analyzed using analysis of covariance model (ANCOVA) with factors of treatment,  sex (male and 
female) as fixed effect, and the baseline age and BMI as covariates.  The missing values will be imputed using a 
pattern mixture model utilizing multiple imputation (MI) assuming the missing values are missing not at 
random (MNAR).  The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model and missing value 
imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on the PP.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy analyses described 
above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed and will be
described in the SAP.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI reduction at 
Week 52. The secondary efficacy endpoint will be analyzed only if the test for the primary efficacy endpoint is 
statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using a logistic 
regression model with factors of treatment, sex (male and female), and baseline BMI as a covariate using FAS.  
Subjects with any missing assessment at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed using 
mixed effect model repeated measurement analysis (MMRM) and categorical variables will be analyzed using
the Cochran Mantel Haenszel test, Chi-square test, or logistic regression as appropriate.  Additional analysis 
may be performed as needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male and female), and 
race (white, black, Asian, and other).  Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using nonlinear mixed 
effects modeling. The effect of covariates such as baseline characteristics or demographics on PK will be 
explored. Derived exposure parameters such as the maximum observed concentration and the area under the 
concentration-time curve from time 0 to 24 hours at steady-state will be calculated from the final PK model 
using individual posterior estimates of the PK parameters and from dosing history. The PK analysis set will be 
used for this analysis.
Pharmacodynamic Analyses
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will be used for this 
analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% and ≥10% BMI 
reduction, and change in waist circumference from baseline) will also be assessed as part of the PD analysis.  
The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure and 
response, including but not limited to change in BMI from baseline and the probability of achieving at least a 
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5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, exposure-safety relationships 
for select safety parameters may be explored graphically depending on the data at the end of study.  Any 
emergent relationship may be modeled as appropriate.  Any parameters based on the study data may be 
considered for exploratory assessment for its relationship to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the incidence 
of AEs (including changes from baseline in physical examination), growth (CDC growth chart and bone age 
determined by x-ray of the hand), sexual maturation (Tanner Staging), out-of-normal-range laboratory safety 
test values, change from baseline in laboratory safety test values, ECGs, and vital sign measurements will be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
Other Safety Analyses
In addition, cognition will be evaluated by the Leiter-3, depression will be evaluated by the PHQ-9, and suicidal 
ideation and behavior will be evaluated by the C-SSRS, and will also be summarized by treatment group using 
descriptive statistics or frequency count as appropriate. For echocardiographic assessments, the proportion of 
subjects who develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
hypertension [pulmonary hypertension is defined when the subject’s systolic pulmonary artery pressure 
(SPAP) ≥40 mmHg evaluated by echocardiograph], and change from baseline in SPAP will be summarized by 
treatment group at Week 28 and Week 52 using descriptive statistics or frequency count as appropriate. (revised 
per Amendment 01)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in BMI from 
Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  Assuming a SD of 
2.2 kg/m2 and a 40% dropout rate, a sample size of 360 subjects in a 1:1 ratio (n=180 in the Belviq XR 20-mg 
treatment group; n=180 in the placebo group) will have at least 90% power to detect a treatment difference of 
1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at least a 5% 
BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, this sample of 360 subjects 
(180 subjects for Belviq XR 20 mg and 180 subjects for placebo) will also have greater than 85% power to 
detect an absolute difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 2-
sided Fisher’s Exact test with α=0.05. The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................11
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................15
5
ETHICS............................................................................................................................17
5.1
Institutional Review Boards/Independent Ethics Committees ..............................17
5.2
Ethical Conduct of the Study.................................................................................18
5.3
Subject Information and Informed Consent...........................................................18
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................20
7
INTRODUCTION ...........................................................................................................21
7.1
Indication ...............................................................................................................21
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................22
7.1.1.1
Mechanism of Action...........................................................................22
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................22
7.1.2
Study Rationale............................................................................................23
8
STUDY OBJECTIVES....................................................................................................25
8.1
Primary Objective..................................................................................................25
8.2
Secondary Objectives.............................................................................................25
9
INVESTIGATIONAL PLAN..........................................................................................27
9.1
Overall Study Design and Plan..............................................................................27
9.1.1
Prerandomization Phase...............................................................................27
9.1.1.1
Screening Period..................................................................................27
9.1.2
Randomization Phase...................................................................................28
9.1.3
Extension Phase ...........................................................................................28
9.2
Discussion of Study Design, Including Choice of Control Groups.......................28
9.3
Selection of Study Population................................................................................29
9.3.1
Inclusion Criteria .........................................................................................29
9.3.2
Exclusion Criteria ........................................................................................29
9.3.3
Removal of Subjects From Therapy or Assessment....................................32
9.4
Treatments..............................................................................................................33
9.4.1
Treatments Administered.............................................................................33
9.4.2
Identity of Investigational Product...............................................................33
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................33
9.4.2.2
Comparator Drug .................................................................................33
9.4.2.3
Labeling for Study Drug......................................................................33
9.4.2.4
Storage Conditions...............................................................................34
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9.4.3
Method of Assigning Subjects to Treatment Groups...................................35
9.4.4
Selection and Timing of Dose for Each Subject..........................................35
9.4.5
Blinding........................................................................................................35
9.4.6
Prior and Concomitant Therapy...................................................................35
9.4.7
Treatment Compliance.................................................................................36
9.4.8
Drug Supplies and Accountability...............................................................37
9.5
Study Assessments.................................................................................................38
9.5.1
Assessments.................................................................................................38
9.5.1.1
Demography.........................................................................................38
9.5.1.2
Baseline Assessments ..........................................................................38
9.5.1.2.1
Medical History .............................................................................38
9.5.1.2.2
Urine Drug Screen .........................................................................39
9.5.1.3
Efficacy Assessments...........................................................................39
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................39
9.5.1.4.1
Pharmacokinetic Assessments .......................................................39
9.5.1.4.2
Pharmacodynamic Assessments ....................................................40
9.5.1.4.3
Pharmacogenomic and Other Biomarker Assessments .................40
9.5.1.5
Safety Assessments..............................................................................40
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...40
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................42
9.5.1.5.3
Laboratory Measurements .............................................................44
9.5.1.5.4
Vital Signs and Weight Measurements..........................................45
9.5.1.5.5
Height Measurements ....................................................................46
9.5.1.5.6
CDC Growth Measurements..........................................................46
9.5.1.5.7
Waist Circumference .....................................................................46
9.5.1.5.8
Physical Examinations...................................................................46
9.5.1.5.9
Electrocardiograms ........................................................................46
9.5.1.5.10
Other Safety Assessments..............................................................47
9.5.1.6
Other Assessments...............................................................................48
9.5.1.6.1
Pregnancy Test...............................................................................48
9.5.2
Schedule of Procedures/Assessments ..........................................................48
9.5.2.1
Schedule of Procedures/Assessments ..................................................48
9.5.2.2
Description of Procedures/Assessments Schedule...............................52
9.5.2.3
Total Volume of Blood Sampling........................................................52
9.5.3
Appropriateness of Measurements...............................................................52
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................53
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9.5.4.1
Reporting of Serious Adverse Events..................................................53
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................53
9.5.4.3
Reporting of Events Association with Special Situations....................54
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................54
9.5.4.3.2
Reporting of Study-Specific Events...............................................55
9.5.4.4
Expedited Reporting ............................................................................55
9.5.4.5
Breaking the Blind...............................................................................55
9.5.4.6
Regulatory Reporting of Adverse Events ............................................56
9.5.5
Completion/Discontinuation of Subjects.....................................................56
9.5.6
Abuse or Diversion of Study Drug ..............................................................56
9.5.7
Confirmation of Medical Care by Another Physician .................................57
9.6
Data Quality Assurance .........................................................................................57
9.6.1
Data Collection ............................................................................................57
9.6.2
Clinical Data Management ..........................................................................57
9.7
Statistical Methods.................................................................................................57
9.7.1
Statistical and Analytical Plans....................................................................58
9.7.1.1
Study Endpoints...................................................................................58
9.7.1.1.1
Primary Efficacy Endpoint ............................................................58
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................58
9.7.1.2
Definitions of Analysis Sets.................................................................58
9.7.1.3
Subject Disposition..............................................................................59
9.7.1.4
Demographic and Other Baseline Characteristics ...............................59
9.7.1.5
Prior and Concomitant Therapy...........................................................59
9.7.1.6
Efficacy Analyses ................................................................................60
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................61
9.7.1.7.1
Pharmacokinetic Analyses.............................................................61
9.7.1.7.2
Pharmacodynamic Analyses..........................................................61
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................62
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................62
9.7.1.8
Safety Analyses....................................................................................62
9.7.1.8.1
Extent of Exposure.........................................................................62
9.7.1.8.2
Adverse Events ..............................................................................62
9.7.1.8.3
Laboratory Values..........................................................................63
9.7.1.8.4
Vital Signs......................................................................................64
9.7.1.8.5
Electrocardiograms ........................................................................64
9.7.1.8.6
Other Safety Analyses....................................................................65
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9.7.2
Determination of Sample Size .....................................................................65
9.7.3
Interim Analysis...........................................................................................65
9.7.4
Other Statistical/Analytical Issues ...............................................................65
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................65
10
REFERENCE LIST .........................................................................................................66
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......68
11.1
Changes to the Protocol .........................................................................................68
11.2
Adherence to the Protocol......................................................................................68
11.3
Monitoring Procedures...........................................................................................68
11.4
Recording of Data..................................................................................................69
11.5
Identification of Source Data.................................................................................69
11.6
Retention of Records..............................................................................................70
11.7
Auditing Procedures and Inspection......................................................................70
11.8
Handling of Study Drug.........................................................................................70
11.9
Publication of Results ............................................................................................71
11.10 Disclosure and Confidentiality ..............................................................................71
11.11 Discontinuation of Study .......................................................................................71
11.12 Subject Insurance and Indemnity...........................................................................72
12
APPENDIX......................................................................................................................73
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests (revised per Amendment 01)...........................45
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  
(revised per Amendment 01) .....................................................................49
Table 3
Summary of Blood Sample Volumes (revised per Amendment 01) ........52
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
(revised per Amendment 01)
Abbreviation
Term
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
Leiter-3
Leiter-3 International Performance Scale
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Term
MAR
missing at random
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PHQ-9
The Patient Health Questionnaire
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
RVOTAT
right ventricular outflow tract
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SPAP
systolic pulmonary artery pressure  
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TR
tricuspid regurgitation
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity has become a global epidemic, causing a serious public health concern.  In the 
United States, the prevalence of obesity in adolescents ages 12 and 19 years has almost 
doubled over the past 2 decades.  The rate increased from 10.5% between 1988 and 1994 to 
20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, defined in the 
United States as greater than or equal to the 95th percentile in gender- and age-specific body 
mass index (BMI), continues to grow at an alarming rate in the United States and globally.  
Based on data (Wang and Lobstein, 2006) using various criteria for the definition of obesity 
that included more than 30 countries in Europe, North America, Asia, and the West Pacific, 
prevalence of obesity in these countries has also increased significantly, at a rate comparable 
to that in the United States.
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may 
result in a decrease in life expectancy for the 1st time in 200 years (Peeters, et al., 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese adolescents are likely to become 
tomorrow’s obese adults (Whitaker, et al., 1997).
Current approaches to weight management in adults include lifestyle modification, 
pharmacotherapy, and invasive bariatric procedures.  Lifestyle modification involves a 
combination of diet, exercise, and behavioral change, and is the preferred and essential 
strategy for weight management in obese and overweight individuals, including adolescents.  
Although lifestyle modification can be very efficacious in some patients, adherence to the 
prescribed regimens is often poor.  As such, lifestyle modification alone is often not adequate 
and the weight loss is often transient.  On the other hand, bariatric surgery and various other 
invasive procedures are generally reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise, but are rarely used 
for adolescents.
The current standard of care for treatment of obesity in adolescent subjects ranges from
behavioral therapy including lifestyle intervention to the rare use of pharmacotherapy in 
adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
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(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies that will be 
used in the present study to help retain participants.  These include a highly trained and 
competent staff, ample waiting area, readily available parking (at no cost), access to mass 
transit, and reminder and follow-up calls.  In addition, we will provide fun and interactive 
group sessions with games and hands-on nutrition and physical activity demonstrations, 
random raffle drawings, social events, birthday and holiday cards, and newsletters.  
Furthermore, we will make home visits for assessments of families, as needed, to maximize 
data collection. 
By using these retention strategies, we hope that we will maximize 
participant retention, which will help us cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:

A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) was 
significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
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used for adolescent subjects with body weight greater than 60 kg.
In adolescent obese populations, it is anticipated that Belviq XR will result in similar effects.
As part of FDA postmarketing requirements, this study is designed to characterize the 
efficacy and safety of Belviq XR in adolescent obese populations in the United States.  It is 
also intended to support an indication for chronic weight management for obese adolescents 
ages 12 to 17 years old. 
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of subjects 
in the placebo-treated group who lose at least 5% of baseline body weight, and the 
difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in obese adolescents, where weight loss will be assessed using BMI
measurements to account for growth. In this study, the objective is to demonstrate that BMI
reduction will be achieved during 52 weeks of treatment with Belviq XR 20 mg administered 
once daily (QD) compared to placebo in obese adolescents.
In the Phase 3 orlistat study in obese adolescents mentioned above, the proportion of subjects 
who lost at least 5% body weight is relatively low. At the end of the study at Week 52, only 
26.5% of the subjects achieved a 5% or greater BMI reduction compared to 15.7% in the 
placebo group. The placebo-corrected BMI reduction was about 0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years
(Peirson, et al, 2015).  Thirty-one studies (29 behavioral, 2 pharmacological and behavioral) 
were included in a meta-analysis of randomized studies conducted in primary care centers in 
overweight and obese children and youth ages 2 to 18 years using behavioral (diet, exercise,
and lifestyle) and pharmacological interventions and providing 6-month postbaseline BMI or 
prevalence of overweight or obesity. Both interventions showed a significant effect on BMI 
in favor of treatment (behavioral: 
standardized mean difference [SMD] -0.54, 
95% confidence interval [CI]
-0.73, -0.36; orlistat plus behavioral: 
SMD -0.43, 
95% CI -0.60, -0.25). The studies reported no significant difference between groups in the 
likelihood of reduced prevalence of overweight or overweight and obese. A great deal of 
variation was noted across efficacious interventions.
In conclusion, this meta-analysis 
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demonstrated low-quality evidence that behavioral treatments alone are associated with a 
smaller effect in terms of reduced BMI compared with the effect shown by combined 
behavioral and pharmacological interventions. This may be because the effect size in the 
randomized, double blind, placebo controlled, phase 3 orlistat study in adolescents was 
relatively low and there was a lack of maintenance effect. These subjects started to regain 
their BMI after 6 months of treatment. At end of the study, only 26.5% of subjects achieved 
a 5% or greater BMI reduction compared to 15.7% in placebo group. In a sibutramine 
Phase 3 study in obese adolescents, a substantially higher proportion of subjects (69%) 
treated with sibutramine achieved at least a 5% BMI reduction compared to 21% of subjects 
in the placebo group. In addition, sibutramine resulted in a substantial reduction in mean 
BMI (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 
8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the weight loss effect of Belviq
in adults and sibutramine in adolescents, subjects in the orlistat study started to increase their 
BMI after 6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of 360 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
and sibutramine) (FDA, 2003; Chanoine, et al, 2005; Berkowitz, et al, 2006) and other 
metabolic or dyslipidemia medication products (ezetimibe, simvastatin) (FDA, 2007).
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8
STUDY OBJECTIVES
8.1
Primary Objective

To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment with 
Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR
20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of 
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in 
BMI during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo
(revised per Amendment 01)

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% 
BMI reduction, change in waist circumference) at the end of 52 weeks of treatment
-
Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin 
Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) during 52 weeks of 
treatment
-
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high 
density lipoprotein [HDL], and low density lipoprotein [LDL]) during 52 weeks of 
treatment
•
To assess the safety of Belviq XR, including the effects on cognition by Leiter-3 
International Performance Scale (Leiter-3), depression with the Patient Health 
Questionnaire 
(PHQ-9), 
signal 
of 
suicidal 
ideation 
or 
behavior 
with 
the 
Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by CDC growth 
chart, sexual maturation (pubescence) measured by Tanner Staging scores, and other 
growth and development parameters by measuring sex hormones, thyroid function, 
adrenal function, bone age, and biochemical markers of bone health assessments valvular 
function, pulmonary arterial pressure. (revised per Amendment 01)
•
To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling
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•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
probability of achieving at least a 5% and at least a 10% reduction in BMI from baseline 
at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents ages 12 to 17 years.  Approximately 360 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will be 
stratified by sex.  Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up 
to 52 weeks. Throughout the duration of the study, subjects will be encouraged to adhere to 
a lifestyle modification program that includes a standardized, age-appropriate diet and 
exercise counseling (see Appendix 2).  
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be rescreened only once after 60 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.
9.1.1
Prerandomization Phase
Screening will occur during the Prerandomization Phase at Visit 1.
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
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9.1.2
Randomization Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025.  Overall, the PK parameters of Belviq and its main 
metabolites, M1 and M5, were similar to those in adults.  Following a single, oral 
administration of Belviq 10 mg to a total of 8 healthy adolescent (ages 12 to 17 years old) 
obese subjects, the mean maximum concentration observed and the area under the 
concentration-time curve from time zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 
464 hr×ng/mL, respectively.  The mean Belviq terminal phase half-life was 9.70 hours, 
similar to that observed in adults, thus supporting a similar dosing frequency (QD) in 
adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric or adolescent subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of subjects who are older than 12 years of age 
having a body weight of less than 60 kg is very low; therefore, the current study as designed 
to enroll subjects between 12 to 17 years of age with body weight at least 60 kg, will cover
majority of the population of interest.  The targeted study population comprises 360 obese 
adolescents 12 to 17 years of age, with a body weight at least 60 kg.
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
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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, 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 700 subjects will be screened to ensure that 360 subjects will be randomized.
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug. Subjects who screen fail can be re-screened only once after 
60 days.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, ages 12 to 17 years old at Screening, with a BMI 
that is greater than or equal to the United States (US)-weighted mean of the 
95th percentile based on age and sex with a body weight greater than 60 kg
2. Subjects and their families are not planning to move away from the area for the duration 
of the study
3. Subjects able and willing to comply with all aspects of the study, including a 
standardized, reduced-calorie diet and an age-appropriate, increased physical activity 
program
4. Subjects considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may affect 
the subject’s ability to fulfill the study requirements or significantly confound the 
assessments
2. Subjects who cannot swallow investigational products
3. Any of the following findings on screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater
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
Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, 
mean gradient >25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean 
gradient >5 mm Hg and mitral valve area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure
(SPAP) >40 mm Hg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
-
In cases where an actual SPAP value is not measurable due to lack of adequate 
TR jet, the pulmonary flow acceleration time measured at the right ventricular 
outflow tract (RVOTAT), will be used to assess eligibility. Patients with a 
RVOTAT ≤100 msec will be excluded, suggesting an elevated mean SPAP; 
eligibility for the those patients with RVOTAT between 100 and 120 msec will be 
determined based on combined assessment of the TR jet, septal motion and right 
ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with 
hemodynamic compromise)
4. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
5. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, bipolar disorder, or schizophrenia
6. Any suicidal ideation with intent with or without a plan, at the time of or within 6 months 
of Screening, as indicated by answering “Yes” to questions 4 or 5 on the Suicidal 
Ideation section of the C-SSRS.
7. Any suicidal behavior in the past based on the C-SSRS (revised per Amendment 01)
8. Known secondary causes (genetic, endocrine, or metabolic) for obesity (eg, Prader-Willi 
syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated hypothyroidism, 
Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 30 days, 
history of significant exposure to corticosteroids for chronic illness during the past year)
9. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before Screening
10. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans 
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
St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
11. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and 
cabergoline
12. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), Type 2 diabetes treated with oral anti-diabetic 
agents (excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive 
sleep apnea, dyslipidemia, and nonalcoholic fatty liver disease
13. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or 
any of the excipients
14. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
15. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 6 months
before Screening
16. History of alcohol or drug dependence or abuse
17. Recreational drug use within 2 years before Screening
18. Known to be human immunodeficiency virus positive
19. Known to have active viral hepatitis (B or C) (revised per Amendment 01)
20. Malignancy within 5 years before Screening
21. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
22. Special needs subjects who are unable to comprehend study-related instructions (eg, mild 
to profound mental retardation [IQ <70], moderate to severe cognitive developmental 
delay, pervasive development disorders, autism)
23. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
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24. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate 
readings recorded on 2 separate days.  Those subjects who had uncontrolled hypertension 
at Screening can be rescreened more than 1 month after initiation or adjustment of 
antihypertensive therapy 1 time.
25. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
26. Planned bariatric surgery during the study
27. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
28. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
29. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 
28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after 
study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use 
the same contraceptive during the study and for 28 days after study drug 
discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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.
Investigators should do their best to bring all subject who discontinued early from the study
in for the their primary endpoint collection regardless of the reason for ED. (revised per 
Amendment 01)
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9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD at 
approximately the same time each day.
Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled with text that is in full regulatory compliance with each 
participating country. As the study is being conducted in US only, the study drug label will 
be printed in English. 
The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
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5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal (US) law to 
investigational use.”
All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug was 
dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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.
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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.
Subjects will be centrally stratified by sex (male and female).  Within each stratum, subjects 
will be randomized to receive either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  
Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily at approximately the same time of 
every day, and be encouraged to take the study medication with an adequate amount of water 
(8 oz. or 240 mL).
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
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being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs
will review treatment compliance during site visits and at the completion of the study.
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
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9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 (US 
sites only).  Must be appropriate to handle schedule IV products and not be expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
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supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
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9.5.1.2.2
URINE DRUG SCREEN
A 30-mL urine sample will be collected at Screening, as specified in the Schedule of 
Procedures/Assessments (Table 2).  This sample will be tested for common drugs of 
use/abuse (eg, ethyl alcohol, cocaine, cannabinoids, phencyclidine, nicotine/cotinine, opioids 
[as a group], benzodiazepines, barbiturates, amphetamines). (revised per Amendment 01)
9.5.1.3
Efficacy Assessments

Body weight and height will be measured using a standard stadiometer method (Lohman 
T, et al, 1988) to calculate changes in BMI; BMI will then be used to calculate the 
proportion (%) of patients achieving at least a 5% and at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total cholesterol, 
HDL cholesterol, LDL cholesterol, and triglycerides), fasting plasma glucose, fasting 
insulin, hemoglobin A1c (HbA1c), and HOMA-IR to assess changes in cardiovascular and 
metabolic risk profiles from Baseline to Week 52

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 
(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents, 2011)

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for Population PK analyses.    (revised per Amendment 01)
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take 
their study drug at home before the visit, but to bring their study drug to the clinic visit and 
take their daily dose at the clinic.  Two blood samples for determination of plasma 
concentrations of lorcaserin will be taken 1 predose (within 30 minutes before dosing) and 1
within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times 
before the day of clinic visit. Week 52 PK samples should only be collected if the sample can 
be drawn within 60 hours of the last dose of study drug. (revised per Amendment 01)
On the day of the Week 36 clinic visit, subjects will take their study drug at home, and will 
be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood 
sample for PK assessment will be collected.  Dose times must be recorded for the last 2 
dosing times prior to the clinic visit. (revised per Amendment 01)
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Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
coupled with tandem mass spectrometry method. The collection, handling, and shipping 
procedures for PK samples will be described in a manual to be provided to the study sites.
At Unscheduled Visits, PK samples should only be collected if subject has experienced a 
serious adverse event (SAE) while on study drug and the sample can be drawn within 60 
hours of the initiation of the SAE. (revised per Amendment 01)
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Lorcaserin plasma exposure from PK analysis and population PK/PD modeling will be used 
to explore the relationship between lorcaserin plasma exposure and following response to 
lorcaserin: 

Change from Baseline in BMI 

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC AND OTHER BIOMARKER ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs; electrocardiograms 
(ECGs); laboratory evaluations for hematology, metabolic function (fasting glucose, lipids,
and thyroid), adrenal functions, and biochemical blood and urine bone health assessments;
blood chemistry and urine values; neuropsychiatric events; periodic measurements of vital 
signs, neuromuscular signs for screening potential serotonin syndrome, and signs and 
symptoms of priapism and hyperprolactinemia; and performance of physical examinations.  
In subjects with potential prolactin-related AEs, such galactorrhea, changes in libido, or
changes to menstrual cycle, prolactin level will be measured and assessed.  
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
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symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
It is the responsibility of the investigator to review the results of the Leiter-3, C-SSRS, and 
PHQ-9 for all subjects and determine if any result constitutes an AE.  Medical and scientific 
judgment should be exercised in deciding whether an isolated suicidality rating scale 
response should be classified as an AE (see Section 9.5.1.5.10 for a description of the 
C-SSRS).  (revised per Amendment 01)
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.
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Assessing Severity of Adverse Events
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of the 
event
•
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
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•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious 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
•
Priapism
•
New onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas of 
the skin
•
Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study specific event 
does not meet serious criteria.  If the event meets seriousness criteria, it should be reported as 
an SAE as above.  However, if the event listed below does not meet serious criteria, it should 
be noted as nonserious on the Adverse Event CRF:  
•
Suicidal ideation   
•
Euphoria 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
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misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for administration 
of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was in
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
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Table 1
Clinical Laboratory Tests (revised per Amendment 01)
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function
T4, TSH
Adrenal function
AM serum Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects)
Bone health assessments
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other (revised per Amendment 01)
Albumin, calcium, globulin, fasting glucose, HbA1c, HDL 
cholesterol, fasting insulin, lactate dehydrogenase, LDL cholesterol,
fasting lipid panel, phosphorus, total protein, total cholesterol,
triglycerides,, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
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method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2).  
9.5.1.5.6
CDC GROWTH MEASUREMENTS
Investigators will calculate the height for age percentile and weight for age percentile 
utilizing the most recent CDC 95th Percentile Growth Chart and the height and weight 
measurements obtained, as designated in the Schedule of Procedures/Assessments (Table 2).  
(revised per Amendment 01)
9.5.1.5.7
WAIST CIRCUMFERENCE
Waist circumference (cm) measurements will be taken 3 times at each visit as designated in 
the Schedule of Procedures/Assessments (Table 2).  (revised per Amendment 01)
9.5.1.5.8
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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 eCRF.
As part of the physical examination, a neuromuscular sign assessment for serotonin 
syndrome will be performed for potential serotonergic syndrome components.  Serotonergic 
syndromes that meet the diagnostic criteria will be captured by AE eCRF.
(revised per 
Amendment 01)
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will also be captured in the AE eCRF. (revised per 
Amendment 01)
9.5.1.5.9
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
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An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.10 OTHER SAFETY ASSESSMENTS
Leiter-3
The Leiter International Performance Scale–Third Edition (Leiter-3) is widely used 
non verbal measure of intelligence, memory, and attention in those between the ages of 3 and 
75 years. 
The Attention/Memory Battery consists of 5 subtests: 2 measure nonverbal 
attention; 2 measure memory; and 1 measures cognitive interference (nonverbal Stroop test). 
These subtests are combined to produce a Memory and Processing Speed composite scores, 
normalized to a mean of 100 and standard deviation of 15. The Leiter-3 will be used to 
assess lorcaserin effects on cognition, specifically, attention and memory. In addition, signs 
and symptoms of cognition-related AEs, including impairments in attention, memory, and 
adverse effects on schoolwork will be captured in the eCRF. (revised per Amendment 01)
PHQ-9
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and 
measuring the severity of depression:

The PHQ-9 incorporates Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV) depression diagnostic criteria with other leading major depressive 
symptoms into a brief self-report tool.

The tool rates the frequency of the symptoms which factors into the scoring severity 
index.

Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.

A follow-up, non-scored question on the PHQ-9 assigns weight to the degree to which 
depressive problems have affected the patient's level of function. 
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. Qualified personnel must evaluate positive 
responses on the C-SSRS and take appropriate action as detailed in the training and 
certification process for administering the C-SSRS.  It will be performed at Screening and at 
study visits as designated in the Schedule of Procedures/Assessments (Table 2). (revised per 
Amendment 01)
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Hand X-Ray
A hand x-ray for evaluation of any potential negative effect on bone age will be performed 
on the same hand at each visit as designated in the Schedules/Assessments (Table 2).  
(revised per Amendment 01)
Tanner Staging
The pubic hair growth (both sexes), genital (males only) and breast (females only) 
development of subjects will be using Tanner Staging (Marshall, 1970). Subjects will be 
examined by the investigator as designated in the Schedules/Assessments (Table 2). (revised 
per Amendment 01)
Echocardiogram
Echocardiograms will be obtained on the Schedule of Procedures/Assessments (Table 2). 
Valvular regurgitation in echocardiogram will be rated absent, trace, mild, moderate, or 
severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve.  The evaluations will be based on guidelines from the American Society of 
Echocardiography. Pulmonary artery pressure will be estimated from the TR regurgitant jet 
velocity.
9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at designated time points as 
specified in the Schedule of Procedures/Assessments (Table 2).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendment 01)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatment
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USb
ED
Day:
-30 to -1
1
Weeksc,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examinatione
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, fasting insulin, and HbA1c sampling
X
X
X
X
X
X
T4 and TSH
X
X
X
X
Testosterone, Estradiol
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendment 01)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatment
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USb
ED
Day:
-30 to -1
1
Weeksc,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Pregnancy test (urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
Prolactin (fasting)
X
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Fasting lipid panel
X
X
X
X
Urine NTX
X
X
X
X
PK/PD blood sampling
X
X
X
Xf
Xg
X
AM serum cortisol
X
X
X
ECG
X
X
X
X
X
Echocardiograph
Xh
X
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
Leiter-3
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
X
Standardized age-appropriate lifestyle modification 
counselingi
X
X
X
X
X
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403  (revised per Amendment 01)
Phase:
Prerandomizationa
Randomization
Period:
Screening
Treatment
Follow-
Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
USb
ED
Day:
-30 to -1
1
Weeksc,d:
0
1
5
8
12
20
28
36
44
52
56
Procedure
AE = adverse event, AM = morning; CDC = Centers for Disease Control and Prevention, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, ED = 
early discontinuation, EOS = End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, IxRS = interactive voice or web response system, NTX = N-telopeptide, OC 
= osteocalcin; PHQ-9 = The Patient Health Questionnaire, PICP = carboxyterminal propeptide of type I procollagen,  PD = pharmacodymanic, PK = pharmacokinetics, SAE = 
serious adverse event; T4 = thyroxine, TSH = thyroid stimulating hormone, US = unscheduled.
a: Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b: Unscheduled visits may be conducted at any time that additional assessments are indicated in the clinical judgment of the investigator.  Note that not all assessments listed 
under Unscheduled Visit need to be conducted – actual assessments needed will be determined by the investigator and will be based on the specific visit needs.  At 
Unscheduled Visits, PK samples should only be collected if subject has experienced a serious adverse event (SAE) while on study drug and the sample can be drawn within 
60 hours of the initiation of the SAE. (revised per Amendment 01)
c: Window ±7 days for all visits. (revised per Amendment 01)
d:
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed not to take their study drug at home before the visit, but to bring their study drug to the clinic 
visit and take their daily dose at the clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken:  1 predose (within 30 minutes before 
dosing) and 1 within 1 to 3 hours after dosing. Dose times must be recorded for the last 2 dosing times before the day of clinic visit. Week 52 PK samples should only be 
collected if the sample can be drawn within 60 hours of the last dose of study drug.  On the day of the Week 36 clinic visit, subjects will take the morning dose at home, and 
will be asked to visit the clinic within 4 to 6 hours of dosing that day, during which 1 blood sample for PK assessments will be collected  Dose times must be recorded for 
the last 2 dosing times prior to the clinic visit. (revised per Amendment 01)
e:
Includes a neuromuscular assessment and signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle abnormalities or galactorrhea) 
(revised per Amendment 01)
f: PK samples should only be collected if the sample can be drawn within 60 hours of the last dose of study drug.
g: PK samples should only be collected if subject has experienced an SAE while on study drug and the sample can be drawn within 60 hours of the initiation of the SAE.
h: Echocardiographic assessments will be performed during screening period after subjects have met all other inclusion and exclusion criteria.
i: Lifestyle modification counseling will also be performed at Weeks 3, 16, 24, 32, 40, and 48 in addition to counseling at the scheduled visits in Appendix 2.
.
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes (revised per Amendment 01)
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
(Chemistry and Hematology)
5
Screening: 1
Visits 2, 3, 4, 6, 8, 11 (EOT),
EOS or ED
58=40
T4, TSH, AM Serum 
Cortisol, Testosterone, 
estradiol 
6
Screening:  1
Visits 8, 11 (EOT), or ED
6×3=18
Serum OC and PICP, 
Hydroxy-proline; Fasting 
lipid panel (HDL cholesterol, 
LDL cholesterol, total 
cholesterol, triglycerides)
8
Visits 2, 8, 11 (EOT), or ED
8×3=24
Fasting Prolactin, FPG, 
fasting insulin, and HbA1c
sampling
5
Screening:  1
Visits 2, 6, 8, 11 (EOT) or ED
5×5=25
PK/PD blood sampling
4
Visits 6, 8, and 11 (EOT) or ED
(2 samples each); Visit  9 (1 
sample only)
7×4=28
Total
135
ED= early discontinuation from study, EOS = End of Study, EOT = End of Treatment, FPG = fasting plasma glucose, 
HbA1c = hemoglobin A1c, OC = osteocalcin, PD = pharmacodynamic, PICP = carboxyterminal propeptide of type I 
procollagen, PK = pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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.
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
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criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas of
the skin

Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study-specific 
event does not meet serious criteria.  If the event meets seriousness criteria, it should be 
reported as an SAE as above.  However, if the event listed below does not meet serious 
criteria, it should be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation

Euphoria 
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 
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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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue treatment prematurely will be followed up until study completion.  
All subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments Table 2).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
Detailed retention strategies will be developed and included in study manual. These include 
a highly trained and competent staff, easy access to the clinic, reminder and follow-up calls, 
interactive group sessions with games and hands-on nutrition and physical activity 
demonstrations, random raffle drawings, social events, birthday and holiday cards, and
newsletters. In addition, home visits for assessments of families will be an option, as needed, 
to maximize data collection. This detailed retention plan will help prevent missing data.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.  The DEA Registrant has 
the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
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9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from Baseline to Week 52 and proportion (%) of 
subjects achieving at least a 5% or 10% BMI reduction at Week 52 by the outcome of 
achieving at least a 5% BMI reduction at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
9.7.1.2
Definitions of Analysis Sets

The 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.
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
The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or 
greater compliant with study medication, completed the study, have no major protocol 
deviations, have no violations of inclusion or exclusion criteria, and have BMI data at 
Baseline and Week 52.  The determination of subjects to be excluded from this 
population based on the above criteria and list of major protocol violations will be 
included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 
1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and 
who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
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medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using analysis of covariance model (ANCOVA) with 
factors of treatment, sex (male and female) as fixed effect, and the baseline age and BMI as 
covariates.  The missing values will be imputed using a pattern mixture model utilizing 
multiple imputation (MI) assuming the missing values are missing not at random (MNAR).  
The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model 
and missing value imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated based 
on the PP.

Change from baseline in standardized BMI score (Z-score): The same primary efficacy 
analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed 
and will be described in the SAP.  
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Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, and sex (male and 
female), and baseline BMI as a covariate using FAS.  Subjects with any missing assessment 
at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using mixed effect model repeated measurement analysis (MMRM) and categorical
variables will be analyzed using the Cochran Mantel Haenszel test, Chi-square test, or 
logistic regression as appropriate.  Additional analysis may be performed as needed using 
appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male 
and female), race (white, black, Asian, and other). Additional subgroups may be explored, if 
deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Change from Baseline in BMI will be assessed as the PD endpoint.  The PD analysis set will 
be used for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also be 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
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9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination, 
neuromuscular 
sign 
assessment, 
and 
signs 
and 
symptoms 
of 
priapism 
and 
hyperprolactinemia), out-of-normal-range laboratory safety test values, change from baseline 
in laboratory safety test values, ECGs, and vital sign measurements will be summarized by 
treatment group using descriptive statistics or frequency count as appropriate.  (revised per 
Amendment 01)
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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.
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A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No [not 
related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
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baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, 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
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and greater 
than 60 msec from the baseline visit.
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9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including adolescent growth evaluations using 95th percentile CDC 
growth charts and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, study drug effect on cognition assessed by Leiter-3, assessment of suicidality using 
C-SSRS, and depression assessment using PHQ-9 will be summarized by treatment group at 
each scheduled visit.  For echocardiographic assessments, the proportion of subjects who 
develop FDA-defined valvulopathy, the proportion of subjects who develop pulmonary 
hypertension (defined as when a subject’s SPAP is
≥40 mmHg evaluated by 
echocardiograph], and change from baseline in SPAP will also be summarized by treatment 
group at Week 28 and Week 52. (revised per Amendment 01)
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of
360 subjects in a 1:1 ratio (n=180 in the Belviq XR 20-mg treatment group; n=180 in the 
placebo group) will have at least 90% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 360 subjects (180 subjects for Belviq XR 20 mg and 180 subjects for placebo) 
will also have greater than 85% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Fisher’s Exact test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.
Lohman T, Roche AF, Martorell R. Anthropometric Standardization Reference Manual.  
Champaign, IL:  Human Kinetics Books; 1988.
Marshall WA, Tanner JM. Variation in pattern of pubertal changes in boys. Arch. 
Dis.Childhd 1970; 45, 13-23.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.
Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L.  
NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A 
Life-Table Analysis. Ann Intern Med. 2003; 138:24-32.
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Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al. A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang Y, Lobstein, T.
Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
Whitaker RC, et al. Predicting obesity in young adulthood from childhood and parental 
obesity. N Engl J Med. 1997 Sep 25;337(13):869-73.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
<LLN – 2.5 mg/dL
<2.5 – 2.0 mg/dL
<2.0 – 1.0 mg/dL
<1.0 mg/dL
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
(hypophosphatemia) 
<LLN – 0.8 mmol/L
<0.8 – 0.6 mmol/L
<0.6 – 0.3 mmol/L
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will be 
encouraged to participate in a standardized weight management program for adolescents 
consisting of multicomponent behavior therapy.  The therapy will focus on healthy eating, 
physical activity, and lifestyle changes that will facilitate weight loss and weight-loss 
maintenance. The role of the caregivers is to support their child or adolescents’ lifestyle 
changes and their taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress but 
caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neurology Business Group
Eisai Inc.
Date
 Medicine Development Group
Eisai Inc.
Date
Neurology Business Group
Eisai Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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Clinical Study Protocol
APD356-A001-403
Eisai
FINAL (v5.0):  22 Feb 2017
Confidential
Page i of x
Revision History
Previous Version (Revision): v4.0
Current Version (Revision):  v5.0
Date of Revisions: 22 Feb 2017
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
A full physical examination 
will be performed at Week 1
Correction
Synopsis
•
Safety Assessment
Section 9.5.1.5
PHQ-9 questionnaire has 
been added to every 
scheduled visit.
Per FDA 
recommendation
Synopsis
•
Safety Assessment 
Section 9.5.1.5
Section 9.5.2.1
The mixed model repeated 
measures (MMRM) model 
was replaced with the 
analysis of covariance 
(ANCOVA) model
analyzing Week 52 only.
Per FDA 
recommendation
Synopsis
•
Primary Efficacy Analysis
Section 9.7.1.6
All postdiscontinuation data 
will be used in the primary 
analysis
Clarification per FDA 
feedback
Synopsis
•
Primary Efficacy Analysis
Section 9.7.1.6
Labeling information for 
study drug was updated
Correction as the study 
will only be conducted 
in the US
Section 9.4.2.3
The order of assessments 
was reorganized in the 
Schedule of Assessments 
To better align the 
assessments by 
grouping them
Section 9.5.2.1
Urinalysis will be performed 
at Visit 2 instead of Visit 9
Correction
Section 9.5.2.1
Assessment for testosterone, 
estradiol will be performed 
at Week 28, not Week 20
Correction
Section 9.5.2.1
Section 9.5.2.3
Prior/concomitant 
medication assessment will 
be performed at Week 56
Correction
Section 9.5.2.1
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Eisai
FINAL (v5.0):  22 Feb 2017
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Page ii of x
Revision History
Previous Version (Revision): v4.0
Current Version (Revision):  v5.0
Date of Revisions: 22 Feb 2017
Change
Rationale
Affected Protocol Section(s)
Assessments performed at 
early discontinuation from 
the study
Correction
Section 9.5.2.1
Summary of blood volumes 
table was updated
Correction
Section 9.5.2.3
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Clinical Study Protocol
APD356-A001-403
Eisai
FINAL (v5.0):  22 Feb 2017
Confidential
Page iii of x
Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Subject population to 
include children ages 12 to 
17 years
Changes were made 
upon regulatory advice 
received at the Type C 
meeting.
Title Page
Synopsis
•
Study Protocol Title
•
Study Design
•
Inclusion Criteria
•
Exclusion Criteria
•
Safety Assessments
•
Efficacy Analyses
•
Safety Analyses
Section 7.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.7.1.6
Section 9.7.1.8
Protocol Signature Page
Investigator Signature Page
All subjects will be 
evaluated for cardiac 
valvular disease or 
pulmonary hypertension via 
echocardiographic 
assessment.
Changes were made
upon regulatory advice 
received at the Type C 
meeting.
Synopsis
•
Other Secondary Objectives
•
Exclusion Criteria
•
Safety Assessments
•
Safety Analyses
Section 8.2
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Section 9.3.2
Section 9.5.1.5.8
Section 9.5.2
Section 9.7.1.8
Section 9.7.1.8.6
Study drug administration 
will be taken at 
approximately the same 
time each day.  On the days 
of PK sampling and the day 
before the subjects come to 
the clinic for PK sampling, 
study drug will be taken in 
the morning and doses 
recorded 2 days prior to the 
clinic visit.
This will ensure lower
variability with regard 
to PK/PD 
measurements.
Synopsis
•
Pharmacokinetic Assessments
Section 9.4.1
Section 9.4.4
Section 9.5.1.4.1
Section 9.5.2.1
Screening, diagnosing, 
monitoring, and measuring 
the severity of depression 
will be assessed using the 
Patient Health 
Questionnaire (PHQ-9), and 
not the Children’s 
Depression Inventory 2 
(CDI-2).
The PHQ-9 was 
originally proposed by 
the FDA for the 
population in the 
current study.
Synopsis
•
Other Secondary Objectives
•
Safety Assessments
•
Safety Analyses
Section 8.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.1.5.1
Section 9.5.1.5.9
Section 9.7.1.8
Section 9.7.1.8.6
Primary analysis changed 
from MMRM to using a 
pattern mixture model 
utilizing multiple 
imputations (MI) to impute
missing values.
Changes were made 
upon regulatory advice 
received at the Type C 
meeting.
Synopsis
•
Primary Efficacy Analysis
Section 9.7.1.6
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FINAL (v5.0):  22 Feb 2017
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Page v of x
Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Clarified fasting lipids
Fasting lipid levels 
provide uniformity in 
lipid measurements for 
definition of 
dyslipidemia
Synopsis
•
Other Secondary Objectives
•
Efficacy Assessments
•
Other Secondary Efficacy 
Endpoints
Section 8.2
Section 9.5.1.3
Appendix 3 removed
The current study will 
not conduct any 
biomarker or 
pharmacogenomic
evaluation. PK/PD 
measurements will be 
done during study.
Appendix 3
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Confidential
Page vi of x
Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, and 
formatting changes 
Throughout
Prehypertension was 
deleted from the 
inclusion criterion.  
Subjects with Stage 1 
primary 
hypertension, with an 
upper limit defined as 
99% plus 5 mmHg 
for age, sex, and 
height are included in 
the study. 
Prehypertension does not 
qualify as a comorbid 
condition.  The limitation 
on BP is to further define 
the proper study 
population.
Synopsis
•
Inclusion Criteria
Section 9.3.1
Removed the 
restriction that 
subjects need to have 
less than 44 kg/m2
BMI for study entry
Per United States Food and 
Drug Administration 
(FDA) request
Synopsis
•
Inclusion Criteria
•
Analysis Sets
•
Pharmacodynamic Analyses
•
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study 
entry requirement 
that the caregiver 
cannot have a history 
of ADD, substance 
abuse, depression, 
suicidal 
ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and 
Drug Administration 
(FDA) request
Synopsis
•
Inclusion Criteria
Section 9.3.1
The secondary 
efficacy objective 
To explore the 
predictability of 12-week 
Synopsis
•
Secondary Efficacy Objectives
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Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
and endpoint were 
revised
responders for long-term 
sustainable weight loss 
effect
•
Other Secondary Efficacy 
Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with 
symptoms or signs of 
cardiac valvular 
disease or pulmonary 
hypertension are not 
required to have 
further evaluation by 
centralized 
echocardiogram 
assessment.  In 
addition, no 
adjudication will be 
performed.  Local 
echocardiograms can 
be performed if 
deemed medically 
necessary by the 
investigator.
This change allows for the 
investigator to make the 
decision to perform local 
echocardiograms 
on 
a 
pediatric subject if deemed 
medically indicated rather 
than burden the subject to 
undergo 
a 
mandated, 
unnecessary procedure. 
Synopsis
•
Safety Assessments
Section 9.5.1.5
Updated study 
rationale
Clarification 
Section 7.1.1.2
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FINAL (v5.0):  22 Feb 2017
Confidential
Page viii of x
Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, and 
formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will 
replace the IR formulation in 
the United States market to 
support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to
include children ages 9 to 
17 years
Expand the age of the 
population due to the change of 
pediatric development strategy
A single dose pharmacokinetic 
study in pediatric obese subjects 
(APD356-A001-026) indicated 
that patients with body weight 
greater than or equal to 60 kg 
can be administered a dose 
similar to that given to adults 
and adolescents.  Based on 
Centers for Disease Control and 
Prevention (CDC) growth chart 
data, almost all subjects over 
9 years of age are likely to be at 
or over 60 kg body weight.  
Therefore, children age 9 to 
11 years have been included in 
the current study.
Title Page
Synopsis
•
Study Protocol Title
•
Objectives
•
Study Design
•
Inclusion Criteria
•
Assessments
•
Efficacy Analyses
•
Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.9
Section 9.7.1.6
Section 9.7.1.8
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Page ix of x
Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Additional safety 
assessments including 
cognitive function, 
serotonin syndrome 
components, bone health 
and endocrine function, 
priapism, and symptoms 
associated with 
hyperprolactinemia were 
added.
Per United States Food and 
Drug Administration (FDA)
request
Synopsis

Efficacy Assessments

Pharmacokinetic 
Assessments

Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.9
Section 9.7.1.8
Section 9.7.1.8.1
Change to primary and 
key secondary endpoints
Per FDA request
Synopsis

Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary 
endpoint changed
Per FDA request
Synopsis

Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of 
study-specific adverse 
events
To provide clearer guidance for 
the correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and 
prohibited prior and 
concomitant therapies
For clarification
Synopsis

Exclusion Criteria

Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of 
adverse events
To provide clearer guidance for 
the correct reporting of adverse
events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
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APD356-A001-403
Eisai
FINAL (v5.0):  22 Feb 2017
Confidential
Page x of x
Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Update to Introduction 
and to Completion/ 
Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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Clinical Study Protocol
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Page 1 of 81
1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction With Lifestyle Modification for Weight 
Loss in Obese Adolescents, Age 12 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
v4.0
03 Nov 2016 (Revision)
v5.0
22 Feb 2017 (Revision)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use and all applicable 
local Good Clinical Practice (GCP) and regulations.  All required 
study documentation will be archived as required by regulatory 
authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.: APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the 
Efficacy and Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in 
Obese Adolescents, Age 12 to 17 Years
Investigators
Unknown
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
-
Approximately 24 months from the 1st subject enrolled to last subject’s last visit or last 
assessment 
-
Phase 4
Objectives
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks 
of treatment with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with 
at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD as compared to placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with 
at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg 
administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of 
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in BMI 
during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 
10% BMI reduction, change in waist circumference) at the end of 52 weeks of 
treatment
-
Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin 
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Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) during 52 weeks of 
treatment

Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high density 
lipoprotein [HDL], and low density lipoprotein [LDL]) during 52 weeks of treatment. To 
assess the safety of Belviq XR, including the effects on cognitive function by Wide Range 
Assessment of Memory and Learning-2 (WRAML-2), on depression by the Patient Health 
Questionnaire (PHQ-9), on signal of
suicidal ideation
or behavior
with the 
Columbia-Suicide Severity Rating Scale (C-SSRS), on growth measured by Centers for 
Disease Control and Prevention (CDC) growth chart, on sexual maturation (pubescence) 
measured by Tanner Staging scores, and on other growth and development parameters by 
measuring sex hormones, thyroid function, valvular function and pulmonary arterial 
pressure, adrenal function, bone age, and biochemical markers of bone health assessments

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) 
parameters including but not limited to reduction from baseline in BMI and probability of 
achieving at least a 5% and at least a 10% reduction in BMI from baseline at Week 52 using 
population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese
adolescents, ages 12 to 17 years.  Approximately 360 subjects will be randomized in a 1:1 ratio to 
Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will be stratified by sex.  
Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout 
the duration of the study, subjects will be encouraged to adhere to a lifestyle modification program 
that includes a standardized, age-appropriate diet and exercise counseling.
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization 
Phase will last up to 30 days and consist of 1 visit during which subjects will be screened for 
eligibility.  The Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The 
Treatment Period will last for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36,
44, and 52.  The Follow-Up Period will extend from the End of Treatment visit to the End of Study 
visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will continue in the 
study until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely 
will be followed up until study completion.  
Number of Subjects
Approximately 700 subjects will be screened to provide 360 randomized subjects.
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that is 
greater than or equal to the United States (US)-weighted mean of the 95th percentile based on 
age and sex with a body weight greater than 60 kg
2.
Subjects and their families not planning to move away from the area for the duration of the 
study
3.
Subjects able and willing to comply with all aspects of the study, including a standardized, 
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reduced-calorie diet and an age-appropriate, increased physical activity program
4.
Subjects considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the 
subject’s ability to fulfill the study requirements or significantly confound the assessments
2.
Subjects who cannot swallow investigational products
3.
Any of the following findings on Screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, 
mean gradient >25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean 
gradient >5 mm Hg and mitral valve area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure
(SPAP) >40 mmHg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
In cases where an actual SPAP value is not measurable due to lack of adequate TR jet, the 
pulmonary flow acceleration time measured at the right ventricular outflow tract (RVOTAT), 
will be used to assess eligibility. Patients with a RVOTAT ≤100 msec will be excluded, 
suggesting an elevated mean SPAP; eligibility for the those patients with RVOTAT between 
100 and 120 msec will be determined based on combined assessment of the TR jet, septal
motion and right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with
hemodynamic compromise)
4.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper 
limit of normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater 
than 1.5×ULN in absence of Gilbert’s syndrome
5.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or schizophrenia
6.
Known 
secondary 
causes 
(chromosomal, 
endocrine, 
or 
metabolic) 
for 
obesity 
(eg,
Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 
30 days, history of significant exposure to corticosteroids for chronic illness during the past 
year, known genetic causes of obesity)
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7.
Use of other products intended for weight loss including prescription drugs, over-the-counter 
(OTC) drugs, and herbal preparations within 1 month before Screening 
8.
Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
9.
Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and cabergoline
10. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), type 2 diabetes treated with oral anti-diabetic agents 
(excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive sleep 
apnea, dyslipidemia, and nonalcoholic fatty liver disease
11. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any 
of the excipients
12. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
13. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before 
Screening
14. History of alcohol or drug dependence or abuse
15. Recreational drug use within 2 years before Screening
16. Known to be human immunodeficiency virus positive
17. Active viral hepatitis (B or C) as demonstrated by positive serology
18. Malignancy within 5 years before Screening
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19. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
20. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to 
profound mental retardation [IQ <70], moderate to severe cognitive developmental delay, 
pervasive development disorders, autism)
21. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
22. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate 
readings recorded on 2 separate days.  Those subjects who had hypertension at Screening can 
be rescreened more than 1 month after initiation or adjustment of antihypertensive therapy
1 time.
23. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
24. Planned bariatric surgery during the study
25. Not suitable to participate in the study in the opinion of the investigator, including
consideration of any existing physical, medical, or mental condition that prevents compliance 
with the protocol
26. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive β-human chorionic gonadotropin test).  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.
27. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 28 days 
after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after study 
drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have 
been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated,
biconvex tablets with one 20-mg tablet administered orally QD.
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Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  up to 30 days
Randomization Phase: approximately 56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal 
preparations, are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days with study medication temporarily stopped for that 
time period and resumed the next day after the OTC cold medicine is stopped.  Any of the following 
serotonergic agents or other agents in combination with Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to 
calculate the proportion (%) of patients achieving at least a 5% and at least a 10% BMI 
reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total cholesterol, HDL
cholesterol, LDL cholesterol, and triglycerides), fasting plasma glucose, fasting insulin,
hemoglobin A1c (HbA1c), and Homeostasis Model Assessment (HOMA) IR to assess
cardiovascular and metabolic risk profiles from Baseline to Week 52
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
Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents
Pharmacokinetic Assessments
Plasma lorcaserin concentrations will be measured at Weeks 12, 28, 36, and 52 for analysis of 
population PK.  All subjects will be instructed to take their study drug in the morning on the day 
before their scheduled clinic visit at Weeks 12, 28, 36, and 52.  No additional doses should be taken 
that day for those subjects who have been taking their doses in the evening.  Dose times must be 
recorded for the last 2 dosing times prior to the clinic visit.
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed to take their study drug 
at approximately the same time as the morning before, with no additional doses taken that day.  Two 
blood samples for determination of plasma concentrations of lorcaserin will be taken at each of these 
visits: within 30 minutes before dosing and within 1 to 3 hours after dosing.  
On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at home.  
One blood sample for determination of plasma concentrations of lorcaserin will be collected at the 
clinic within 4 to 6 hours after dosing.
Subjects can resume their usual dose schedule the day after the PK clinic visits.  
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their 
relationships with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious 
adverse events (SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, metabolic 
function (glucose, fasting lipids, and thyroid), adrenal function and biochemical blood and urine bone 
health assessments; blood chemistry and urine values; neuropsychiatric events; periodic measurement 
of vital signs, neuromuscular signs for screening potential serotonin syndrome, and signs or 
symptoms of priapism and prolactinemia; and performance of physical examinations.
In patients 
with potential prolactin-related AEs, such as galactorrhea, changes in libido, or changes to menstrual 
cycle, prolactin level will be measured and assessed. Study drug effect on growth will be evaluated 
using the CDC growth chart at Baseline, and Weeks 5, 12, 28, 36, 52, and at Follow-Up; a full 
physical examination, at Baseline, Weeks 1, 12, 28, 52, and at Follow-Up; and bone age 
determination by x-ray of the hand at Baseline, Weeks 12, 28, and 52. Sexual maturation will be 
evaluated by assessing sex hormones and self-reported changes in Tanner Staging at Baseline, 
Weeks 28 and 52, and at Follow-Up.   
The C-SSRS will be used to assess all subjects in the study for any signal of depression or suicidal 
ideation or behavior at every visit.  Additionally, screening, diagnosing, monitoring, and measuring 
the severity of depression will be assessed using the PHQ-9 at every visit and effects on cognitive 
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function will be assessed using the WRAML-2 at Baseline, Weeks 5, 28, 52, and end of study (EOS).
Echocardiographic assessments will be used to exclude subjects with FDA-defined valvulopathy, 
pulmonary hypertension, and other major cardiovascular disease (as outlined in Exclusion Criterion 
No. 3) during the Screening Period.  Additionally, cardiac valvular function and pulmonary systolic 
pressure changes at Weeks 28 and 52 will be assessed.
Valvular regurgitation as assessed in the 
echocardiogram will be rated absent, trace, mild, moderate, or severe for the aortic, mitral, and 
tricuspid valves; the rating will be absent or present for the pulmonic valve. The evaluations will be 
based on guidelines from the American Society of Echocardiography. Pulmonary artery pressure will 
be estimated from the TR jet velocity.
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography method coupled with 
tandem mass spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from baseline to Week 52 and proportion (%) of 
subjects achieving at least a 5% or 10% BMI reduction at Week 52 by the outcome of 
achieving at least a 5% BMI reduction at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 post dose safety assessment.
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
The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to 
study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater 
compliant with study medication, completed the study, have no major protocol deviations, have 
no violations of inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  
The determination of subjects to be excluded from this population based on the above criteria 
and a list of major protocol violations will be included in the statistical analysis plan (SAP) and 
finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD 
parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who 
have at least 1 adequately documented measurement of BMI.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as 
a supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in 
all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from 
baseline in BMI will be analyzed using analysis of covariance model (ANCOVA) with factors of 
treatment,  sex (male and female) as fixed effect, and the baseline age and BMI as covariates.  The 
missing values will be imputed using a pattern mixture model utilizing multiple imputation (MI) 
assuming the missing values are missing not at random (MNAR).  The missing values will be 
imputed at each visit using all available values including the retrieved measurement from the 
postdiscontinuation data.  The details of the analysis model and missing value imputation method 
will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on 
the PP.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy 
analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed and will 
be described in the SAP.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI 
reduction at Week 52. The secondary efficacy endpoint will be analyzed only if the test for the 
primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using 
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a logistic regression model with factors of treatment, sex (male and female), and baseline BMI as a 
covariate using FAS.  Subjects with any missing assessment at Week 52 will be considered as 
treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed 
using mixed effect model repeated measurement analysis (MMRM) and categorical variables will be 
analyzed using the Cochran Mantel Haenszel test, Chi-square test, or logistic regression as 
appropriate.  Additional analysis may be performed as needed using appropriate statistical 
methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male and 
female), and race (white, black, Asian, and other).  Additional subgroups may be explored, if deemed 
necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity 
analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling. The effect of covariates such as baseline characteristics or 
demographics on PK will be explored. Derived exposure parameters such as the maximum observed 
concentration and the area under the concentration-time curve from time 0 to 24 hours at steady-state 
will be calculated from the final PK model using individual posterior estimates of the PK parameters 
and from dosing history. The PK analysis set will be used for this analysis.
Pharmacodynamic Analyses
Change from Baseline in BMI will be assessed as the PD analysis.  The PD analysis set will be used 
for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% and 
≥10% BMI reduction, and change in waist circumference from baseline) will also be assessed as part 
of the PD analysis.  The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma 
exposure and response, including but not limited to change in BMI from baseline and the probability 
of achieving at least a 5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, 
exposure-safety relationships for select safety parameters may be explored graphically depending on 
the data at the end of study.  Any emergent relationship may be modeled as appropriate.  Any 
parameters based on the study data may be considered for exploratory assessment for its relationship 
to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the 
incidence of AEs (including changes from baseline in physical examination), growth (CDC growth 
chart and bone age determined by x-ray of the hand), sexual maturation (Tanner Staging), 
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out-of-normal-range laboratory safety test values, change from baseline in laboratory safety test 
values, ECGs, and vital sign measurements will be summarized by treatment group using descriptive 
statistics or frequency count as appropriate.  In addition, cognitive function will be evaluated by the
WRAML-2, depression will be evaluated by the PHQ-9, and suicidal ideation and behavior will be 
evaluated by the C-SSRS, and will also be summarized by treatment group using descriptive statistics 
or frequency count as appropriate.
All WRAML-2 raw scores from the Core Battery will be 
converted to age and gender standard scores for purposes of intra-individual comparisons. For 
echocardiographic assessments, the proportion of subjects who develop FDA-defined valvulopathy, 
the proportion of subjects who develop pulmonary hypertension [pulmonary hypertension is defined 
when the subject’s systolic pulmonary artery pressure (SPAP) ≥40 mmHg evaluated by 
echocardiograph], and change from baseline in SPAP will be summarized by treatment group at 
Week 28 and Week 52 using descriptive statistics or frequency count as appropriate.
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in 
BMI from Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  
Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 360 subjects in a 1:1 ratio 
(n=180 in the Belviq XR 20-mg treatment group; n=180 in the placebo group) will have at least 
90% power to detect a treatment difference of 1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  
Assuming the proportion of subjects achieving at least a 5% BMI reduction at Week 52 is 20% for 
the placebo group and a 40% dropout rate, this sample of 360 subjects (180 subjects for Belviq XR 
20 mg and 180 subjects for placebo) will also have greater than 85% power to detect an absolute 
difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 2-sided 
Fisher’s Exact test with α=0.05. The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic 
adult subjects.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................19
5.1
Institutional Review Boards/Independent Ethics Committees ..............................19
5.2
Ethical Conduct of the Study.................................................................................20
5.3
Subject Information and Informed Consent...........................................................20
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................22
7
INTRODUCTION ...........................................................................................................23
7.1
Indication ...............................................................................................................23
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................24
7.1.1.1
Mechanism of Action...........................................................................24
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................24
7.1.2
Study Rationale............................................................................................25
8
STUDY OBJECTIVES....................................................................................................27
8.1
Primary Objective..................................................................................................27
8.2
Secondary Objectives.............................................................................................27
9
INVESTIGATIONAL PLAN..........................................................................................29
9.1
Overall Study Design and Plan..............................................................................29
9.1.1
Prerandomization/Pretreatment Phase .........................................................29
9.1.1.1
Screening Period..................................................................................29
9.1.2
Randomization/Treatment Phase .................................................................30
9.1.3
Extension Phase ...........................................................................................30
9.2
Discussion of Study Design, Including Choice of Control Groups.......................30
9.3
Selection of Study Population................................................................................31
9.3.1
Inclusion Criteria .........................................................................................31
9.3.2
Exclusion Criteria ........................................................................................31
9.3.3
Removal of Subjects From Therapy or Assessment....................................35
9.4
Treatments..............................................................................................................35
9.4.1
Treatments Administered.............................................................................35
9.4.2
Identity of Investigational Product...............................................................35
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................35
9.4.2.2
Comparator Drug .................................................................................35
9.4.2.3
Labeling for Study Drug......................................................................35
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9.4.2.4
Storage Conditions...............................................................................36
9.4.3
Method of Assigning Subjects to Treatment Groups...................................37
9.4.4
Selection and Timing of Dose for Each Subject..........................................37
9.4.5
Blinding........................................................................................................37
9.4.6
Prior and Concomitant Therapy...................................................................37
9.4.7
Treatment Compliance.................................................................................38
9.4.8
Drug Supplies and Accountability...............................................................39
9.5
Study Assessments.................................................................................................40
9.5.1
Assessments.................................................................................................40
9.5.1.1
Demography.........................................................................................40
9.5.1.2
Baseline Assessments ..........................................................................41
9.5.1.2.1
Medical History .............................................................................41
9.5.1.3
Efficacy Assessments...........................................................................41
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................41
9.5.1.4.1
Pharmacokinetic Assessments .......................................................41
9.5.1.4.2
Pharmacodynamic Assessments ....................................................42
9.5.1.4.3
Pharmacogenomic and Other Biomarker Assessments .................42
9.5.1.5
Safety Assessments..............................................................................42
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...43
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................45
9.5.1.5.3
Laboratory Measurements .............................................................46
9.5.1.5.4
Vital Signs and Weight Measurements..........................................48
9.5.1.5.5
Height Measurements ....................................................................48
9.5.1.5.6
Physical Examinations...................................................................48
9.5.1.5.7
Electrocardiograms ........................................................................48
9.5.1.5.8
Echocardiogram .............................................................................48
9.5.1.5.9
Other Safety Assessments..............................................................49
9.5.1.6
Other Assessments...............................................................................50
9.5.1.6.1
Pregnancy Test...............................................................................50
9.5.1.6.2
Urine Drug and Cotinine Test........................................................50
9.5.2
Schedule of Procedures/Assessments ..........................................................50
9.5.2.1
Schedule of Procedures/Assessments ..................................................50
9.5.2.2
Description of Procedures/Assessments Schedule...............................54
9.5.2.3
Total Volume of Blood Sampling........................................................54
9.5.3
Appropriateness of Measurements...............................................................54
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9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................55
9.5.4.1
Reporting of Serious Adverse Events..................................................55
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................55
9.5.4.3
Reporting of Events Association with Special Situations....................56
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................56
9.5.4.3.2
Reporting of Study-Specific Events...............................................57
9.5.4.4
Expedited Reporting ............................................................................57
9.5.4.5
Breaking the Blind...............................................................................58
9.5.4.6
Regulatory Reporting of Adverse Events ............................................58
9.5.5
Completion/Discontinuation of Subjects.....................................................58
9.5.6
Abuse or Diversion of Study Drug ..............................................................59
9.5.7
Confirmation of Medical Care by Another Physician .................................59
9.6
Data Quality Assurance .........................................................................................59
9.6.1
Data Collection ............................................................................................59
9.6.2
Clinical Data Management ..........................................................................59
9.7
Statistical Methods.................................................................................................60
9.7.1
Statistical and Analytical Plans....................................................................60
9.7.1.1
Study Endpoints...................................................................................60
9.7.1.1.1
Primary Efficacy Endpoint ............................................................60
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................60
9.7.1.2
Definitions of Analysis Sets.................................................................61
9.7.1.3
Subject Disposition..............................................................................61
9.7.1.4
Demographic and Other Baseline Characteristics ...............................62
9.7.1.5
Prior and Concomitant Therapy...........................................................62
9.7.1.6
Efficacy Analyses ................................................................................62
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................63
9.7.1.7.1
Pharmacokinetic Analyses.............................................................63
9.7.1.7.2
Pharmacodynamic Analyses..........................................................63
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................64
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................64
9.7.1.8
Safety Analyses....................................................................................64
9.7.1.8.1
Extent of Exposure.........................................................................64
9.7.1.8.2
Adverse Events ..............................................................................65
9.7.1.8.3
Laboratory Values..........................................................................66
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9.7.1.8.4
Vital Signs......................................................................................66
9.7.1.8.5
Electrocardiograms ........................................................................67
9.7.1.8.6
Other Safety Analyses....................................................................67
9.7.2
Determination of Sample Size .....................................................................67
9.7.3
Interim Analysis...........................................................................................68
9.7.4
Other Statistical/Analytical Issues ...............................................................68
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................68
10
REFERENCE LIST .........................................................................................................69
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......71
11.1
Changes to the Protocol .........................................................................................71
11.2
Adherence to the Protocol......................................................................................71
11.3
Monitoring Procedures...........................................................................................71
11.4
Recording of Data..................................................................................................72
11.5
Identification of Source Data.................................................................................72
11.6
Retention of Records..............................................................................................73
11.7
Auditing Procedures and Inspection......................................................................73
11.8
Handling of Study Drug.........................................................................................73
11.9
Publication of Results ............................................................................................74
11.10 Disclosure and Confidentiality ..............................................................................74
11.11 Discontinuation of Study .......................................................................................74
11.12 Subject Insurance and Indemnity...........................................................................75
12
APPENDIX......................................................................................................................76
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests...........................................................................47
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 .........51
Table 3
Summary of Blood Sample Volumes ........................................................54
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
MAR
missing at random
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Abbreviation
Term
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PHQ-9
The Patient Health Questionnaire
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
RVOTAT
right ventricular outflow tract
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SPAP
systolic pulmonary artery pressure  
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TR
tricuspid regurgitation
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
WRAML-2
Wide Range Assessment of Memory and Learning-2
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity
Obesity has become a global epidemic in western civilization, causing a serious public health 
concern.  In the United States, the prevalence of obesity in adolescents ages 12 and 19 years
has almost doubled over the past 2 decades.  The rate increased from 10.5% between 1988 
and 1994 to 20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, 
defined in the United States as greater than or equal to the 95th percentile in gender- and 
age-specific body mass index (BMI), continues to grow at an alarming rate in the United 
States and globally.  Based on data (Wang and Lobstein, 2006) using various criteria for the 
definition of obesity that included more than 30 countries in Europe, North America, Asia, 
and the West Pacific, prevalence of obesity in these countries has also increased 
significantly, at a rate comparable to that in the United States.
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may 
result in a decrease in life expectancy for the 1st time in 200 years (Peeters, et al., 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese adolescents are likely to become 
tomorrow’s obese adults (Whitaker, et al., 1997).
Current approaches to weight management in adults include lifestyle modification, 
pharmacotherapy, and invasive bariatric procedures.  Lifestyle modification involves a 
combination of diet, exercise, and behavioral change, and is the preferred and essential 
strategy for weight management in obese and overweight individuals, including adolescents.  
Although lifestyle modification can be very efficacious in some patients, adherence to the 
prescribed regimens is often poor.  As such, lifestyle modification alone is often not adequate 
and the weight loss is often transient.  On the other hand, bariatric surgery and various other 
invasive procedures are generally reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise, but are rarely used 
for adolescents.
The current standard of care for treatment of obesity in adolescent subjects ranges from
behavioral therapy including lifestyle intervention to the rare use of pharmacotherapy in 
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adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies that will be 
used in the present study to help retain participants.  These include a highly trained and 
competent staff, ample waiting area, readily available parking (at no cost), access to mass 
transit, and reminder and follow-up calls.  In addition, we will provide fun and interactive 
group sessions with games and hands-on nutrition and physical activity demonstrations, 
random raffle drawings, social events, birthday and holiday cards, and newsletters.  
Furthermore, we will make home visits for assessments of families, as needed, to maximize 
data collection. 
By using these retention strategies, we hope that we will maximize 
participant retention, which will help us cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:

A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) 
was significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
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weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
used for adolescent subjects with body weight greater than 60 kg.
In adolescent obese populations, it is anticipated that Belviq XR will result in similar effects.
As part of FDA postmarketing requirements, this study is designed to characterize the 
efficacy and safety of Belviq XR in adolescent obese populations in the United States.  It is 
also intended to support an indication for chronic weight management for obese adolescents 
ages 12 to 17 years old. 
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of 
subjects in the placebo-treated group who lose at least 5% of baseline body weight, 
and the difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in obese adolescents, where weight loss will be assessed using BMI
measurements to account for growth. In this study, the objective is to demonstrate that BMI
reduction will be achieved during 52 weeks of treatment with Belviq XR 20 mg administered 
once daily (QD) compared to placebo in obese adolescents.
In the Phase 3 orlistat study in obese adolescents mentioned above, the proportion of subjects 
who lost at least 5% body weight is relatively low. At the end of the study at Week 52, only 
26.5% of the subjects achieved a 5% or greater BMI reduction compared to 15.7% in the 
placebo group. The placebo-corrected BMI reduction was about 0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years
(Peirson, et al, 2015).  Thirty-one studies (29 behavioral, 2 pharmacological and behavioral) 
were included in a meta-analysis of randomized studies conducted in primary care centers in 
overweight and obese children and youth ages 2 to 18 years using behavioral (diet, exercise,
and lifestyle) and pharmacological interventions and providing 6-month postbaseline BMI or 
prevalence of overweight or obesity. Both interventions showed a significant effect on BMI 
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in favor of treatment (behavioral: 
standardized mean difference [SMD] -0.54, 
95% confidence interval [CI]
-0.73, -0.36; orlistat plus behavioral: 
SMD -0.43, 
95% CI -0.60, -0.25). The studies reported no significant difference between groups in the 
likelihood of reduced prevalence of overweight or overweight and obese. A great deal of 
variation was noted across efficacious interventions.
In conclusion, this meta-analysis 
demonstrated low-quality evidence that behavioral treatments alone are associated with a 
smaller effect in terms of reduced BMI compared with the effect shown by combined 
behavioral and pharmacological interventions. This may be because the effect size in the 
randomized, double blind, placebo controlled, phase 3 orlistat study in adolescents was 
relatively low and there was a lack of maintenance effect. These subjects started to regain 
their BMI after 6 months of treatment. At end of the study, only 26.5% of subjects achieved 
a 5% or greater BMI reduction compared to 15.7% in placebo group. In a sibutramine 
Phase 3 study in obese adolescents, a substantially higher proportion of subjects (69%) 
treated with sibutramine achieved at least a 5% BMI reduction compared to 21% of subjects 
in the placebo group. In addition, sibutramine resulted in a substantial reduction in mean 
BMI (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 
8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the weight loss effect of Belviq
in adults and sibutramine in adolescents, subjects in the orlistat study started to increase their 
BMI after 6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of 360 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
and sibutramine) (FDA, 2003; Chanoine, et al, 2005; Berkowitz, et al, 2006) and other 
metabolic or dyslipidemia medication products (ezetimibe, simvastatin) (FDA, 2007).
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8
STUDY OBJECTIVES
8.1
Primary Objective
To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of 
subjects with at least a 5% reduction in BMI after an initial 12 weeks of treatment 
with Belviq XR 20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 
12 weeks of treatment with Belviq XR 20 mg administered QD is predictive of 
sustained change in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
• Other weight loss effects (eg, proportion [%] of subjects achieving at least a 
10% BMI reduction, change in waist circumference) at the end of 52 weeks 
of treatment
• Effects on glycemia, insulin levels, and Homeostatic Model Assessment of 
Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405)
during 52 weeks of treatment
• Changes 
in 
cardiovascular 
risk 
factors 
associated 
with 
obesity 
(eg, hypertension, dyslipidemia) including fasting lipid changes (total 
cholesterol, triglycerides, high density lipoprotein [HDL], and low density 
lipoprotein [LDL]) during 52 weeks of treatment
•
To assess the safety of Belviq XR, including the effects on cognitive function by 
Wide Range Assessment of Memory and Learning-2 (WRAML-2), on depression by 
the Patient Health Questionnaire (PHQ-9), on signal of suicidal ideation or behavior 
with the Columbia-Suicide Severity Rating Scale (C-SSRS), on growth measured by 
CDC growth chart, on sexual maturation (pubescence) measured by Tanner Staging 
scores, and on other growth and development parameters by measuring sex 
hormones, thyroid function, valvular function, pulmonary arterial pressure, adrenal 
function, bone age, and biochemical markers of bone health assessments
•
To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling
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•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
probability of achieving at least a 5% and at least a 10% reduction in BMI from 
baseline at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents ages 12 to 17 years.  Approximately 360 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will be 
stratified by sex.  Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up 
to 52 weeks. Throughout the duration of the study, subjects will be encouraged to adhere to 
a lifestyle modification program that includes a standardized, age-appropriate diet and 
exercise counseling (see Appendix 2).  
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.
9.1.1
Prerandomization/Pretreatment Phase
Screening will occur during the Prerandomization Phase at Visit 1
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
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9.1.2
Randomization/Treatment Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025.  Overall, the PK parameters of Belviq and its main 
metabolites, M1 and M5, were similar to those in adults.  Following a single, oral 
administration of Belviq 10 mg to a total of 8 healthy adolescent (ages 12 to 17 years old) 
obese subjects, the mean maximum concentration observed and the area under the 
concentration-time curve from time zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 
464 hr×ng/mL, respectively.  The mean Belviq terminal phase half-life was 9.70 hours, 
similar to that observed in adults, thus supporting a similar dosing frequency (QD) in 
adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric or adolescent subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of subjects who are older than 12 years of age 
having a body weight of less than 60 kg is very low; therefore, the current study as designed 
to enroll subjects between 12 to 17 years of age with body weight at least 60 kg, will cover
majority of the population of interest.  The targeted study population comprises 360 obese 
adolescents 12 to 17 years of age, with a body weight at least 60 kg.
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
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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, 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 700 subjects will be screened to ensure that 360 subjects will be randomized.
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug. Subjects who screen fail can be re-screened only once after 
60 days.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, ages 12 to 17 years old at Screening, with a BMI 
that is greater than or equal to the United States (US)-weighted mean of the 
95th percentile based on age and sex with a body weight greater than 60 kg
2. Subjects and their families are not planning to move away from the area for the 
duration of the study
3. Subjects able and willing to comply with all aspects of the study, including a 
standardized, reduced-calorie diet and an age-appropriate, increased physical activity 
program
4. Subjects considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may 
affect the subject’s ability to fulfill the study requirements or significantly confound 
the assessments
2. Subjects who cannot swallow investigational products
3. Any of the following findings on screening echocardiography:

Aortic regurgitation mild or greater
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
Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: 
jet >3.0 m/s, mean gradient >25 mm Hg, and aortic valve area [AVA] 
<1.5 cm2; MS: mean gradient >5 mm Hg and mitral valve area [MVA] 
<1.5 cm2)

Systolic pulmonary artery pressure (SPAP) >40 mm Hg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
-
In cases where an actual SPAP value is not measurable due to lack of 
adequate TR jet, the pulmonary flow acceleration time measured at the 
right ventricular outflow tract (RVOTAT), will be used to assess 
eligibility. Patients with a RVOTAT ≤100 msec will be excluded, 
suggesting an elevated mean SPAP; eligibility for the those patients with 
RVOTAT between 100 and 120 msec will be determined based on 
combined assessment of the TR jet, septal motion and right ventricular 
size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with 
hemodynamic compromise)
4. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
5. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or 
schizophrenia
6. Known secondary causes (chromosomal, endocrine, or metabolic) for obesity 
(eg Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for 
longer than 30 days, history of significant exposure to corticosteroids for chronic 
illness during the past year, and known genetic causes of obesity)
7. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before 
Screening
8. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or
monoamine oxidase inhibitors (MAOIs) within 30 days before Randomization, 
including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 
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
bupropion

triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
9. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months 
before Screening, including but not limited to pergolide, ergotamine, methysergide, 
and cabergoline
10. History or evidence of clinically significant disease (eg, malignancy; cardiac, 
respiratory, gastrointestinal, renal, or psychiatric disease) other than prediabetes 
(impaired fasting glucose or impaired glucose tolerance), Type 2 diabetes treated with 
oral anti-diabetic agents (excluding sulfonylurea)
or
non-insulin injectable 
antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver 
disease
11. Use of Belviq XR within 6
months before Screening or hypersensitivity to 
Belviq XR or any of the excipients
12. Significant change in diet or level of physical activity within 1 month before dosing 
or change in weight of more than 5 kg within 3 months before Screening
13. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 
6 months before Screening
14. History of alcohol or drug dependence or abuse
15. Recreational drug use within 2 years before Screening
16. Known to be human immunodeficiency virus positive
17. Active viral hepatitis (B or C) as demonstrated by positive serology
18. Malignancy within 5 years before Screening
19. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
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20. Special needs subjects who are unable to comprehend study-related instructions 
(eg, mild to profound mental retardation [IQ <70], moderate to severe cognitive 
developmental delay, pervasive development disorders, autism)
21. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure 
disorder within 6 months of screening or any time between screening and 
randomization
22. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 
2 separate readings recorded on 2 separate days.  Those subjects who had 
uncontrolled hypertension at Screening can be rescreened more than 1 month after 
initiation or adjustment of antihypertensive therapy 1 time.
23. Currently enrolled in another clinical study or has used any investigational drug or 
device within 30 days before providing informed consent
24. Planned bariatric surgery during the study
25. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
26. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
27. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do 
not agree to use a highly effective method of contraception (eg, total abstinence, 
an intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study 
period and for 28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexual activity during the study period and for 
28 days after study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do not 
agree to use the same contraceptive during the study and for 28 days after study 
drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD at 
approximately the same time each day.
Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled with text that is in full regulatory compliance with each 
participating country. As the study is being conducted in US only, the study drug label will 
be printed in English. 
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The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal 
(US) law to investigational use.”
All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug 
was dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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 
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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.
Subjects will be centrally stratified by sex (male and female).  Within each stratum, subjects 
will be randomized to receive either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  
Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily at approximately the same time of 
every day, and be encouraged to take the study medication with an adequate amount of water 
(8 oz. or 240 mL).
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
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Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs
will review treatment compliance during site visits and at the completion of the study.
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
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9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 
(US sites only).  Must be appropriate to handle schedule IV products and not be 
expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
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shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
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9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.3
Efficacy Assessments

Body weight and height will be measured using a standard stadiometer
method (Lohman T, et al, 1988) to calculate changes in BMI; BMI will then 
be used to calculate the proportion (%) of patients achieving at least a 5% and 
at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total 
cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), fasting 
plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and HOMA-IR to 
assess changes in cardiovascular and metabolic risk profiles from Baseline to 
Week 52
o
Prehypertension and primary hypertension as defined by the Expert 
Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children 
and Adolescents, 2011)
o
Dyslipidemia as defined by the Expert Panel on Integrated Guidelines 
for Cardiovascular Health and Risk Reduction in Children and 
Adolescents (Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents, 2011)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for population PK analyses.  All subjects will be instructed to take their study 
drug in the morning on the day before their scheduled clinic visit at Weeks 12, 28, 36, 
and 52.  No additional doses should be taken that day for those subjects who have been 
taking their doses in the evening.  Dose times must be recorded for the last 2 dosing times 
prior to the clinic visit.
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed to take their 
study drug at approximately the same time as the morning before, with no additional doses 
taken that day.  Two blood samples for determination of plasma concentrations of lorcaserin 
will be taken at each of these visits: within 30 minutes before dosing and within 1 to 3 hours 
after dosing.  
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On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at 
home.  One blood sample for determination of plasma concentration of lorcaserin will be 
collected at the clinic within 4 to 6 hours after dosing.  
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
method coupled with tandem mass spectrometry method. The collection, handling, and 
shipping procedures for PK samples will be described in a manual to be provided to the study 
sites.
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Blood samples will be collected to determine lorcaserin plasma exposure and population 
PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure 
and following response to lorcaserin: 

Change from Baseline in BMI 

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in 
BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC AND OTHER BIOMARKER ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs);
electrocardiograms (ECGs);
laboratory evaluations
for hematology,
metabolic function (glucose, lipids, and thyroid), adrenal functions, and biochemical blood 
and urine bone health assessments; blood chemistry and urine values; neuropsychiatric 
events; periodic measurements of vital signs, neuromuscular signs for screening potential 
serotonin syndrome, and signs and symptoms of priapism and prolactinemia; and 
performance of physical examinations.  In subjects with potential prolactin-related AEs, such 
galactorrhea, changes in libido, or changes to menstrual cycle, prolactin level will be 
measured and assessed.  Study drug effect on growth of adolescents will be evaluated using 
the CDC growth chart at Baseline, and Weeks 5, 12, 28, 36, 52, and at Follow-Up; a full 
physical examination at Baseline, Weeks 1, 12, 28, 52, and at Follow-Up; and bone age 
determination by x-ray of the hand at Baseline, Weeks 12, 28, and 52.  Sexual maturation 
will be evaluated by assessing sex hormones and self-reported changes in Tanner Staging at 
Baseline, Weeks 28 and 52, and at Follow-Up.
The C-SSRS will be used to assess all subjects in the study for any signal of depression or 
suicidal ideation or behavior at every visit.  Additionally, screening, diagnosing, monitoring, 
and measuring the severity of depression will be assessed using the PHQ-9 at every visit, and 
effects on cognitive function will be assessed using the WRAML-2 at Baseline, Weeks 5, 28, 
52, and EOS.
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Echocardiographic assessments will be used to exclude subjects with FDA-defined 
valvulopathy, pulmonary hypertension, and other major cardiovascular disease (as outlined in 
Exclusion Criterion No. 3) during the Screening Period.  Additionally, cardiac valvular 
function and pulmonary systolic pressure changes at Weeks 28 and 52 will be assessed.  
Valvular regurgitation as assessed in the echocardiogram will be rated absent, trace, mild, 
moderate, or severe for the aortic, mitral, and tricuspid valves; the rating will be absent or 
present for the pulmonic valve. The evaluations will be based on guidelines from the 
American Society of Echocardiography. Pulmonary artery pressure will be estimated from 
the tricuspid regurgitant jet velocity.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
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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 (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
It is the responsibility of the investigator to review the results of the C-SSRS, PHQ-9, and 
WRAML-2 in all subjects and determine if any result constitutes an AE.  Medical and 
scientific judgment should be exercised in deciding whether an isolated suicidality rating 
scale response should be classified as an AE (see Section 9.5.1.5.9 for a description of the 
C-SSRS).
All AEs must be followed for 28 days after the subject’s last dose or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of 
the event
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•
The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious 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 onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin
•
Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study specific event 
does not meet serious criteria.  If the event meets seriousness criteria, it should be reported as 
an SAE as above.  However, if the event listed below does not meet serious criteria, it should 
be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation   

Euphoria 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for 
administration of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was 
in place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
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points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function
T4, TSH
Adrenal function
Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects), 
Bone health assessments
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other
Albumin, calcium, globulin, glucose, HbA1c, HDL cholesterol, 
lactate dehydrogenase, LDL cholesterol, phosphorus, total protein,
total cholesterol, triglycerides, prolactin, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
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9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2).  
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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.
9.5.1.5.7
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.8
ECHOCARDIOGRAM
Echocardiograms will be obtained on the Schedule of Procedures/Assessments (Table 2). 
Valvular regurgitation in echocardiogram will be rated absent, trace, mild, moderate, or 
severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve. The evaluations will be based on guidelines from the American Society of 
Echocardiography. Pulmonary artery pressure will be estimated from the tricuspid 
regurgitant jet velocity.
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9.5.1.5.9
OTHER SAFETY ASSESSMENTS
WRAML-2
The WRAML-2 administration will consist of the Core Battery, which provides scores on 
Verbal Memory, Visual Memory, and Attention/Concentration.  There are 6 subtests (2 for 
each area).
The tests provide standardized scores based on age and gender, and are 
appropriate for ages 5 to 90 years.  The WRAML-2 will be used to assess lorcaserin effects 
on cognitive function. In addition, signs and symptoms of cognitive related AEs, including 
impairments in attention, memory, and adverse effects on schoolwork will be captured in the 
eCRF.
PHQ-9
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and 
measuring the severity of depression:

The PHQ-9 incorporates Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV) depression diagnostic criteria with other leading major depressive 
symptoms into a brief self-report tool.

The tool rates the frequency of the symptoms which factors into the scoring severity 
index.

Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.

A follow-up, non-scored question on the PHQ-9 assigns weight to the degree to 
which depressive problems have affected the patient's level of function. 
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. It will be performed at Baseline and at study 
visits as designated in the Schedule of Procedures/Assessments (Table 2).
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will be captured in the eCRF.
Hand X-Ray will be evaluated for any potential negative effect on bone age as designated in 
the Schedules/Assessments (Table 2). 
Neuromuscular sign assessment for serotonin 
syndrome will be performed as designated in the Schedule of Procedures/Assessments 
(Table 2) to screen for potential serotonergic syndrome components. 
Serotonergic 
syndromes that meet the diagnostic criteria will be captured by AE eCRF.
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9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at designated time points as 
specified in the Schedule of Procedures/Assessments (Table 2).
9.5.1.6.2
URINE DRUG AND COTININE TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 2).  This sample will be tested for common 
drugs 
of 
use/abuse 
(eg, 
ethyl 
alcohol, 
cocaine, 
cannabinoids, 
phencyclidine, 
nicotine/cotinine, opioids [as a group], benzodiazepines, barbiturates, amphetamines).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
from study
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication 
assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examinationd
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, fasting 
X
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
from study
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
insulin, and HbA1c sampling
T4 and TSH
X
X
X
X
Testosterone, Estradiol
X
X
X
Pregnancy test (Urine)
X
X
X
X
X
X
X
X
X
X
X
X
Prolactin
X
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Fasting lipid panel
X
X
X
X
Urine NTX
X
X
X
X
PK/PD blood sampling 
X
X
X
X
X
AM serum cortisol
X
X
ECG
X
X
X
X
X
Echocardiograph
Xf
X
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
from study
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Hand x-ray for bone age
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
WRAML-2
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
X
X
X
X
X
X
X
Standardized age-appropriate 
lifestyle modification counselinge
X
X
X
X
X
X
X
X
X
X
AE = adverse event, AM = morning; CDC = Centers for Disease Control and Prevention, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, EOS 
= End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, IxRS = interactive voice or web response system, NTX = N-telopeptide, OC = osteocalcin; PHQ-9 = 
The Patient Health Questionnaire, PICP = carboxyterminal propeptide of type I procollagen,  PD = pharmacodymanic, PK = pharmacokinetics, T4 = thyroxine, TSH = thyroid 
stimulating hormone, WRAML-2 = Wide Range Assessment of Memory and Learning-2.
a:
Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b:
Window ±7 days for all visits after Visit 2 except for Weeks 12 and 28 (the window for these visits will be broader at ±14 days). Week is shown unless otherwise 
indicated.
c:
On the day of the Week 12, 28, and 52 clinic visits, subjects will take their morning dose of study drug on the day before their scheduled clinic visit.  On the day of the 
clinic visit, subjects will be instructed to take their study drug at approximately the same time as the morning before, with no additional doses taken that day.  Two 
blood samples for determination of plasma concentrations of lorcaserin will be taken: predose (within 30 minutes before dosing) and within 1 to 3 hours after dosing. 
On the day of the Week 36 clinic visit, subjects will take the morning dose at home, and 1 blood sample for determination of plasma concentrations of lorcaserin will be 
collected at the investigational site within 4 to 6 hours after dosing.  Dose times must be recorded for the last 2 dosing times prior to the clinic visit.
d:
Includes a neuromuscular assessment
e:
Lifestyle modification counseling will also be performed at Weeks 3, 24, 32, 40, and 48 in addition to counseling at the scheduled visits in Table 2.
f:
Echocardiographic
assessments
will be performed during screening period after subjects have met all other inclusion and exclusion criteria.
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
(Chemistry and Hematology)
5
Screening: 1
Visits 2, 3, 4, 6, 8, 11 (EOT), or 
Early discontinuation from study, 
EOS
58=40
T4, TSH, Cortisol, 
Testosterone, estradiol 
6
Screening:  1
Visits  8, 11 (EOT), or Early 
discontinuation from the study
6×3=18
Serum OC and PICP, 
Hydroxy-proline; Fasting 
lipid panel (HDL cholesterol, 
LDL cholesterol, total 
cholesterol, triglycerides)
8
Visits 2, 8, 11 (EOT), or Early 
discontinuation from the study
8×3=24
Fasting Prolactin, FPG, 
Insulin, and HbA1c sampling
5
Screening:  1
Visits 2, 6, 8, 11 (EOT) or Early 
discontinuation from the study
5×5=25
PK/PD blood sampling
4
Visits 6, 8, and 11 (EOT) or 
Early discontinuation from the 
study (2 samples each); Visit  9 
(1 sample only)
7×4=28
Total
135
EOS = End of Study; EOT = End of Treatment; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; OC = osteocalcin; 
PD = pharmacodynamic; PICP = carboxyterminal propeptide of type I procollagen; PK = pharmacokinetics; T4 = thyroxine; 
TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported.
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If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin

Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study-specific 
event does not meet serious criteria.  If the event meets seriousness criteria, it should 
be reported as an SAE as above.  However, if the event listed below does not meet 
serious criteria, it should be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation

Euphoria 
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.
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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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue treatment prematurely will be followed up until study completion.  
All subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 2).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
Detailed retention strategies will be developed and included in study manual. These include 
a highly trained and competent staff, easy access to the clinic, reminder and follow-up calls, 
interactive group sessions with games and hands-on nutrition and physical activity 
demonstrations, random raffle drawings, social events, birthday and holiday cards, and
newsletters. In addition, home visits for assessments of families will be an option, as needed, 
to maximize data collection. This detailed retention plan will help prevent missing data.
A subject removed from the study for any reason may not be replaced.
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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.  The DEA Registrant has 
the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from Baseline to Week 52 and proportion (%) 
of subjects achieving at least a 5% or 10% BMI reduction at Week 52 by the outcome 
of achieving at least a 5% BMI reduction at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52
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
Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 
80% or greater compliant with study medication, completed the study, have no major 
protocol deviations, have no violations of inclusion or exclusion criteria, and have 
BMI data at Baseline and Week 52.  The determination of subjects to be excluded 
from this population based on the above criteria and list of major protocol violations 
will be included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at 
least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 
1 valid lorcaserin plasma concentration was obtained with associated documented 
dosing history.

The population PK/PD set is the group of randomized subjects with PK information 
and who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
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9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using analysis of covariance model (ANCOVA) with 
factors of treatment, sex (male and female) as fixed effect, and the baseline age and BMI as 
covariates.  The missing values will be imputed using a pattern mixture model utilizing 
multiple imputation (MI) assuming the missing values are missing not at random (MNAR).  
The missing values will be imputed at each visit using all available values including the 
retrieved measurement from the postdiscontinuation data.  The details of the analysis model 
and missing value imputation method will be further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated 
based on the PP.

Change from baseline in standardized BMI score (Z-score):
The same primary 
efficacy analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed 
and will be described in the SAP.  
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Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, and sex (male and 
female), and baseline BMI as a covariate using FAS.  Subjects with any missing assessment 
at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using mixed effect model repeated measurement analysis (MMRM) and categorical
variables will be analyzed using the Cochran Mantel Haenszel test, Chi-square test, or 
logistic regression as appropriate.  Additional analysis may be performed as needed using 
appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male 
and female), race (white, black, Asian, and other). Additional subgroups may be explored, if 
deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Change from Baseline in BMI will be assessed as the PD analysis.  The PD analysis set will 
be used for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also be 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
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9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination), 
growth (CDC growth chart and bone age determined by x-ray of the hand), sexual maturation 
(Tanner Staging), out-of-normal-range laboratory safety test values, change from baseline in 
laboratory safety test values, ECGs, and vital sign measurements will be summarized by 
treatment group using descriptive statistics or frequency count as appropriate.  In addition, 
cognitive function will be evaluated by the WRAML-2, depression will be evaluated by the 
PHQ-9, and suicidal ideation and behavior will be evaluated by the C-SSRS, and will also be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
All WRAML-2 raw scores from the Core Battery will be converted to age and gender 
standard scores for purposes of intra individual comparisons.  For echocardiographic 
assessments, the proportion of subjects who develop FDA-defined valvulopathy, the 
proportion of subjects who develop pulmonary hypertension [pulmonary hypertension is 
defined when the subject’s systolic pulmonary artery pressure (SPAP) ≥40 mmHg evaluated 
by echocardiograph], and change from baseline in SPAP will be summarized by treatment 
group at Week 28 and Week 52 using descriptive statistics or frequency count as appropriate.
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
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9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No 
[not related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
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The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit
and treatment group.
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9.7.1.8.5
ELECTROCARDIOGRAMS
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and 
greater than 60 msec from the baseline visit.
9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including adolescent growth evaluations using 95th percentile CDC 
growth charts and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, neuromuscular sign assessment for serotonin syndrome, signs and symptoms of 
priapism and prolactinemia, study drug effect on cognitive function assessed by WRAML-2, 
assessment of suicidality using C-SSRS, and depression assessment using PHQ-9 will be 
summarized by treatment group at each scheduled visit.  For echocardiographic assessments, 
the proportion of subjects who develop FDA-defined valvulopathy, the proportion of subjects 
who develop pulmonary hypertension (defined as when a subject’s SPAP is ≥40 mmHg 
evaluated by echocardiograph], and change from baseline in SPAP will also be summarized 
by treatment group at Week 28 and Week 52.
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
360 subjects in a 1:1 ratio (n=180 in the Belviq XR 20-mg treatment group; n=180 in the 
placebo group) will have at least 90% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 360 subjects (180 subjects for Belviq XR 20 mg and 180 subjects for placebo) 
will also have greater than 85% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Fisher’s Exact test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.
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9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
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 Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
Whitaker RC, et al. Predicting obesity in young adulthood from childhood and parental 
obesity. N Engl J Med. 1997 Sep 25;337(13):869-73.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will be 
encouraged to participate in a standardized weight management program for adolescents 
consisting of multicomponent behavior therapy.  The therapy will focus on healthy eating, 
physical activity, and lifestyle changes that will facilitate weight loss and weight-loss 
maintenance. The role of the caregivers is to support their child or adolescents’ lifestyle 
changes and their taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress 
but caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neuroscience Business Group
Eisai Inc.
Date
Eisai Inc.
Date
Neuroscience Business Group
Eisai Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, typographical, 
and formatting changes 
Throughout
Subject population to 
include children ages 12 to 
17 years
Changes were made 
upon regulatory advice 
received at the Type C 
meeting.
Title Page
Synopsis
•
Study Protocol Title
•
Study Design
•
Inclusion Criteria
•
Exclusion Criteria
•
Safety Assessments
•
Efficacy Analyses
•
Safety Analyses
Section 7.1
Section 9.1
Section 9.2
Section 9.3.1
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.7.1.6
Section 9.7.1.8
Protocol Signature Page
Investigator Signature Page
All subjects will be 
evaluated for cardiac 
valvular disease or 
pulmonary hypertension via 
echocardiographic 
assessment.
Changes were 
made 
upon regulatory advice 
received at the Type C 
meeting.
Synopsis
•
Other Secondary Objectives
•
Exclusion Criteria
•
Safety Assessments
•
Safety Analyses
Section 8.2
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Section 9.3.2
Section 9.5.1.5.8
Section 9.5.2
Section 9.7.1.8
Section 9.7.1.8.6
Study drug administration 
will be taken at 
approximately the same 
time each day.  On the days 
of PK sampling and the day 
before the subjects come to 
the clinic for PK sampling, 
study drug will be taken in 
the morning and doses 
recorded 2 days prior to the 
clinic visit.
This will ensure lower
variability with regard 
to PK/PD 
measurements.
Synopsis
•
Pharmacokinetic Assessments
Section 9.4.1
Section 9.4.4
Section 9.5.1.4.1
Section 9.5.2.1
Screening, diagnosing, 
monitoring, and measuring 
the severity of depression 
will be assessed using the 
Patient Health 
Questionnaire (PHQ-9), and 
not the Children’s 
Depression Inventory 2 
(CDI-2).
The PHQ-9 was 
originally proposed by 
the FDA for the 
population in the 
current study.
Synopsis
•
Other Secondary Objectives
•
Safety Assessments
•
Safety Analyses
Section 8.2
Section 9.5.1.5
Section 9.5.2
Section 9.5.1.5.1
Section 9.5.1.5.9
Section 9.7.1.8
Section 9.7.1.8.6
Primary analysis changed 
from MMRM to using a 
pattern mixture model 
utilizing multiple 
imputations (MI) to impute
missing values.
Changes were made 
upon regulatory advice 
received at the Type C 
meeting.
Synopsis
•
Primary Efficacy Analysis
Section 9.7.1.6
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Revision History
Previous Version (Revision): v3.0
Current Version (Revision):  v4.0
Date of Revisions: 03 Nov 2016
Change
Rationale
Affected Protocol Section(s)
Clarified fasting lipids
Fasting lipid levels 
provide uniformity in 
lipid measurements for 
definition of 
dyslipidemia
Synopsis
•
Other Secondary Objectives
•
Efficacy Assessments
•
Other Secondary Efficacy 
Endpoints
Section 8.2
Section 9.5.1.3
Appendix 3 removed
The current study will 
not conduct any 
biomarker or 
pharmacogenomic
evaluation. PK/PD 
measurements will be 
done during study.
Appendix 3
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Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, and 
formatting changes 
Throughout
Prehypertension was 
deleted from the 
inclusion criterion.  
Subjects with Stage 1 
primary 
hypertension, with an 
upper limit defined as 
99% plus 5 mmHg 
for age, sex, and 
height are included in 
the study. 
Prehypertension does not 
qualify as a comorbid 
condition.  The limitation 
on BP is to further define 
the proper study 
population.
Synopsis
•
Inclusion Criteria
Section 9.3.1
Removed the 
restriction that 
subjects need to have 
less than 44 kg/m2
BMI for study entry
Per United States Food and 
Drug Administration 
(FDA) request
Synopsis
•
Inclusion Criteria
•
Analysis Sets
•
Pharmacodynamic Analyses
•
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study 
entry requirement 
that the caregiver 
cannot have a history 
of ADD, substance 
abuse, depression, 
suicidal 
ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and 
Drug Administration 
(FDA) request
Synopsis
•
Inclusion Criteria
Section 9.3.1
The secondary 
efficacy objective 
To explore the 
predictability of 12-week 
Synopsis
•
Secondary Efficacy Objectives
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Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
and endpoint were 
revised
responders for long-term 
sustainable weight loss 
effect
•
Other Secondary Efficacy 
Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with 
symptoms or signs of 
cardiac valvular 
disease or pulmonary 
hypertension are not 
required to have 
further evaluation by 
centralized 
echocardiogram 
assessment.  In 
addition, no 
adjudication will be 
performed.  Local 
echocardiograms can 
be performed if 
deemed medically 
necessary by the 
investigator.
This change allows for the 
investigator to make the 
decision to perform local 
echocardiograms 
on 
a 
pediatric subject if deemed 
medically indicated rather 
than burden the subject to 
undergo 
a 
mandated, 
unnecessary procedure. 
Synopsis
•
Safety Assessments
Section 9.5.1.5
Updated study 
rationale
Clarification 
Section 7.1.1.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, and 
formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will 
replace the IR formulation in 
the United States market to 
support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to
include children ages 9 to 
17 years
Expand the age of the 
population due to the change of 
pediatric development strategy
A single dose pharmacokinetic 
study in pediatric obese subjects 
(APD356-A001-026) indicated 
that patients with body weight 
greater than or equal to 60 kg 
can be administered a dose 
similar to that given to adults 
and adolescents.  Based on 
Centers for Disease Control and 
Prevention (CDC) growth chart 
data, almost all subjects over 
9 years of age are likely to be at 
or over 60 kg body weight.  
Therefore, children age 9 to 
11 years have been included in 
the current study.
Title Page
Synopsis
•
Study Protocol Title
•
Objectives
•
Study Design
•
Inclusion Criteria
•
Assessments
•
Efficacy Analyses
•
Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.9
Section 9.7.1.6
Section 9.7.1.8
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Additional safety 
assessments including 
cognitive function, 
serotonin syndrome 
components, bone health 
and endocrine function, 
priapism, and symptoms 
associated with 
hyperprolactinemia were 
added.
Per United States Food and 
Drug Administration (FDA)
request
Synopsis

Efficacy Assessments

Pharmacokinetic 
Assessments

Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.9
Section 9.7.1.8
Section 9.7.1.8.1
Change to primary and 
key secondary endpoints
Per FDA request
Synopsis

Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary 
endpoint changed
Per FDA request
Synopsis

Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of 
study-specific adverse 
events
To provide clearer guidance for 
the correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and 
prohibited prior and 
concomitant therapies
For clarification
Synopsis

Exclusion Criteria

Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of 
adverse events
To provide clearer guidance for 
the correct reporting of adverse
events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Update to Introduction 
and to Completion/ 
Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction With Lifestyle Modification for Weight 
Loss in Obese Adolescents, Age 12 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
v4.0
03 Nov 2016 (Revision)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use and all applicable 
local Good Clinical Practice (GCP) and regulations.  All required 
study documentation will be archived as required by regulatory 
authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.: APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the 
Efficacy and Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in 
Obese Adolescents, Age 12 to 17 Years
Investigators
Unknown
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
-
Approximately 24 months from the 1st subject enrolled to last subject’s last visit or last 
assessment 
-
Phase 4
Objectives
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks 
of treatment with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with 
at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD as compared to placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with 
at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg 
administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of 
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in BMI 
during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
-
Other weight loss effects (eg, proportion [%] of subjects achieving at least a 
10% BMI reduction, change in waist circumference) at the end of 52 weeks of 
treatment
-
Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin 
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Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405) during 52 weeks of 
treatment

Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high density 
lipoprotein [HDL], and low density lipoprotein [LDL]) during 52 weeks of treatment. To 
assess the safety of Belviq XR, including the effects on cognitive function by Wide Range 
Assessment of Memory and Learning-2 (WRAML-2), on depression by the Patient Health 
Questionnaire (PHQ-9), on signal of
suicidal ideation
or behavior
with the 
Columbia-Suicide Severity Rating Scale (C-SSRS), on growth measured by Centers for 
Disease Control and Prevention (CDC) growth chart, on sexual maturation (pubescence) 
measured by Tanner Staging scores, and on other growth and development parameters by 
measuring sex hormones, thyroid function, valvular function and pulmonary arterial 
pressure, adrenal function, bone age, and biochemical markers of bone health assessments

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) 
parameters including but not limited to reduction from baseline in BMI and probability of 
achieving at least a 5% and at least a 10% reduction in BMI from baseline at Week 52 using 
population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese
adolescents, ages 12 to 17 years.  Approximately 360 subjects will be randomized in a 1:1 ratio to 
Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will be stratified by sex.  
Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout 
the duration of the study, subjects will be encouraged to adhere to a lifestyle modification program 
that includes a standardized, age-appropriate diet and exercise counseling.
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization 
Phase will last up to 30 days and consist of 1 visit during which subjects will be screened for 
eligibility.  The Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The 
Treatment Period will last for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36,
44, and 52.  The Follow-Up Period will extend from the End of Treatment visit to the End of Study 
visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will continue in the 
study until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely 
will be followed up until study completion.  
Number of Subjects
Approximately 700 subjects will be screened to provide 360 randomized subjects.
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that is 
greater than or equal to the United States (US)-weighted mean of the 95th percentile based on 
age and sex with a body weight greater than 60 kg
2.
Subjects and their families not planning to move away from the area for the duration of the 
study
3.
Subjects able and willing to comply with all aspects of the study, including a standardized, 
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reduced-calorie diet and an age-appropriate, increased physical activity program
4.
Subjects considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the 
subject’s ability to fulfill the study requirements or significantly confound the assessments
2.
Subjects who cannot swallow investigational products
3.
Any of the following findings on Screening echocardiography:

Aortic regurgitation mild or greater

Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: jet >3.0 m/s, 
mean gradient >25 mm Hg, and aortic valve area [AVA] <1.5 cm2; MS: mean 
gradient >5 mm Hg and mitral valve area [MVA] <1.5 cm2)

Systolic pulmonary artery pressure
(SPAP) >40 mmHg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
In cases where an actual SPAP value is not measurable due to lack of adequate TR jet, the 
pulmonary flow acceleration time measured at the right ventricular outflow tract (RVOTAT), 
will be used to assess eligibility. Patients with a RVOTAT ≤100 msec will be excluded, 
suggesting an elevated mean SPAP; eligibility for the those patients with RVOTAT between 
100 and 120 msec will be determined based on combined assessment of the TR jet, septal
motion and right ventricular size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with
hemodynamic compromise)
4.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper 
limit of normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater 
than 1.5×ULN in absence of Gilbert’s syndrome
5.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or schizophrenia
6.
Known 
secondary 
causes 
(chromosomal, 
endocrine, 
or 
metabolic) 
for 
obesity 
(eg,
Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 
30 days, history of significant exposure to corticosteroids for chronic illness during the past 
year, known genetic causes of obesity)
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7.
Use of other products intended for weight loss including prescription drugs, over-the-counter 
(OTC) drugs, and herbal preparations within 1 month before Screening 
8.
Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
9.
Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and cabergoline
10. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), type 2 diabetes treated with oral anti-diabetic agents 
(excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive sleep 
apnea, dyslipidemia, and nonalcoholic fatty liver disease
11. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any 
of the excipients
12. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
13. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before 
Screening
14. History of alcohol or drug dependence or abuse
15. Recreational drug use within 2 years before Screening
16. Known to be human immunodeficiency virus positive
17. Active viral hepatitis (B or C) as demonstrated by positive serology
18. Malignancy within 5 years before Screening
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19. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
20. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to 
profound mental retardation [IQ <70], moderate to severe cognitive developmental delay, 
pervasive development disorders, autism)
21. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
22. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 2 separate 
readings recorded on 2 separate days.  Those subjects who had hypertension at Screening can 
be rescreened more than 1 month after initiation or adjustment of antihypertensive therapy
1 time.
23. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
24. Planned bariatric surgery during the study
25. Not suitable to participate in the study in the opinion of the investigator, including
consideration of any existing physical, medical, or mental condition that prevents compliance 
with the protocol
26. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive β-human chorionic gonadotropin test).  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.
27. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 28 days 
after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after study 
drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have 
been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated,
biconvex tablets with one 20-mg tablet administered orally QD.
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Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  up to 30 days
Randomization Phase: approximately 56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal 
preparations, are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days with study medication temporarily stopped for that 
time period and resumed the next day after the OTC cold medicine is stopped.  Any of the following 
serotonergic agents or other agents in combination with Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to 
calculate the proportion (%) of patients achieving at least a 5% and at least a 10% BMI 
reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total cholesterol, HDL
cholesterol, LDL cholesterol, and triglycerides), fasting plasma glucose, fasting insulin,
hemoglobin A1c (HbA1c), and Homeostasis Model Assessment (HOMA) IR to assess
cardiovascular and metabolic risk profiles from Baseline to Week 52
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
Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents
Pharmacokinetic Assessments
Plasma lorcaserin concentrations will be measured at Weeks 12, 28, 36, and 52 for analysis of 
population PK.  All subjects will be instructed to take their study drug in the morning on the day 
before their scheduled clinic visit at Weeks 12, 28, 36, and 52.  No additional doses should be taken 
that day for those subjects who have been taking their doses in the evening.  Dose times must be 
recorded for the last 2 dosing times prior to the clinic visit.
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed to take their study drug 
at approximately the same time as the morning before, with no additional doses taken that day.  Two 
blood samples for determination of plasma concentrations of lorcaserin will be taken at each of these 
visits: within 30 minutes before dosing and within 1 to 3 hours after dosing.  
On the day of the Week 36 clinic visit, subjects will take their study drug in the morning at home.  
One blood sample for determination of plasma concentrations of lorcaserin will be collected at the 
clinic within 4 to 6 hours after dosing.
Subjects can resume their usual dose schedule the day after the PK clinic visits.  
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their 
relationships with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious 
adverse events (SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, metabolic 
function (glucose, fasting lipids, and thyroid), adrenal function and biochemical blood and urine bone 
health assessments; blood chemistry and urine values; neuropsychiatric events; periodic measurement 
of vital signs, neuromuscular signs for screening potential serotonin syndrome, and signs or 
symptoms of priapism and prolactinemia; and performance of physical examinations.
In patients 
with potential prolactin-related AEs, such as galactorrhea, changes in libido, or changes to menstrual 
cycle, prolactin level will be measured and assessed. Study drug effect on growth will be evaluated 
using the CDC growth chart at Baseline, and Weeks 5, 12, 28, 36, 52, and at Follow-Up; a full 
physical examination, at Baseline, Weeks 12, 28, 52, and at Follow-Up; and bone age determination 
by x-ray of the hand at Baseline, Weeks 12, 28, and 52. Sexual maturation will be evaluated by 
assessing sex hormones and self-reported changes in Tanner Staging at Baseline, Weeks 28 and 52, 
and at Follow-Up.   
The C-SSRS will be used to assess all subjects in the study for any signal of depression or suicidal 
ideation or behavior.  Additionally, screening, diagnosing, monitoring, and measuring the severity of 
depression will be assessed using the PHQ-9 and effects on cognitive function will be assessed using 
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WRAML-2.
Echocardiographic assessments will be used to exclude subjects with FDA-defined valvulopathy, 
pulmonary hypertension, and other major cardiovascular disease (as outlined in Exclusion Criterion 
No. 3) during the Screening Period.  Additionally, cardiac valvular function and pulmonary systolic 
pressure changes at Weeks 28 and 52 will be assessed.
Valvular regurgitation as assessed in the 
echocardiogram will be rated absent, trace, mild, moderate, or severe for the aortic, mitral, and 
tricuspid valves; the rating will be absent or present for the pulmonic valve. The evaluations will be 
based on guidelines from the American Society of Echocardiography. Pulmonary artery pressure will 
be estimated from the TR jet velocity.
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography method coupled with 
tandem mass spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from baseline to Week 52 and proportion (%) of 
subjects achieving at least a 5% or 10% BMI reduction at Week 52 by the outcome of 
achieving at least a 5% BMI reduction at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 post dose safety assessment.
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
The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to 
study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater 
compliant with study medication, completed the study, have no major protocol deviations, have 
no violations of inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  
The determination of subjects to be excluded from this population based on the above criteria 
and a list of major protocol violations will be included in the statistical analysis plan (SAP) and 
finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD 
parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who 
have at least 1 adequately documented measurement of BMI.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as 
a supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in 
all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from 
baseline in BMI will be analyzed using the repeated measures analysis of covariance model 
(ANCOVA) with factors of treatment visits (Baseline, Week 1, 5, 8, 12, 20, 28, 36, 44, and 52), , sex 
(male and female), treatment-by-visit interaction as fixed effect, subjects as random effect, and the 
baseline age and BMI as covariates.  The missing values will be imputed using a pattern mixture 
model utilizing multiple imputation (MI) using the same model as the analysis model.  The missing 
values will be imputed for a visit at a time using the complete cases up to and include the current visit 
for a particular visit.  The unstructured covariance matrix will be used in the analysis and the 
treatment comparison at Week 52 will be the event of interest.  In case of a convergence issue, the 
Toeplitz covariance structure will be used in the model.  As a sensitivity analysis, the missing values 
will also be imputed using pattern mixture MI method assuming the missing value is missing not at 
random (MNAR). The details of the analysis model and missing value imputation method will be 
further described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on 
the PP.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy 
analyses described above will be repeated using Z-score.
Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed and will 
be described in the SAP.
Key Secondary Efficacy Analyses
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The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI
reduction at Week 52. The secondary efficacy endpoint will be analyzed only if the test for the 
primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using 
a logistic regression model with factors of treatment, sex (male and female), and baseline BMI as a 
covariate using FAS.  Subjects with any missing assessment at Week 52 will be considered as 
treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed 
using mixed effect model repeated measurement analysis (MMRM) and categorical variables will be 
analyzed using the Cochran Mantel Haenszel test, Chi-square test, or logistic regression as 
appropriate.  Additional analysis may be performed as needed using appropriate statistical 
methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male and 
female), and race (white, black, Asian, and other).  Additional subgroups may be explored, if deemed 
necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity 
analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling. The effect of covariates such as baseline characteristics or 
demographics on PK will be explored. Derived exposure parameters such as the maximum observed 
concentration and the area under the concentration-time curve from time 0 to 24 hours at steady-state 
will be calculated from the final PK model using individual posterior estimates of the PK parameters 
and from dosing history. The PK analysis set will be used for this analysis.
Pharmacodynamic Analyses
Change from Baseline in BMI will be assessed as the PD analysis.  The PD analysis set will be used 
for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% and 
≥10% BMI reduction, and change in waist circumference from baseline) will also be assessed as part 
of the PD analysis.  The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma 
exposure and response, including but not limited to change in BMI from baseline and the probability 
of achieving at least a 5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, 
exposure-safety relationships for select safety parameters may be explored graphically depending on 
the data at the end of study.  Any emergent relationship may be modeled as appropriate.  Any 
parameters based on the study data may be considered for exploratory assessment for its relationship 
to PK.
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Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the 
incidence of AEs (including changes from baseline in physical examination), growth (CDC growth 
chart and bone age determined by x-ray of the hand), sexual maturation (Tanner Staging), 
out-of-normal-range laboratory safety test values, change from baseline in laboratory safety test 
values, ECGs, and vital sign measurements will be summarized by treatment group using descriptive 
statistics or frequency count as appropriate.  In addition, cognitive function will be evaluated by the
WRAML-2, depression will be evaluated by the PHQ-9, and suicidal ideation and behavior will be 
evaluated by the C-SSRS, and will also be summarized by treatment group using descriptive statistics 
or frequency count as appropriate.
All WRAML-2 raw scores from the Core Battery will be 
converted to age and gender standard scores for purposes of intra individual comparisons. For 
echocardiographic assessments, the proportion of subjects who develop FDA-defined valvulopathy, 
the proportion of subjects who develop pulmonary hypertension [pulmonary hypertension is defined 
when the subject’s systolic pulmonary artery pressure (SPAP) ≥40 mmHg evaluated by 
echocardiograph], and change from baseline in SPAP will be summarized by treatment group at 
Week 28 and Week 52 using descriptive statistics or frequency count as appropriate.
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in 
BMI from Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  
Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 360 subjects in a 1:1 ratio 
(n=180 in the Belviq XR 20-mg treatment group; n=180 in the placebo group) will have at least 
90% power to detect a treatment difference of 1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  
Assuming the proportion of subjects achieving at least a 5% BMI reduction at Week 52 is 20% for 
the placebo group and a 40% dropout rate, this sample of 360 subjects (180 subjects for Belviq XR 
20 mg and 180 subjects for placebo) will also have greater than 85% power to detect an absolute 
difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 2-sided 
Fisher’s Exact test with α=0.05. The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic 
adult subjects.
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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................17
5
ETHICS.......................................................................................................................19
5.1
Institutional Review Boards/Independent Ethics Committees.............................19
5.2
Ethical Conduct of the Study..............................................................................20
5.3
Subject Information and Informed Consent ........................................................20
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................22
7
INTRODUCTION.......................................................................................................23
7.1
Indication...........................................................................................................23
7.1.1
APD356/Belviq (lorcaserin hydrochloride)...............................................24
7.1.1.1
Mechanism of Action........................................................................24
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride) ..................................................................................24
7.1.2
Study Rationale ........................................................................................25
8
STUDY OBJECTIVES................................................................................................27
8.1
Primary Objective ..............................................................................................27
8.2
Secondary Objectives.........................................................................................27
9
INVESTIGATIONAL PLAN ......................................................................................29
9.1
Overall Study Design and Plan...........................................................................29
9.1.1
Prerandomization/Pretreatment Phase.......................................................29
9.1.1.1
Screening Period...............................................................................29
9.1.2
Randomization/Treatment Phase ..............................................................30
9.1.3
Extension Phase .......................................................................................30
9.2
Discussion of Study Design, Including Choice of Control Groups......................30
9.3
Selection of Study Population ............................................................................31
9.3.1
Inclusion Criteria......................................................................................31
9.3.2
Exclusion Criteria.....................................................................................31
9.3.3
Removal of Subjects From Therapy or Assessment ..................................35
9.4
Treatments.........................................................................................................35
9.4.1
Treatments Administered..........................................................................35
9.4.2
Identity of Investigational Product............................................................35
9.4.2.1
Chemical Name, Structural Formula of Belviq XR ...........................35
9.4.2.2
Comparator Drug..............................................................................35
9.4.2.3
Labeling for Study Drug ...................................................................35
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9.4.2.4
Storage Conditions ...........................................................................36
9.4.3
Method of Assigning Subjects to Treatment Groups.................................37
9.4.4
Selection and Timing of Dose for Each Subject........................................37
9.4.5
Blinding ...................................................................................................37
9.4.6
Prior and Concomitant Therapy................................................................37
9.4.7
Treatment Compliance .............................................................................38
9.4.8
Drug Supplies and Accountability ............................................................39
9.5
Study Assessments.............................................................................................40
9.5.1
Assessments .............................................................................................40
9.5.1.1
Demography.....................................................................................40
9.5.1.2
Baseline Assessments .......................................................................41
9.5.1.2.1
Medical History ..........................................................................41
9.5.1.3
Efficacy Assessments .......................................................................41
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................41
9.5.1.4.1
Pharmacokinetic Assessments.....................................................41
9.5.1.4.2
Pharmacodynamic Assessments..................................................42
9.5.1.4.3
Pharmacogenomic and Other Biomarker Assessments ................42
9.5.1.5
Safety Assessments...........................................................................42
9.5.1.5.1
Adverse Events and Events Associated with Special Situations...43
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................45
9.5.1.5.3
Laboratory Measurements...........................................................46
9.5.1.5.4
Vital Signs and Weight Measurements........................................48
9.5.1.5.5
Height Measurements .................................................................48
9.5.1.5.6
Physical Examinations ................................................................48
9.5.1.5.7
Electrocardiograms .....................................................................48
9.5.1.5.8
Echocardiogram..........................................................................48
9.5.1.5.9
Other Safety Assessments ...........................................................49
9.5.1.6
Other Assessments............................................................................50
9.5.1.6.1
Pregnancy Test ...........................................................................50
9.5.1.6.2
Urine Drug and Cotinine Test .....................................................50
9.5.2
Schedule of Procedures/Assessments........................................................50
9.5.2.1
Schedule of Procedures/Assessments................................................50
9.5.2.2
Description of Procedures/Assessments Schedule .............................54
9.5.2.3
Total Volume of Blood Sampling .....................................................54
9.5.3
Appropriateness of Measurements............................................................54
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9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................55
9.5.4.1
Reporting of Serious Adverse Events................................................55
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding....................................................................................55
9.5.4.3
Reporting of Events Association with Special Situations...................56
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error...........................56
9.5.4.3.2
Reporting of Study-Specific Events.............................................57
9.5.4.4
Expedited Reporting .........................................................................57
9.5.4.5
Breaking the Blind............................................................................57
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................58
9.5.5
Completion/Discontinuation of Subjects...................................................58
9.5.6
Abuse or Diversion of Study Drug............................................................58
9.5.7
Confirmation of Medical Care by Another Physician................................59
9.6
Data Quality Assurance......................................................................................59
9.6.1
Data Collection.........................................................................................59
9.6.2
Clinical Data Management .......................................................................59
9.7
Statistical Methods.............................................................................................60
9.7.1
Statistical and Analytical Plans.................................................................60
9.7.1.1
Study Endpoints................................................................................60
9.7.1.1.1
Primary Efficacy Endpoint..........................................................60
9.7.1.1.2
Secondary Efficacy Endpoints.....................................................60
9.7.1.2
Definitions of Analysis Sets..............................................................61
9.7.1.3
Subject Disposition...........................................................................61
9.7.1.4
Demographic and Other Baseline Characteristics..............................62
9.7.1.5
Prior and Concomitant Therapy ........................................................62
9.7.1.6
Efficacy Analyses.............................................................................62
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................63
9.7.1.7.1
Pharmacokinetic Analyses ..........................................................63
9.7.1.7.2
Pharmacodynamic Analyses........................................................63
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses.............................64
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses......................64
9.7.1.8
Safety Analyses ................................................................................64
9.7.1.8.1
Extent of Exposure......................................................................64
9.7.1.8.2
Adverse Events...........................................................................65
9.7.1.8.3
Laboratory Values.......................................................................66
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9.7.1.8.4
Vital Signs ..................................................................................66
9.7.1.8.5
Electrocardiograms .....................................................................67
9.7.1.8.6
Other Safety Analyses.................................................................67
9.7.2
Determination of Sample Size ..................................................................67
9.7.3
Interim Analysis.......................................................................................68
9.7.4
Other Statistical/Analytical Issues ............................................................68
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................68
10
REFERENCE LIST.....................................................................................................69
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......71
11.1
Changes to the Protocol......................................................................................71
11.2
Adherence to the Protocol..................................................................................71
11.3
Monitoring Procedures.......................................................................................71
11.4
Recording of Data..............................................................................................72
11.5
Identification of Source Data..............................................................................72
11.6
Retention of Records..........................................................................................73
11.7
Auditing Procedures and Inspection ...................................................................73
11.8
Handling of Study Drug .....................................................................................73
11.9
Publication of Results ........................................................................................74
11.10 Disclosure and Confidentiality ...........................................................................74
11.11 Discontinuation of Study....................................................................................74
11.12 Subject Insurance and Indemnity........................................................................75
12
APPENDIX.................................................................................................................76
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests........................................................................47
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403.........51
Table 3
Summary of Blood Sample Volumes......................................................54
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
MAR
missing at random
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Abbreviation
Term
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PHQ-9
The Patient Health Questionnaire
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
RVOTAT
right ventricular outflow tract
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SPAP
systolic pulmonary artery pressure  
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TR
tricuspid regurgitation
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
WRAML-2
Wide Range Assessment of Memory and Learning-2
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity
Obesity has become a global epidemic in western civilization, causing a serious public health 
concern.  In the United States, the prevalence of obesity in adolescents ages 12 and 19 years
has almost doubled over the past 2 decades.  The rate increased from 10.5% between 1988 
and 1994 to 20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, 
defined in the United States as greater than or equal to the 95th percentile in gender- and 
age-specific body mass index (BMI), continues to grow at an alarming rate in the United 
States and globally.  Based on data (Wang and Lobstein, 2006) using various criteria for the 
definition of obesity that included more than 30 countries in Europe, North America, Asia, 
and the West Pacific, prevalence of obesity in these countries has also increased 
significantly, at a rate comparable to that in the United States.
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may 
result in a decrease in life expectancy for the 1st time in 200 years (Peeters, et al., 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese adolescents are likely to become 
tomorrow’s obese adults (Whitaker, et al., 1997).
Current approaches to weight management in adults include lifestyle modification, 
pharmacotherapy, and invasive bariatric procedures.  Lifestyle modification involves a 
combination of diet, exercise, and behavioral change, and is the preferred and essential 
strategy for weight management in obese and overweight individuals, including adolescents.  
Although lifestyle modification can be very efficacious in some patients, adherence to the 
prescribed regimens is often poor.  As such, lifestyle modification alone is often not adequate 
and the weight loss is often transient.  On the other hand, bariatric surgery and various other 
invasive procedures are generally reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise, but are rarely used
for adolescents.
The current standard of care for treatment of obesity in adolescent subjects ranges from
behavioral therapy including lifestyle intervention to the rare use of pharmacotherapy in 
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adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies that will be 
used in the present study to help retain participants.  These include a highly trained and 
competent staff, ample waiting area, readily available parking (at no cost), access to mass 
transit, and reminder and follow-up calls.  In addition, we will provide fun and interactive 
group sessions with games and hands-on nutrition and physical activity demonstrations, 
random raffle drawings, social events, birthday and holiday cards, and newsletters.  
Furthermore, we will make home visits for assessments of families, as needed, to maximize 
data collection. 
By using these retention strategies, we hope that we will maximize 
participant retention, which will help us cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:

A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) 
was significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
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weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
used for adolescent subjects with body weight greater than 60 kg.
In adolescent obese populations, it is anticipated that Belviq XR will result in similar effects.
As part of FDA postmarketing requirements, this study is designed to characterize the 
efficacy and safety of Belviq XR in adolescent obese populations in the United States.  It is 
also intended to support an indication for chronic weight management for obese adolescents 
ages 12 to 17 years old. 
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of 
subjects in the placebo-treated group who lose at least 5% of baseline body weight, 
and the difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in obese adolescents, where weight loss will be assessed using BMI
measurements to account for growth. In this study, the objective is to demonstrate that BMI
reduction will be achieved during 52 weeks of treatment with Belviq XR 20 mg administered 
once daily (QD) compared to placebo in obese adolescents.
In the Phase 3 orlistat study in obese adolescents mentioned above, the proportion of subjects 
who lost at least 5% body weight is relatively low. At the end of the study at Week 52, only 
26.5% of the subjects achieved a 5% or greater BMI reduction compared to 15.7% in the 
placebo group. The placebo-corrected BMI reduction was about 0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years
(Peirson, et al, 2015).  Thirty-one studies (29 behavioral, 2 pharmacological and behavioral) 
were included in a meta-analysis of randomized studies conducted in primary care centers in 
overweight and obese children and youth ages 2 to 18 years using behavioral (diet, exercise,
and lifestyle) and pharmacological interventions and providing 6-month postbaseline BMI or 
prevalence of overweight or obesity. Both interventions showed a significant effect on BMI 
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in favor of treatment (behavioral: 
standardized mean difference [SMD] -0.54, 
95% confidence interval [CI] -0.73, -0.36; orlistat plus behavioral: SMD -0.43, 95% CI -
0.60, -0.25). The studies reported no significant difference between groups in the likelihood 
of reduced prevalence of overweight or overweight and obese. A great deal of variation was 
noted across efficacious interventions.
In conclusion, this meta-analysis demonstrated
low-quality evidence that behavioral treatments alone are associated with a smaller effect in 
terms of reduced BMI compared with the effect shown by combined behavioral and
pharmacological interventions. This may be because the effect size in the randomized,
double blind, placebo controlled, phase 3 orlistat study in adolescents was relatively low and 
there was a lack of maintenance effect. These subjects started to regain their BMI after 
6 months of treatment. At end of the study, only 26.5% of subjects achieved a 5% or greater
BMI reduction compared to 15.7% in placebo group. In a sibutramine Phase 3 study in obese 
adolescents, a substantially higher proportion of subjects (69%) treated with sibutramine 
achieved at least a 5% BMI reduction compared to 21% of subjects in the placebo group. In 
addition, sibutramine resulted in a substantial reduction in mean BMI (between-group 
difference, 2.9 kg/m2) and mean weight (between-group difference, 8.4 kg) compared to 
placebo (Berkowitz, et al, 2006).  Unlike the weight loss effect of Belviq in adults and 
sibutramine in adolescents, subjects in the orlistat study started to increase their BMI after 
6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of 360 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
and sibutramine) (FDA, 2003; Chanoine, et al, 2005; Berkowitz, et al, 2006) and other 
metabolic or dyslipidemia medication products (ezetimibe, simvastatin) (FDA, 2007).
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8
STUDY OBJECTIVES
8.1
Primary Objective
To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of 
subjects with at least a 5% reduction in BMI after an initial 12 weeks of treatment 
with Belviq XR 20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 
12 weeks of treatment with Belviq XR 20 mg administered QD is predictive of 
sustained change in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
• Other weight loss effects (eg, proportion [%] of subjects achieving at least a 
10% BMI reduction, change in waist circumference) at the end of 52 weeks 
of treatment
• Effects on glycemia, insulin levels, and Homeostatic Model Assessment of 
Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L]/405)
during 52 weeks of treatment
• Changes 
in 
cardiovascular 
risk 
factors 
associated 
with 
obesity 
(eg, hypertension, dyslipidemia) including fasting lipid changes (total 
cholesterol, triglycerides, high density lipoprotein [HDL], and low density 
lipoprotein [LDL]) during 52 weeks of treatment
•
To assess the safety of Belviq XR, including the effects on cognitive function by 
Wide Range Assessment of Memory and Learning-2 (WRAML-2), on depression by 
the Patient Health Questionnaire (PHQ-9), on signal of suicidal ideation or behavior 
with the Columbia-Suicide Severity Rating Scale (C-SSRS), on growth measured by 
CDC growth chart, on sexual maturation (pubescence) measured by Tanner Staging 
scores, and on other growth and development parameters by measuring sex 
hormones, thyroid function, valvular function, pulmonary arterial pressure, adrenal 
function, bone age, and biochemical markers of bone health assessments
•
To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling
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•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
probability of achieving at least a 5% and at least a 10% reduction in BMI from 
baseline at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents ages 12 to 17 years.  Approximately 360 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will be 
stratified by sex.  Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up 
to 52 weeks. Throughout the duration of the study, subjects will be encouraged to adhere to 
a lifestyle modification program that includes a standardized, age-appropriate diet and
exercise counseling (see Appendix 2).  
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.
9.1.1
Prerandomization/Pretreatment Phase
Screening will occur during the Prerandomization Phase at Visit 1
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
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9.1.2
Randomization/Treatment Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025.  Overall, the PK parameters of Belviq and its main 
metabolites, M1 and M5, were similar to those in adults.  Following a single, oral 
administration of Belviq 10 mg to a total of 8 healthy adolescent (ages 12 to 17 years old) 
obese subjects, the mean maximum concentration observed and the area under the 
concentration-time curve from time zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 
464 hr×ng/mL, respectively.  The mean Belviq terminal phase half-life was 9.70 hours, 
similar to that observed in adults, thus supporting a similar dosing frequency (QD) in 
adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric or adolescent subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of subjects who are older than 12 years of age 
having a body weight of less than 60 kg is very low; therefore, the current study as designed 
to enroll subjects between 12 to 17 years of age with body weight at least 60 kg, will cover
majority of the population of interest.  The targeted study population comprises 360 obese 
adolescents 12 to 17 years of age, with a body weight at least 60 kg.
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
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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, 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 700 subjects will be screened to ensure that 360 subjects will be randomized.
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug. Subjects who screen fail can be re-screened only once after 
60 days.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, ages 12 to 17 years old at Screening, with a BMI 
that is greater than or equal to the United States (US)-weighted mean of the 
95th percentile based on age and sex with a body weight greater than 60 kg
2. Subjects and their families are not planning to move away from the area for the 
duration of the study
3. Subjects able and willing to comply with all aspects of the study, including a 
standardized, reduced-calorie diet and an age-appropriate, increased physical activity 
program
4. Subjects considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may 
affect the subject’s ability to fulfill the study requirements or significantly confound 
the assessments
2. Subjects who cannot swallow investigational products
3. Any of the following findings on screening echocardiography:

Aortic regurgitation mild or greater
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
Mitral regurgitation moderate or greater

Mitral or aortic valve stenosis greater than mild (ie, aortic stenosis [AS]: 
jet >3.0 m/s, mean gradient >25 mm Hg, and aortic valve area [AVA] 
<1.5 cm2; MS: mean gradient >5 mm Hg and mitral valve area [MVA] 
<1.5 cm2)

Systolic pulmonary artery pressure (SPAP) >40 mm Hg (and/or tricuspid 
regurgitation (TR) jet velocity >2.9 m/s)
-
In cases where an actual SPAP value is not measurable due to lack of 
adequate TR jet, the pulmonary flow acceleration time measured at the 
right ventricular outflow tract (RVOTAT), will be used to assess 
eligibility. Patients with a RVOTAT ≤100 msec will be excluded, 
suggesting an elevated mean SPAP; eligibility for the those patients with 
RVOTAT between 100 and 120 msec will be determined based on 
combined assessment of the TR jet, septal motion and right ventricular 
size.

Left ventricular ejection fraction <45%

Intracardiac mass, tumor or thrombus

Evidence of congenital heart disease

Clinically significant pericardial effusion (eg, moderate or larger or with 
hemodynamic compromise)
4. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
5. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or 
schizophrenia
6. Known secondary causes (chromosomal, endocrine, or metabolic) for obesity 
(eg Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for 
longer than 30 days, history of significant exposure to corticosteroids for chronic 
illness during the past year, and known genetic causes of obesity)
7. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before 
Screening
8. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or
monoamine oxidase inhibitors (MAOIs) within 30 days before Randomization, 
including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 
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
bupropion

triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
9. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months 
before Screening, including but not limited to pergolide, ergotamine, methysergide, 
and cabergoline
10. History or evidence of clinically significant disease (eg, malignancy; cardiac, 
respiratory, gastrointestinal, renal, or psychiatric disease) other than prediabetes 
(impaired fasting glucose or impaired glucose tolerance), Type 2 diabetes treated with 
oral anti-diabetic agents (excluding sulfonylurea)
or
non-insulin injectable 
antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver 
disease
11. Use of Belviq XR within 6
months before Screening or hypersensitivity to 
Belviq XR or any of the excipients
12. Significant change in diet or level of physical activity within 1 month before dosing 
or change in weight of more than 5 kg within 3 months before Screening
13. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 
6 months before Screening
14. History of alcohol or drug dependence or abuse
15. Recreational drug use within 2 years before Screening
16. Known to be human immunodeficiency virus positive
17. Active viral hepatitis (B or C) as demonstrated by positive serology
18. Malignancy within 5 years before Screening
19. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
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20. Special needs subjects who are unable to comprehend study-related instructions 
(eg, mild to profound mental retardation [IQ <70], moderate to severe cognitive 
developmental delay, pervasive development disorders, autism)
21. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure 
disorder within 6 months of screening or any time between screening and 
randomization
22. Subjects with a BP in the 95th percentile or greater for age, sex, and height on 
2 separate readings recorded on 2 separate days.  Those subjects who had 
uncontrolled hypertension at Screening can be rescreened more than 1 month after 
initiation or adjustment of antihypertensive therapy 1 time.
23. Currently enrolled in another clinical study or has used any investigational drug or 
device within 30 days before providing informed consent
24. Planned bariatric surgery during the study
25. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
26. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
27. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do 
not agree to use a highly effective method of contraception (eg, total abstinence, 
an intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study 
period and for 28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexual activity during the study period and for 
28 days after study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do not 
agree to use the same contraceptive during the study and for 28 days after study 
drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD at 
approximately the same time each day.
Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled 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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The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal 
(US) law to investigational use.”
All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug 
was dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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 
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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.
Subjects will be centrally stratified by sex (male and female).  Within each stratum, subjects 
will be randomized to receive either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  
Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily at approximately the same time of 
every day, and be encouraged to take the study medication with an adequate amount of water 
(8 oz. or 240 mL).
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
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Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs
will review treatment compliance during site visits and at the completion of the study.
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
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9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 
(US sites only).  Must be appropriate to handle schedule IV products and not be 
expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
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shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
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9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.3
Efficacy Assessments

Body weight and height will be measured using a standard stadiometer
method (Lohman T, et al, 1988) to calculate changes in BMI; BMI will then 
be used to calculate the proportion (%) of patients achieving at least a 5% and 
at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, fasting lipids (total 
cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides), fasting 
plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and HOMA-IR to 
assess changes in cardiovascular and metabolic risk profiles from Baseline to 
Week 52
o
Prehypertension and primary hypertension as defined by the Expert 
Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children 
and Adolescents, 2011)
o
Dyslipidemia as defined by the Expert Panel on Integrated Guidelines 
for Cardiovascular Health and Risk Reduction in Children and 
Adolescents (Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents, 2011)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for population PK analyses.  All subjects will be instructed to take their study 
drug in the morning on the day before their scheduled clinic visit at Weeks 12, 28, 36, 
and 52.  No additional doses should be taken that day for those subjects who have been 
taking their doses in the evening.  Dose times must be recorded for the last 2 dosing times 
prior to the clinic visit.
On the day of the Week 12, 28, and 52 clinic visits, subjects will be instructed to take their 
study drug at approximately the same time as the morning before, with no additional doses 
taken that day.  Two blood samples for determination of plasma concentrations of lorcaserin 
will be taken at each of these visits: within 30 minutes before dosing and within 1 to 3 hours 
after dosing.  
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On the day of the Week 36 clinic visit, subjects will take their study drug at home in the
morning in the morning at home.  One blood sample for determination of plasma 
concentration of lorcaserin will be collected at the clinic within 4 to 6 hours after dosing.  
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
method coupled with tandem mass spectrometry method. The collection, handling, and 
shipping procedures for PK samples will be described in a manual to be provided to the study 
sites.
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS
Blood samples will be collected to determine lorcaserin plasma exposure and population 
PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure 
and following response to lorcaserin: 

Change from Baseline in BMI 

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in 
BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC AND OTHER BIOMARKER ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs);
electrocardiograms (ECGs);
laboratory evaluations
for hematology,
metabolic function (glucose, lipids, and thyroid), adrenal functions, and biochemical blood 
and urine bone health assessments; blood chemistry and urine values; neuropsychiatric 
events; periodic measurements of vital signs, neuromuscular signs for screening potential 
serotonin syndrome, and signs and symptoms of priapism and prolactinemia; and 
performance of physical examinations.  In subjects with potential prolactin-related AEs, such 
galactorrhea, changes in libido, or changes to menstrual cycle, prolactin level will be 
measured and assessed.  Study drug effect on growth of adolescents will be evaluated using 
the CDC growth chart at Baseline, and Weeks 5, 12, 28, 36, 52, and at Follow-Up; a full 
physical examination at Baseline, Weeks 12, 28, 52, and at Follow-Up; and bone age 
determination by x-ray of the hand at Baseline, Weeks 12, 28, and 52.  Sexual maturation 
will be evaluated by assessing sex hormones and self-reported changes in Tanner Staging at 
Baseline, Weeks 28 and 52, and at Follow-Up.
The C-SSRS will be used to assess all subjects in the study for any signal of depression or 
suicidal ideation or behavior.  Additionally, screening, diagnosing, monitoring, and 
measuring the severity of depression will be assessed using the PHQ-9 and effects on 
cognitive function will be assessed using WRAML-2.
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Echocardiographic assessments will be used to exclude subjects with FDA-defined 
valvulopathy, pulmonary hypertension, and other major cardiovascular disease (as outlined in 
Exclusion Criterion No. 3) during the Screening Period.  Additionally, cardiac valvular 
function and pulmonary systolic pressure changes at Weeks 28 and 52 will be assessed.  
Valvular regurgitation as assessed in the echocardiogram will be rated absent, trace, mild, 
moderate, or severe for the aortic, mitral, and tricuspid valves; the rating will be absent or 
present for the pulmonic valve. The evaluations will be based on guidelines from the 
American Society of Echocardiography. Pulmonary artery pressure will be estimated from 
the tricuspid regurgitant jet velocity.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs,
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
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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 (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
It is the responsibility of the investigator to review the results of the C-SSRS, PHQ-9, and 
WRAML-2 in all subjects and determine if any result constitutes an AE.  Medical and 
scientific judgment should be exercised in deciding whether an isolated suicidality rating 
scale response should be classified as an AE (see Section 9.5.1.5.9 for a description of the 
C-SSRS).
All AEs must be followed for 28 days after the subject’s last dose or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of 
the event
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•
The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious 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 onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin
•
Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study specific event 
does not meet serious criteria.  If the event meets seriousness criteria, it should be reported as 
an SAE as above.  However, if the event listed below does not meet serious criteria, it should 
be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation   

Euphoria 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for 
administration of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was 
in place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
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points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function
T4, TSH
Adrenal function
Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects), 
Bone health assessments
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other
Albumin, calcium, globulin, glucose, HbA1c, HDL cholesterol, 
lactate dehydrogenase, LDL cholesterol, phosphorus, total protein,
total cholesterol, triglycerides, prolactin, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
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9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2).  
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical
examinations 
will 
be 
performed 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2).  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.
9.5.1.5.7
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.8
ECHOCARDIOGRAM
Echocardiograms will be obtained on the Schedule of Procedures/Assessments (Table 2). 
Valvular regurgitation in echocardiogram will be rated absent, trace, mild, moderate, or 
severe for the aortic, mitral, and tricuspid valves; the rating will be absent or present for the 
pulmonic valve. The evaluations will be based on guidelines from the American Society of 
Echocardiography. Pulmonary artery pressure will be estimated from the tricuspid 
regurgitant jet velocity.
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9.5.1.5.9
OTHER SAFETY ASSESSMENTS
WRAML-2
The WRAML-2 administration will consist of the Core Battery, which provides scores on 
Verbal Memory, Visual Memory, and Attention/Concentration.  There are 6 subtests (2 for 
each area).
The tests provide standardized scores based on age and gender, and are 
appropriate for ages 5 to 90 years.  The WRAML-2 will be used to assess lorcaserin effects 
on cognitive function. In addition, signs and symptoms of cognitive related AEs, including 
impairments in attention, memory, and adverse effects on schoolwork will be captured in the 
eCRF.
PHQ-9
The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and 
measuring the severity of depression:

The PHQ-9 incorporates Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition (DSM-IV) depression diagnostic criteria with other leading major depressive 
symptoms into a brief self-report tool.

The tool rates the frequency of the symptoms which factors into the scoring severity 
index.

Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation.

A follow-up, non-scored question on the PHQ-9 assigns weight to the degree to 
which depressive problems have affected the patient's level of function. 
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. It will be performed at Baseline and at study 
visits as designated in the Schedule of Procedures/Assessments (Table 2).
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will be captured in the eCRF.
Hand X-Ray will be evaluated for any potential negative effect on bone age as designated in 
the Schedules/Assessments (Table 2). 
Neuromuscular sign assessment for serotonin 
syndrome will be performed as designated in the Schedule of Procedures/Assessments 
(Table 2) to screen for potential serotonergic syndrome components. 
Serotonergic 
syndromes that meet the diagnostic criteria will be captured by AE eCRF.
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9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at designated time points as 
specified in the Schedule of Procedures/Assessments (Table 2).
9.5.1.6.2
URINE DRUG AND COTININE TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 2).  This sample will be tested for common 
drugs 
of 
use/abuse 
(eg, 
ethyl 
alcohol, 
cocaine, 
cannabinoids, 
phencyclidine, 
nicotine/cotinine, opioids [as a group], benzodiazepines, barbiturates, amphetamines).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examinationd
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, Fasting Insulin, HOMA-
IR, and HbA1c sampling
X
X
X
X
X
X
T4 and TSH
X
X
X
X
AM serum cortisol
X
X
Testosterone, Estradiol
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Pregnancy test (Urine)
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
Echocardiograph
Xf
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
WRAML-2
X
X
X
X
X
X
PHQ-9
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Urine NTX
X
X
X
PK/PD blood sampling
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Prolactin
X
X
X
X
Standardized age-appropriate lifestyle 
modification counselinge
X
X
X
X
X
X
X
X
X
X
AE = adverse event, AM = morning; CDC = Centers for Disease Control and Prevention, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, EOS 
= End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, HOMA-IR = Homeostatic Model Assessment of Insulin Resistance, IxRS = interactive voice or web 
response system, NTX = N-telopeptide, OC = osteocalcin; PHQ-9 = The Patient Health Questionnaire, PICP = carboxyterminal propeptide of type I procollagen,  PK = 
pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone, WRAML-2 = Wide Range Assessment of Memory and Learning-2.
a:
Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b:
Window ±7 days for all visits after Visit 2 except for Weeks 12 and 28 (the window for these visits will be broader at ±14 days). Week is shown unless otherwise 
indicated.
c:
On the day of the Week 12, 28, and 52 clinic visits, subjects will take their morning dose of study drug on the day before their scheduled clinic visit.  On the day of the 
clinic visit, subjects will be instructed to take their study drug at approximately the same time as the morning before, with no additional doses taken that day.  Two 
blood samples for determination of plasma concentrations of lorcaserin will be taken: predose (within 30 minutes before dosing) and within 1 to 3 hours after dosing. 
On the day of the Week 36 clinic visit, subjects will take the morning dose at home, and 1 blood sample for determination of plasma concentrations of lorcaserin will be 
collected at the investigational site within 4 to 6 hours after dosing.  Dose times must be recorded for the last 2 dosing times prior to the clinic visit.
d:
Includes a neuromuscular assessment
e:
Lifestyle modification counseling will also be performed at Weeks 3, 24, 32, 40, and 48 in addition to counseling at the scheduled visits in Table 2.
f:
Echocardiographic
assessments
will be performed during screening period after subjects have met all other inclusion and exclusion criteria.
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
12
Screening: 1
Visits 2, 3, 4, 6, 8; 11/EOT, EOS
128=96
T4, TSH, Cortisol, 
Testosterone, estradiol, 
Serum OC and PICP, 
Hydroxy-proline; Fasting 
prolactin levels
10
Screening:  1
Visits  8; 11/EOT/Early 
discontinuation
10×3=30
Prolactin, FPG, Insulin, and 
HbA1c sampling
4
Screening:  1
Visits 2, 6, 8; 11/EOT/Early 
discontinuation
4×5=20
PK/PD blood sampling
4
Visits 6, 8, and 11/EOT/Early 
discontinuation (2 samples each);
Visit  9 (1 sample only)
7×4=28
Total
174
EOS = End of Study; EOT = End of Treatment; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; OC = osteocalcin;
PD = pharmacodynamic; PICP = carboxyterminal propeptide of type I procollagen; PK = pharmacokinetics; T4 = thyroxine; 
TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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.
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration,
education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
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AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin

Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study-specific 
event does not meet serious criteria.  If the event meets seriousness criteria, it should 
be reported as an SAE as above.  However, if the event listed below does not meet 
serious criteria, it should be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation

Euphoria 
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 
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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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue treatment prematurely will be followed up until study completion.  
All subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 2).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
Detailed retention strategies will be developed and included in study manual. These include 
a highly trained and competent staff, easy access to the clinic, reminder and follow-up calls, 
interactive group sessions with games and hands-on nutrition and physical activity 
demonstrations, random raffle drawings, social events, birthday and holiday cards, and
newsletters. In addition, home visits for assessments of families will be an option, as needed, 
to maximize data collection. This detailed retention plan will help prevent missing data.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.  The DEA Registrant has 
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the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from Baseline to Week 52 and proportion (%) 
of subjects achieving at least a 5% or 10% BMI reduction at Week 52 by the outcome 
of achieving at least a 5% BMI reduction at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52
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
Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 
80% or greater compliant with study medication, completed the study, have no major 
protocol deviations, have no violations of inclusion or exclusion criteria, and have 
BMI data at Baseline and Week 52.  The determination of subjects to be excluded 
from this population based on the above criteria and list of major protocol violations 
will be included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at 
least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 
1 valid lorcaserin plasma concentration was obtained with associated documented 
dosing history.

The population PK/PD set is the group of randomized subjects with PK information 
and who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
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9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using the repeated measures analysis of covariance 
model (ANCOVA) with factors of treatment, visits (Baseline, Week 1, 5, 8, 12, 20, 28, 36, 
44, and 52), sex (male and female), treatment-by-visit interaction as fixed effect, subjects as 
random effect, and the baseline age and BMI as covariates.  The missing values will be 
imputed using a pattern mixture model utilizing multiple imputation (MI) using the same 
model as the analysis model.  The missing values will be imputed for a visit at a time using 
the complete cases up to and include the current visit for a particular visit.  The unstructured 
covariance matrix will be used in the analysis and the treatment comparison at Week 52 will 
be the event of interest.  In case of a convergence issue, the Toeplitz covariance structure will 
be used in the model.  As a sensitivity analysis, the missing values will also be imputed using 
pattern mixture MI method assuming the missing value is missing not at random (MNAR). 
The details of the analysis model and missing value imputation method will be further 
described in the SAP.
In addition, the following analyses will also be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated 
based on the PP.

Change from baseline in standardized BMI score (Z-score):
The same primary 
efficacy analyses described above will be repeated using Z-score.
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Subgroup analyses and additional sensitivity analyses, if appropriate, may also be performed 
and will be described in the SAP.  
Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, and sex (male and 
female), and baseline BMI as a covariate using FAS.  Subjects with any missing assessment 
at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using mixed effect model repeated measurement analysis (MMRM) and categorical
variables will be analyzed using the Cochran Mantel Haenszel test, Chi-square test, or 
logistic regression as appropriate.  Additional analysis may be performed as needed using 
appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including sex (male 
and female), race (white, black, Asian, and other). Additional subgroups may be explored, if 
deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Change from Baseline in BMI will be assessed as the PD analysis.  The PD analysis set will 
be used for this analysis.
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Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also be 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination), 
growth (CDC growth chart and bone age determined by x-ray of the hand), sexual maturation 
(Tanner Staging), out-of-normal-range laboratory safety test values, change from baseline in 
laboratory safety test values, ECGs, and vital sign measurements will be summarized by 
treatment group using descriptive statistics or frequency count as appropriate.  In addition, 
cognitive function will be evaluated by the WRAML-2, depression will be evaluated by the 
PHQ-9, and suicidal ideation and behavior will be evaluated by the C-SSRS, and will also be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
All WRAML-2 raw scores from the Core Battery will be converted to age and gender 
standard scores for purposes of intra individual comparisons.  For echocardiographic 
assessments, the proportion of subjects who develop FDA-defined valvulopathy, the 
proportion of subjects who develop pulmonary hypertension [pulmonary hypertension is 
defined when the subject’s systolic pulmonary artery pressure (SPAP) ≥40 mmHg evaluated 
by echocardiograph], and change from baseline in SPAP will be summarized by treatment 
group at Week 28 and Week 52 using descriptive statistics or frequency count as appropriate.
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
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Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No 
[not related])
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
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The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit
and treatment group.
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9.7.1.8.5
ELECTROCARDIOGRAMS
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and 
greater than 60 msec from the baseline visit.
9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including adolescent growth evaluations using 95th percentile CDC 
growth charts and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, neuromuscular sign assessment for serotonin syndrome, signs and symptoms of 
priapism and prolactinemia, study drug effect on cognitive function assessed by WRAML-2, 
assessment of suicidality using C-SSRS, and depression assessment using PHQ-9 will be 
summarized by treatment group at each scheduled visit.  For echocardiographic assessments, 
the proportion of subjects who develop FDA-defined valvulopathy, the proportion of subjects 
who develop pulmonary hypertension (defined as when a subject’s SPAP is ≥40 mmHg 
evaluated by echocardiograph], and change from baseline in SPAP will also be summarized 
by treatment group at Week 28 and Week 52.
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
360 subjects in a 1:1 ratio (n=180 in the Belviq XR 20-mg treatment group; n=180 in the 
placebo group) will have at least 90% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 360 subjects (180 subjects for Belviq XR 20 mg and 180 subjects for placebo) 
will also have greater than 85% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Fisher’s Exact test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.
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9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.Lohman T, Roche 
AF, Martorell R. 
Anthropometric Standardization Reference Manual.  Champaign, IL:  
Human Kinetics Books; 1988.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials.
J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux 
L.  NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A Life-
Table Analysis. Ann Intern Med. 2003; 138:24-32.
Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
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Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al.
A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
Whitaker RC, et al. Predicting obesity in young adulthood from childhood and parental 
obesity. N Engl J Med. 1997 Sep 25;337(13):869-73.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will be 
encouraged to participate in a standardized weight management program for adolescents 
consisting of multicomponent behavior therapy.  The therapy will focus on healthy eating, 
physical activity, and lifestyle changes that will facilitate weight loss and weight-loss 
maintenance. The role of the caregivers is to support their child or adolescents’ lifestyle 
changes and their taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress 
but caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neuroscience Business Group
Eisai Inc.
Date
Eisai Inc.
Date
Neuroscience Business Group
Eisai Inc.
Date
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PPD
PPD
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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Clinical Study Protocol
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Page i of v
Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, and 
formatting changes 
Throughout
Prehypertension was 
deleted from the 
inclusion criterion.  
Subjects with Stage 1 
primary 
hypertension, with an
upper limit defined as 
99% plus 5 mmHg 
for age, sex, and 
height are included in 
the study. 
Prehypertension does not 
qualify as a comorbid 
condition.  The limitation 
on BP is to further define 
the proper study 
population.
Synopsis
•
Inclusion Criteria
Section 9.3.1
Removed the 
restriction that 
subjects need to have 
less than 44 kg/m2
BMI for study entry
Per United States Food and 
Drug Administration 
(FDA) request
Synopsis
•
Inclusion Criteria
•
Analysis Sets
•
Pharmacodynamic Analyses
•
Pharmacokinetic/Pharmacodynamic 
Analyses
Section 9.3.1
Section 9.7.1.7.2
Section 9.7.1.7.3
Removal of study 
entry requirement 
that the caregiver 
cannot have a history 
of ADD, substance 
abuse, depression, 
suicidal 
ideation/behavior, 
bipolar disorder, or 
schizophrenia  
Per United States Food and 
Drug Administration 
(FDA) request
Synopsis
•
Inclusion Criteria
Section 9.3.1
The secondary 
efficacy objective 
To explore the 
predictability of 12-week 
Synopsis
•
Secondary Efficacy Objectives
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Revision History
Previous Version (Revision): v2.0
Current Version (Revision):  v3.0
Date of Revisions: 14 Sep 2016
Change
Rationale
Affected Protocol Section(s)
and endpoint were 
revised
responders for long-term 
sustainable weight loss 
effect
•
Other Secondary Efficacy 
Endpoints
Section 8.2
Section 9.7.1.1.2
Subjects with 
symptoms or signs of 
cardiac valvular 
disease or pulmonary 
hypertension are not 
required to have 
further evaluation by 
centralized 
echocardiogram 
assessment.  In 
addition, no 
adjudication will be 
performed.  Local 
echocardiograms can 
be performed if 
deemed medically 
necessary by the 
investigator.
This change allows for the 
investigator to make the 
decision to perform local 
echocardiograms 
on 
a 
pediatric subject if deemed 
medically indicated rather 
than burden the subject to 
undergo 
a 
mandated, 
unnecessary procedure. 
Synopsis
•
Safety Assessments
Section 9.5.1.5
Updated study 
rationale
Clarification 
Section 7.1.1.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, and 
formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will 
replace the IR formulation in 
the United States market to 
support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to
include children ages 9 to 
17 years
Expand the age of the 
population due to the change of 
pediatric development strategy
A single dose pharmacokinetic 
study in pediatric obese subjects 
(APD356-A001-026) indicated 
that patients with body weight 
greater than or equal to 60 kg 
can be administered a dose 
similar to that given to adults 
and adolescents.  Based on 
Centers for Disease Control and 
Prevention (CDC) growth chart 
data, almost all subjects over 
9 years of age are likely to be at 
or over 60 kg body weight.  
Therefore, children age 9 to 
11 years have been included in 
the current study.
Title Page
Synopsis
•
Study Protocol Title
•
Objectives
•
Study Design
•
Inclusion Criteria
•
Assessments
•
Efficacy Analyses
•
Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.1
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.8
Section 9.7.1.6
Section 9.7.1.8
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Additional safety 
assessments including 
cognitive function, 
serotonin syndrome 
components, bone health 
and endocrine function, 
priapism, and symptoms 
associated with 
hyperprolactinemia were 
added.
Per United States Food and 
Drug Administration (FDA)
request
Synopsis

Efficacy Assessments

Pharmacokinetic 
Assessments

Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.8
Section 9.7.1.8
Section 9.7.1.8.1
Change to primary and 
key secondary endpoints
Per FDA request
Synopsis

Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary 
endpoint changed
Per FDA request
Synopsis

Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of 
study-specific adverse 
events
To provide clearer guidance for 
the correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and 
prohibited prior and 
concomitant therapies
For clarification
Synopsis

Exclusion Criteria

Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of 
adverse events
To provide clearer guidance for 
the correct reporting of adverse
events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Update to Introduction 
and to Completion/ 
Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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Page 1 of 85
1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction With Lifestyle Modification for Weight 
Loss in Obese Children and Adolescents, Age 9 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
v3.0
14 Sep 2016 (Revision)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use and all applicable 
local Good Clinical Practice (GCP) and regulations.  All required 
study documentation will be archived as required by regulatory 
authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.: APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the 
Efficacy and Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in 
Obese Children and Adolescents, Age 9 to 17 Years
Investigators
Unknown
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
Approximately 24 months from first subject enrolled to last subject’s last visit or last assessment 
Phase 4
Objectives
Primary Objective
To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks 
of treatment with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at 
least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD as compared to placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at 
least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg 
administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of 
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in BMI 
during 52 weeks of treatment with Belviq XR 20 mg administered QD.

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:

Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% BMI 
reduction, change in waist circumference) at the end of 52 weeks of treatment

Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin 
Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L] / 405) during 52 weeks of 
treatment
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
Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) during 52 weeks of treatment

To assess the safety of Belviq XR, including the effects on cognitive function by Wide Range 
Assessment of Memory and Learning-2 (WRAML-2), on mood by Children’s Depression 
Inventory 2 (CDI-2), on signal of suicidal ideation or behavior with the Columbia-Suicide 
Severity Rating Scale (C-SSRS), on growth measured by Centers for Disease Control and 
Prevention (CDC) growth chart, on sexual maturation measured by Tanner Staging scores, 
and on other growth and development parameters by measuring sex hormones, thyroid 
function, adrenal function, bone age, and biochemical markers of bone health.

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) 
parameters including but not limited to reduction from baseline in BMI and probability of 
achieving at least a 5% and at least a 10% reduction in BMI from baseline at Week 52 using 
population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese 
children and adolescents, ages 9 to 17 years.  Approximately 360 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will be 
stratified by age group and sex.  At least 30% of the total subjects should be ages 9 to 11 years.  
Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout 
the duration of the study, subjects will be encouraged to adhere to a lifestyle modification program 
that includes diet and exercise counseling.
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization 
Phase will last up to 30 days and consist of 1 visit during which subjects will be screened for 
eligibility.  The Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The 
Treatment Period will last for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36,
44, and 52.  The Follow-Up Period will extend from the End of Treatment visit to the End of Study 
visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will continue in the 
study until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely 
will be followed up until study completion.  
Number of Subjects
Approximately 700 subjects will be screened to provide 360 randomized subjects.
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that is 
greater than or equal to the United States (US)-weighted mean of the 95th percentile based on 
age and sex with a body weight greater than 60 kg
OR
Otherwise healthy male or female children, age 9 to 11 years at Screening, with a BMI that is 
greater than or equal to US-weighted mean of the 99th percentile based on age and sex, and a 
body weight greater than 60 kg associated with at least 1 co-morbid weight-related condition
(eg, type 2 diabetes mellitus, hypertension, dyslipidemia)
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
Type 2 Diabetes as defined by American Diabetes Association Standards of Diabetes 
Care, 2013.

Stage 1 primary hypertension (blood pressure in the 95th to 99th percentile plus 5 mmHg 
for age, sex, and height) as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents (Expert Panel on 
Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and 
Adolescents, 2011) during the Screening Period

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011).
2.
Subjects and their families not planning to move away from the area for the duration of the 
study
3.
Subjects able and willing to comply with all aspects of the study, including a reduced-calorie 
diet and an increased physical activity program
4.
Subjects considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the 
subject’s ability to fulfill the study requirements or significantly confound the assessments
2.
Subjects who cannot swallow investigational products
3.
Documented pulmonary hypertension by objective assessments (ie, imaging modality or 
cardiac catheterization)
4.
Known valvular disease defined by clinical diagnosis or most recent echocardiography.  
History of valvular disease is allowed if it has been corrected by valve replacement or repair.
5.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper 
limit of normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater 
than 1.5×ULN in absence of Gilbert’s syndrome
6.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or schizophrenia
7.
Known 
secondary 
causes 
(chromosomal, 
endocrine, 
or 
metabolic) 
for 
obesity 
(eg,
Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 
30 days, history of significant exposure to corticosteroids for chronic illness during the past 
year, known genetic causes of obesity)
8.
Use of other products intended for weight loss including prescription drugs, over-the-counter 
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(OTC) drugs, and herbal preparations within 1 month before Screening 
9.
Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
10. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and cabergoline
11. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), type 2 diabetes treated with oral anti-diabetic agents 
(excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive sleep 
apnea, dyslipidemia, and nonalcoholic fatty liver disease
12. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any 
of the excipients
13. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
14. Any use of a very-low-calorie (<1000 calories/day) weight loss diet within 6 months before 
Screening
15. History of alcohol or drug dependence or abuse
16. Recreational drug use within 2 years before Screening
17. Known to be human immunodeficiency virus positive
18. Active viral hepatitis (B or C) as demonstrated by positive serology
19. Malignancy within 5 years before Screening
20. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
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guardian to supervise study participation
21. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to 
profound mental retardation [IQ <70], moderate to severe cognitive developmental delay, 
pervasive development disorders, autism)
22. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
23. Subjects 12 to 17 years old with a BP in the 95th percentile or greater for age, sex, and height 
on 2 separate readings recorded on 2 separate days.  Those subjects over 12 years old who 
had hypertension at Screening can be rescreened more than 1 month after initiation or 
adjustment of antihypertensive therapy 1 time.
24. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
25. Planned bariatric surgery during the study
26. Not suitable to participate in the study in the opinion of the investigator, including
consideration of any existing physical, medical, or mental condition that prevents compliance 
with the protocol
27. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive β-human chorionic gonadotropin test).  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.
28. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 28 days 
after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after study 
drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have 
been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated,
biconvex tablets with one 20-mg tablet administered orally QD.
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Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  30 days
Randomization Phase:  56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal 
preparations, are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days with study medication temporarily stopped for that 
time period and resumed the next day after the OTC cold medicine is stopped.  Any of the following 
serotonergic agents or other agents in combination with Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications, including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to 
calculate the proportion (%) of patients achieving at least a 5% and at least a 10% BMI 
reduction.

Measurement of systolic and diastolic BP, heart rate, triglycerides, total cholesterol, high 
density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, fasting 
plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and Homeostasis Model 
Assessment (HOMA) IR to assess cardiovascular and metabolic risk profiles from Baseline 
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to Week 52

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents
Pharmacokinetic Assessments
Plasma lorcaserin concentrations will be measured at Weeks 12, 28, 36, and 52 for analysis of 
population PK.  At Weeks 12, 28, and 52, subjects will be instructed to take their morning dose at the 
clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken at 
each of these visits: within 30 minutes before dosing and within 1 to 3 hours after dosing.  At the 
Week 36 visit, subjects will take the morning dose at home, and 1 blood sample for determination of 
plasma concentrations of lorcaserin will be collected at the investigational site within 4 to 6 hours 
after dosing.
Pharmacodynamic Assessments

Change from baseline in BMI 

Proportion (%) of subjects achieving at least a 5% and at least a 10% reduction in BMI
Other PD endpoints will be considered based on the data at the end of the study to explore their 
relationships with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious 
adverse events (SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, thyroid 
function, adrenal function and biochemical blood and urine biomarkers of bone health; blood 
chemistry and urine values; neuropsychiatric events; periodic measurement of vital signs,
neuromuscular signs for screening potential serotonin syndrome, and signs or symptoms of priapism 
and prolactinemia; and performance of physical examinations.
In patients with potential 
prolactin-related AEs, such as galactorrhea, changes in libido, or changes to menstrual cycle, 
prolactin level will be measured and assessed.
Study drug effect on growth of children and 
adolescents will be evaluated using the CDC growth chart at Baseline, and Weeks 5, 12, 28, 36, 52, 
and at Follow-Up; a full physical examination, at Baseline, Weeks 12, 28, 52, and at Follow-Up; and 
bone age determination by x-ray of the hand at Baseline, Weeks 12, 28, and 52.
Children and 
adolescent sexual maturation will be evaluated by assessing sex hormones and self-reported changes 
in Tanner Staging at Baseline, Weeks 28 and 52, and at Follow-Up. Any subject with symptoms or 
signs of cardiac valvular disease or pulmonary hypertension may be evaluated by local 
echocardiographic assessment at the discretion of the investigator if deemed medically indicated.  
The (C-SSRS) will be used to assess all children and adolescents in the study for any signal of 
depression or suicidal ideation or behavior.  Additionally, mood will be assessed using the CDI-2 and 
effects on cognitive function will be assessed using WRAML-2.
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography method coupled with 
tandem mass spectrometry.
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Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from baseline to Week 52 and proportion (%) of 
subjects achieving at least a 5% or 10% BMI reduction at Week 52 by the outcome of 
achieving at least a 5% BMI reduction at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) 
from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 post dose safety assessment.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to 
study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater 
compliant with study medication, completed the study, have no major protocol deviations, have 
no violations of inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  
The determination of subjects to be excluded from this population based on the above criteria 
and a list of major protocol violations will be included in the statistical analysis plan (SAP) and 
finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD 
parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.
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
The population PK/PD set is the group of randomized subjects with PK information and who 
have at least 1 adequately documented measurement of BMI.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as 
a supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in 
all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from 
baseline in BMI will be analyzed using the mixed effect model repeated measurement analysis 
(MMRM) assuming the missing data is missing at random (MAR), with factors of treatment visits 
(Baseline, Week 1, 5, 8, 12, 20, 28, 36, 44, and 52), age group (9 to 11 years old and 12 to 17 years 
old), sex (male and female), treatment-by-visit interaction as fixed effect, subjects as random effect,
and the baseline BMI as a covariate.  The unstructured covariance matrix will be used in the analysis 
and the treatment comparison at Week 52 will be the event of interest.  In case of a convergence 
issue, the Toeplitz covariance structure will be used in the model.
Subgroup analyses and additional sensitivity analyses will be performed as appropriate including 
multiple imputation methods assuming the missing values are MAR and missing not at random 
(MNAR) to handle missing data.
The following analyses will be considered as sensitivity analyses:

PP analysis:  The same primary efficacy analyses described above will be repeated based on 
the PP.

Multiple imputation (MI):  the same primary efficacy analyses described above will be 
analyzed using MI for impute the missing data, assuming the missing values are MAR and 
MNAR.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy 
analyses described above will be repeated using Z-score.
Additional sensitivity analyses may also be explored and described in the SAP, if deemed 
appropriate.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI 
reduction at Week 52. The secondary efficacy endpoint will be analyzed only if the test for the 
primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using 
a logistic regression model with factors of treatment, age group (9 to 11 years old and 12 to 17 years 
old), sex (male and female), and baseline BMI as a covariate using FAS.  Subjects with any missing 
assessment at Week 52 will be considered as treatment failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be analyzed 
using MMRM and categorical variables will be analyzed using the Cochran Mantel Haenszel test, 
Chi-square test, or logistic regression as appropriate.  Additional analysis may be performed as 
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needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including age group (9 to 
11 years old and 12 to 17 years old), sex (male and female), and race (white, black, Asian, and other).  
Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity 
analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling. The effect of covariates such as baseline characteristics or 
demographics on PK will be explored. Derived exposure parameters such as the maximum observed 
concentration and the area under the concentration-time curve from time 0 to 24 hours at steady-state 
will be calculated from the final PK model using individual posterior estimates of the PK parameters 
and from dosing history. The PK analysis set will be used for this analysis.
Pharmacodynamic Analyses
Change from Baseline in BMI will be assessed as the PD analysis.  The PD analysis set will be used 
for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% and 
≥10% BMI reduction, and change in waist circumference from baseline) will also assessed as part of 
the PD analysis.  The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma 
exposure and response, including but not limited to change in BMI from baseline and the probability 
of achieving at least a 5% and at least a 10% change in BMI from baseline to Week 52.  Additionally, 
exposure-safety relationships for select safety parameters may be explored graphically depending on 
the data at the end of study.  Any emergent relationship may be modeled as appropriate.  Any 
parameters based on the study data may be considered for exploratory assessment for its relationship 
to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the 
incidence of AEs (including changes from baseline in physical examination), growth (CDC growth 
chart and bone age determined by x-ray of the hand), sexual maturation (Tanner Staging), 
out-of-normal-range laboratory safety test values, change from baseline in laboratory safety test 
values (including biomarkers), ECGs, and vital sign measurements will be summarized by treatment 
group using descriptive statistics or frequency count as appropriate.  In addition, suicidal ideation, 
cognitive function, behavior, and mood will be evaluated by the C-SSRS, WRAML-2, CDI-2, and 
C-SSRS, respectively, and will also be summarized by treatment group using descriptive statistics or 
frequency count as appropriate. All WRAML-2 raw scores from the Core Battery will be converted 
to age and gender standard scores for purposes of intra individual comparisons
No hypothesis testing will be performed for the safety assessment.
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Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in 
BMI from Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  
Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 360 subjects in a 1:1 ratio 
(n=180 in the Belviq XR 20-mg treatment group; n=180 in the placebo group) will have at least 
90% power to detect a treatment difference of 1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  
Assuming the proportion of subjects achieving at least a 5% BMI reduction at Week 52 is 20% for 
the placebo group and a 40% dropout rate, this sample of 360 subjects (180 subjects for Belviq XR 
20 mg and 180 subjects for placebo) will also have greater than 85% power to detect an absolute 
difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 2-sided 
Fisher’s Exact test with α=0.05. The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic 
adult subjects.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................19
5.1
Institutional Review Boards/Independent Ethics Committees ..............................19
5.2
Ethical Conduct of the Study.................................................................................20
5.3
Subject Information and Informed Consent...........................................................20
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................22
7
INTRODUCTION ...........................................................................................................23
7.1
Indication ...............................................................................................................23
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................24
7.1.1.1
Mechanism of Action...........................................................................24
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................24
7.2
Study Rationale......................................................................................................25
8
STUDY OBJECTIVES....................................................................................................28
8.1
Primary Objective..................................................................................................28
8.2
Secondary Objectives.............................................................................................28
9
INVESTIGATIONAL PLAN..........................................................................................30
9.1
Overall Study Design and Plan..............................................................................30
9.1.1
Prerandomization/Pretreatment Phase .........................................................30
9.1.1.1
Screening Period..................................................................................30
9.1.2
Randomization/Treatment Phase .................................................................31
9.1.3
Extension Phase ...........................................................................................31
9.2
Discussion of Study Design, Including Choice of Control Groups.......................31
9.3
Selection of Study Population................................................................................32
9.3.1
Inclusion Criteria .........................................................................................32
9.3.2
Exclusion Criteria ........................................................................................33
9.3.3
Removal of Subjects From Therapy or Assessment....................................36
9.4
Treatments..............................................................................................................36
9.4.1
Treatments Administered.............................................................................36
9.4.2
Identity of Investigational Product...............................................................36
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................36
9.4.2.2
Comparator Drug .................................................................................36
9.4.2.3
Labeling for Study Drug......................................................................36
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9.4.2.4
Storage Conditions...............................................................................37
9.4.3
Method of Assigning Subjects to Treatment Groups...................................38
9.4.4
Selection and Timing of Dose for Each Subject..........................................38
9.4.5
Blinding........................................................................................................38
9.4.6
Prior and Concomitant Therapy...................................................................39
9.4.7
Treatment Compliance.................................................................................40
9.4.8
Drug Supplies and Accountability...............................................................40
9.5
Study Assessments.................................................................................................42
9.5.1
Assessments.................................................................................................42
9.5.1.1
Demography.........................................................................................42
9.5.1.2
Baseline Assessments ..........................................................................42
9.5.1.2.1
Medical History .............................................................................42
9.5.1.3
Efficacy Assessments...........................................................................42
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................42
9.5.1.4.1
Pharmacokinetic Assessments .......................................................42
9.5.1.4.2
Pharmacodynamic Assessments ....................................................43
9.5.1.4.3
Pharmacogenomic/Pharmacogenetic Assessments........................43
9.5.1.5
Safety Assessments..............................................................................43
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...44
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................46
9.5.1.5.3
Laboratory Measurements .............................................................47
9.5.1.5.4
Vital Signs and Weight Measurements..........................................48
9.5.1.5.5
Height Measurements ....................................................................49
9.5.1.5.6
Physical Examinations...................................................................49
9.5.1.5.7
Electrocardiograms ........................................................................49
9.5.1.5.8
Other Safety Assessments..............................................................50
9.5.1.6
Other Assessments...............................................................................50
9.5.1.6.1
Pregnancy Test...............................................................................50
9.5.1.6.2
Urine Drug and Cotinine Test........................................................50
9.5.2
Schedule of Procedures/Assessments ..........................................................51
9.5.2.1
Schedule of Procedures/Assessments ..................................................51
9.5.2.2
Description of Procedures/Assessments Schedule...............................55
9.5.2.3
Total Volume of Blood Sampling........................................................55
9.5.3
Appropriateness of Measurements...............................................................55
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................56
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9.5.4.1
Reporting of Serious Adverse Events..................................................56
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................56
9.5.4.3
Reporting of Events Association with Special Situations....................57
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................57
9.5.4.3.2
Reporting of Study-Specific Events...............................................58
9.5.4.4
Expedited Reporting ............................................................................58
9.5.4.5
Breaking the Blind...............................................................................58
9.5.4.6
Regulatory Reporting of Adverse Events ............................................59
9.5.5
Completion/Discontinuation of Subjects.....................................................59
9.5.6
Abuse or Diversion of Study Drug ..............................................................59
9.5.7
Confirmation of Medical Care by Another Physician .................................60
9.6
Data Quality Assurance .........................................................................................60
9.6.1
Data Collection ............................................................................................60
9.6.2
Clinical Data Management ..........................................................................60
9.7
Statistical Methods.................................................................................................61
9.7.1
Statistical and Analytical Plans....................................................................61
9.7.1.1
Study Endpoints...................................................................................61
9.7.1.1.1
Primary Efficacy Endpoint ............................................................61
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................61
9.7.1.2
Definitions of Analysis Sets.................................................................62
9.7.1.3
Subject Disposition..............................................................................62
9.7.1.4
Demographic and Other Baseline Characteristics ...............................63
9.7.1.5
Prior and Concomitant Therapy...........................................................63
9.7.1.6
Efficacy Analyses ................................................................................63
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................64
9.7.1.7.1
Pharmacokinetic Analyses.............................................................64
9.7.1.7.2
Pharmacodynamic Analyses..........................................................65
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................65
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................65
9.7.1.8
Safety Analyses....................................................................................65
9.7.1.8.1
Extent of Exposure.........................................................................65
9.7.1.8.2
Adverse Events ..............................................................................66
9.7.1.8.3
Laboratory Values..........................................................................67
9.7.1.8.4
Vital Signs......................................................................................67
9.7.1.8.5
Electrocardiograms ........................................................................68
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9.7.1.8.6
Other Safety Analyses....................................................................68
9.7.2
Determination of Sample Size .....................................................................68
9.7.3
Interim Analysis...........................................................................................68
9.7.4
Other Statistical/Analytical Issues ...............................................................69
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................69
10
REFERENCE LIST .........................................................................................................70
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......72
11.1
Changes to the Protocol .........................................................................................72
11.2
Adherence to the Protocol......................................................................................72
11.3
Monitoring Procedures...........................................................................................72
11.4
Recording of Data..................................................................................................73
11.5
Identification of Source Data.................................................................................73
11.6
Retention of Records..............................................................................................74
11.7
Auditing Procedures and Inspection......................................................................74
11.8
Handling of Study Drug.........................................................................................74
11.9
Publication of Results ............................................................................................75
11.10 Disclosure and Confidentiality ..............................................................................75
11.11 Discontinuation of Study .......................................................................................75
11.12 Subject Insurance and Indemnity...........................................................................76
12
APPENDIX......................................................................................................................77
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests...........................................................................48
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 .........52
Table 3
Summary of Blood Sample Volumes ........................................................55
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CDI-2
Children’s Depression Inventory 2
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Term
MAR
missing at random
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PI
principal investigator
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
WRAML-2
Wide Range Assessment of Memory and Learning-2
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity
Obesity has become a global epidemic in western civilization, causing a serious public health 
concern.  In the United States, the prevalence of obesity in adolescents ages 12 and 19 years
has almost doubled over the past 2 decades.  The rate increased from 10.5% between 1988 
and 1994 to 20.5% between 2011 and 2012 (CDC/NCHS, 2013).  The prevalence of obesity 
in children in United States is also high.  The United States Centers for Disease Control and
Prevention (CDC) reported in 2012 that 17.7% of children ages 6 to 11 years are obese.
Obesity in children and adolescents, defined in the United States as greater than or equal to 
the 95th percentile in gender- and age-specific body mass index (BMI), continues to grow at 
an alarming rate in the United States and globally.  Based on data (Wang and Lobstein, 2006) 
using various criteria for the definition of obesity that included more than 30 countries in 
Europe, North America, Asia, and the West Pacific, prevalence of obesity in these countries 
has also increased significantly, at a rate comparable to that in the United States.
Childhood and adolescent obesity has many negative implications for both the health and 
well-being of the individual as well as for society.  These include increased susceptibility to a 
host of diseases, chronic health disorders, psychological disorders, and premature death 
(Flegal, et al., 2005; Rofey, et al., 2009).  Increases in the prevalence of overweight and 
obese adolescents may result in a decrease in life expectancy for the 1st time in 200 years
(Peeters , et al, 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese children are likely to become tomorrow’s 
obese adults.
Current approaches to weight management include lifestyle modification, pharmacotherapy, 
and invasive bariatric procedures.  Lifestyle modification involves a combination of diet, 
exercise, and behavioral change, and is the preferred and essential strategy for weight 
management in obese and overweight individuals.  Although lifestyle modification can be 
very efficacious in some patients, adherence to the prescribed regimens is often poor.  As 
such, lifestyle modification alone is often not adequate and the weight loss is often transient.  
On the other hand, bariatric surgery and various other invasive procedures are generally 
reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise.
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The current standard of care for treatment of obesity in pediatric subjects ranges from 
lifestyle intervention in children less than 8 years of age to use of pharmacotherapy in 
adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies that will be 
used in the present study to help retain participants.  These include a highly trained and 
competent staff, ample waiting area, readily available parking (at no cost), access to mass 
transit, and reminder and follow-up calls.  In addition, we will provide fun and interactive 
group sessions with games and hands-on nutrition and physical activity demonstrations, 
random raffle drawings, social events, birthday and holiday cards, and newsletters.  Further, 
we will make home visits for assessments for families, as needed, to maximize data 
collection. We anticipate achieving a 75% or greater retention rate at Month 12. By using 
these retention strategies, we hope that we will maximize participant retention, which will 
help us cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:
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
A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) 
was significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
used for children and adolescent subjects with body weight greater than 60 kg.
In preadolescent and adolescent obese populations, it is anticipated that Belviq XR will result 
in similar effects.
As part of FDA postmarketing requirements, this study is designed to 
characterize the efficacy and safety of Belviq XR in adolescent obese populations in the 
United States, as well as in children ages 9 to 11 years.  It is also intended to support an 
indication for chronic weight management for obese children and adolescents ages 9 to 
17 years. 
It is intended to have 20 subjects treated with lorcaserin XR in each age group and 
10 subjects on lorcaserin XR for 52 weeks in each age groups, which is well above the 
numbers of subjects in adolescent studies with other products (ie, ezetimibe combination 
therapy with reductase inhibitors in primary hypercholesterolemia and heterozygous familial 
hypercholesterolemia in study involved 10 to 17 years old). The total number of subjects at 
baseline for combination therapy was 5 subjects at age 10 years old and 9 subjects at age 
11 years old group (FDA, 2007).
7.1.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for children and 
adolescents. In adults, the Division’s 2007 draft Guidance for Industry Developing Products 
for Weight Management indicate that the product needs to satisfy either of the following
mean or categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of 
subjects in the placebo-treated group who lose at least 5% of baseline body weight, 
and the difference between groups is statistically significant.
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FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in older children (9 to 11 years of age) and obese adolescents, where weight 
loss will be assessed using BMI measurements to account for growth. In this study, the 
objective is to demonstrate that BMI reduction will be achieved during 52 weeks of treatment 
with Belviq XR 20 mg administered once daily (QD) compared to placebo in obese children 
and adolescents.
In the Phase 3 orlistat study in obese adolescents and children mentioned above, the 
proportion of subjects who lost at least 5% body weight is relatively low. At the end of the 
study at Week 52, only 26.5% of the subjects achieved a 5% or greater BMI reduction 
compared to 15.7% in the placebo group. The placebo-corrected BMI reduction was about 
0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years,
and none in children under the age of 9 years (Peirson, et al, 2015).  Thirty-one studies 
(29 behavioral, 2 pharmacological and behavioral) were included in a meta-analysis of 
randomized studies conducted in primary care centers in overweight and obese children and 
youth ages 2 to 18 years using behavioral (diet, exercise, and lifestyle) and pharmacological 
interventions and providing 6-month postbaseline BMI or prevalence of overweight or 
obesity. 
Both interventions showed a significant effect on BMI in favor of treatment 
(behavioral: 
standardized mean difference [SMD] -0.54, 95% confidence interval 
[CI] -0.73, -0.36; orlistat plus behavioral: SMD -0.43, 95% CI -0.60, -0.25). The studies 
reported no significant difference between groups in the likelihood of reduced prevalence of 
overweight or overweight and obese. A great deal of variation was noted across efficacious 
interventions.
In conclusion, this meta-analysis demonstrated low-quality evidence that 
behavioral treatments alone are associated with a smaller effect in terms of reduced BMI 
compared with the effect shown by combined behavioral and pharmacological interventions. 
This may be because the effect size in the randomized, double blind, placebo controlled,
phase 3 orlistat study in adolescents was relatively low and there was a lack of maintenance 
effect. These subjects started to regain their BMI after 6 months of treatment. At end of the 
study, only 26.5% of subjects achieved a 5% or greater BMI reduction compared to 15.7% in 
placebo group. In a sibutramine Phase 3 study in obese adolescents, a substantially higher 
proportion of subjects (69%) treated with sibutramine achieved at least a 5% BMI reduction 
compared to 21% of subjects in the placebo group. In addition, sibutramine resulted in a
substantial reduction in mean BMI (between-group difference, 2.9 kg/m2) and mean weight 
(between-group difference, 8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the 
weight loss effect of Belviq in adults and sibutramine in adolescents, subjects in the orlistat 
study started to increase their BMI after 6 months of treatment.
In this study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI reduction
of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 5% and 
10% BMI reduction compared to placebo.  A between-group difference of 24% is the basis 
for the conservative assumption of a 20% effect size in the current study.
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In addition, the total sample size of 360 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
and sibutramine) (FDA, 2003; Chanoine, et al, 2005; Berkowitz, et al, 2006) and other 
metabolic or dyslipidemia medication products (ezetimibe, simvastatin) (FDA, 2007).
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8
STUDY OBJECTIVES
8.1
Primary Objective
To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of 
subjects with at least a 5% reduction in BMI after an initial 12 weeks of treatment 
with Belviq XR 20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 
12 weeks of treatment with Belviq XR 20 mg administered QD is predictive of 
sustained change in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
• Other weight loss effects (eg, proportion [%] of subjects achieving at least a 
10% BMI reduction, change in waist circumference) at the end of 52 weeks 
of treatment
• Effects on glycemia, insulin levels, and Homeostatic Model Assessment of 
Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L] / 405)
during 52 weeks of treatment
• Changes 
in 
cardiovascular 
risk 
factors 
associated 
with 
obesity 
(eg hypertension, dyslipidemia) during 52 weeks of treatment
•
To assess the safety of Belviq XR, including the effects on cognitive function by 
Wide Range Assessment of Memory and Learning-2 (WRAML-2), on mood by 
Children’s Depression Inventory 2 (CDI-2), on signal of suicidal ideation or behavior 
with the Columbia-Suicide Severity Rating Scale (C-SSRS), on growth measured by 
CDC growth chart, on sexual maturation measured by Tanner Staging scores, and on 
other growth and development parameters by measuring sex hormones, thyroid 
function, adrenal function, bone age, and biochemical markers of bone health.
•
To assess the PK of lorcaserin using population PK modeling
•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
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probability of achieving at least a 5% and at least a 10% reduction in BMI from 
baseline at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese children and adolescents ages 9 to 17 years.  Approximately 360 subjects will be 
randomized in a 1:1 ratio to Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  
Subjects will be stratified by age group and sex.  At least 30% of total subjects should be 
ages 9 to 11 years for the reasons outlined above in Section 7.1.1.2.  Subjects will receive 
Belviq XR 20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout the duration 
of the study, subjects will be encouraged to adhere to a lifestyle modification program that 
includes diet and exercise counseling (see Appendix 2).  
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.
9.1.1
Prerandomization/Pretreatment Phase
Screening will occur during the Prerandomization Phase at Visit 1
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
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9.1.2
Randomization/Treatment Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025 and healthy, obese pediatric subjects ages 6 to 11 years in 
Study APD356-A001-026.  Overall, the PK parameters of Belviq and its main metabolites, 
M1 and M5, were similar to those in adults.  Following a single, oral administration of 
Belviq 10 mg to a total of 8 healthy adolescent (age 12 to 17 years) obese subjects, the mean 
maximum concentration observed and the area under the concentration-time curve from time 
zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 464 hr×ng/mL, respectively.  The mean 
Belviq terminal phase half-life was 9.70 hours, similar to that observed in adults, thus 
supporting a similar dosing frequency (QD) in adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was performed. The PK analysis after a single 10-mg dose of lorcaserin revealed that 
the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight and age.
However, the body weight normalized AUC(0-inf) values were similar across the age groups, 
therefore the data indicated no effect of age on the lorcaserin PK. Integrated assessment of 
the PK versus body weight relationship, pooling the data from pediatric and adult subjects 
from previous studies, suggested that the lorcaserin area under the curve values for subjects 
with body weight of at least 60 kg overlapped with the area under the curve values from 
adolescents and adults. Therefore, no dose adjustment relative to adults and adolescents is 
deemed necessary for pediatric subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of enrolling subjects who are younger than 
9 years of age with body weight of at least 60 kg is low; therefore, the current study is 
designed to enroll the subjects between 9 to 17 years of age.
The targeted study population comprises 360 obese children and adolescents 9 to 17 years of
age.
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
Obesity in children will be identified using 
gender- and age-specific BMI measurement.  Obesity in children (9 to 11 years of age) is 
defined by The American Academy of Pediatrics 2007 recommendation as BMI in the 
99th percentile and at least 1 co-morbidity (Spear, et al, 2007).
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The proposed patient population is consistent with the recommendations in the 
2007 American Academy of Pediatrics article, Recommendations for Treatment of Child and 
Adolescent Overweight and Obesity (Spear, et al, 2007), which supports medication use in 
the 6 to 11 year age group as part of a staged approach (Tertiary Care Intervention in patients 
with a BMI 99th percentile and at least 1 co-morbidity).  
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, 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 700 subjects will be screened to ensure that 360 subjects will be randomized.
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug. Subjects who screen fail can be re-screened only once after 
60 days.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that 
is greater than or equal to the United States (US)-weighted mean of the 
95th percentile based on age and sex with a body weight greater than 60 kg
OR
Healthy male or female children, age 9 to 11 years at Screening, with a BMI that is 
greater than or equal to the US-weighted mean of the 99th percentile based on age 
and sex, and a body weight greater than 60 kg associated with at least 1 co-morbid 
weight-related condition (eg, type 2 diabetes mellitus, hypertension, dyslipidemia)

Type 2 Diabetes as defined by American Diabetes Association Standards of 
Diabetes Care, 2013.

Stage 1 primary hypertension (blood pressure in the 95th to 99th percentile 
plus 5 mmHg for age, sex, and height) as defined by the Expert Panel on 
Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents (Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011) during the Screening Period

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents 
(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents, 2011).
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2. Subjects and their families are not planning to move away from the area for the 
duration of the study
3. Subjects able and willing to comply with all aspects of the study, including a 
reduced-calorie diet and an increased physical activity program
4. Subjects considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may 
affect the subject’s ability to fulfill the study requirements or significantly confound 
the assessments
2. Subjects who cannot swallow investigational products
3. Documented pulmonary hypertension by objective assessments (ie, imaging modality 
or cardiac catheterization)
4. Known 
valvular disease 
defined by 
clinical diagnosis 
or 
most recent 
echocardiography.  History of valvular disease is allowed if it has been corrected by 
valve replacement or repair.
5. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
6. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or 
schizophrenia
7. Known secondary causes (chromosomal, endocrine, or metabolic) for obesity 
(eg Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for 
longer than 30 days, history of significant exposure to corticosteroids for chronic 
illness during the past year, and known genetic causes of obesity)
8. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before 
Screening
9. Use of any of the following medications:
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a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or
monoamine oxidase inhibitors (MAOIs) within 30 days before Randomization, 
including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 

bupropion

triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
10. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months 
before Screening, including but not limited to pergolide, ergotamine, methysergide, 
and cabergoline
11. History or evidence of clinically significant disease (eg, malignancy; cardiac, 
respiratory, gastrointestinal, renal, or psychiatric disease) other than prediabetes 
(impaired fasting glucose or impaired glucose tolerance), Type 2 diabetes treated with 
oral anti-diabetic agents (excluding sulfonylurea)
or
non-insulin injectable 
antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver 
disease
12. Use of Belviq XR within 6
months before Screening or hypersensitivity to 
Belviq XR or any of the excipients
13. Significant change in diet or level of physical activity within 1 month before dosing 
or change in weight of more than 5 kg within 3 months before Screening
14. Any use of a of very-low-calorie (<1000 calories/day) weight loss diet within 
6 months before Screening
15. History of alcohol or drug dependence or abuse
16. Recreational drug use within 2 years before Screening
17. Known to be human immunodeficiency virus positive
18. Active viral hepatitis (B or C) as demonstrated by positive serology
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19. Malignancy within 5 years before Screening
20. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
21. Special needs subjects who are unable to comprehend study-related instructions 
(eg, mild to profound mental retardation [IQ <70], moderate to severe cognitive 
developmental delay, pervasive development disorders, autism)
22. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure 
disorder within 6 months of screening or any time between screening and 
randomization
23. Subjects 12 to 17 years old with a BP in the 95th percentile or greater for age, sex, 
and height on 2 separate readings recorded on 2 separate days.  Those subjects over 
12 years old who had uncontrolled hypertension at Screening can be rescreened more 
than 1 month after initiation or adjustment of antihypertensive therapy 1 time.
24. Currently enrolled in another clinical study or has used any investigational drug or 
device within 30 days before providing informed consent
25. Planned bariatric surgery during the study
26. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
27. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
28. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do 
not agree to use a highly effective method of contraception (eg, total abstinence, 
an intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study 
period and for 28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexual activity during the study period and for 
28 days after study drug discontinuation
c.
Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do not 
agree to use the same contraceptive during the study and for 28 days after study 
drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
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9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD.
Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled 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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The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal 
(US) law to investigational use.”
All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug 
was dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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 
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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.
Subjects will be centrally stratified by age group (9 to 11 years old and 12 to 17 years old)
and sex (male and female).  Within each stratum, subjects will be randomized to receive 
either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  It is planned that at least 30% of the 
subjects will be enrolled into the 9 to 11 year age group.  
Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily, and be encouraged to take the study 
medication with an adequate amount of water (8 oz. or 240 mL).
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
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9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
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9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs
will review treatment compliance during site visits and at the completion of the study.
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 
(US sites only).  Must be appropriate to handle schedule IV products and not be 
expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
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Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
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9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.3
Efficacy Assessments

Body weight and height will be measured using standard method (Lohman T, et al, 
1988) to calculate changes in BMI; BMI will then be used to calculate the proportion 
(%) of patients achieving at least a 5% and at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, triglycerides, total cholesterol, 
high density lipoprotein (HDL)
cholesterol, low density lipoprotein (LDL)
cholesterol, fasting plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and 
HOMA-IR to assess changes in cardiovascular and metabolic risk profiles from 
Baseline to Week 52

Prehypertension and primary hypertension as defined by the Expert Panel on 
Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and 
Adolescents (Expert Panel on Integrated Guidelines for Cardiovascular Health and 
Risk Reduction in Children and Adolescents, 2011)

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents (Expert Panel 
on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children 
and Adolescents, 2011)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for population PK analyses.  At Weeks 12, 28, and 52, subjects will be 
instructed to take their morning dose at the clinic.  Two blood samples for determination of 
plasma concentrations of lorcaserin will be taken at each of these visits: within 30 minutes 
before dosing and within 1 to 3 hours after dosing.  At the Week 36 visit, subjects will take 
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the morning dose at home, and 1 blood sample for determination of plasma concentration of 
lorcaserin will be collected at the investigational site within 4 to 6 hours after dosing.
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
method coupled with tandem mass spectrometry method. The collection, handling, and 
shipping procedures for PK samples will be described in a manual to be provided to the study 
sites.
9.5.1.4.2 PHARMACODYNAMIC ASSESSMENTS
Blood samples will be collected to determine lorcaserin plasma exposure and population 
PK/PD modeling will be used to explore the relationship between lorcaserin plasma exposure 
and following response to lorcaserin: 

Change from Baseline in BMI 

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in 
BMI 
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3 PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs); electrocardiograms (ECGs); laboratory evaluations for hematology, thyroid 
function, adrenal functions, and biochemical blood and urine biomarkers of bone health;
blood chemistry and urine values; neuropsychiatric events; periodic measurements of vital 
signs, neuromuscular signs for screening potential serotonin syndrome, and signs and 
symptoms of priapism and prolactinemia; and performance of physical examinations.  In 
subjects with potential prolactin-related AEs, such galactorrhea, changes in libido, or changes 
to menstrual cycle, prolactin level will be measured and assessed.  Study drug effect on 
growth of children and adolescents will be evaluated using the CDC growth chart at 
Baseline, and Weeks 5, 12, 28, 36, 52, and at Follow-Up; a full physical examination at 
Baseline, Weeks 12, 28, 52, and at Follow-Up; and bone age determination by x-ray of the 
hand at Baseline, Weeks 12, 28, and 52.  Children and adolescent sexual maturation will be 
evaluated by assessing sex hormones and self-reported changes in Tanner Staging at 
Baseline, Weeks 28 and 52, and at Follow-Up.
Any subject with symptoms or signs of 
cardiac valvular disease or pulmonary hypertension may be evaluated by local 
echocardiographic assessment at the discretion of the investigator if deemed medically 
indicated.
The C-SSRS will be used to assess all children and adolescents in the study for any signal of 
depression or suicidal ideation or behavior.  Additionally, mood will be assessed using the 
CDI-2 and effects on cognitive function will be assessed using WRAML-2.
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9.5.1.5.1 ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
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It is the responsibility of the investigator to review the results of the C-SSRS, CDI-2, and 
WRAML-2 in all subjects and determine if any result constitutes an AE.  Medical and 
scientific judgment should be exercised in deciding whether an isolated suicidality rating 
scale response should be classified as an AE (see Section 9.5.1.5.8 for a description of the 
C-SSRS).
All AEs must be followed for 28 days after the subject’s last dose or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of 
the event
•
The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
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Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2 SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL 
SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious 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
•
Priapism
•
New onset valvular heart disease
•
New onset pulmonary hypertension
•
Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin
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•
Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study specific event 
does not meet serious criteria.  If the event meets seriousness criteria, it should be reported as 
an SAE as above.  However, if the event listed below does not meet serious criteria, it should 
be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation   

Euphoria 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 1 of 
the above criteria.  All AEs associated with special situations are to be reported on the 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for 
administration of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was 
in place before study entry
9.5.1.5.3 LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
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Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function
T4, TSH
Adrenal function
Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects), 
Biomarkers of bone health
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other
Albumin, calcium, globulin, glucose, HbA1c, HDL cholesterol, 
lactate dehydrogenase, LDL cholesterol, phosphorus, total protein,
total cholesterol, triglycerides, prolactin, uric acid, urine ß-hCG, 
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs,
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4 VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
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method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5 HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2).  
9.5.1.5.6 PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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.
9.5.1.5.7 ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
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9.5.1.5.8 OTHER SAFETY ASSESSMENTS
WRAML-2
The WRAML-2 administration will consist of the Core Battery, which provides scores on 
Verbal Memory, Visual Memory, and Attention/Concentration.  There are 6 subtests (2 for 
each area).
The tests provide standardized scores based on age and gender, and are 
appropriate for ages 5 to 90 years.  The WRAML-2 will be used to assess lorcaserin effects 
on cognitive function. In addition, signs and symptoms of cognitive related AEs, including 
impairments in attention, memory, and adverse effects on schoolwork will be captured in the 
eCRF.
CDI-2
The CDI-2 is a self-administered depression rating scale for use in children ages 7 to 
17 years.  It consists of 28 items and provides a total score, scores on 2 scales, and 
4 subscales.  CDI-2 will be used to assess lorcaserin effect on mood changes.
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. It will be performed at Baseline and at study 
visits as designated in the Schedule of Procedures/Assessments (Table 2).
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will be captured in the eCRF.
Hand X-Ray will be evaluated for any potential negative effect on bone age as designated in 
the Schedules/Assessments (Table 2). Echocardiograms will be performed on the subjects 
with signs or symptoms of potential valvular disease or pulmonary hypertension. 
Echocardiogram confirmed cases of FDA-defined valvulopathy or pulmonary hypertension
will be captured by AE eCRF. Neuromuscular sign assessment for serotonin syndrome will 
be performed as designated in the Schedule of Procedures/Assessments (Table 2) to screen 
for potential serotonergic syndrome components. Serotonergic syndromes that meet the 
diagnostic criteria will be captured by AE eCRF.
9.5.1.6
Other Assessments
9.5.1.6.1 PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at designated time points as 
specified in the Schedule of Procedures/Assessments (Table 2).
9.5.1.6.2 URINE DRUG AND COTININE TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 2).  This sample will be tested for common 
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drugs 
of 
use/abuse 
(eg, 
ethyl 
alcohol, 
cocaine, 
cannabinoids, 
phencyclidine, 
nicotine/cotinine, opioids [as a group], benzodiazepines, barbiturates, amphetamines).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examination
X
X
X
X
X
X
X
X
Neuromuscular sign assessment for serotonin 
syndromed
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
Urine drug and cotinine test
X
Fasting plasma glucose, Fasting Insulin, HOMA-
IR, and HbA1c sampling
X
X
X
X
X
X
T4 and TSH
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
AM serum cortisol
X
X
Testosterone, Estradiol
X
Pregnancy test (Urine)
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
WRAML-2
X
X
X
X
X
X
CDI-2
X
X
X
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
Urine NTX
X
X
X
PK sample
X
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Prolactin
X
X
X
X
Lifestyle modification counselinge
X
X
X
X
X
X
X
X
X
X
AE = adverse event; AM = morning; CDC = Centers for Disease Control and Prevention; CDI-2 = Children’s Depression Inventory 2; C-SSRS = Columbia-Suicide Severity 
Rating Scale, ECG = electrocardiogram, EOS = End of Study, EOT = End of Treatment, HbA1c = hemoglobin A1c, HOMA-IR = Homeostatic Model Assessment of Insulin 
Resistance; IxRS = interactive voice or web response system, NTX = N-telopeptide, OC = osteocalcin; PICP = carboxyterminal propeptide of type I procollagen  PK = 
pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone, WRAML-2 = Wide Range Assessment of Memory and Learning-2.
a:
Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b:
Window ±7 days for all visits after Visit 2 except for Weeks 12 and 28 (the window for these visits will be broader at ±14 days). Week is shown unless otherwise 
indicated.
c:
On Weeks 12, 28, and 52, subjects will take the morning dose at the clinic, and 2 blood samples for determination of plasma concentrations of lorcaserin will be taken:
predose (within 30 minutes before dosing) and within 1 to 3 hours after dosing (time in which the dose was taken on the night previous to the visit must be recorded). On 
Week 36, the subjects will take the morning dose at home (time of morning dosing at home must be recorded), and 1 blood sample for determination of plasma 
concentrations of lorcaserin will be collected at the investigational site within 4 to 6 hours after dosing.
d:
Accompanied by an abbreviated physical examination for clonus
e:
Lifestyle modification counseling will also be performed at Weeks 3, 24, 32, 40, and 48 in addition to counseling at the visits in the schedule of assessments table above. 
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
12
Screening: 1
Visits 2, 3, 4, 6, 8; 11/EOT, EOS
128=96
T4, TSH, Cortisol, 
Testosterone, estradiol, 
Serum OC and PICP, 
Hydroxy-proline; Fasting 
prolactin levels
10
Screening:  1
Visits  8; 11/EOT/Early 
discontinuation
10×3=30
Prolactin, FPG, Insulin, and 
HbA1c sampling
4
Screening:  1
Visits 2, 6, 8; 11/EOT/Early 
discontinuation
4×5=20
PK/PD blood sampling
4
Visits 6, 8, 9, and 11/EOT/Early 
discontinuation (2 samples each)
8×4=32
Total
178
EOS = End of Study; EOT = End of Treatment; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; OC = osteocalcin;
PD = pharmacodynamic; PICP = carboxyterminal propeptide of type I procollagen; PK = pharmacokinetics; T4 = thyroxine; 
TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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.
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 30 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.
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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1 REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
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AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2 REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset pulmonary hypertension

Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin

Fibroadenomas of the breast or ductal carcinoma in situ
The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study-specific 
event does not meet serious criteria.  If the event meets seriousness criteria, it should 
be reported as an SAE as above.  However, if the event listed below does not meet 
serious criteria, it should be noted as nonserious on the Adverse Event CRF:  

Suicidal ideation

Euphoria 
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 
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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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52-week evaluation is completed.  
Subjects who discontinue treatment prematurely will be followed up until study completion.  
All subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 2).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
Detailed retention strategies will be developed and included in study manual. These include 
a highly trained and competent staff, easy access to the clinic, reminder and follow-up calls, 
interactive group sessions with games and hands-on nutrition and physical activity 
demonstrations, random raffle drawings, social events, birthday and holiday cards, and
newsletters. In addition, home visits for assessments of families will be an option, as needed, 
to maximize data collection. This detailed retention plan will help prevent missing data.
A subject removed from the study for any reason may not be replaced.
9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the Abuse or Diversion of Study Drug CRF.  The DEA Registrant has 
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the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1 PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2 SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Change and percentage change in BMI from Baseline to Week 52 and proportion (%) 
of subjects achieving at least a 5% or 10% BMI reduction at Week 52 by the outcome 
of achieving at least a 5% BMI reduction at Week 12

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52
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
Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 
80% or greater compliant with study medication, completed the study, have no major 
protocol deviations, have no violations of inclusion or exclusion criteria, and have 
BMI data at Baseline and Week 52.  The determination of subjects to be excluded 
from this population based on the above criteria and list of major protocol violations 
will be included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at 
least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 
1 valid lorcaserin plasma concentration was obtained with associated documented 
dosing history.

The population PK/PD set is the group of randomized subjects with PK information 
and who have at least 1 adequately documented measurement of BMI.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
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9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using the mixed effect model repeated measurement 
analysis (MMRM) assuming the missing data is missing at random (MAR) with factors of 
treatment, visits (Baseline, Week 1, 5, 8, 12, 20, 28, 36, 44, and 52), age group (9 to 11 years 
old and 12 to 17 years old), sex (male and female), treatment-by-visit interaction as fixed 
effect, subjects as random effect, and the baseline BMI as a covariate.  The unstructured 
covariance matrix will be used in the analysis and the treatment comparison at Week 52 will 
be the event of interest.  In case of a convergence issue, the Toeplitz covariance structure will 
be used in the model.
Subgroup analyses and additional sensitivity analyses will be performed as appropriate 
including multiple imputation methods assuming the missing values are MAR and missing 
not at random (MNAR) to handle missing data.
The following analyses will be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated 
based on the PP.

Multiple imputation (MI): the same primary efficacy analyses described above will 
be analyzed using MI for impute the missing data, assuming the missing values are 
MAR and MNAR.
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
Change from baseline in standardized BMI score (Z-score):
The same primary 
efficacy analyses described above will be repeated using Z-score.
Additional sensitivity analyses may also be explored and described in the SAP, if deemed 
appropriate.  
Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, age group (9 to 11 years 
old and 12 to 17 years old) and sex (male and female), and baseline BMI as a covariate using 
FAS.  Subjects with any missing assessment at Week 52 will be considered as treatment 
failures in this analysis.
Other Secondary Efficacy Analyses
Unless specified, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using MMRM and categorical variables will be analyzed using the Cochran Mantel 
Haenszel test, Chi-square test, or logistic regression as appropriate.  Additional analysis may
be performed as needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including age group 
(9 to 11 years old and 12 to 17 years old), sex (male and female), race (white, black, Asian,
and other). Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1 PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
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9.7.1.7.2 PHARMACODYNAMIC ANALYSES
Change from Baseline in BMI will be assessed as the PD analysis.  The PD analysis set will 
be used for this analysis.
Other assessments (eg, percentage of BMI change, proportion [%] of patients achieving ≥5% 
and ≥10% BMI reduction, and change in waist circumference from baseline) will also 
assessed as part of the PD analysis.  The PK/PD analysis set will be used for this analysis.
9.7.1.7.3 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in BMI from baseline and 
the probability of achieving at least a 5% and at least a 10% change in BMI from baseline to 
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be 
explored graphically, depending on the data at the end of study.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered 
for exploratory assessment for its relationship to PK.
9.7.1.7.4 PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination), 
growth (CDC growth chart and bone age determined by x-ray of the hand), sexual maturation 
(Tanner Staging), out-of-normal-range laboratory safety test values, change from baseline in 
laboratory safety test values (including biomarkers), ECGs, and vital sign measurements will 
be summarized by treatment group using descriptive statistics or frequency count as 
appropriate.  In addition, suicidal ideation, cognitive function, behavior, and mood will be 
evaluated by the C-SSRS, WRAML-2, CDI-2, and C-SSRS, respectively, and will also be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
All WRAML-2 raw scores from the Core Battery will be converted to age and gender 
standard scores for purposes of intra individual comparisons
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1 EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
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drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
9.7.1.8.2 ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No 
[not related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
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The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
9.7.1.8.3 LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4 VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit
and treatment group.
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9.7.1.8.5 ELECTROCARDIOGRAMS
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and 
greater than 60 msec from the baseline visit.
9.7.1.8.6 OTHER SAFETY ANALYSES
Other safety assessments including children and adolescent growth evaluations using CDC 
growth chart and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, neuromuscular sign assessment for serotonin syndrome, signs and symptoms of 
priapism and prolactinemia, study drug effect on cognitive function assessed by WRAML-2, 
assessment of suicidality using C-SSRS, and mood assessment using CDI-2 will be also be 
summarized by treatment group at each scheduled visit.
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
360 subjects in a 1:1 ratio (n=180 in the Belviq XR 20-mg treatment group; n=180 in the 
placebo group) will have at least 90% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 360 subjects (180 subjects for Belviq XR 20 mg and 180 subjects for placebo) 
will also have greater than 85% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Fisher’s Exact test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
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9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.Lohman T, Roche 
AF, Martorell R. Anthropometric Standardization Reference Manual.  Champaign, IL:  
Human Kinetics Books; 1988.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux 
L.  NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A Life-
Table Analysis. Ann Intern Med. 2003; 138:24-32.
Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
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Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al. A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.Trasande, L. Chatterjee, S.  The Impact of Obesity on Health 
Service Utilization and Costs in Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang, Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will 
participate in a standardized weight management program for adolescents consisting of 
multicomponent behavior therapy.  The therapy will focus on healthy eating, physical 
activity, and lifestyle changes that will facilitate weight loss and weight-loss maintenance. 
The role of the caregivers is to support their child or adolescents’ lifestyle changes and their 
taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their
caregivers (caregivers are instructed in methods to support their adolescents’ progress
but caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the
lifestyle program
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Appendix 3
Pharmacodynamic and Other Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), and other biomarker analysis.  These samples may be used for 
discovery or validation to identify biomarkers that may be used for exploratory evaluation of 
response or safety-related outcomes as well as for use in diagnostic development.
The pharmacogenetics (PG) samples may be used to identify genetic factors that may 
influence a subject’s exposure to the study drug, as well as genetic factors that may have an 
effect on clinical response or potential adverse events (AEs) related to study treatment, and to 
explore the role of genetic variability in response.  Samples may be analyzed to determine a 
subject’s genotypes or sequence for a number of genes or non-coding regulatory regions.  
The research may include the investigation of polymorphisms in genes that are likely to 
influence the study drug pharmacokinetic (PK) or therapeutic response.
Collection of the PD, and other biomarker samples will be bound by the sample principles 
and processes outlined in the main study protocol.  Sample collection for PD, PG, and other 
biomarker analysis is required as per the study protocol unless the collection and use of the 
samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:
•
Clinical research organizations retained by the sponsor
•
Independent ethics committees or institutional review boards that have responsibility for
this research study
•
National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
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scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PG, and other biomarker analysis, it will not be possible 
to return individual data to subjects.  The results that may be generated are not currently 
anticipated to have clinical relevance to the patients or their family members.  Therefore, 
these results will not be disclosed to the patients or their physicians.
If at any time, PD, PG, or other biomarker results are obtained that may have clinical 
relevance, Institutional Review Board review and approval will be sought to determine the 
most appropriate manner of disclosure and to determine whether or not validation in a 
Clinical Laboratory Improvement Amendments-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in Clinical Laboratory Improvement 
Amendments-approved laboratories.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Children and Adolescents, Age 9 to 
17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neuroscience Business Group
Eisai Inc.
Date
Eisai Inc.
Date
Neuroscience Business Group
Eisai Inc.
Date
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Children and Adolescents, Age 9 to 
17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Grammatical, 
typographical, and 
formatting changes 
Throughout
Belviq to Belviq XR
The XR formulation will 
replace the IR formulation in 
the United States market to 
support the ease of 
administration
Throughout
Patients to Subjects
Corrected per Style Guide
Throughout
Subject population to
include children ages 9 to 
17 years
Expand the age of the 
population due to the change of 
pediatric development strategy
A single dose pharmacokinetic 
study in pediatric obese subjects 
(APD356-A001-026) indicated 
that patients with body weight 
greater than or equal to 60 kg 
can be administered a dose 
similar to that given to adults 
and adolescents.  Based on 
Centers for Disease Control and 
Prevention (CDC) growth chart 
data, almost all subjects over 
9 years of age are likely to be at 
or over 60 kg body weight.  
Therefore, children age 9 to 
11 years have been included in 
the current study.
Title Page
Synopsis
•
Study Protocol Title
•
Objectives
•
Study Design
•
Inclusion Criteria
•
Assessments
•
Efficacy Analyses
•
Safety Analyses
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.2
Section 9.3.2
Section 9.4.3
Section 9.5.1.5
Section 9.5.1.5.1
Section 9.5.2
Section 9.5.1.5.3
Section 9.5.1.5.8
Section 9.7.1.6
Section 9.7.1.8
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Additional safety 
assessments including 
cognitive function, 
serotonin syndrome 
components, bone health 
and endocrine function, 
priapism, and symptoms 
associated with 
hyperprolactinemia were 
added.
Per United States Food and 
Drug Administration (FDA)
request
Synopsis

Efficacy Assessments

Pharmacokinetic 
Assessments

Safety Assessments
Section 9.5.1.3
Section 9.5.1.5
Section 9.5.1.5.8
Section 9.7.1.8
Section 9.7.1.8.1
Change to primary and 
key secondary endpoints
Per FDA request
Synopsis

Other Secondary 
Efficacy Endpoints
Section 8.1
Section 8.2
Analysis of primary 
endpoint changed
Per FDA request
Synopsis

Primary Efficacy 
Analysis
Section 9.5.1.3
Section 9.7.1.1.2
Section 9.7.1.6
Update to reporting of 
study-specific adverse 
events
To provide clearer guidance for 
the correct reporting of 
study-specific events of interest
Section 9.5.4.3.2
Inserted Section 9.3.3:  
Removal of Subjects From 
Therapy or Assessment
Per protocol template
Section 9.3.3
Updated allowed and 
prohibited prior and 
concomitant therapies
For clarification
Synopsis

Exclusion Criteria

Concomitant 
Drug/Therapy
Section 9.3.2
Section 9.4.6
Update to reporting of 
adverse events
To provide clearer guidance for 
the correct reporting of adverse
events 
Section 9.5.1.5.1
Section 9.5.4.1
Section 9.7.1.8.2
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Revision History
Previous Version (Original Protocol): v1.0
Current Version (Revision): v2.0
Date of Revisions: 22 Jul 2016
Change
Rationale
Affected Protocol Section(s)
Update to Introduction 
and to Completion/ 
Discontinuation of 
Subjects
To provide details of plans to 
maximize subject retention
Section 7.1
Section 9.5.5
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 
52-Week 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction With Lifestyle Modification for Weight 
Loss in Obese Children and Adolescents, Age 9 to 17 Years
Sponsor:
Eisai Inc.
100 Tice Boulevard
Woodcliff Lake, New Jersey 07677
United States
Investigational 
Product Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
v1.0
16 Apr 2015 (original protocol)
v2.0
22 Jul 2016 (Revision)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use and all applicable 
local Good Clinical Practice (GCP) and regulations.  All required 
study documentation will be archived as required by regulatory 
authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.: APD356
Name of Active Ingredient:  Belviq XR® (lorcaserin hydrochloride)
Study Protocol Title
A 52-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the 
Efficacy and Safety of Belviq XR® in Conjunction With Lifestyle Modification for Weight Loss in 
Obese Children and Adolescents, Age 9 to 17 Years
Investigators
Unknown
Site
Approximately 30 sites in the United States
Study Period and Phase of Development
Approximately 24 months from first subject enrolled to last subject’s last visit or last assessment 
Phase 4
Objectives
Primary Objective
To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks 
of treatment with Belviq XR 20 mg administered once daily (QD) as compared to placebo
Key Secondary Objective
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at 
least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD as compared to placebo
Other Secondary Objectives

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with at 
least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR 20 mg 
administered QD compared to placebo

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 
52 weeks of treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:

Other weight loss effects (eg, proportion [%] of subjects achieving at least a 10% BMI 
reduction, change in waist circumference) at the end of 52 weeks of treatment

Effects on glycemia, insulin levels, and Homeostatic Model Assessment of Insulin 
Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L] / 405) during 52 weeks of 
treatment

Changes in cardiovascular risk factors associated with obesity (eg, hypertension, 
dyslipidemia) during 52 weeks of treatment

To assess the safety of Belviq XR, including the effects on cognitive function by Wide Range 
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Assessment of Memory and Learning-2 (WRAML-2), on mood by Children’s Depression 
Inventory 2 (CDI-2), on signal of suicidal ideation or behavior with the Columbia-Suicide 
Severity Rating Scale (C-SSRS), on growth measured by Centers for Disease Control and 
Prevention (CDC) growth chart, on sexual maturation measured by Tanner Staging scores, 
and on other growth and development parameters by measuring sex hormones, thyroid 
function, adrenal function, bone age, and biochemical markers of bone health.

To assess the pharmacokinetics (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamic (PD) 
parameters including but not limited to reduction from baseline in BMI and body weight and 
probability of achieving at least a 5% and at least a 10% reduction in BMI and body weight 
from baseline at Week 52 using population PK/ PD modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese 
children and adolescents, ages 9 to 17 years.  Approximately 360 subjects will be randomized in a 
1:1 ratio to Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will be 
stratified by age group and sex.  At least 30% of the total subjects should be ages 9 to 11 years.  
Subjects will receive Belviq XR 20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout 
the duration of the study, subjects will be encouraged to adhere to a lifestyle modification program 
that includes diet and exercise counseling.
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization 
Phase will last up to 30 days and consist of 1 visit during which subjects will be screened for 
eligibility.  The Randomization Phase consists of a Treatment Period and a Follow-Up Period.  The 
Treatment Period will last for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36,
44, and 52.  The Follow-Up Period will extend from the End of Treatment visit to the End of Study 
visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will continue in the 
study until the 52-week evaluation is completed.  Subjects who discontinue treatment prematurely 
will be followed up until study completion.  
Number of Subjects
Approximately 700 subjects will be screened to provide 360 randomized subjects.
Inclusion Criteria
1.
Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that is 
greater than or equal to the United States (US)-weighted mean of the 95th percentile based on 
age and sex, but is less than 44 kg/m2
OR
Healthy male or female children, age 9 to 11 years at Screening, with a BMI that is greater 
than or equal to US-weighted mean of the 99th percentile based on age and sex, but is less 
than 44 kg/m2, and a body weight greater than 60 kg associated with at least 1 co-morbid
weight-related condition (eg, type 2 diabetes mellitus, hypertension, dyslipidemia)

Type 2 Diabetes is defined by American Diabetes Association Standards of Diabetes 
Care, 2013.

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents 
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(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents, 2011).

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011).
2.
Subjects and their families not planning to move away from the area for the duration of the 
study
3.
Subjects able and willing to comply with all aspects of the study, including a reduced-calorie 
diet and an increased physical activity program
4.
Subjects considered in stable health in the opinion of the investigator
5.
Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b.
Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
c.
No history of Attention Deficit Hyperactivity Disorder, substance abuse, depression, 
suicidal ideation/behavior, bipolar disorder, or schizophrenia
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the 
subject’s ability to fulfill the study requirements or significantly confound the assessments
2.
Subjects who cannot swallow investigational products
3.
Documented pulmonary hypertension (PH) by objective assessments (ie, imaging modality or 
cardiac catheterization)
4.
Known valvular disease defined by clinical diagnosis or most recent echocardiography.  
History of valvular disease is allowed if it has been corrected by valve replacement or repair.
5.
Significant renal or hepatic disease as evidenced by a serum creatinine greater than 1.5×upper 
limit of normal (ULN), serum transaminases greater than 3×ULN, or total bilirubin greater 
than 1.5×ULN in absence of Gilbert’s syndrome
6.
Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or schizophrenia
7.
Known 
secondary 
causes 
(chromosomal, 
endocrine, 
or 
metabolic) 
for 
obesity 
(eg
Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 
30 days, history of significant exposure to corticosteroids for chronic illness during the past 
year, known genetic causes of obesity)
8.
Use of other products intended for weight loss including prescription drugs, over-the-counter 
(OTC) drugs, and herbal preparations within 1 month before Screening 
9.
Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or monoamine 
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oxidase inhibitors (MAOIs) within 30 days before Randomization, including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs)

bupropion

triptans

St. John’s Wort 

tryptophan  

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate, and
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine, and Dexedrine)

benzodiazepines
10. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
Screening, including but not limited to pergolide, ergotamine, methysergide, and cabergoline
11. History or evidence of clinically significant disease (eg, malignancy; cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or impaired glucose tolerance), type 2 diabetes treated with oral anti-diabetic agents 
(excluding sulfonylurea) or non-insulin injectable antidiabetic agents, obstructive sleep 
apnea, dyslipidemia, and nonalcoholic fatty liver disease
12. Use of Belviq XR within 6 months before Screening or hypersensitivity to Belviq XR or any 
of the excipients
13. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of more than 5 kg within 3 months before Screening
14. Adherence to a very-low-calorie (<1000 calories/day) weight loss diet within 6 months
before Screening
15. History of alcohol or drug dependence or abuse
16. Recreational drug use within 2 years before Screening
17. Known to be human immunodeficiency virus positive
18. Active viral hepatitis (B or C) as demonstrated by positive serology
19. Malignancy within 5 years before Screening
20. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
21. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to 
profound mental retardation [IQ <70], moderate to severe cognitive developmental delay, 
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pervasive development disorders, autism)
22. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening or any time between screening and randomization
23. Uncontrolled hypertension, defined as blood pressure (BP) in the 95th percentile or greater 
for age, sex, and height on 2 separate readings recorded on 2 separate days.  Subjects who 
had uncontrolled hypertension at Screening can be rescreened more than 1 month after
initiation or adjustment of antihypertensive therapy one time.
24. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
25. Planned bariatric surgery during the study
26. Not suitable to participate in the study in the opinion of the investigator, including
consideration of any existing physical, medical, or mental condition that prevents compliance 
with the protocol
27. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive β-human chorionic gonadotropin test).  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.
28. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized
partner with confirmed azoospermia) throughout the entire study period and for 28 days 
after study drug discontinuation
b.
Are currently abstinent and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period and for 28 days after study 
drug discontinuation
c.
Are using hormonal contraceptives, but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study and for 28 days after study drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless they have 
been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
29. Male subjects who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 28 days after 
study drug discontinuation).  No sperm donation is allowed during the study period and for 
28 days after study drug discontinuation.
Study Treatment(s)
Test drug 
Belviq XR (lorcaserin hydrochloride) will be provided as orange-colored, round, film-coated,
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biconvex tablets with one 20-mg tablet administered orally QD.
Comparator Drug
Matching placebo, 1 tablet administered orally QD
Duration of Treatment
Prerandomization Phase:  30 days
Randomization Phase:  56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal 
preparations, are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days with study medication temporarily stopped for that 
time period and resumed the next day after the OTC cold medicine is stopped.  Any of the following 
serotonergic agents or other agents in combination with Belviq XR are prohibited:
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort

tryptophan

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (eg, Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
Assessments
Efficacy Assessments

Body weight and height will be measured to calculate BMI; BMI will then be used to 
calculate the proportion (%) of patients achieving at least a 5% and at least a 10% BMI 
reduction.

Measurement of systolic and diastolic BP, heart rate, triglycerides, total cholesterol, high 
density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, fasting 
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plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and Homeostasis Model 
Assessment (HOMA) IR to assess cardiovascular and metabolic risk profiles from Baseline 
to Week 52

Prehypertension and primary hypertension as defined by the Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents
Pharmacokinetic Assessments
Plasma lorcaserin concentrations will be measured at Weeks 12, 28, 36, and 52 for analysis of 
population PK.  At Weeks 12, 28, and 52, subjects will be instructed to take their morning dose at the 
clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken at 
each of these visits: within 30 minutes before dosing and within 1 to 3 hours after dosing.  At the 
Week 36 visit, subjects will take the morning dose at home, and 1 blood sample for determination of 
plasma concentrations of lorcaserin will be collected at the investigational site within 4 to 6 hours 
after dosing.
Pharmacodynamic Assessments

Change from baseline in BMI and body weight

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in BMI and 
body weight
Other PD endpoints will be considered based on the data at the end of the study to explore their 
relationships with lorcaserin plasma exposure.
Pharmacogenomic/Pharmacogenetic Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious 
adverse events (SAEs); electrocardiograms (ECGs); laboratory evaluation for hematology, thyroid 
function, adrenal function and biochemical blood and urine biomarkers of bone health; blood 
chemistry and urine values; neuropsychiatric events; periodic measurement of vital signs,
neuromuscular signs for screening potential serotonin syndrome, and signs or symptoms of priapism 
and prolactinemia; and performance of physical examinations.
In patients with potential 
prolactin-related AEs, such as galactorrhea, changes in libido, or changes to menstrual cycle, 
prolactin level will be measured and assessed.
Study drug effect on growth of children and 
adolescents will be evaluated using the CDC growth chart at Baseline, and Weeks 5, 12, 28, 36, 52, 
and at Follow-Up; a full physical examination, at Baseline, Weeks 12, 28, 52, and at Follow-Up; and 
bone age determination by x-ray of the hand at Baseline, Weeks 12, 28, and 52.
Children and 
adolescent sexual maturation will be evaluated by assessing sex hormones and self-reported changes 
in Tanner Staging at Baseline, Weeks 28 and 52, and at Follow-Up. Any subject with symptoms or 
signs of cardiac valvular disease or PH will be further evaluated by centralized echocardiogram
assessments.
The assessments will be adjudicated and be followed up by echocardiogram
assessments at end of the study.
The events of confirmed United States Food and Drug 
Administration (FDA) defined valvulopathy and PH will be captured in AE electronic Case Report 
Form (eCRF).
The (C-SSRS) will be used to assess all children and adolescents in the study for any signal of 
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depression or suicidal ideation or behavior.  Additionally, mood will be assessed using the CDI-2 and 
effects on cognitive function will be assessed using WRAML-2.
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography method coupled with 
tandem mass spectrometry.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

Change in BMI from Baseline to Week 52
Key Secondary Efficacy Endpoint

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
Other Secondary Efficacy Endpoints

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52 

Percentage change in BMI from Baseline to Week 52

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) 
from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
Analysis Sets

The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 post dose safety assessment.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of adherence to 
study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater 
compliant with study medication, completed the study, have no major protocol deviations, have 
no violations of inclusion or exclusion criteria, and have BMI data at Baseline and Week 52.  
The determination of subjects to be excluded from this population based on the above criteria 
and a list of major protocol violations will be included in the statistical analysis plan (SAP) and 
finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD 
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parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who 
have at least 1 adequately documented measurement of body weight.
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, and the PP will be used as 
a supportive analysis.  Unless otherwise specified, a 2-sided α=0.05 significance level will be used in 
all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change from 
baseline in BMI will be analyzed using the mixed effect model repeated measurement analysis 
(MMRM) with factors of treatment visits (Baseline, Week 1, 5, 8, 12, 20, 28, 36, 44, and 52), age 
group (9 to 11 years old and 12 to 17 years old), sex (male and female), treatment-by-visit interaction 
as fixed effect, subjects as random effect, and the baseline BMI as a covariate.  The unstructured 
covariance matrix will be used in the analysis and the treatment comparison at Week 52 will be the 
event of interest.  In case of a convergence issue, the Toeplitz covariance structure will be used in the 
model.
Subgroup analyses and additional sensitivity analyses will be performed as appropriate including 
multiple imputation methods assuming the missing values are missing at random (MAR) and missing 
not at random (MNAR) to handle missing data.
The following analyses will be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated based on 
the PP.

Multiple imputation (MI):  the same primary efficacy analyses described above will be 
analyzed using MI for impute the missing data, assuming the missing values are MAR and 
MNAR.

Change from baseline in standardized BMI score (Z-score):  The same primary efficacy 
analyses described above will be repeated using Z-score.
Additional sensitivity analyses may also be explored and described in the SAP, if deemed 
appropriate.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 5% BMI 
reduction at Week 52. The secondary efficacy endpoint will be analyzed only if the test for the 
primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be analyzed using 
a logistic regression model with factors of treatment, age group (9 to 11 years old and 12 to 17 years 
old), sex (male and female), and baseline BMI as a covariate using FAS.  Subjects with any missing 
assessment at Week 52 will be considered as treatment failures in this analysis.
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Other Secondary Efficacy Analyses
In general, for all other secondary efficacy endpoints, the continuous variables will be analyzed using 
MMRM and categorical variables will be analyzed using the Cochran Mantel Haenszel test, 
Chi-square test, or logistic regression as appropriate.  Additional analysis may be performed as 
needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including age group (9 to 
11 years old and 12 to 17 years old), sex (male and female), and race (white, black, Asian, and other).  
Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and sensitivity 
analyses.
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling. The effect of covariates such as baseline characteristics or 
demographics on PK will be explored. Derived exposure parameters such as the maximum observed 
concentration and the area under the concentration-time curve from time 0 to 24 hours at steady-state 
will be calculated from the final PK model using individual posterior estimates of the PK parameters 
and from dosing history. The PK analysis set will be used for this analysis.
Pharmacodynamic Analyses
Probability of achieving at least a 5% and at least a 10% body weight reduction and change from 
Baseline in body weight will be assessed as the PD analysis.  The PD analysis set will be used for this 
analysis.
Other assessments (eg, BMI change, percentage of BMI change, proportion [%] of patients achieving 
≥10% BMI reduction, and change in waist circumference from baseline) will also assessed as part of 
the PD analysis.  The PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between lorcaserin plasma 
exposure and response, including but not limited to change in body weight from baseline and the 
probability of achieving at least a 5% and at least a 10% change in body weight from baseline to
Week 52.  Additionally, exposure-safety relationships for select safety parameters may be explored 
graphically depending on the data at the end of study.  Any emergent relationship may be modeled as 
appropriate.  Any parameters based on the study data may be considered for exploratory assessment 
for its relationship to PK.
Pharmacogenomic/Pharmacogenetic Analyses
Not applicable
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments including the 
incidence of AEs (including changes from baseline in physical examination), growth (CDC growth 
chart and bone age determined by x-ray of the hand), sexual maturation (Tanner Staging), 
out-of-normal-range laboratory safety test values, change from baseline in laboratory safety test 
values (including biomarkers), ECGs, and vital sign measurements will be summarized by treatment 
group using descriptive statistics or frequency count as appropriate.  In addition, suicidal ideation, 
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cognitive function, behavior, and mood will be evaluated by the C-SSRS, WRAML-2, CDI-2, and 
C-SSRS, respectively, and will also be summarized by treatment group using descriptive statistics or 
frequency count as appropriate. All WRAML-2 raw scores from the Core Battery will be converted 
to age and gender standard scores for purposes of intra individual comparisons
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
Interim Analyses
Not applicable
Sample Size Rationale
The proposed sample size is based on the comparison of the primary efficacy endpoint, change in 
BMI from Baseline to Week 52 between the Belviq XR 20-mg treatment group and placebo group.  
Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 360 subjects in a 1:1 ratio 
(n=180 in the Belviq XR 20-mg treatment group; n=180 in the placebo group) will have at least 
90% power to detect a treatment difference of 1 kg/m2 in BMI, using a 2-sided t-test with α=0.05.  
Assuming the proportion of subjects achieving at least a 5% BMI reduction at Week 52 is 20% for 
the placebo group and a 40% dropout rate, this sample of 360 subjects (180 subjects for Belviq XR 
20 mg and 180 subjects for placebo) will also have greater than 85% power to detect an absolute 
difference of 20% between the Belviq XR 20-mg group and the placebo group, using a 2-sided 
Fisher’s Exact test with α=0.05. The assumption used in the sample size calculation is based on the 
2 pivotal lorcaserin studies APD356-009 and APD356-011 in obese and overweight non-diabetic 
adult subjects.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................13
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................17
5
ETHICS............................................................................................................................19
5.1
Institutional Review Boards/Independent Ethics Committees ..............................19
5.2
Ethical Conduct of the Study.................................................................................20
5.3
Subject Information and Informed Consent...........................................................20
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................22
7
INTRODUCTION ...........................................................................................................23
7.1
Indication ...............................................................................................................23
7.1.1
APD356/Belviq (lorcaserin hydrochloride).................................................24
7.1.1.1
Mechanism of Action...........................................................................24
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin 
hydrochloride)......................................................................................24
7.2
Study Rationale......................................................................................................25
8
STUDY OBJECTIVES....................................................................................................27
8.1
Primary Objective..................................................................................................27
8.2
Secondary Objectives.............................................................................................27
9
INVESTIGATIONAL PLAN..........................................................................................29
9.1
Overall Study Design and Plan..............................................................................29
9.1.1
Prerandomization/Pretreatment Phase .........................................................29
9.1.1.1
Screening Period..................................................................................29
9.1.2
Randomization/Treatment Phase .................................................................30
9.1.3
Extension Phase ...........................................................................................30
9.2
Discussion of Study Design, Including Choice of Control Groups.......................30
9.3
Selection of Study Population................................................................................31
9.3.1
Inclusion Criteria .........................................................................................31
9.3.2
Exclusion Criteria ........................................................................................32
9.3.3
Removal of Subjects From Therapy or Assessment....................................35
9.4
Treatments..............................................................................................................35
9.4.1
Treatments Administered.............................................................................35
9.4.2
Identity of Investigational Product...............................................................35
9.4.2.1
Chemical Name, Structural Formula of Belviq XR.............................35
9.4.2.2
Comparator Drug .................................................................................36
9.4.2.3
Labeling for Study Drug......................................................................36
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9.4.2.4
Storage Conditions...............................................................................37
9.4.3
Method of Assigning Subjects to Treatment Groups...................................37
9.4.4
Selection and Timing of Dose for Each Subject..........................................37
9.4.5
Blinding........................................................................................................37
9.4.6
Prior and Concomitant Therapy...................................................................38
9.4.7
Treatment Compliance.................................................................................39
9.4.8
Drug Supplies and Accountability...............................................................39
9.5
Study Assessments.................................................................................................41
9.5.1
Assessments.................................................................................................41
9.5.1.1
Demography.........................................................................................41
9.5.1.2
Baseline Assessments ..........................................................................41
9.5.1.2.1
Medical History .............................................................................41
9.5.1.3
Efficacy Assessments...........................................................................41
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................41
9.5.1.4.1
Pharmacokinetic Assessments .......................................................41
9.5.1.4.2
Pharmacodynamic Assessments ....................................................42
9.5.1.4.3
Pharmacogenomic/Pharmacogenetic Assessments........................42
9.5.1.5
Safety Assessments..............................................................................42
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...43
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................45
9.5.1.5.3
Laboratory Measurements .............................................................46
9.5.1.5.4
Vital Signs and Weight Measurements..........................................47
9.5.1.5.5
Height Measurements ....................................................................48
9.5.1.5.6
Physical Examinations...................................................................48
9.5.1.5.7
Electrocardiograms ........................................................................48
9.5.1.5.8
Other Safety Assessments..............................................................49
9.5.1.6
Other Assessments...............................................................................49
9.5.1.6.1
Pregnancy Test...............................................................................49
9.5.1.6.2
Urine Drug and Cotinine Test........................................................49
9.5.2
Schedule of Procedures/Assessments ..........................................................50
9.5.2.1
Schedule of Procedures/Assessments ..................................................50
9.5.2.2
Description of Procedures/Assessments Schedule...............................54
9.5.2.3
Total Volume of Blood Sampling........................................................54
9.5.3
Appropriateness of Measurements...............................................................54
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................55
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9.5.4.1
Reporting of Serious Adverse Events..................................................55
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................55
9.5.4.3
Reporting of Events Association with Special Situations....................56
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................56
9.5.4.3.2
Reporting of Study-Specific Events...............................................57
9.5.4.4
Expedited Reporting ............................................................................57
9.5.4.5
Breaking the Blind...............................................................................57
9.5.4.6
Regulatory Reporting of Adverse Events ............................................58
9.5.5
Completion/Discontinuation of Subjects.....................................................58
9.5.6
Abuse or Diversion of Study Drug ..............................................................59
9.5.7
Confirmation of Medical Care by Another Physician .................................59
9.6
Data Quality Assurance .........................................................................................59
9.6.1
Data Collection ............................................................................................59
9.6.2
Clinical Data Management ..........................................................................59
9.7
Statistical Methods.................................................................................................60
9.7.1
Statistical and Analytical Plans....................................................................60
9.7.1.1
Study Endpoints...................................................................................60
9.7.1.1.1
Primary Efficacy Endpoint ............................................................60
9.7.1.1.2
Secondary Efficacy Endpoints.......................................................60
9.7.1.2
Definitions of Analysis Sets.................................................................61
9.7.1.3
Subject Disposition..............................................................................61
9.7.1.4
Demographic and Other Baseline Characteristics ...............................61
9.7.1.5
Prior and Concomitant Therapy...........................................................62
9.7.1.6
Efficacy Analyses ................................................................................62
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................63
9.7.1.7.1
Pharmacokinetic Analyses.............................................................63
9.7.1.7.2
Pharmacodynamic Analyses..........................................................63
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................64
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................64
9.7.1.8
Safety Analyses....................................................................................64
9.7.1.8.1
Extent of Exposure.........................................................................64
9.7.1.8.2
Adverse Events ..............................................................................64
9.7.1.8.3
Laboratory Values..........................................................................66
9.7.1.8.4
Vital Signs......................................................................................66
9.7.1.8.5
Electrocardiograms ........................................................................66
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9.7.1.8.6
Other Safety Analyses....................................................................67
9.7.2
Determination of Sample Size .....................................................................67
9.7.3
Interim Analysis...........................................................................................67
9.7.4
Other Statistical/Analytical Issues ...............................................................67
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................67
10
REFERENCE LIST .........................................................................................................68
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......70
11.1
Changes to the Protocol .........................................................................................70
11.2
Adherence to the Protocol......................................................................................70
11.3
Monitoring Procedures...........................................................................................70
11.4
Recording of Data..................................................................................................71
11.5
Identification of Source Data.................................................................................71
11.6
Retention of Records..............................................................................................72
11.7
Auditing Procedures and Inspection......................................................................72
11.8
Handling of Study Drug.........................................................................................72
11.9
Publication of Results ............................................................................................73
11.10 Disclosure and Confidentiality ..............................................................................73
11.11 Discontinuation of Study .......................................................................................73
11.12 Subject Insurance and Indemnity...........................................................................74
12
APPENDIX......................................................................................................................75
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests...........................................................................47
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 .........51
Table 3
Summary of Blood Sample Volumes ........................................................54
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
AUC
area under the concentration-time curve
AUC(0-inf)
area under the concentration-time curve from time zero to infinity
BID
twice per day
BMI
body mass index
BP
blood pressure
CDC
Centers for Disease Control and Prevention
CDI-2
Children’s Depression Inventory 2
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DEA
Drug Enforcement Administration
ECG
electrocardiogram
eCRF
electronic case report form
EOS
end of study
EOT
end of treatment
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDL
low density lipoprotein
LNH
low/normal/high
IxRS
interactive voice or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Term
MAR
missing at random
MI
multiple imputation
MMRM
mixed effect model repeated measurement analysis
MNAR
missing not at random
NTX
N-telopeptide
OC
osteocalcin
OTC
over-the-counter
PD
pharmacodynamic(s)
PG
pharmacogenetic(s)
PH
pulmonary hypertension
PI
principal investigator
PICP
carboxyterminal propeptide of type I procollagen
PK
pharmacokinetic(s)
PP
Per Protocol Analysis Set
PT
preferred term
QD
once daily
QTc
corrected QT interval
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SMD
standardized mean difference
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
system organ class
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T4
thyroxine
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States
WBC
white blood cell
WRAML-2
Wide Range Assessment of Memory and Learning-2
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, Informed Consent Form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (ICH E6), Section 3, and any local regulations 
(eg, Federal Regulations, Title 21 Code of Federal Regulations [21 CFR] Part 56).  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB/IEC for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in clinical research associate [CRA], change of telephone number[s]).  
Documentation of IRB/IEC compliance with the ICH E6 and any local regulations regarding 
constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
within 90 days.  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/IEC with a summary of the study’s 
outcome.
In the case of early termination or a temporary halt of the study, the investigator should 
notify the IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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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
•
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with 
ICH E6, Section 4, and all applicable local regulations (Federal Regulations, 
Title 21 CFR Part 50, for studies in the United States).  Each subject must sign an approved 
ICF before study participation.  The form must be signed and dated by the appropriate 
parties.  The original, signed ICF for each subject will be verified by the sponsor and kept on 
file according to local procedures at the site.
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The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
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7
INTRODUCTION
7.1
Indication
Obesity
Obesity has become a global epidemic in western civilization, causing a serious public health 
concern.  In the United States, the prevalence of obesity in adolescents ages 12 and 19 years
has almost doubled over the past 2 decades.  The rate increased from 10.5% between 1988 
and 1994 to 20.5% between 2011 and 2012 (CDC/NCHS, 2013).  The prevalence of obesity 
in children in United States is also high.  The United States Centers for Disease Control and 
Prevention (CDC) reported in 2012 that 17.7% of children ages 6 to 11 years are obese.
Obesity in children and adolescents, defined in the United States as greater than or equal to 
the 95th percentile in gender- and age-specific body mass index (BMI), continues to grow at 
an alarming rate in the United States and globally.  Based on data (Wang and Lobstein, 2006) 
using various criteria for the definition of obesity that included more than 30 countries in 
Europe, North America, Asia, and the West Pacific, prevalence of obesity in these countries 
has also increased significantly, at a rate comparable to that in the United States.
Childhood and adolescent obesity has many negative implications for both the health and 
well-being of the individual as well as for society.  These include increased susceptibility to a 
host of diseases, chronic health disorders, psychological disorders, and premature death 
(Flegal, et al., 2005; Rofey, et al., 2009).  Increases in the prevalence of overweight and 
obese adolescents may result in a decrease in life expectancy for the 1st time in 200 years
(Peeters , et al, 2003).
As a result, there is a significant impact on the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately $14 billion per year in the United 
States (Trasande and Chatterjee, 2009).  Obesity-related medical costs in general are
expected to rise significantly because today’s obese children are likely to become tomorrow’s 
obese adults.
Current approaches to weight management include lifestyle modification, pharmacotherapy, 
and invasive bariatric procedures.  Lifestyle modification involves a combination of diet, 
exercise, and behavioral change, and is the preferred and essential strategy for weight 
management in obese and overweight individuals.  Although lifestyle modification can be 
very efficacious in some patients, adherence to the prescribed regimens is often poor.  As 
such, lifestyle modification alone is often not adequate and the weight loss is often transient.  
On the other hand, bariatric surgery and various other invasive procedures are generally 
reserved for the severely obese population. 
Pharmacotherapy can play a significant role in weight management programs, and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise.
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The current standard of care for treatment of obesity in pediatric subjects ranges from 
lifestyle intervention in children less than 8 years of age to use of pharmacotherapy in 
adolescents over 12 years of age (McGovern, et al, 2008; Spear, et al, 2007).  Xenical®
(orlistat) is currently the only product available for weight control in obese adolescent 
patients 12 to 16 years of age.  However, it is associated with gastrointestinal side effects 
(Xenical PI. 2015), and the treatment effect of Xenical is modest. In a study that included 
539 obese adolescents with BMI above the 97th percentile, Xenical demonstrated a 0.86 BMI 
reduction relative to placebo after 52 weeks of treatment (-0.55 BMI in the Xenical treatment 
group versus +0.31 BMI in the placebo group) (FDA, 2003; Chanoine, et al, 2005).
Obtaining maximum retention in the study is a major goal in order to minimize missing data.  
A number of strategies have been used in prior adolescent weight loss studies that will be 
used in the present study to help retain participants.  These include a highly trained and 
competent staff, ample waiting area, readily available parking (at no cost), access to mass 
transit, and reminder and follow-up calls.  In addition, we will provide fun and interactive 
group sessions with games and hands-on nutrition and physical activity demonstrations, 
random raffle drawings, social events, birthday and holiday cards, and newsletters.  Families 
will receive a reimbursement of $30 per family for assessments completed at Baseline and 
Month 6, and $100 at Month 12.
Further, we will make home visits for assessments for 
families, as needed, to maximize data collection. We anticipate achieving a 75% or greater 
retention rate at Month 12.
By using these retention strategies, we hope that we will 
maximize participant retention, which will help us cope with missing data.
7.1.1
APD356/Belviq (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
Belviq is a selective serotonin 2c receptor agonist which was approved by the US Food and 
Drug Administration (FDA) on 27 Jun 2012 as an adjunct to a reduced-calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI of at 
least 30 kg/m2 (obese), or adult patients with a BMI greater than or equal to 27 kg/m2
(overweight) in the presence of at least 1 weight-related comorbid condition.
7.1.1.2
Clinical Experience with APD356/Belviq (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of Belviq in studies of more than 7700 adult subjects, 
including 604 subjects with Type 2 diabetes mellitus, demonstrated clinically meaningful 
efficacy and a safety profile that includes minimal and easily managed risks.  In each of the 
individual studies and in the pooled efficacy analyses, the Belviq dose met the following 
prespecified endpoints:
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
A significantly greater proportion of adult subjects taking Belviq 10 mg twice per day 
(BID) (47%) lost at least 5% of baseline body weight at 52 weeks as compared to 
subjects taking placebo (23%).  A significantly greater proportion of subjects taking 
Belviq 10 mg BID (22.4%) lost at least 10% of baseline body weight at 1 year as 
compared to subjects taking placebo (8.7%). 

The mean weight loss at 1 year in adult subjects taking Belviq 10 mg BID (-5.8 kg) 
was significantly greater than that in subjects taking placebo (-2.5 kg).
An integrated evaluation of the data from the pediatric, adolescent, and adult subjects 
revealed that the relationship between lorcaserin area under the curve (AUC) and body 
weight in pediatric and adult subjects is consistent irrespective of the individual studies or 
age range of the study population. Irrespective of age, lorcaserin AUC values in the pediatric 
subjects with body weight of greater than 60 kg overlapped with the data observed from the 
studies involving adult subjects, suggesting a fixed dose approach similar to adults can be 
used for children and adolescent subjects with body weight greater than 60 kg.
In preadolescent and adolescent obese populations, it is anticipated that Belviq XR will result 
in similar effects.
As part of FDA postmarketing requirements, this study is designed to 
characterize the efficacy and safety of Belviq XR in adolescent obese populations in the 
United States, as well as in children ages 9 to 11 years.  It is also intended to support an 
indication for chronic weight management for obese children and adolescents ages 9 to 
17 years. Thirty percent of the subjects 9 to 11 years of age from this study will be stratified 
and added to the 50 subjects 6 to 8 years of age in the open label pharmacokinetic (PK) only 
cohort in the APD356-404 study to be used to support a safety population (n=110) in the 
open label study designed for obese subjects 6 to 8 years of age using partial extrapolation 
with PK for efficacy.
7.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product for children and 
adolescents.  In adults, the Division’s 2007 draft Guidance for Industry Developing Products 
for Weight Management indicate that the product needs to satisfy either of the following
mean or categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant.

The proportion of subjects who lose at least 5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of 
subjects in the placebo-treated group who lose at least 5% of baseline body weight, 
and the difference between groups is statistically significant.
FDA awarded a weight management indication for Belviq based on Phase 3 study results 
which achieved the categorical criteria. In a Phase 3 study, a significantly greater proportion 
of subjects taking Belviq (47%) lost at least 5% of baseline body weight at 1 year as 
compared to subjects taking a placebo (23%).  It is anticipated that a similar effect will be 
demonstrated in older children (9 to 11 years of age) and obese adolescents, where weight 
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loss will be assessed using BMI measurements to account for growth. In this study, the 
objective is to demonstrate that BMI reduction will be achieved during 52 weeks of treatment 
with Belviq XR 20 mg administered once daily (QD) compared to placebo in obese children 
and adolescents.
In the Phase 3 orlistat study in obese adolescents and children mentioned above, the 
proportion of subjects who lost at least 5% body weight is relatively low. At the end of the 
study at Week 52, only 26.5% of the subjects achieved a 5% or greater BMI reduction 
compared to 15.7% in the placebo group. The placebo-corrected BMI reduction was about 
0.86 kg/m2.  
There are limited trials for weight reduction in the adolescent population, ages 12 to 17 years,
and none in children under the age of 9 years (Peirson, et al, 2015).  Thirty-one studies 
(29 behavioral, 2 pharmacological and behavioral) were included in a meta-analysis of 
randomized studies conducted in primary care centers in overweight and obese children and 
youth ages 2 to 18 years using behavioral (diet, exercise, and lifestyle) and pharmacological 
interventions and providing 6-month postbaseline BMI or prevalence of overweight or 
obesity. 
Both interventions showed a significant effect on BMI in favor of treatment 
(behavioral: 
standardized mean difference [SMD] -0.54, 95% confidence interval 
[CI] -0.73, -0.36; orlistat plus behavioral: SMD -0.43, 95% CI -0.60, -0.25). The studies 
reported no significant difference between groups in the likelihood of reduced prevalence of 
overweight or overweight and obese. A great deal of variation was noted across efficacious 
interventions.
In conclusion, this meta-analysis demonstrated low-quality evidence that 
behavioral treatments alone are associated with a smaller effect in terms of reduced BMI 
compared with the effect shown by combined behavioral and pharmacological interventions. 
This may be because the effect size in the randomized, double blind, placebo controlled,
phase 3 orlistat study in adolescents was relatively low and there was a lack of maintenance 
effect. These subjects started to regain their BMI after 6 months of treatment. At end of the 
study, only 26.5% of subjects achieved a 5% or greater BMI reduction compared to 15.7% in 
placebo group. In a sibutramine Phase 3 study in obese adolescents, a substantially higher 
proportion of subjects (69%) treated with sibutramine achieved at least a 5% BMI reduction 
compared to 21% of subjects in the placebo group. In addition, sibutramine resulted in a
substantial reduction in mean BMI (between-group difference, 2.9 kg/m2) and mean weight 
(between-group difference, 8.4 kg) compared to placebo (Berkowitz, et al, 2006).  Unlike the 
weight loss effect of Belviq in adults and sibutramine in adolescents, subjects in the orlistat 
study started to increase their BMI after 6 months of treatment.
In this proposed study, it is assumed that treatment with Belviq XR 20 mg will lead to a BMI
reduction of more than 1 kg/m2, and a higher proportion of subjects will achieve more than a 
5% and 10% BMI reduction compared to placebo.  A between-group difference of 24% is the 
basis for the conservative assumption of a 20% effect size in the current study.
In addition, the total sample size of 360 subjects will be adequate to assess safety and 
exposure based on previous adolescent studies with weight management products (orlistat 
and sibutramine) (FDA, 2003; Chanoine, et al, 2005; Berkowitz, et al, 2006) and other 
metabolic or dyslipidemia medication products (ezetimibe, simvastatin) (FDA, 2007).
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8
STUDY OBJECTIVES
8.1
Primary Objective
To demonstrate weight loss efficacy by change in BMI during 52 weeks of treatment 
with Belviq XR 20 mg administered QD as compared to placebo
8.2
Secondary Objectives
KEY SECONDARY OBJECTIVE
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with a at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 
20 mg administered QD as compared to placebo
OTHER SECONDARY OBJECTIVES 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of 
subjects with at least a 5% reduction in BMI after an initial 12 weeks of treatment 
with Belviq XR 20 mg administered QD compared to placebo

To demonstrate weight loss efficacy by percentage change from baseline in BMI 
during 52 weeks of treatment with Belviq XR 20 mg administered QD compared 
to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:
•
Other weight loss effects (eg, proportion [%] of subjects achieving at least 
a 10% BMI reduction, change in waist circumference) at the end of 
52 weeks of treatment
•
Effects on glycemia, insulin levels, and Homeostatic Model Assessment of 
Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin [mU/L] / 405)
during 52 weeks of treatment
•
Changes in cardiovascular risk factors associated with obesity 
(eg hypertension, dyslipidemia) during 52 weeks of treatment
•
To assess the safety of Belviq XR, including the effects on cognitive function by 
Wide Range Assessment of Memory and Learning-2 (WRAML-2), on mood by 
Children’s Depression Inventory 2 (CDI-2), on signal of suicidal ideation or behavior 
with the Columbia-Suicide Severity Rating Scale (C-SSRS), on growth measured by 
CDC growth chart, on sexual maturation measured by Tanner Staging scores, and on 
other growth and development parameters by measuring sex hormones, thyroid 
function, adrenal function, bone age, and biochemical markers of bone health.
•
To assess the PK of lorcaserin using population PK modeling
•
To assess relationships between plasma exposure to lorcaserin and pharmacodynamic 
(PD) parameters including but not limited to reduction from baseline in BMI and 
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body weight and probability of achieving at least a 5% and at least a 10% reduction in 
BMI and body weight from baseline at Week 52 using population PK/ PD modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese children and adolescents ages 9 to 17 years.  Approximately 360 subjects will be 
randomized in a 1:1 ratio to Belviq XR 20 mg QD (180 subjects) and placebo (180 subjects).  
Subjects will be stratified by age group and sex.  At least 30% of total subjects should be 
ages 9 to 11 years for the reasons outlined above in Section 7.1.1.2.  Subjects will receive 
Belviq XR 20 mg or placebo QD in a 1:1 ratio for up to 52 weeks. Throughout the duration 
of the study, subjects will be encouraged to adhere to a lifestyle modification program that 
includes diet and exercise counseling (see Appendix 2).  
The study will consist of 2 phases:
Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-Up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period will extend from the 
End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be re-screened only once after 60 days.  All subjects will 
continue in the study until the 52-week evaluation is completed.  Subjects who discontinue 
treatment prematurely will be followed up until study completion.
9.1.1
Prerandomization/Pretreatment Phase
Screening will occur during the Prerandomization Phase at Visit 1
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and assent and to 
establish protocol eligibility.  Procedures to be followed when obtaining informed consent 
are detailed in Section 5.3.  Careful initial screening is important in the recruitment of 
families who both fully understand the requirements of this 1 year, randomized, controlled 
trial and are truly interested in participation.  Interested caregivers and adolescents will be 
screened by phone to assess preliminary entry criteria.  Candidates will be given a brief 
description of the program and general study requirements, with an adolescent and a 
caregiver who is willing to participate.  If preliminary entry criteria are met, adolescents and 
their caregivers will be invited to an initial in-clinic meeting to further discuss the study.  A 
complete description of the study including assessments, the number of visits, the lifestyle 
program, the fact that the adolescent would be taking either the study drug or a placebo, the
duration of the study, and the necessity of having an adolescent wishing to participate as well 
as a participating caregiver will be described.  Consent and assent will be obtained and copies 
of the signed forms will be provided to families.  The importance of the study and its 
scientific merit will be discussed.  Ineligible adolescents will be referred to local weight 
management resources.  Screening period assessments and timing thereof are shown in 
Section 9.5.2.
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9.1.2
Randomization/Treatment Phase
The Randomization Phase will consist of 2 periods: the Treatment Period and the Follow-Up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency of Belviq XR in this study is 20 mg QD.  The PK 
parameters of a single 10-mg dose of Belviq were evaluated in healthy, adolescent obese 
subjects in Study APD356-025 and healthy, obese pediatric subjects ages 6 to 11 years in 
Study APD356-A001-026.  Overall, the PK parameters of Belviq and its main metabolites, 
M1 and M5, were similar to those in adults.  Following a single, oral administration of 
Belviq 10 mg to a total of 8 healthy adolescent (age 12 to 17 years) obese subjects, the mean 
maximum concentration observed and the area under the concentration-time curve from time 
zero to infinity (AUC(0-inf)) were 36.5 ng/mL and 464 hr×ng/mL, respectively.  The mean 
Belviq terminal phase half-life was 9.70 hours, similar to that observed in adults, thus 
supporting a similar dosing frequency (QD) in adolescent subjects.
Additionally, a single dose PK study in 8 healthy obese pediatric subjects ages 6 to 11 years 
of age was recently completed.
The PK analysis after a single 10-mg dose of lorcaserin 
revealed that the lorcaserin AUC(0-inf) values tended to increase with decreasing body weight 
and age. However, the body weight normalized AUC(0-inf) values were similar across the age 
groups, therefore the data indicated no effect of age on the lorcaserin PK.
Integrated 
assessment of the PK versus body weight relationship, pooling the data from pediatric and 
adult subjects from previous studies, suggested that the lorcaserin area under the curve values 
for subjects with body weight of at least 60 kg overlapped with the area under the curve
values from adolescents and adults. Therefore, no dose adjustment relative to adults and 
adolescents is deemed necessary for pediatric subjects with a body weight of at least 60 kg.
Based on CDC growth charts, the likelihood of enrolling subjects who are younger than 
9 years of age with body weight of at least 60 kg is low; therefore, the current study is 
designed to enroll the subjects between 9 to 17 years of age.
The targeted study population comprises 360 obese children and adolescents 9 to 17 years of
age.
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI in or 
above the 95th percentile (Barlow, 2007).
Obesity in children will be identified using 
gender- and age-specific BMI measurement.  Obesity in children (9 to 11 years of age) is 
defined by The American Academy of Pediatrics 2007 recommendation as BMI in the 
99th percentile and at least 1 co-morbidity (Spear, et al, 2007).
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The proposed patient population is consistent with the recommendations in the 
2007 American Academy of Pediatrics article, Recommendations for Treatment of Child and 
Adolescent Overweight and Obesity (Spear, et al, 2007), which supports medication use in 
the 6 to 11 year age group as part of a staged approach (Tertiary Care Intervention in patients 
with a BMI 99th percentile and at least 1 co-morbidity).  Although we acknowledge that 
recommendations are not necessarily different for the older children and adolescents in this 
publication, utilizing broader inclusion criteria in the 12 to 17 year age group allows for more 
generalizability, whereas the more stringent approach in the 6 to 11 year age group better 
balances potential benefits with some of the uncertainties of treatment in this age group.
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, 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 700 subjects will be screened to ensure that 360 subjects will be randomized.
Subjects who do not meet all inclusion criteria or do meet any exclusion criteria will not be 
eligible to receive study drug. Subjects who screen fail can be re-screened only once after 
60 days.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Healthy male or female adolescents, age 12 to 17 years at Screening, with a BMI that 
is greater than or equal to the United States (US)-weighted mean of the 
95th percentile based on age and sex, but is less than 44 kg/m2
OR
Healthy male or female children, age 9 to 11 years at Screening, with a BMI that is 
greater than or equal to the US-weighted mean of the 99th percentile based on age 
and sex, but is less than 44 kg/m2, and a body weight greater than 60 kg associated 
with at least 1 co-morbid weight-related condition (eg, type 2 diabetes mellitus, 
hypertension, dyslipidemia)

Type 2 Diabetes is defined by American Diabetes Association Standards of 
Diabetes Care, 2013.

Prehypertension and primary hypertension as defined by the Expert Panel on 
Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents (Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents, 
2011).
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
Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents 
(Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents, 2011).
2. Subjects and their families are not planning to move away from the area for the 
duration of the study
3. Subjects able and willing to comply with all aspects of the study, including a 
reduced-calorie diet and an increased physical activity program
4. Subjects considered in stable health in the opinion of the investigator
5. Caregivers or guardians meet the following requirements:
a.
Able and willing to support and supervise study participation in the opinion of the 
investigator, including consideration of any existing physical, medical, or mental 
condition that prevents compliance with the protocol
b. Able and willing to personally comply with and execute all aspects of the study 
requirements for the caregivers or guardians
c.
No history of Attention Deficit Hyperactivity Disorder, substance abuse, 
depression, suicidal ideation/behavior, bipolar disorder, or schizophrenia.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 1 month before randomization that may 
affect the subject’s ability to fulfill the study requirements or significantly confound 
the assessments
2. Subjects who cannot swallow investigational products
3. Documented pulmonary hypertension (PH) by objective assessments (ie, imaging
modality or cardiac catheterization)
4. Known 
valvular disease 
defined by 
clinical diagnosis 
or 
most recent 
echocardiography.  History of valvular disease is allowed if it has been corrected by 
valve replacement or repair.
5. Significant renal or hepatic disease as evidenced by a serum creatinine greater than 
1.5×upper limit of normal (ULN), serum transaminases greater than 3×ULN, or total 
bilirubin greater than 1.5×ULN in absence of Gilbert’s syndrome
6. Any history of anorexia or bulimia within 2 years before Screening, Attention Deficit 
Hyperactivity Disorder, any Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition depressive disorder, suicidal ideation or behavior, bipolar disorder, or 
schizophrenia
7. Known secondary causes (chromosomal, endocrine, or metabolic) for obesity 
(eg Prader-Willi syndrome, Bardet Biedl syndrome, Down’s Syndrome, untreated 
hypothyroidism, Cushing’s syndrome, daily systemic corticosteroid exposure for 
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longer than 30 days, history of significant exposure to corticosteroids for chronic 
illness during the past year, and known genetic causes of obesity)
8. Use of other products intended for weight loss including prescription drugs, 
over-the-counter (OTC) drugs, and herbal preparations within 1 month before 
Screening
9. Use of any of the following medications:
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer) or
monoamine oxidase inhibitors (MAOIs) within 30 days before Randomization, 
including:

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 

bupropion

triptans 

St. John’s Wort 

tryptophan 

linezolid

dextromethorphan in any form (eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists
b) Others

antiseizure medications including valproic acid, zonisamide, topiramate and 
lamotrigine

oral steroids (topical and inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
10. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months 
before Screening, including but not limited to pergolide, ergotamine, methysergide, 
and cabergoline
11. History or evidence of clinically significant disease (eg, malignancy; cardiac, 
respiratory, gastrointestinal, renal, or psychiatric disease) other than prediabetes 
(impaired fasting glucose or impaired glucose tolerance), Type 2 diabetes treated with 
oral anti-diabetic agents (excluding sulfonylurea)
or
non-insulin injectable 
antidiabetic agents, obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty liver 
disease
12. Use of Belviq XR within 6
months before Screening or hypersensitivity to 
Belviq XR or any of the excipients
13. Significant change in diet or level of physical activity within 1 month before dosing 
or change in weight of more than 5 kg within 3 months before Screening
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14. Adherence to a of very-low-calorie (<1000 calories/day) weight loss diet within 
6 months before Screening
15. History of alcohol or drug dependence or abuse
16. Recreational drug use within 2 years before Screening
17. Known to be human immunodeficiency virus positive
18. Active viral hepatitis (B or C) as demonstrated by positive serology
19. Malignancy within 5 years before Screening
20. Unable to attend scheduled visits (eg, lack of transportation) or lack of a caregiver or 
guardian to supervise study participation
21. Special needs subjects who are unable to comprehend study-related instructions 
(eg, mild to profound mental retardation [IQ <70], moderate to severe cognitive 
developmental delay, pervasive development disorders, autism)
22. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure 
disorder within 6 months of screening or any time between screening and 
randomization
23. Uncontrolled hypertension, defined as blood pressure (BP) in the 95th percentile or 
greater for age, sex, and height on 2 separate readings recorded on 2 separate days.  
Subjects who had uncontrolled hypertension at Screening can be rescreened more 
than 1 month after initiation or adjustment of antihypertensive therapy one time.
24. Currently enrolled in another clinical study or has used any investigational drug or 
device within 30 days before providing informed consent
25. Planned bariatric surgery during the study
26. Not suitable to participate in the study in the opinion of the investigator, including 
consideration of any existing physical, medical, or mental condition that prevents 
compliance with the protocol
27. Female subjects who are breastfeeding or pregnant at Screening or Baseline (as 
documented by a positive β-human chorionic gonadotropin test).  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.
28. Female subjects of childbearing potential who:
a.
Had unprotected sexual intercourse within 30 days before study entry and who do 
not agree to use a highly effective method of contraception (eg, total abstinence, 
an intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study 
period and for 28 days after study drug discontinuation
b. Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexual activity during the study period and for 
28 days after study drug discontinuation
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c.
Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do not 
agree to use the same contraceptive during the study and for 28 days after study 
drug discontinuation
(NOTE:  All female subjects will be considered to be of childbearing potential unless 
they have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing]).
29. Male subjects who have not had a successful vasectomy (confirmed azoospermia) or 
they and their female partners do not meet the criteria above (ie, not of childbearing 
potential or practicing highly effective contraception throughout the study period and
for 28 days after study drug discontinuation).  No sperm donation is allowed during 
the study period and for 28 days after study drug discontinuation.
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  The subject may stop study drug or withdraw from the study at any 
time for any reason.
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of Belviq XR 20 mg or placebo orally QD.
Belviq XR (lorcaserin hydrochloride) is a Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C–IV) approved by the FDA.
Belviq XR will be provided as orange-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  Belviq XR and matching placebo will be 
supplied by the sponsor in labeled containers.
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of Belviq XR
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
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•
Molecular weight: 246.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled 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.
The clinical study labels will contain, but are not limited to the following requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal 
(US) law to investigational use.”
All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery of
the study drug to the study site, the inventory at the site, use for each subject, and return of
the study drug to a delegate of the sponsor. Total study site accountability will be conducted
at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the following 
information:

Identification (subject ID number and initials) of the subject to whom the study drug 
was dispensed
•
The dates and unique kit or carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
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All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III to V Drugs and 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.
Subjects will be centrally stratified by age group (9 to 11 years old and 12 to 17 years old)
and sex (male and female).  Within each stratum, subjects will be randomized to receive 
either Belviq XR 20 mg or placebo QD in a 1:1 ratio.  It is planned that at least 30% of the 
subjects will be enrolled into the 9 to 11 year age group.  
Randomization will be performed centrally by an interactive voice or web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized identification
numbers to be included on study packaging.  Upon signature of the ICF, the investigator or 
designee will access the IxRS to register the subject information.  At Randomization, the 
IxRS will assign each subject a unique randomization number.  At each subsequent visit 
during the Treatment Period and Follow-Up Period, the investigator or designee will access 
IxRS to obtain dispensing information and to register the subject’s visit.
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily, and be encouraged to take the study 
medication with an adequate amount of water (8 oz. or 240 mL).
9.4.5
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 the SOP.
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A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior and
Concomitant Medication Case Report Form (CRF) or Non-Pharmacological Procedures 
CRF.  The investigator will record on the Adverse Event CRF any AE for which the 
concomitant medication/therapy was administered. If the concomitant medication/therapy is 
being administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  OTC cold medicines containing 
dextromethorphan can be used for up to 7 days and study medication is temporarily stopped 
for that time period and resumed the next day after the OTC cold medicine is stopped.  Any 
of the following serotonergic agents in combination with Belviq XR is prohibited:
a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort 

tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, and lamotrigine
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
oral steroids (topical or inhaled steroids are acceptable)

stimulant medications (Ritalin, Concerta, Biphetamine and Dexedrine)

benzodiazepines
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs
will review treatment compliance during site visits and at the completion of the study.
Per visit schedule, subjects will return unused study drug and be given a new supply; pill 
counts will be made by study staff on returned medication.
9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted
•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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, where applicable
•
Financial Disclosure form(s) for the PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae of the PI including a copy of the PI’s current 
medical license or medical registration number on the curriculum vitae
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate-Form DEA 223 
(US sites only).  Must be appropriate to handle schedule IV products and not be 
expired.
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The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
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Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, and race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.3
Efficacy Assessments

Body weight and height will be measured using standard method (Lohman T, et al, 
1988) to calculate changes in BMI; BMI will then be used to calculate the proportion 
(%) of patients achieving at least a 5% and at least a 10% BMI reduction.

Measurement of systolic and diastolic BP, heart rate, triglycerides, total cholesterol, 
high density lipoprotein (HDL)
cholesterol, low density lipoprotein (LDL)
cholesterol, fasting plasma glucose, fasting insulin, hemoglobin A1c (HbA1c), and 
HOMA-IR to assess changes in cardiovascular and metabolic risk profiles from 
Baseline to Week 52

Prehypertension and primary hypertension as defined by the Expert Panel on 
Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and 
Adolescents (Expert Panel on Integrated Guidelines for Cardiovascular Health and 
Risk Reduction in Children and Adolescents, 2011)

Dyslipidemia as defined by the Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in Children and Adolescents (Expert Panel 
on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children 
and Adolescents, 2011)
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for population PK analyses.  At Weeks 12, 28, and 52, subjects will be 
instructed to take their morning dose at the clinic.  Two blood samples for determination of 
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plasma concentrations of lorcaserin will be taken at each of these visits: within 30 minutes 
before dosing and within 1 to 3 hours after dosing.  At the Week 36 visit, subjects will take 
the morning dose at home, and 1 blood sample for determination of plasma concentration of 
lorcaserin will be collected at the investigational site within 4 to 6 hours after dosing.
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
method coupled with tandem mass spectrometry method. The collection, handling, and 
shipping procedures for PK samples will be described in a manual to be provided to the study 
sites.
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS

Change from Baseline in BMI and body weight

Proportion (%) of patients achieving at least a 5% and at least a 10% reduction in 
BMI and body weight
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with lorcaserin plasma exposure.
9.5.1.4.3
PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS
Not applicable
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs); electrocardiograms (ECGs); laboratory evaluations for hematology, thyroid 
function, adrenal functions, and biochemical blood and urine biomarkers of bone health;
blood chemistry and urine values; neuropsychiatric events; periodic measurements of vital 
signs, neuromuscular signs for screening potential serotonin syndrome, and signs and 
symptoms of priapism and prolactinemia; and performance of physical examinations.  In 
subjects with potential prolactin-related AEs, such galactorrhea, changes in libido, or changes 
to menstrual cycle, prolactin level will be measured and assessed.  Study drug effect on 
growth of children and adolescents will be evaluated using the CDC growth chart at 
Baseline, and Weeks 5, 12, 28, 36, 52, and at Follow-Up; a full physical examination at 
Baseline, Weeks 12, 28, 52, and at Follow-Up; and bone age determination by x-ray of the 
hand at Baseline, Weeks 12, 28, and 52.  Children and adolescent sexual maturation will be 
evaluated by assessing sex hormones and self-reported changes in Tanner Staging at 
Baseline, Weeks 28 and 52, and at Follow-Up.
Any subject with symptoms or signs of 
cardiac valvular disease or PH will be further evaluated by centralized echocardiogram
assessments. The assessments will be adjudicated and be followed up by echocardiogram
assessments at end of the study.  The events of confirmed FDA defined valvulopathy and PH 
will be captured in the AE electronic case report form (eCRF).
The C-SSRS will be used to assess all children and adolescents in the study for any signal of 
depression or suicidal ideation or behavior.  Additionally, mood will be assessed using the 
CDI-2 and effects on cognitive function will be assessed using WRAML-2.
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9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is Belviq XR
(lorcaserin hydrochloride).
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in non-protocol-required measurements of a laboratory value or other 
clinical test (eg, ECG, x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Adverse Event CRF.  All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from the 
time the subject signs the study ICF through the last visit in the Treatment Phase.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 
reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (corrected QT interval [QTc]) results, if not otherwise considered part of a 
clinical symptom that is being reported as an AE, should be considered an AE if the QTc 
interval is greater than 450 msec and there is an increase of more than 60 msec from baseline.  
Any ECG abnormality that the investigator considers as an AE should be reported as such.
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It is the responsibility of the investigator to review the results of the C-SSRS, CDI-2, and 
WRAML-2 in all subjects and determine if any result constitutes an AE.  Medical and 
scientific judgment should be exercised in deciding whether an isolated suicidality rating 
scale response should be classified as an AE (see Section 9.5.1.5.8 for a description of the 
C-SSRS).
All AEs must be followed for 28 days after the subject’s last dose or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
•
The presence of risk factors in the study subject known to increase the occurrence of 
the event
•
The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
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Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious 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
•
Priapism
•
New onset valvular heart disease
•
New onset PH
•
Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin
•
Fibroadenomas of the breast or ductal carcinoma in situ
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In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet 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 “AE” (ie, 
there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care
•
Planned hospitalizations required by the protocol  
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)
•
Hospitalization for administration of study drug or insertion of access for 
administration of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was 
in place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
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Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function
T4, TSH
Adrenal function
Cortisol 
Sex hormones
Testosterone (male subjects), estradiol (female subjects), 
Biomarkers of bone health
Serum OC and PICP, Hydroxy-proline; Urine NTX
Prolactin
Fasting prolactin levels
Other
Albumin, calcium, globulin, glucose, HbA1c, HDL cholesterol, 
lactate dehydrogenase, LDL cholesterol, phosphorus, total protein,
total cholesterol, triglycerides, prolactin, uric acid, urine ß-hCG, 
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs,
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, 
LDL = low density lipoprotein, OC = osteocalcin; NTX = N-telopeptide, PICP = carboxyterminal propeptide of 
type I procollagen; RBC = red blood cell, T4 = thyroxine, TSH = thyroid stimulating hormone, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a validated 
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method.  BP and pulse will be measured after the subject has been sitting for 5 minutes.  All 
BP measurements should be performed on the same arm, preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed before drawing blood samples in order to maximize the 
accuracy of blood sampling times while minimizing the potential effects of blood drawing on 
recordings obtained during safety assessments.
9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2).  
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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.
9.5.1.5.7
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
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9.5.1.5.8
OTHER SAFETY ASSESSMENTS
WRAML-2
The WRAML-2 administration will consist of the Core Battery, which provides scores on 
Verbal Memory, Visual Memory, and Attention/Concentration.  There are 6 subtests (2 for 
each area).
The tests provide standardized scores based on age and gender, and are 
appropriate for ages 5 to 90 years.  The WRAML-2 will be used to assess lorcaserin effects 
on cognitive function. In addition, signs and symptoms of cognitive related AEs, including 
impairments in attention, memory, and adverse effects on schoolwork will be captured in the 
eCRF.
CDI-2
The CDI-2 is a self-administered depression rating scale for use in children ages 7 to 
17 years.  It consists of 28 items and provides a total score, scores on 2 scales, and 
4 subscales.  CDI-2 will be used to assess lorcaserin effect on mood changes.
C-SSRS
The C-SSRS collects information pertinent to suicidal ideation and actions.  It consists of a 
Baseline version which will be administered at baseline and a Since Last Visit version which 
will be administered at the remaining visits.  C-SSRS will be used to assess signal of 
depression and suicidal ideation or behavior. It will be performed at Baseline and at study 
visits as designated in the Schedule of Procedures/Assessments (Table 2).
Signs and symptoms of priapism (painful erection) and hyperprolactinemia (menstrual cycle 
abnormalities or galactorrhea) will be captured in the eCRF.
Hand X-Ray will be evaluated for any potential negative effect on bone age as designated in 
the Schedules/Assessments (Table 2). Echocardiograms will be performed on the subjects 
with signs or symptoms of potential valvular disease or PH. Echocardiogram confirmed 
cases of FDA-defined valvulopathy or PH will be captured by AE eCRF. Neuromuscular 
sign assessment for serotonin syndrome will be performed as designated in the Schedule of 
Procedures/Assessments (Table 2) to screen for potential serotonergic syndrome components. 
Serotonergic syndromes that meet the diagnostic criteria will be captured by AE eCRF.
9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test in female subjects will be performed at designated time points as 
specified in the Schedule of Procedures/Assessments (Table 2).
9.5.1.6.2
URINE DRUG AND COTININE TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 2).  This sample will be tested for common 
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drugs 
of 
use/abuse 
(eg, 
ethyl 
alcohol, 
cocaine, 
cannabinoids, 
phencyclidine, 
nicotine/cotinine, opioids [as a group], benzodiazepines, barbiturates, amphetamines).
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
Prior/concomitant medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examination
X
X
X
X
X
X
X
X
Neuromuscular sign assessment for serotonin 
syndromed
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
Routine clinical laboratory tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
FPG, Fasting Insulin, HOMA-IR and HbA1c
sampling
X
X
X
X
X
T4 and TSH
X
X
X
X
AM serum cortisol
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Testosterone, Estradiol
X
Fasting Plasma Glucose
X
HOMA-IR
X
Fasting Insulin
X
Pregnancy test (Urine)
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and compliance
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDC growth chart
X
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
WRAML-2
X
X
X
X
X
X
CDI-2
X
X
X
X
X
X
X
X
X
X
X
X
Hand x-ray for bone age
X
X
X
X
X
OC, PICP, and Hydroxy-proline
X
X
X
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-Up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Urine NTX
X
X
X
PK sample
X
X
X
X
X
Prolactin
X
X
X
X
Lifestyle modification counselinge
X
X
X
X
X
X
X
X
X
X
AE = adverse event; AM = morning; CDC = Centers for Disease Control and Prevention; CDI-2 = Children’s Depression Inventory 2; C-SSRS = Columbia-Suicide Severity 
Rating Scale, ECG = electrocardiogram, EOS = End of Study, EOT = End of Treatment, FPG = fasting plasma glucose; HbA1c = hemoglobin A1c, HOMA-IR = Homeostatic 
Model Assessment of Insulin Resistance; IxRS = interactive voice or web response system, NTX = N-telopeptide, OC = osteocalcin; PICP = carboxyterminal propeptide of 
type I procollagen  PK = pharmacokinetics, T4 = thyroxine, TSH = thyroid stimulating hormone, WRAML-2 = Wide Range Assessment of Memory and Learning-2.
a:
Baseline measurements will be collected on Day 1, before drug administration unless specified otherwise.
b:
Window ±7 days for all visits after Visit 2 except for Weeks 12 and 28 (the window for these visits will be broader at ±14 days). Week is shown unless otherwise 
indicated.
c:
On Weeks 12, 28, and 52, subjects will take the morning dose at the clinic, and 2 blood samples for determination of plasma concentrations of lorcaserin will be taken:
predose (within 30 minutes before dosing) and within 1 to 3 hours after dosing (time in which the dose was taken on the night previous to the visit must be recorded). On 
Week 36, the subjects will take the morning dose at home (time of morning dosing at home must be recorded), and 1 blood sample for determination of plasma 
concentrations of lorcaserin will be collected at the investigational site within 4 to 6 hours after dosing.
d:
Accompanied by an abbreviated physical examination for clonus
e:
Lifestyle modification counseling will also be performed at Weeks 3, 24, 32, 40, and 48 in addition to counseling at the visits in the schedule of assessments table above. 
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
12
Screening: 1
Visits 2, 3, 4, 6, 8; 11/EOT, EOS
128=96
T4, TSH, Cortisol, 
Testosterone, estradiol, 
Serum OC and PICP, 
Hydroxy-proline; Fasting 
prolactin levels
10
Screening:  1
Visits  8; 11/EOT/Early 
discontinuation
10×4=40
Prolactin, FPG, Insulin, and 
HbA1c sampling
4
Screening:  1
Visits 6, 8; 11/EOT/Early 
discontinuation
4×5=20
PK/PD blood sampling
4
Visits 6, 8, 9, and 11/EOT/Early 
discontinuation (2 samples each)
8×4=32
Total
188
EOS = End of Study; EOT = End of Treatment; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; OC = osteocalcin;
PD = pharmacodynamic; PICP = carboxyterminal propeptide of type I procollagen; PK = pharmacokinetics; T4 = thyroxine; 
TSH = thyroid stimulating hormone.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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.
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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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form by email or fax as soon as possible but no later than 1 business 
day from the date the investigator becomes aware of the event.
SAEs, regardless of causality assessment, must be collected through the through the last visit
and for 28 days after the subject’s last dose.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 30 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.
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A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product
labeling, 
packaging, 
nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
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AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (listed below) should always be considered as serious important 
medical events and be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific 
event does not meet other serious 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 

Priapism

New onset of valvular heart disease

New onset PH

Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin

Fibroadenomas of the breast or ductal carcinoma in situ

The following additional study specific AE of interest should be reported using the 
procedures detailed in Reporting of SAEs (Section 9.5.4.1), even if the study-specific 
event does not meet serious criteria.  If the event meets seriousness criteria, it should 
be reported as an SAE as above.  However, if the event listed below does not meet 
serious criteria, it should be noted as nonserious on the Adverse Event CRF:  Suicidal 
ideation

Euphoria 
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 
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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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52 week evaluation is completed.  
Subjects who discontinue treatment prematurely will be followed up until study completion.  
All subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 2).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
Detailed retention strategies will be developed and included in study manual. These include 
a highly trained and competent staff, easy access to the clinic, reminder and follow-up calls, 
interactive group sessions with games and hands-on nutrition and physical activity 
demonstrations, random raffle drawings, social events, birthday and holiday cards, and
newsletters. In addition, home visits for assessments of families will be an option, as needed, 
to maximize data collection. This detailed retention plan will help prevent missing data.
A subject removed from the study for any reason may not be replaced.
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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.  The DEA Registrant has 
the responsibility to comply with local, state, and Federal laws to notify the Field Division 
Office of the DEA of any theft or significant loss of any controlled substances upon 
discovery of such theft or loss.
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 or she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form 
FDA 1572 must sign the completed CRF to attest to its accuracy, authenticity, and 
completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY EFFICACY ENDPOINT

Change in BMI from Baseline to Week 52 
9.7.1.1.2
SECONDARY EFFICACY ENDPOINTS
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52

Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
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9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects regardless of 
adherence to study drug.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 
80% or greater compliant with study medication, completed the study, have no major 
protocol deviations, have no violations of inclusion or exclusion criteria, and have 
BMI data at Baseline and Week 52.  The determination of subjects to be excluded 
from this population based on the above criteria and list of major protocol violations 
will be included in the SAP and finalized before data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at 
least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 
1 valid lorcaserin plasma concentration was obtained with associated documented 
dosing history.

The population PK/PD set is the group of randomized subjects with PK information 
and who have at least 1 adequately documented measurement of body weight.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis Sets will be 
summarized for each treatment group using descriptive statistics or frequency count.  
Continuous demographic and baseline variables include age, height, BMI, waist 
circumference, and weight; categorical variables include sex and race.
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9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized for
the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical class, and 
World Health Organization Drug Dictionary preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.
9.7.1.6
Efficacy Analyses
The FAS will be used as the primary analysis set for all efficacy analyses, while the PP will 
be used as a supportive analysis.  Unless specified otherwise, a 2-sided α=0.05 significance 
level will be used for all efficacy analyses.
Primary Efficacy Analysis
The primary efficacy endpoint is the change in BMI from Baseline to Week 52.  The change 
from baseline in BMI will be analyzed using the mixed effect model repeated measurement 
analysis (MMRM) with factors of treatment, visits (Baseline, Week 1, 5, 8, 12, 20, 28, 36, 
44, and 52), age group (9 to 11 years old and 12 to 17 years old), sex (male and female), 
treatment-by-visit interaction as fixed effect, subjects as random effect, and the baseline BMI 
as a covariate.  The unstructured covariance matrix will be used in the analysis and the 
treatment comparison at Week 52 will be the event of interest.  In case of a convergence 
issue, the Toeplitz covariance structure will be used in the model.
Subgroup analyses and additional sensitivity analyses will be performed as appropriate 
including multiple imputation methods assuming the missing values are missing at random 
(MAR) and missing not at random (MNAR) to handle missing data.
The following analyses will be considered as sensitivity analyses:

PP analysis: The same primary efficacy analyses described above will be repeated 
based on the PP.

Multiple imputation (MI): the same primary efficacy analyses described above will 
be analyzed using MI for impute the missing data, assuming the missing values are 
MAR and MNAR.

Change from baseline in standardized BMI score (Z-score):
The same primary 
efficacy analyses described above will be repeated using Z-score.
Additional sensitivity analyses may also be explored and described in the SAP, if deemed 
appropriate.  
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Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is the proportion of subjects achieving at least a 
5% BMI reduction at Week 52.  The secondary efficacy endpoint will be analyzed only if the 
test for the primary efficacy endpoint is statistically significant.
The proportion of subjects achieving at least a 5% BMI reduction at Week 52 will be 
analyzed using a logistic regression model with factors of treatment, age group (9 to 11 years 
old and 12 to 17 years old) and sex (male and female), and baseline BMI as a covariate using 
FAS.  Subjects with any missing assessment at Week 52 will be considered as treatment 
failures in this analysis.
Other Secondary Efficacy Analyses
In general, for all other secondary efficacy endpoints, the continuous variables will be 
analyzed using MMRM and categorical variables will be analyzed using the Cochran Mantel 
Haenszel test, Chi-square test, or logistic regression as appropriate.  Additional analysis may
be performed as needed using appropriate statistical methodologies as specified in SAP.
Subgroup analyses will be performed on the primary efficacy endpoint, including age group 
(9 to 11 years old and 12 to 17 years old), sex (male and female), race (white, black, Asian,
and other). Additional subgroups may be explored, if deemed necessary.
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline characteristics
or demographics, on PK will be explored.  Derived exposure parameters such as the 
maximum observed concentration and the area under the concentration-time curve from time
0 to 24 hours at steady-state will be calculated from the final PK model using individual 
posterior estimates of the PK parameters and from dosing history.  The PK analysis set will 
be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Probability of achieving at least a 5% and at least a 10% body weight reduction change from 
Baseline will be assessed as the PD analysis.  The PD analysis set will be used for this 
analysis.
Other assessments (eg, BMI change, percentage of BMI change, proportion [%] of patients 
achieving ≥10% BMI reduction, and change in waist circumference from baseline) will also 
assessed as PD analysis.  The PK/PD analysis set will be used for this analysis.
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9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between lorcaserin 
plasma exposure and response, including but not limited to change in body weight from 
baseline and the probability of achieving at least a 5% and at least a 10% change in body
weight from baseline to Week 52.  Additionally, exposure-safety relationships for select 
safety parameters may be explored graphically, depending on the data at the end of study.  
Any emergent relationship may be modeled as appropriate.  Any parameters based on the 
study data may be considered for exploratory assessment for its relationship to PK.
9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
Not applicable
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination), 
growth (CDC growth chart and bone age determined by x-ray of the hand), sexual maturation 
(Tanner Staging), out-of-normal-range laboratory safety test values, change from baseline in 
laboratory safety test values (including biomarkers), ECGs, and vital sign measurements will 
be summarized by treatment group using descriptive statistics or frequency count as 
appropriate.  In addition, suicidal ideation, cognitive function, behavior, and mood will be 
evaluated by the C-SSRS, WRAML-2, CDI-2, and C-SSRS, respectively, and will also be 
summarized by treatment group using descriptive statistics or frequency count as appropriate.  
All WRAML-2 raw scores from the Core Battery will be converted to age and gender 
standard scores for purposes of intra individual comparisons
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of 
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject 
received the 1st dose of study drug and the date the subject received the last dose of study 
drug.  Duration of exposure will be summarized using descriptive statistics by treatment 
group.  In addition, the duration of exposure will be categorized and will be summarized 
using frequency count by treatment group.
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 
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(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to 
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)

Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No 
[not related]) 
A subject will be counted only once within a SOC or PT, if the subject experienced more 
than 1 TEAE within a specified SOC and PT.
The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
In addition, subjects with TEAEs leading to discontinuation from study drug and AEs of 
special interest as described in Section 9.5.4.3.2 will be summarized by MedDRA SOC and 
PT for each treatment group. 
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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Percentages will be based on the number of subjects with both nonmissing 
baseline and relevant postbaseline results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at the End of Treatment and the Follow-Up visits.  Similar shift tables will also 
compare the baseline LNH classification to the LNH classification for the highest and lowest 
value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (eg, 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
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), and heart rate), the actual value 
and change from baseline will be summarized by visit and treatment group using descriptive 
statistics. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
Maximum postbaseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by treatment 
group as follows:

Number (percentage) of subjects in greater than 450 msec, greater than 480 msec, and 
greater than 500 msec during the treatment, and
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
Number (percentage) of subjects with an increment of greater than 30 msec and 
greater than 60 msec from the baseline visit.
9.7.1.8.6
OTHER SAFETY ANALYSES
Other safety assessments including children and adolescent growth evaluations using CDC 
growth chart and bone age using x-ray of the hand, sexual maturation as measured in Tanner 
Staging, neuromuscular sign assessment for serotonin syndrome, signs and symptoms of 
priapism and prolactinemia, study drug effect on cognitive function assessed by WRAML-2, 
assessment of suicidality using C-SSRS, and mood assessment using CDI-2 will be also be 
summarized by treatment group at each scheduled visit.
9.7.2
Determination of Sample Size
The proposed sample size is based on the comparison of the primary efficacy endpoint, 
change from Baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and 
placebo group.  Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 
360 subjects in a 1:1 ratio (n=180 in the Belviq XR 20-mg treatment group; n=180 in the 
placebo group) will have at least 90% power to detect a treatment difference of 1 kg/m2 in 
BMI, using a 2-sided t-test with α=0.05.  Assuming the proportion of subjects achieving at 
least a 5% BMI reduction at Week 52 is 20% for the placebo group and a 40% dropout rate, 
this sample of 360 subjects (180 subjects for Belviq XR 20 mg and 180 subjects for placebo) 
will also have greater than 85% power to detect an absolute difference of 20% between the 
Belviq XR 20-mg group and placebo group, using a 2-sided Fisher’s Exact test with α=0.05.  
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin 
studies, APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Further statistical and analytical issues will be discussed in the SAP.  
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
American Diabetes Association.  Standards of Medical Care - 2013.  Diabetes Care 2013;36
Suppl 1:S11-S66.
Barlow, SE, and the Expert Committee.  Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity:
summary report. Pediatrics 2007;120 Suppl December 2007:S164-S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J.  Effect of orlistat on weight and 
body composition in obese adolescents:
A randomized controlled trial. 
JAMA 
2005;293:2873-83.
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2003; 
Clinical review for NDA 20-766/S018.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510).  2007; 
Clinical review for NDA 21-687/S023.
Flegal, KM, Graubard, BI, Williamson, DF, Gail, MH.
Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.
Lohman T, Roche AF, Martorell R. Anthropometric Standardization Reference Manual.  
Champaign, IL:  Human Kinetics Books; 1988.
McGovern LI, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab.  2008;93(12):4600-5.  doi: 10.1210/jc.2006-2409.  Epub 
2008 Sep 9.
Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L.  
NEDCOM, the Netherlands Epidemiology and Demography Compression of Morbidity 
Research Group.  Obesity in Adulthood and Its Consequences for Life Expectancy:  A Life-
Table Analysis. Ann Intern Med. 2003; 138:24-32.
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Peirson L, Fitzpatrick-Lewis D, Morrison K, Warren R, Usman M, Raina P.  Treatment of 
overweight and obesity in children and youth:  a systematic review and meta-analysis.  
CMAJ Open 2015.  doi:  10.9778/cmajo.20140047.
Rofey, DL, Kolko, RP, Ana-Maria, I; Silk, JS, Bost, JE, Fang, W. et al. A Longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev 2009; 40(4): 517-26.
Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 Suppl 4.
Trasande, L. Chatterjee, S.  The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2015.
Wang, Y, Lobstein, T. Worldwide trends in childhood overweight and obesity. Int J 
Pediatric Obes 2006;1:11-25.
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  Investigational product will be stored in 
accordance with the DEA Regulations for Scheduled III - V Drugs and labeled storage 
conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (gamma-glutamyl transpeptidase) >ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent or guardian) in Study 403 will 
participate in a standardized weight management program for adolescents consisting of 
multicomponent behavior therapy.  The therapy will focus on healthy eating, physical 
activity, and lifestyle changes that will facilitate weight loss and weight-loss maintenance. 
The role of the caregivers is to support their child or adolescents’ lifestyle changes and their 
taking of study medication.
The objectives of this program are as follows:

Develop a weight management program for all Belviq XR study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress 
but caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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Appendix 3
Pharmacodynamic and Other Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), and other biomarker analysis.  These samples may be used for 
discovery or validation to identify biomarkers that may be used for exploratory evaluation of 
response or safety-related outcomes as well as for use in diagnostic development.
The pharmacogenetics (PG) samples may be used to identify genetic factors that may 
influence a subject’s exposure to the study drug, as well as genetic factors that may have an 
effect on clinical response or potential adverse events (AEs) related to study treatment, and to 
explore the role of genetic variability in response.  Samples may be analyzed to determine a 
subject’s genotypes or sequence for a number of genes or non-coding regulatory regions.  
The research may include the investigation of polymorphisms in genes that are likely to 
influence the study drug pharmacokinetic (PK) or therapeutic response.
Collection of the PD, and other biomarker samples will be bound by the sample principles 
and processes outlined in the main study protocol.  Sample collection for PD, PG, and other 
biomarker analysis is required as per the study protocol unless the collection and use of the 
samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA or RNA extraction, genotyping, sequencing, or other 
analysis will be performed by a laboratory under the direction of the sponsor.  Processing, 
analysis, and storage will be performed at a secure laboratory facility to protect the validity 
of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:
•
Clinical research organizations retained by the sponsor 
•
Independent ethics committees or institutional review boards that have responsibility for 
this research study 
•
National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
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scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the PD, PG, and other biomarker analysis, it will not be possible 
to return individual data to subjects.  The results that may be generated are not currently 
anticipated to have clinical relevance to the patients or their family members.  Therefore, 
these results will not be disclosed to the patients or their physicians.
If at any time, PD, PG, or other biomarker results are obtained that may have clinical 
relevance, Institutional Review Board review and approval will be sought to determine the 
most appropriate manner of disclosure and to determine whether or not validation in a 
Clinical Laboratory Improvement Amendments-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in Clinical Laboratory Improvement 
Amendments-approved laboratories.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Children and Adolescents, Age 9 to 
17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neuroscience Business Group
Eisai Inc.
Date
Eisai Inc.
Date
Neuroscience Business Group
Eisai Inc.
Date
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PPD
PPD
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Children and Adolescents, Age 9 to 
17 Years
Investigational Product 
Name:
APD356/Belviq XR® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use and all applicable local 
Good Clinical Practices guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
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1
TITLE PAGE
CLINICAL STUDY PROTOCOL
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of BELVIQ® in 
Conjunction with Lifestyle Modification for Weight Loss in Obese 
Adolescents, Age 12 to 17 Years
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, New Jersey 07677  US
Investigational 
Product Name:
APD356/BELVIQ® (lorcaserin hydrochloride)
Indication:
Obesity
Phase:
4
Approval Date:
FINAL 
16 Apr 2015 (original protocol)
IND Number:
069888
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation
of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations.  All 
required study documentation will be archived as required by 
regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or 
performing this study.
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.: APD356
Name of Active Ingredient:  BELVIQ® (lorcaserin hydrochloride)
Study Protocol Title
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy 
and Safety of BELVIQ® in Conjunction with Lifestyle Modification for Weight Loss in Obese 
Adolescents, Age 12 to 17 Years
Investigators
Unknown
Site
Approximately 30 sites in the United States (US)
Study Period and Phase of Development
Approximately 24 months from first subject enrolled to last subject’s last visit/last assessment 
Phase 4
Objectives

Primary Objective
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with a 
5% or greater reduction in body mass index (BMI) during 52 weeks of treatment with
BELVIQ 20 mg administered once daily (QD) compared to placebo in obese adolescents.

Secondary Objectives
1.
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with 
≥5% reduction in BMI (kg/m2) after an initial 12 weeks of treatment with BELVIQ 20 mg 
administered QD compared to placebo in obese adolescents
2.
To demonstrate weight loss effect by mean change in BMI during 52 weeks of treatment of 
BELVIQ 20 mg administered QD compared to placebo in obese adolescents
3.
To demonstrate the effects of treatment with BELVIQ 20 mg QD by assessing:

Other weight loss effects (eg, proportion [%] of subjects achieving ≥10% BMI reduction, 
and change in waist circumference) at the end of 52 weeks of treatment

Effects on glycemia, insulin levels, and HOMA-IR during 52 weeks of treatment

Changes in cardiovascular risk factors associated with obesity (ie, hypertension, 
dyslipidemia, Metabolic Syndrome) during 52 weeks of treatment
4.
To assess the safety of BELVIQ, including the effects on growth by growth chart, sexual 
maturation measured by Tanner Staging scores, and signal of suicidal ideation/behavior with
the Columbia-Suicide Severity Rating Scale (C-SSRS)
5.
To assess the pharmacokinetics (PK) of lorcaserin in obese adolescents using population PK 
modeling
6.
To explore potential relationships between exposure to lorcaserin and pharmacodynamic
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(PD) parameters including but not limited to reduction from baseline in BMI and probability 
of achieving ≥5% and ≥10% reduction in BMI from baseline at Week 52, using population 
PK/pharmacodynamics (PD) modeling
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in obese 
adolescents, age 12 to 17 years old.  Approximately 360 subjects will be randomized in a 1:1 ratio to 
BELVIQ 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will receive BELVIQ 20 mg 
or placebo QD for up to 52 weeks. Throughout the duration of the study, subjects will be encouraged 
to adhere to a diet and exercise program.
The study will consist of 2 phases: Prerandomization and Randomization.  The Prerandomization 
Phase will last up to 30 days and consist of 1 visit during which subjects will be screened for 
eligibility.  The Randomization Phase consists of a Treatment Period and a Follow-up Period.  The 
Treatment Period will last for a maximum of 52 weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36,
44, and 52, and a Follow-up Period extending from the end-of-treatment (EOT) visit to the 
end-of-study (EOS) visit.  
All subjects will continue in the study until the 52-week evaluation is completed.  Subjects who 
discontinue treatment prematurely will be followed up until study completion.  
Number of Subjects
Approximately 700 subjects will be screened to provide 360 randomized subjects.
Inclusion Criteria
1.
Healthy, male or female, adolescents, age 12 to 17 years, at Screening with a BMI that is 
greater or equal to the US-weighted mean of the 95th percentile based on age and sex, but is 
less than 44 kg/m2
2.
Subjects in their junior year of high school or earlier, and their families are not planning to
move away from the area for the duration of the study/assessments.
3.
Subjects able and willing to comply with all aspects of the study including with a 
reduced-calorie diet and an increased physical activity program
4.
Subjects considered to be in stable health in the opinion of the investigator.
5.
Caregivers/guardians meeting following requirement:
a.
No history of Attention Deficit Hyperactivity Disorder (ADHD), substance abuse, 
depression, suicidal ideation/behavior, bipolar disorder, or schizophrenia
b.
Able and willing to support, or/and supervise study participation in the opinion of the 
investigator including any existing physical, medical, or mental condition that prevents 
compliance with the protocol
c.
Able and willing to comply with all aspects of the study requirements for the 
caregivers/guardians
Exclusion Criteria
1.
Clinically significant new illness within 1 month before randomization that may affect the 
subject’s ability to fulfill the study requirements and significantly confound the assessments
2.
Subjects who cannot swallow investigational products 
3.
Documented pulmonary hypertension (PH) by objective assessments (ie, imaging modality or 
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cardiac catheterization)
4.
Known valvular disease defined by clinical diagnosis or most recent echocardiography.  
History of valvular disease is allowed if it has been corrected by valve replacement or repair.
5.
Significant renal or hepatic disease, as evidenced by a serum creatinine >1.5 × upper limit of 
normal (ULN), serum transaminases >3 × ULN, or total bilirubin >1.5 × ULN in absence of 
Gilbert’s syndrome
6.
Any history of anorexia or bulimia, ADHD, any DSM-5 depressive disorder, or suicidal 
ideation/behavior, bipolar disorder, or schizophrenia
7.
Known secondary causes (chromosomal, endocrine, or metabolic) for obesity (for example, 
Prader-Willi syndrome, Down’s Syndrome, untreated hypothyroidism, Cushing’s syndrome, 
daily systemic corticosteroid exposure for longer than 30 days, history of significant 
exposure to corticosteroids for chronic illness during the past year, and known genetic causes 
of obesity)
8.
Use of other products intended for weight loss including prescription drugs, over-the-counter 
(OTC) drugs, and herbal preparations within 1 month before Screening 
9.
Use of any of the following medications: 
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer), or MAOIs within 
30 days, prior to Randomization, including: 

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 

bupropion

triptans 

St. John’s Wort and tryptophan 

monoamine oxidase inhibitors (MAOIs)

linezolid

dextromethorphan (in any form, eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists 
b) Others

antiseizure medications including valproic acid, zonisamide, lamotrigine

oral steroids (inhaled steroids are acceptable)

stimulant medications

benzodiazepines
10. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months before 
screening, including, but not limited to pergolide, ergotamine, methysergide, and cabergoline
11. History or evidence of clinically significant disease (eg, malignancy, cardiac, respiratory, 
gastrointestinal, renal, or psychiatric disease) other than prediabetes (impaired fasting 
glucose or glucose intolerance), obstructive sleep apnea, dyslipidemia, and nonalcoholic fatty 
liver disease  
12. Use of BELVIQ within 6 months before screening or hypersensitivity to BELVIQ or any of 
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the excipients
13. Significant change in diet or level of physical activity within 1 month before dosing or 
change in weight of >5 kg within 3 months
14. Adherence to a very-low calorie (<1000/day) weight loss diet within 6 months
15. History of alcohol or drug dependence or abuse 
16. Recreational drug use within 2 years before screening
17. Known to be human immunodeficiency virus (HIV) positive
18. Active viral hepatitis (B or C) as demonstrated by positive serology
19. Malignancy within 5 years before screening
20. Unable to attend scheduled visits (eg, lack of transportation) or lack of a guardian to 
supervise study participation
21. Special needs subjects who are unable to comprehend study-related instructions (eg, mild to 
profound mental retardation [IQ <80], moderate to severe cognitive developmental delay, 
pervasive development disorders[(PDDs], autism)
22. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure disorder 
within 6 months of screening, or any time between screening and randomization
23. Uncontrolled hypertension, defined as blood pressure (BP) in the 95th percentile or greater 
for age, sex, and height on 2 separate readings recorded on 2 separate days; subjects who had 
uncontrolled hypertension at screening can be rescreened >1 month following initiation or 
adjustment of antihypertensive therapy.
24. Currently enrolled in another clinical study or has used any investigational drug or device 
within 30 days before providing informed consent
25. Planned bariatric surgery during the study
26. Not suitable to participate in the study in the opinion of the investigator including any 
existing physical, medical, or mental condition that prevents compliance with the protocol
27. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG]).  A separate baseline assessment is 
required if a negative screening pregnancy test was obtained more than 72 hours before the 
first dose of study drug.
28. Females of childbearing potential who: 
a.
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period or for 30 days 
after study drug discontinuation.
b.
Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from sexual activity during the study period or for 30 days after study 
drug discontinuation.
c.
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
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same contraceptive during the study or for 30 days after study drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are have been 
sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all 
with surgery at least 1 month before dosing]).
29. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period or for 30 days after study drug 
discontinuation).  No sperm donation is allowed during the study period or for 30 days after 
study drug discontinuation.
Study Treatment(s)
Test drug 
BELVIQ (lorcaserin hydrochloride) will be provided as blue-colored, round, film-coated biconvex 
tablets with one 20-mg tablet administered orally, QD.  
Comparator Drug
Matching placebo, 1 tablet administered orally, QD
Duration of Treatment
Prerandomization Phase:  30 days
Randomization Phase:  56 weeks
Concomitant Drug/Therapy
Other products intended for weight loss, including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  Any of the following serotonergic agents in 
combination with BELVIQ are prohibited.  Over-the-counter cold medicines containing 
dextromethorphan can be used for up to 7 days with study medication temporarily stopped for that 
time period and resumed the next day after the OTC cold medicine is stopped.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort and tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
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Others

antiseizure medications including valproic acid, zonisamide, lamotrigine

oral steroids (inhaled steroids are acceptable)

stimulant medications

benzodiazepines
Assessments
Efficacy Assessments

Body weight and height will be assessed to measure BMI and to calculate the proportion (%) 
of patients achieving ≥5% and ≥10% BMI reduction at Week 52.

Measurement of systolic BP, diastolic BP, heart rate (HR), triglycerides, total cholesterol, 
high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, 
fasting plasma glucose, fasting insulin, and haemoglobin A1c (HbA1c) to assess
cardiovascular and metabolic profiles

Metabolic Syndrome as defined by the International Diabetes Federation (IDF) 

Pre-hypertension and primary hypertension as defined by Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents

Dyslipidemia as defined by Expert Panel on Integrated Guidelines for Cardiovascular Health 
and Risk Reduction in Children and Adolescents.
Pharmacokinetic Assessments
Plasma lorcaserin concentrations will be measured at Weeks 12, 28, 36, and 52 for analysis of 
population PK.  At Weeks 12, 24, and 52, subjects will be instructed to take their morning dose at the 
clinic.  Two blood samples for determination of plasma concentrations of lorcaserin will be taken at 
each of these visits: predose (within 30 minutes prior to dosing) and within 1 to 3 hours postdose.  At 
the Week 36 visit, subjects will take the morning dose at home, and 1 sample for determination of 
plasma concentrations of lorcaserin will be collected at the investigational site within 4 to 6 hours 
postdose.
Pharmacodynamic Assessments

Proportion (%) of patients achieving ≥5% and ≥10% BMI reduction

BMI change from baseline
Other pharmacodynamic endpoints will be considered based on the data at the end of the study to 
explore their relationships with exposure to lorcaserin
Pharmacogenomic/Pharmacogenetic Assessments
At the time of randomization, when applicable, a blood sample will be taken for potential 
investigation of genetic variability associated with genotypes relating to response to BELVIQ, weight 
loss, susceptibility to diabetes, and their associated risk factors.
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious 
adverse events (SAEs), laboratory evaluation for hematology, blood chemistry, and urine values; 
neuropsychiatric events, periodic measurement of vital signs, and performance of physical 
examinations. Study drug effect on adolescent growth will be evaluated using the US Center for 
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Disease Control (CDC) growth chart and a full physical examination.  Adolescent sexual maturation 
will be evaluated by self-reported changes in Tanner Staging.  
The C-SSRS will be used to assess all adolescent subjects in the study for any signal of depression 
and suicidal ideation/behavior.
Bioanalytical Methods
Lorcaserin will be quantified in plasma using a validated liquid chromatography method coupled with 
tandem mass spectrometry (LC-MS/MS).
Statistical Methods
Study Endpoints
Primary Endpoint

Proportion (%) of patients achieving ≥5% BMI reduction at Week 52
Secondary Endpoints

Proportion (%) of patients achieving ≥10% BMI reduction at Week 52 

Proportion (%) of patients achieving ≥5% BMI reduction at Week 12

Change and percent change in BMI from Baseline to Week 52

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR (HOMA-IR=glucose [mg/dL] x
insulin [mU/L] /405) from Baseline to Week 52

Change in blood pressure (systolic and diastolic) from Baseline to Week 52

Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) 
from Baseline to Week 52

Proportion of subjects with Metabolic Syndrome at Week 52 

Proportion (%) of subjects with pre-hypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects who received at least 
1 dose of study drug and had at least 1 postdose measurement.

The Intent-to-Treat set (ITT) is the group of all randomized subjects regardless of whether they 
took study drug or not.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 80% or greater 
compliant with study medication, completed the study, have no major protocol deviations, 
violations of inclusion/exclusion criteria, and have BMI data at Baseline, Week 12, and 
Week 52.  The determination of subjects to be excluded from this population based on the 
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above criteria and list of major protocol violations will be included in the SAP and finalized 
prior to data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at least 1 PD 
parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 1 valid 
lorcaserin plasma concentration was obtained with associated documented dosing history.

The population PK/PD set is the group of randomized subjects with PK information and who 
have at least 1 adequately documented measurement of body weight.
Efficacy Analyses
For the primary and secondary endpoints, a 2-sided α=0.05 significance level will be used.
Primary Analysis

The proportion of subjects achieving ≥5% BMI reduction will be analyzed using logistic 
regression model with treatment and site as factors and baseline BMI as a covariate.  
Comparison between BELVIQ and placebo will be made at Week 52.  The FAS analysis set 
will be used for this analysis.  Sensitivity analysis will be conducted treating subjects with 
missing BMI data at Week 52, as nonresponders (did not achieve ≥5% BMI reduction).
Secondary Analyses

The proportion of subjects achieving ≥5% BMI reduction will be analyzed using logistic 
regression model with treatment and site as a factors, and baseline BMI as a covariate.  
Comparison between BELVIQ and placebo will be made at Week 12.  The FAS analysis set 
will be used for this analysis.  Sensitivity analysis will be conducted treating subjects with 
missing BMI data at Week 12, as nonresponders (did not achieve ≥5% BMI reduction).

Change and percent change from baseline in BMI will be analyzed using an analysis of 
covariance model with treatment and site as factors and baseline BMI as a covariate.  
Comparison between BELVIQ and placebo will be made at Week 52 using the last observation 
carried forward (LOCF) approach.  The FAS analysis set will be used for this analysis.  
Additional sensitivity analyses will be performed using model-based imputation methods that 
will be described separately in the SAP.

Rates of growth in height will be summarized by the height distribution of percent change from 
Baseline to Week 52 by treatment group.  The Safety Analysis Set will be used for this 
analysis.

Tanner Staging (II, III, IV, and V) will be summarized using shift tables from Baseline to 
Week 52 by treatment group.  The Safety Analysis Set will be used for this analysis.

C-SSRS: The incidence of suicidal ideation or suicidal behavior will be summarized by 
treatment groups.  The Safety Analysis Set will be used for this analysis.

The change from baseline for the endpoints HbA1c, fasting plasma glucose, fasting insulin,
HOMA-IR, waist circumference, blood pressure (systolic and diastolic), and lipid profile (total 
cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) will be analyzed using a 
mixed-effects model with repeated measures with treatment and site as factors and baseline as a 
covariate.  Comparison between BELVIQ and placebo will be made at Week 52.  The FAS 
analysis set will be used for this analysis.
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
The proportion of subjects achieving ≥10% BMI reduction will be analyzed using logistic 
regression model with treatment and site as factors, and baseline BMI as a covariate.  
Comparison between BELVIQ and placebo will be made at Week 52.  The FAS analysis set 
will be used for this analysis.  Sensitivity analysis will be conducted treating subjects with 
missing BMI data at Week 52 as nonresponders (did not achieve ≥10% BMI reduction).

A logistic regression model with treatment and site as factors will be used to analyze the 
following endpoints.  Comparison between BELVIQ and placebo will be made at Week 52.  
The FAS analysis set will be used for these analyses.  Sensitivity analysis will be conducted 
using LOCF for subjects with missing data at Week 52.
o
Proportion (%) of subjects with confirmed  pre-hypertension or primary 
hypertension
o
Proportion (%) of subjects with dyslipidemia
o
Proportion (%) with metabolic syndrome that met at least 2 IDF criteria
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear 
mixed 
effects 
modeling. 
The 
effect 
of 
covariates, 
such 
as 
baseline 
characteristics/demographics, on PK will be explored. Derived exposure parameters such as the 
maximum observed concentration (Cmax) and the area under the concentration-time curve from time 
zero to 24 hours at steady-state (AUC0-24,ss) will be calculated from the final PK model using 
individual posterior estimates of the PK parameters and from dosing history. The PK analysis set 
will be used for this analysis. 
Pharmacodynamic Analyses
Proportion (%) of patients achieving ≥5% and ≥10% BMI reduction, and BMI change from baseline 
will be assessed as the PD analysis.  The PD analysis set will be used for this analysis.
Other assessments (ie, BMI change, percentage of BMI change, proportion [%] of patients achieving 
≥10% BMI reduction, and waist circumference from baseline) will also assessed as PD analysis.  The 
PK/PD analysis set will be used for this analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Population PK/PD modeling will be used to explore the relationship between exposure to BELVIQ
and response, including but not limited to change in BMI from baseline and the probability of 
achieving ≥5% and ≥10% change in BMI from baseline to Week 52.  Additionally, exposure-safety 
relationships for select safety parameters may be explored graphically.  Any emergent relationship 
may be modeled as appropriate.  Any parameters based on the study data may be considered for 
exploratory assessment for its relationship to PK.
Pharmacogenomic/Pharmacogenetic Analyses
A blood sample for potential investigation of genetic variability associated with genotypes relating to 
response to BELVIQ, weight loss, susceptibility to diabetes, and their associated risk factors will be 
taken at the time of randomization in the study, where applicable.
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs (including 
changes from baseline in physical examination),
suicidal ideation/behavior (C-SSRS), 
neuropsychiatric events, out-of-normal-range laboratory safety test variables, along with change from 
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baseline in laboratory safety test variables, and vital sign measurements at the end of treatment will 
be summarized by treatment group using descriptive statistics.
Interim Analyses
Not applicable
Sample Size Rationale
A sample size of 360 subjects in a 1:1 ratio (n=180 in the BELVIQ 20-mg QD treatment group: 
n=180 in the placebo group) will have 90% power to detect a 20% difference between treatment 
groups in the proportions of subjects with at least 5% reduction in BMI, assuming the placebo 
response is 20%, using a 2-sided test and α=0.05, assuming a 35% dropout rate. The assumption is 
based on lorcaserin adult Phase 3 and adolescent studies with orlistat and sibutramine.
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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................2
3
TABLE OF CONTENTS.................................................................................................12
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................16
5
ETHICS............................................................................................................................18
5.1
Institutional Review Boards/Independent Ethics Committees ..............................18
5.2
Ethical Conduct of the Study.................................................................................18
5.3
Subject Information and Informed Consent...........................................................19
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................20
7
INTRODUCTION ...........................................................................................................20
7.1
Indication ...............................................................................................................20
7.1.1
APD356/BELVIQ (lorcaserin hydrochloride).............................................21
7.1.1.1
Mechanism of Action...........................................................................21
7.1.1.2
Clinical Experience with APD356/BELVIQ (lorcaserin 
hydrochloride)......................................................................................21
7.2
Study Rationale......................................................................................................22
8
STUDY OBJECTIVES....................................................................................................24
8.1
Primary Objective..................................................................................................24
8.2
Secondary Objectives.............................................................................................24
9
INVESTIGATIONAL PLAN..........................................................................................25
9.1
Overall Study Design and Plan..............................................................................25
9.1.1
Prerandomization/Pretreatment Phase .........................................................25
9.1.1.1
Screening Period..................................................................................25
9.1.2
Randomization/Treatment Phase .................................................................25
9.1.3
Extension Phase ...........................................................................................25
9.2
Discussion of Study Design, Including Choice of Control Groups.......................25
9.3
Selection of Study Population................................................................................26
9.3.1
Inclusion Criteria .........................................................................................26
9.3.2
Exclusion Criteria ........................................................................................27
9.4
Treatments..............................................................................................................29
9.4.1
Treatments Administered.............................................................................29
9.4.2
Identity of Investigational Product...............................................................30
9.4.2.1
Chemical Name, Structural Formula of BELVIQ ...............................30
9.4.2.2
Comparator Drug .................................................................................30
9.4.2.3
Labeling for Study Drug......................................................................30
9.4.2.4
Storage Conditions...............................................................................31
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9.4.3
Method of Assigning Subjects to Treatment Groups...................................31
9.4.4
Selection and Timing of Dose for Each Subject..........................................32
9.4.5
Blinding........................................................................................................32
9.4.6
Prior and Concomitant Therapy...................................................................32
9.4.7
Treatment Compliance.................................................................................33
9.4.8
Drug Supplies and Accountability...............................................................33
9.5
Study Assessments.................................................................................................35
9.5.1
Assessments.................................................................................................35
9.5.1.1
Demography.........................................................................................35
9.5.1.2
Baseline Assessments ..........................................................................35
9.5.1.2.1
Medical History .............................................................................35
9.5.1.3
Efficacy Assessments...........................................................................35
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................36
9.5.1.4.1
Pharmacokinetic Assessments .......................................................36
9.5.1.4.2
Pharmacodynamic Assessments ....................................................36
9.5.1.4.3
Pharmacogenomic/Pharmacogenetic Assessments........................36
9.5.1.5
Safety Assessments..............................................................................37
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...37
9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................39
9.5.1.5.3
Laboratory Measurements .............................................................40
9.5.1.5.4
Vital Signs and Weight Measurements..........................................41
9.5.1.5.5
Height Measurements ....................................................................42
9.5.1.5.6
Physical Examinations...................................................................42
9.5.1.5.7
Electrocardiograms ........................................................................42
9.5.1.5.8
Other Safety Assessments..............................................................42
9.5.1.6
Other Assessments...............................................................................42
9.5.1.6.1
Pregnancy Test...............................................................................42
9.5.1.6.2
Urine Drug and Cotinine Test........................................................42
9.5.2
Schedule of Procedures/Assessments ..........................................................43
9.5.2.1
Schedule of Procedures/Assessments ..................................................43
9.5.2.2
Description of Procedures/Assessments Schedule...............................47
9.5.2.3
Total Volume of Blood Sampling........................................................47
9.5.3
Appropriateness of Measurements...............................................................47
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................47
9.5.4.1
Reporting of Serious Adverse Events..................................................47
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9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding .......................................................................................48
9.5.4.3
Reporting of Events Association 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 Study-Specific Events...............................................49
9.5.4.4
Expedited Reporting ............................................................................50
9.5.4.5
Breaking the Blind...............................................................................50
9.5.4.6
Regulatory Reporting of Adverse Events ............................................50
9.5.5
Completion/Discontinuation of Subjects.....................................................50
9.5.6
Abuse or Diversion of Study Drug ..............................................................51
9.5.7
Confirmation of Medical Care by Another Physician .................................51
9.6
Data Quality Assurance .........................................................................................51
9.6.1
Data Collection ............................................................................................51
9.6.2
Clinical Data Management ..........................................................................51
9.7
Statistical Methods.................................................................................................52
9.7.1
Statistical and Analytical Plans....................................................................52
9.7.1.1
Study Endpoints...................................................................................52
9.7.1.1.1
Primary Endpoint...........................................................................52
9.7.1.1.2
Secondary Endpoints .....................................................................52
9.7.1.2
Definitions of Analysis Sets.................................................................53
9.7.1.3
Subject Disposition..............................................................................53
9.7.1.4
Demographic and Other Baseline Characteristics ...............................53
9.7.1.5
Prior and Concomitant Therapy...........................................................54
9.7.1.6
Efficacy Analyses ................................................................................54
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................55
9.7.1.7.1
Pharmacokinetic Analyses.............................................................55
9.7.1.7.2
Pharmacodynamic Analyses..........................................................55
9.7.1.7.3
Pharmacokinetic/Pharmacodynamic Analyses ..............................56
9.7.1.7.4
Pharmacogenomic and Pharmacogenetic Analyses.......................56
9.7.1.8
Safety Analyses....................................................................................56
9.7.1.8.1
Extent of Exposure.........................................................................56
9.7.1.8.2
Adverse Events ..............................................................................56
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....................................................................59
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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
APPENDIX......................................................................................................................67
LIST OF IN-TEXT TABLES
Table 1
Clinical Laboratory Tests...........................................................................41
Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403 .........44
Table 3
Summary of Blood Sample Volumes ........................................................47
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADHD
Attention Deficit Hyperactivity Disorder
AE
adverse event
ATC
Anatomical Therapeutic Chemical
AUCinf
area under the concentration × time curve from time zero to 
infinity
AUC0-24,ss
area under the concentration - time curve from zero time to 24 
hours at steady state
ß-hCG
beta-human chorionic gonadotropin
BMI
body mass index defined as weight divided by height squared
BP
blood pressure
CA
Competent Authority
CDC
Center for Disease Control
Cmax
maximum observed concentration 
CRA
clinical research associate
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
curriculum vitae
DEA
Drug Enforcement Administration
ECG
Electrocardiogram
EOS
end of study
EOT
end of treatment
ET
early termination
FAS
Full Analysis Set
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practices
HbA1c
hemoglobin A1c
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HR
heart rate
ICF
informed consent form
ICH E6
International Conference on Harmonisation Good Clinical 
Practice
IDF
International Diabetes Federation
IEC
Independent Ethics Committee
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Abbreviation
Term
IRB
Institutional Review Board
ITT
Intent –to-Treat
LDL
low density lipoprotein
LNH
low/normal/high
LOCF
Last Observation Carried Forward
IxRS
interactive voice and/or web response system
MAOIs
monoamine oxidase inhibitors
MedDRA
Medical Dictionary for Regulatory Activities
OTC
over-the-counter
PD
Pharmacodynamics
PDD
pervasive development disorders
PH
pulmonary hypertension
PI
principal investigator
PK
Pharmacokinetics
PT
preferred term
QD
once daily
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SI
Système International
SNRIs
serotonin norepinephrine reuptake inhibitors
SOC
System Organ Class
SOPs
standard operating procedures
SSRI
selective serotonin reuptake inhibitors
T2DM
type 2 diabetes mellitus
TCAs
tricyclic antidepressants
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
ULN
upper limit of normal
US
United States
US 21 CFR
United States Code of Federal Regulations
WBC
white blood cell
WHO DD
World Health Organization Drug Dictionary
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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH E6), Section 3, and any local regulations (eg, 
Federal Regulations, Title 21 CFR Part 56).  Any protocol amendment or revision to the ICF 
will be resubmitted to the IRB/IEC for review and approval, except for changes involving 
only logistical or administrative aspects of the study (eg, change in clinical research associate 
[CRA]), change of telephone number[s]).  Documentation of IRB/IEC compliance with the 
ICH E6 and any local regulations regarding constitution and review conduct will be provided 
to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days.  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/IEC 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/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures (SOPs) of the 
sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice 
(GCP) guidelines as required by the following:
•
Principles of the World Medical Association Declaration of Helsinki
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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, 
International Conference on Harmonisation of Pharmaceuticals for Human Use
•
Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent 
and IRB regulations and applicable sections of US 21 CFR Part 312
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject and guardian/legally authorized representative the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.  The adolescent participant will 
provide written assent and the caregiver/guardian will provide written informed consent.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations (Federal Regulations, Title 21 CFR 
Part 50, for studies in the United States [US]).  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.  
The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.
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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 30 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 (CRO) are listed in the investigator
Study File or Regulatory Binder provided to each site.
7
INTRODUCTION
7.1
Indication
Obesity
Obesity has become a global epidemic as well as a serious public health concern.  In the 
United States (US), the prevalence of obesity in adolescents between 12 and 19 years of age 
has almost doubled over the past 2 decades.  The rate increased from 10.5% between 1988 
and 1994 to 20.5% between 2011 and 2012 (CDC/NCHS, 2013).  Obesity in adolescents, 
defined in the US as ≥95th percentile in gender- and age-specific body mass index (BMI), 
continues to grow at an alarming rate in the US and globally.  Based on data (Wang and 
Lobstein, 2006) using various criteria for the definition of obesity that included more than 
30 countries in Europe, North America, Asia, and West Pacific countries, prevalence rates in 
these countries also have increased significantly, comparable to that in the US.   
Adolescent obesity has many negative implications for both the health and well-being of the 
individual as well as for society.  These include increased susceptibility to a host of diseases, 
chronic health disorders, psychological disorders, and premature death (Flegal, et al., 2005; 
Rofey, et al., 2009).  Increases in the prevalence of overweight and obese adolescents may 
result in a decrease in life expectancy for the first time in 200 years.
As a result, there is a significant impact to the cost of healthcare.  It is estimated that medical 
costs due to overweight adolescents are approximately more than $14 billion per year in the 
US (Trasande, et al., 2009).  Obesity-related medical costs in general are expected to rise 
significantly, especially because today’s obese children are likely to become tomorrow’s 
obese adults.
Current approaches to weight management include lifestyle modification, pharmacotherapy, 
and invasive bariatric procedures.  Lifestyle modification involves a combination of diet, 
exercise, and behavioral change, and is the preferred and essential strategy for weight 
management in obese and overweight individuals.  Although lifestyle modification can be 
very efficacious in some patients, adherence to the prescribed regimens is often poor.  As 
such, lifestyle modification alone is often not adequate and the weight loss is often transient.  
On the other hand, bariatric surgery and various other invasive procedures are generally 
reserved for the severely obese population. 
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Pharmacotherapy can play a significant role in weight management programs and is often 
combined with lifestyle modification to enhance weight loss beyond that which is normally 
achieved with diet and exercise alone.  Current pharmacotherapies offer the potential to 
significantly augment weight loss when combined with diet and exercise.
The current standard of care for treatment of obesity in pediatric subjects ranges from 
lifestyle intervention in children younger than 8 years old to use of pharmacotherapy in 
adolescents older than 12 years (McGovern, 2008; Spear, 2007).  Xenical® (orlistat) is 
currently the only product available for weight control in obese adolescent patients 12 to 
16 years of age; however, it is associated with gastrointestinal side effects (Xenical PI. 2006), 
and the treatment effect of Xenical is modest. In a study that included 539 obese adolescents 
with BMI >97th percentile, Xenical demonstrated a 0.86 BMI reduction relative to placebo 
after 52 weeks of treatment (-0.55 BMI in the Xenical treatment group versus +0.31 BMI in 
the placebo group) (FDA, 2003; Chanoine JP, 2005). 
7.1.1
APD356/BELVIQ (lorcaserin hydrochloride)
7.1.1.1
Mechanism of Action
BELVIQ® is a selective serotonin 2c receptor agonist which was approved by the US Food 
and Drug Administration (FDA) on 27 June 2012 as an adjunct to a reduced calorie diet and 
increased physical activity for chronic weight management in adult patients with a BMI 
≥30 kg/m2 (obese), or adult patients with a BMI ≥27 kg/m2 (overweight) in the presence of at 
least 1 weight-related comorbid condition. 
7.1.1.2
Clinical Experience with APD356/BELVIQ (lorcaserin hydrochloride)
The Phase 3 clinical evaluation of BELVIQ in clinical studies of more than 7700 adult 
subjects, including 604 subjects with type 2 diabetes mellitus (T2DM), demonstrated 
clinically meaningful efficacy, and a safety profile that includes minimal and easily managed 
risks.  Additionally, in studies APD356-009 and APD356-011, more than 2% of the subjects
developed biochemical criteria for T2DM during the study (hemoglobin A1c [HbA1c] ≥6.5).  
The proportion of subjects developing new criteria for diabetes was 1.6-fold greater in the 
placebo as compared with the BELVIQ 20 mg once daily (QD) group (P=0.003).  In the 
pooled efficacy analyses, the BELVIQ 20 mg QD dose met the following prespecified 
endpoints:

A significantly greater proportion of subjects taking BELVIQ (47%) lost ≥5% of 
baseline body weight at 1 year as compared to placebo (23%).  A significantly greater 
proportion of subjects taking BELVIQ (22.4%) lost ≥10% of baseline body weight at 
1 year as compared to placebo (8.7%). 

The mean weight loss at 1 year in subjects taking BELVIQ (-5.8 kg) was significantly 
greater than that in subjects taking placebo (-2.5 kg).  
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
Glycemic benefits were also demonstrated by a 0.5% HbA1c reduction among subjects 
with T2DM and reduction in incidence of new diabetes in the prediabetes population 
compared to placebo
In adolescent obese populations, it is anticipated that BELVIQ will result in similar effects. 
As part of the FDA post marketing requirements, this study is designed to characterize the 
efficacy and safety of BELVIQ in adolescent obese populations in the US; it is also intended 
to support an indication for chronic weight management for obese adolescents.
7.2
Study Rationale
There is no specific FDA guidance for the approval of a weight loss product in adolescents.  
In adults, the Division’s 2007 draft Guidance for Industry Developing Products for Weight 
Management indicate that the product needs to satisfy either of the following mean or 
categorical criteria after 1 year of treatment:

The difference in mean weight loss between the active-product and placebo-treated 
groups is at least 5% and the difference is statistically significant, or

The proportion of subjects who lose ≥5% of baseline body weight in the 
active-product group is at least 35%, is approximately double the proportion of 
subjects in the placebo-treated group who lose ≥5% of baseline body weight, and the 
difference between groups is statistically significant.
The FDA awarded a weight management indication for BELVIQ based on Phase-3 study 
results which achieved the categorical criteria. In a Phase 3 study, a significantly greater 
proportion of subjects taking BELVIQ (47%) lost ≥5% of baseline body weight at 1 year as 
compared to placebo (23%).  It is anticipated that a similar effect will be demonstrated in an 
obese adolescent population, where weight loss will be assessed using BMI (kg/m2)
measurements to account for growth. In this study, the objective is to demonstrate that 
BELVIQ will achieve a greater proportion (%) of subjects with ≥5% reduction in BMI during 
52 weeks of treatment with BELVIQ 20 mg administered QD compared to placebo in obese 
adolescents. 
There are limited clinical studies of weight loss products in obese adolescent populations. In 
the Phase 3 orlistat study mentioned above, the proportion of subjects who lost at least 
5% body weight is relatively low. At the end of the study at Week 52, only 26.5% of 
subjects achieved a 5% or more BMI reduction compared to 15.7% in the placebo group.  In 
a sibutramine Phase-3 study in obese adolescents, a substantially higher proportion of 
subjects (69%) treated with sibutramine achieved at least 5% BMI reduction compared to 
21% of subjects in the placebo group (Berkowitz. 2006).  Unlike the weight loss effect of 
BELVIQ in adults and sibutramine in adolescents, subjects in the orlistat study started to 
increase their BMI after 6 months of treatment (Chanoine, 2005).
In this proposed study, it is assumed that 20% of subjects in the placebo group will achieve at 
least a 5% reduction in BMI, based mostly on placebo group results in the above-mentioned
sibutramine study (21%) and the BELVIQ Phase-3 studies (23%).
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After 1 year, pooled analyses from the two Phase 3 BELVIQ pivotal studies showed that
47% of the BELVIQ-treated subjects achieved at least a 5% reduction in weight compared 
with 23% of the placebo subjects.  This between-group difference of 24.5% is the basis for 
the conservative assumption of a 20% effect size in the current study. 
In addition, the total sample size of 360 subjects will be adequate to assess safety and 
exposure, based on previous adolescent studies with weight management products (orlistat 
and sibutramine) (FDA, 2003; Chanoine,
2005; Berkowitz,
2006), and other 
metabolic/dyslipidemia medication products (ezetimibe/simvastatin) (FDA, 2007).
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8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to demonstrate weight loss efficacy by achieving a 
greater proportion (%) of subjects with a 5% or greater reduction in BMI during 52 weeks of 
treatment with BELVIQ 20 mg administered once daily (QD) compared to placebo in obese 
adolescents.
8.2
Secondary Objectives
The secondary objectives of the study are:
1. To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects 
with ≥5% reduction in BMI (kg/m2) after an initial 12 weeks of treatment with
BELVIQ 20 mg administered QD compared to placebo in obese adolescents
2. To demonstrate weight loss effect by mean change in BMI during 52 weeks of 
treatment with BELVIQ 20 mg administered QD compared to placebo in obese 
adolescents.
3. To demonstrate the effects of treatment with BELVIQ 20 mg QD by assessing:

Other weight loss effects (eg, proportion [%] of subjects achieving ≥10% BMI 
reduction, and change in waist circumference) at the end of 52 weeks of treatment

Effects on glycemia, insulin levels, and HOMA-IR during 52 weeks of treatment

Changes in cardiovascular risk factors associated with obesity (ie, hypertension, 
dyslipidemia, Metabolic Syndrome) during 52 weeks of treatment
4. To assess the safety of BELVIQ, including the effects on growth by growth chart, 
sexual maturation measured by Tanner Staging scores, and signal of suicidal 
ideation/behavior with the Columbia-Suicide Severity Rating Scale (C-SSRS) 
5. To assess the pharmacokinetics (PK) of lorcaserin in obese adolescents using 
population PK modeling
6. To 
explore 
potential 
relationships 
between 
exposure 
to 
lorcaserin 
and 
pharmacodynamic (PD)  parameters including but not limited to reduction from 
baseline in BMI and probability of achieving ≥5% and ≥10% reduction in BMI from 
baseline at Week 52, using population PK/pharmacodynamics (PD) modeling
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 
obese adolescents, age 12 to 17 years old.  Approximately 360 subjects will be randomized in 
a 1:1 ratio to BELVIQ 20 mg QD (180 subjects) and placebo (180 subjects).  Subjects will 
receive BELVIQ 20 mg or placebo QD for up to 52 weeks. Throughout the duration of the 
study, subjects will be encouraged to adhere to a lifestyle modification program that includes 
diet and exercise counseling (see Appendix 2).  
The study will consist of 2 phases: Prerandomization and Randomization.  The 
Prerandomization Phase will last up to 30 days and consists of 1 visit during which subjects 
will be screened for eligibility.  The Randomization Phase consists of a Treatment Period and 
a Follow-up Period.  The Treatment Period will last for a maximum of 52 weeks, with visits 
at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-up Period will extend from the 
end-of-treatment (EOT) visit to the end-of-study (EOS) visit.  
All subjects will continue in the study until the 52 week evaluation is completed.  Subjects 
who discontinue treatment prematurely will be followed up until study completion.  
9.1.1
Prerandomization/Pretreatment Phase
Screening will occur during the Prerandomization Phase at Visit 1.
9.1.1.1
Screening Period
The purpose of the Screening Period is to obtain the informed consent and to establish 
protocol eligibility.  Procedures to be followed when obtaining informed consent are detailed 
in Section 5.3.  Screening period assessments and timing thereof are shown in Section 9.5.2.
9.1.2
Randomization/Treatment Phase
The Randomization Phase will consist of 2 periods, the Treatment Period and the Follow-up 
Period. The Treatment Period assessments and timing thereof are shown in Section 9.5.2.
9.1.3
Extension Phase
Not applicable
9.2
Discussion of Study Design, Including Choice of Control Groups
The proposed dose and dosing frequency in this study is 20 mg QD which is the 
FDA-approved regimen for obesity in adults. The PK parameters of a single 10-mg dose of 
BELVIQ were evaluated in healthy, adolescent obese subjects in Study APD356-025. 
Overall, the PK parameters of BELVIQ and its main metabolites, M1 and M5, were similar 
to those in adults.  Following a single, oral administration of BELVIQ 10 mg to a total of 
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8 healthy adolescent (age 12 to 17 years, inclusive) obese subjects, the mean maximum 
concentration observed (Cmax) and the area under the concentration- time curve from time 
zero to infinity (AUC(0-inf) were 36.5 ng/mL and 464 hr·ng/mL, respectively.  The mean 
BELVIQ terminal phase half-life (t1/2) was 9.70 hours, similar to that observed in adults, thus 
supporting a similar dosing frequency (ie, once daily) in adolescent subjects.
The targeted study population comprises 360 obese adolescents 12 to 17 years of age, 
inclusive. 
Obese adolescents will be identified using gender- and age-specific BMI measurement.  
Obesity in adolescents is defined by US Expert committee recommendations as BMI ≥95th 
percentile (Barlow, 2007). 
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 700 subjects will be screened to ensure that 360 subjects will be randomized.
Subjects who do not meet all inclusion criteria or do meet any 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. Healthy, male or female adolescents, age 12 to 17 years, at Screening with a BMI that 
is greater or equal to the US weighted mean of the 95th percentile based on age and 
sex, but is less than 44 kg/m2. 
2. Subjects in their junior year of high school or earlier, and their families are not 
planning to move away from the area for the duration of the study/assessments
3. Subjects able and willing to comply with all aspects of the study including with a 
reduced-calorie diet and an increased physical activity program
4. Subjects considered to be in stable health in the opinion of the investigator
5. Caregivers/guardians meeting following requirement:
a.
No history of Attention Deficit Hyperactivity Disorder (ADHD, substance abuse, 
depression, suicidal ideation/behavior, bipolar disorder, or schizophrenia)
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b. Able and willing to support, or/and supervise study participation in the opinion of 
the investigator including any existing physical, medical, or mental condition that 
prevents compliance with the protocol
c.
Able and willing to comply with all aspects of the study requirements for the 
caregivers/guardians
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Clinically significant new illness within 30 days before randomization that may affect 
the subject’s ability to fulfill the study requirements and significantly confound the 
assessments
2. Subjects who cannot swallow investigational products 
3. Documented pulmonary hypertension (PH) by objective assessments (ie, imaging
modality or cardiac catherization)
4. Known 
valvular disease 
defined by 
clinical diagnosis 
or 
most recent 
echocardiography.  History of valvular disease is allowed if it has been corrected by 
valve replacement or repair.
5. Significant renal or hepatic disease, as evidenced by a serum creatinine >1.5 × upper 
limit of normal (ULN), serum transaminases >3 × ULN, or total bilirubin >1.5 × ULN 
in absence of Gilbert’s syndrome
6. Any history of anorexia or bulimia, ADHD, any DSM-5 depressive disorder, or 
suicidal ideation/behavior, bipolar disorder, or schizophrenia
7. Known secondary causes (chromosomal, endocrine, or metabolic) for obesity (for 
example, Prader-Willi syndrome, Down’s Syndrome, untreated hypothyroidism, 
Cushing’s syndrome, daily systemic corticosteroid exposure for longer than 30 days, 
history of significant exposure to corticosteroids for chronic illness during the past 
year, and known genetic causes of obesity)
8. Use of other products intended for weight loss including prescription drugs, over-the-
counter (OTC) drugs, and herbal preparations within 1 month before Screening 
9. Use of any of the following medications: 
a) Serotonergic drugs within 7 days (or 5 half-lives, whichever is longer), or MAOIs 
within 30 days, prior to Randomization, including: 

selective serotonin reuptake inhibitors (SSRIs)

serotonin norepinephrine reuptake inhibitors (SNRIs)

tricyclic antidepressants (TCAs) 

bupropion

triptans 

St. John’s Wort and tryptophan 

monoamine oxidase inhibitors (MAOIs)
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
linezolid

dextromethorphan (in any form, eg, OTC cold medicines)

lithium

tramadol

antipsychotics or other dopamine antagonists 
b) Others

antiseizure medications including valproic acid, zonisamide, lamotrigine

oral steroids (inhaled steroids are acceptable)

stimulant medications

benzodiazepines
10. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months 
before Screening, including, but not limited to pergolide, ergotamine, methysergide, 
and cabergoline
11. History or evidence of clinically significant disease (eg, malignancy, cardiac, 
respiratory, gastrointestinal, renal, or psychiatric disease) other than prediabetes 
(impaired fasting glucose or glucose intolerance), obstructive sleep apnea, 
dyslipidemia, and nonalcoholic fatty liver disease
12. Use of BELVIQ within 6 months before Screening or hypersensitivity to BELVIQ or 
any of the excipients
13. Significant change in diet or level of physical activity within 1 month before dosing 
or change in weight of >5 kg within 3 months
14. Adherence to a of very-low calorie (<1000/day) weight loss diet within 6 months
15. History of alcohol or drug dependence or abuse 
16. Recreational drug use within 2 years before Screening
17. Known to be human immunodeficiency virus (HIV) positive
18. Active viral hepatitis (B or C) as demonstrated by positive serology
19. Malignancy within 5 years before Screening
20. Unable to attend scheduled visits (eg, lack of transportation) or lack of a guardian to 
supervise study participation
21. Special needs subjects who are unable to comprehend study-related instructions 
(eg, mild to profound mental retardation [IQ <80], moderate to severe cognitive 
developmental delay, pervasive development disorders (PDD), autism
22. Ongoing epilepsy or other seizure disorder, or use of medications for a seizure 
disorder within 6 months of screening, or any time between screening and 
randomization
23. Uncontrolled hypertension, defined as blood pressure (BP) in the 95th percentile or 
greater for age, sex, and height on 2 separate readings recorded on 2 separate days; 
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subjects who had uncontrolled hypertension at Screening can be rescreened >1 month 
following initiation or adjustment of antihypertensive therapy.
24. Currently enrolled in another clinical study or has used any investigational drug or 
device within 30 days before providing informed consent
25. Planned bariatric surgery during the study
26. Not suitable to participate in the study in the opinion of the investigator including any 
existing physical, medical, or mental condition that prevents compliance with the 
protocol
27. Females who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive beta-human chorionic gonadotropin [ß-hCG]).  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the first dose of study drug.
28. Females of childbearing potential who: 
a.
Had unprotected sexual intercourse within 30 days before study entry and who do 
not agree to use a highly effective method of contraception (eg, total abstinence, 
an intrauterine device, a double-barrier method [such as condom plus diaphragm 
with spermicide], a contraceptive implant, an oral contraceptive, or have a 
vasectomized partner with confirmed azoospermia) throughout the entire study 
period or for 30 days after study drug discontinuation.
b. Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexual activity during the study period or for 
30 days after study drug discontinuation.
c.
Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do not 
agree to use the same contraceptive during the study or for 30 days after study 
drug discontinuation.
(NOTE:  All females will be considered to be of childbearing potential unless they are 
have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy, all with surgery at least 1 month before dosing]).
29. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential 
or practicing highly effective contraception throughout the study period or for 30 days 
after study drug discontinuation).  No sperm donation is allowed during the study 
period or for 30 days after study drug discontinuation.
9.4
Treatments
9.4.1
Treatments Administered
Subjects will be administered a single tablet of BELVIQ 20 mg or placebo orally QD.
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BELVIQ (lorcaserin hydrochloride) is a (US) Drug Enforcement Administration (DEA) 
Scheduled IV Drug Product (C – IV).
BELVIQ XR will be provided as blue-colored, round, film-coated, biconvex 20-mg tablets 
(microcrystalline cellulose; mannitol, hypromellose 2208, ethylcellulose dispersion Type B, 
hypromellose 2910; colloidal silicon dioxide, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, FD&C yellow #6/sunset yellow FCF aluminum lake, iron oxide 
yellow, iron oxide red, and magnesium stearate).  BELVIQ XR and matching placebo will be 
supplied by the sponsor in labeled containers.  
9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of BELVIQ
•
Test drug code:  APD356
•
Generic name:  lorcaserin hydrochloride
•
Chemical name:  (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 
hydrochloride hemihydrate
•
Molecular formula:  C11H15Cl2N•0.5 H2O
•
Molecular weight: 241.16 g/mol (hemihydrate form)
9.4.2.2
Comparator Drug
Not applicable
9.4.2.3
Labeling for Study Drug
Study drug will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and is translated into the required language(s) for each of those 
countries.
The clinical study labels will contain, but are not limited to the following
requirements:
1. Name and address of the sponsor
2. Pharmaceutical dosage form, quantity of dosage units, and strength
3. Lot number or Packaging Reference number
4. Protocol number
5. Directions of use (if applicable)
6. Storage conditions
7. Storage restrictions (if applicable)
8. US Caution Statement:  “CAUTION:  New Drug – Limited by Federal 
(US) law to investigational use.”
All packaging and labeling will be performed according to Good Manufacturing Practices 
and GCP guidelines.
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Study drug must be stored as instructed on the study drug label and in accordance with the
DEA Regulations for Schedule IV Controlled Drugs (US sites). Study drug must be kept
in a secure location as required by DEA regulations and carefully stored at the study site
within its original container.
The investigator (or pharmacist, as appropriate) must maintain records of the delivery
of the study drug to the study site, the inventory at the site, use for each subject, and return
of the study drug to a delegate of the sponsor. Total study site accountability will be
conducted at the end of the study and the investigator must explain any discrepancies.
A Drug Dispensing Log must be kept current and should contain at least the
following information:
•
Identification (subject ID number and initials) of the subject to whom the study drug 
was dispensed
•
The dates and unique kit/carton identifiers for dispensed study drug
•
Initial inventory on receipt of drug at the site
•
Final inventory on completion of the study
All records and inventory must be available for inspection by the clinical study
monitor.
9.4.2.4
Storage Conditions
Where applicable, investigational product will be stored in accordance with the DEA 
Regulations for Scheduled III - V Drugs and 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 Prerandomization Phase, subjects will be randomized to 1 of 2 treatment groups in 
a ratio of 1:1.  Each treatment group will receive either BELIVIQ or placebo QD.  
Randomization will be performed centrally by an interactive voice and/or web response 
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system (IxRS).  The IxRS or clinical supply vendor will generate the randomized 
identification numbers to be included on study packaging.  Upon signature of the ICF, the 
investigator or designee will access the IxRS to register the subject information.  At 
Randomization, the IxRS will assign each subject a unique randomization number.  At each 
subsequent visit during the Treatment Period and Follow-up Period, the investigator or 
designee will access IxRS to obtain dispensing information and to register the subject’s visit. 
9.4.4
Selection and Timing of Dose for Each Subject
Subjects should take the study medication once daily, and be encouraged to take the study 
medication with an adequate amount of water (8 oz. or 240 mL).
9.4.5
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 the SOP.
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 
given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.4.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor or designee to ascertain the 
necessity of breaking the code.  
9.4.6
Prior and Concomitant Therapy
Any medication (including OTC medications) or therapy administered to the subject during 
the study (starting at the date of informed consent) will be recorded on the Prior & 
Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  The investigator 
will record on the Adverse Event CRF any AE for which the concomitant medication/therapy 
was administered. If the concomitant medication/therapy is being administered for a medical 
condition present at the time of entry into the study, the investigator will record the medical 
condition on the Medical History and Current Medical Condition CRF’
Other products intended for weight loss including prescription drugs, OTC drugs, and herbal 
preparations are prohibited as concomitant medications.  Any of the following serotonergic 
agents in combination with BELVIQ is prohibited, with the exception that OTC cold 
medicines containing dextromethorphan can be used for up to 7 days and study medication is 
temporarily stopped for that time period (and should be resumed the next day after the OTC 
cold medicine is stopped).
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a.
Serotonergic drugs

SSRIs

SNRIs

TCAs 

bupropion

triptans 

St. John’s Wort and tryptophan 

MAOIs

linezolid

dextromethorphan

lithium

tramadol

antipsychotics or other dopamine antagonists
b.
Others

antiseizure medications including valproic acid, zonisamide, lamotrigine

oral steroids (inhaled steroids are acceptable)

stimulant medications

benzodiazepines
9.4.7
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs
will review treatment compliance during site visits and at the completion of the study.
Subjects will return unused study drug approximately every 4 weeks and be given a new 
4-week supply per visit schedule; pill counts will be made by study staff on returned 
medication. 
9.4.8
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor:
•
A signed and dated confidentiality agreement
•
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator
•
Written proof of approval of the protocol, the ICFs, and any other information 
provided to the subjects by the IRB/IEC for the institution where the study is to be 
conducted
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•
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study
•
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number
•
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, where applicable
•
Financial Disclosure form(s) for the principal PI and all sub-investigators listed on 
Form FDA 1572, where applicable
•
A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s 
current medical license or medical registration number on the CV
•
A signed and dated clinical studies agreement
•
A copy of the current Controlled Substance Registration Certificate- Form DEA 223 
(US sites only).  Must be appropriate to handle schedule IV products and not be 
expired.
The investigational product can only be shipped to the exact address detailed on the site’s 
form DEA 223.  If a site requires drug to be shipped to a particular location, then an 
appropriate form DEA 223 certificate must be provided for that location.
The investigator and the study staff will be responsible for the accountability of all study 
drugs/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study. 
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to:  (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies accountability log, (d) all shipping service receipts, 
(e) documentation of returns to the sponsor, and (f) certificates of destruction for any 
destruction of study drugs/study supplies that occurs at the site.  All forms will be provided 
by the sponsor.  Any comparable forms that the site wishes to use must be approved by the 
sponsor.
The study drugs/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
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authority (eg, FDA, Medicine and Healthcare Products Regulatory Agency).  As applicable, 
all unused study drugs/study supplies and empty and partially empty containers from used 
study drugs/study supplies are to be returned to the investigator by the subject and together 
with unused study drugs/study supplies that were shipped to the site but not dispensed to 
subjects are to be returned to the sponsor’s designated central or local depot(s) during the 
study or at the conclusion of the study, unless provision is made by the sponsor for 
destruction of study drugs/study supplies and containers at the site.  Destruction at the site 
will only occur under circumstances where regulation or supply type prohibits the return of 
study drugs/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs/study supplies that are to be returned to 
the sponsor’s designated central or local depot(s) must be boxed and sealed and shipped back 
to the central or local depot(s) following all local regulatory requirements.  In some regions, 
study drugs/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies are approved for 
destruction at the site, destruction will occur following the site’s standard procedures and 
certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the first visit.  Demography information 
includes date of birth (or age), sex, race/ethnicity.  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY
Medical and surgical history and current medical conditions will be recorded at the first visit.  
All medical and surgical history within 5 years must be noted in the Medical History and 
Current Medical Conditions CRF.
9.5.1.3
Efficacy Assessments

Body weight and height will be assessed to measure change in BMI from Baseline to 
Week 52 and to calculate the proportion (%) of patients achieving ≥5% and 
≥10% BMI reduction at Week 52.

Measurement of systolic BP, diastolic BP, heart rate (HR), triglycerides, total 
cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein 
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(LDL) cholesterol, fasting plasma glucose, fasting insulin, and HbA1c will be used to 
assess the change in cardiovascular and metabolic profiles from Baseline to Week 52.

Metabolic Syndrome as defined by the International Diabetes Federation (IDF) (IDF, 
2014) 

Pre-hypertension and primary hypertension as defined by Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and 
Adolescents (Expert Panel on Integrated Guidelines for Cardiovascular Health and 
Risk Reduction in Children and Adolescents: Summary Report Pediatrics.
2011; 
128:S213-S256).

Dyslipidemia as defined by Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents (Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and 
Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256).
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Blood samples (approximately 4 mL each) for PK assessments will be collected at Weeks 12, 
28, 36, and 52 for population/PK analyses.  At Weeks 12, 28, and 52, subjects will be 
instructed to take their morning dose at the clinic.  Two blood samples for determination of 
plasma concentrations of lorcaserin will be taken at each of these visits: predose (within 
30 minutes prior to dosing) and within 1 to 3 hours postdose.  At the Week 36 visit, subjects 
will take the morning dose at home, and 1 sample for determination of plasma concentrations 
of lorcaserin will be collected at the investigational site within 4 to 6 hours postdose.
Plasma lorcaserin concentrations will be measured using a validated liquid chromatography 
method coupled with tandem mass spectrometry (LC-MS/MS) method. The collection, 
handling, and shipping procedures for PK samples will be described in a manual to be 
provided to the study sites.
9.5.1.4.2
PHARMACODYNAMIC ASSESSMENTS

Proportion (%) of patients achieving ≥5% and ≥10% BMI reduction

BMI change from baseline
Other PD endpoints will be considered based on the data at the end of the study to explore 
their relationships with exposure to lorcaserin.
9.5.1.4.3
PHARMACOGENOMIC/PHARMACOGENETIC ASSESSMENTS
Not applicable
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9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse 
events (SAEs), ECGs, laboratory evaluations for hematology, blood chemistry, and urine 
values; neuropsychiatric events, periodic measurements of vital signs, and performance of 
physical examinations.  Adolescent growth will be evaluated using the US Center for Disease 
Control (CDC) growth chart at Baseline, and Weeks 5, 12, 28, 36, 52, and at Follow-up, and 
a full physical examination at Baseline and Weeks 12, 28, 36, 52, and at Follow-up.  
Adolescent sexual maturation will be evaluated by self-reported changes in Tanner Staging at 
Baseline, Week 28, and Week 52.  
The C-SSRS will be used to assess all adolescent subjects in the study with any signal of 
depression and suicidal ideation/behavior.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is BELVIQ 
(lorcaserin hydrochloride). 
The criteria for identifying AEs in this study are:
•
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)
•
Any new disease or exacerbation of an existing disease 
•
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, electrocardiogram (ECG) or x-ray) that results in symptoms, a change in 
treatment, or discontinuation of study drug
•
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)
•
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the Screening Disposition CRF.  All 
AEs, regardless of relationship to study drug or procedure, should be collected beginning 
from the time the subject signs the study ICF through the last visit in the Treatment Phase.
Subjects who fail screening primarily due to AE(s) must have the AE(s) leading to screen 
failure reported on the Screening Disposition CRF.  Serious AEs will be collected for 30 days 
after the last dose.
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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) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is >450 ms and 
there is an increase of >60 ms from baseline.  Any ECG abnormality that the investigator 
considers as an AE should be reported as such.
It is the responsibility of the investigator to review the results of the C-SSRS in all subjects 
and determine if any result constitutes an AE.  Medical and scientific judgment should be 
exercised in deciding whether an isolated suicidality rating scale response should be 
classified as an AE (see Section 9.5.1.5.8 for a description of the C-SSRS).
All AEs must be followed for 30 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
Adverse events will be graded on a 3-point scale (mild, moderate, severe) and reported in the 
detail indicated on the CRF.  The definitions are as follows:
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating, with inability to work or to perform normal daily activity
The criteria for assessing severity are different than those used for seriousness (see
Section 9.5.1.5.2 for the definition of an SAE).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:
•
Temporal relationship of the onset of the event to the initiation of the study treatment
•
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable
•
Whether the event is known to be associated with the study treatment or with other 
similar treatments
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•
The presence of risk factors in the study subject known to increase the occurrence of 
the event
•
The presence of nonstudy, treatment-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An SAE is any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious criteria:
•
Serotonin syndrome (must have at least one 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 onset valvular heart disease
•
New onset PH
•
Malignant neoplasms, with the exception of basal cell and squamous cell carcinomas 
of the skin
•
Fibroadenomas of the breast or ductal carcinoma in situ
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:
•
Hospitalizations for respite care 
•
Planned hospitalizations required by the protocol
•
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)
•
Hospitalization for administration of study drug or insertion of access for 
administration of study drug
•
Hospitalization for routine maintenance of a device (eg, battery replacement) that was 
in place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 1.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 2) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study.
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Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
Chemistry
Electrolytes
Chloride, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, gamma glutamyl transpeptidase, direct bilirubin, 
total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Other
Albumin, calcium, globulin, glucose, HbA1c, HDL cholesterol, 
lactate dehydrogenase, LDL cholesterol, phosphorus, total protein,
total cholesterol, triglycerides, prolactin, uric acid, urine ß-hCG
Urinalysis
Bacteria, casts, crystals, epithelial cells, glucose, ketones, occult 
blood, pH, protein, RBCs, specific gravity, WBCs
ß-hCG = beta-human chorionic gonadotropin, HbA1c = hemoglobin A1c , HDL = high density lipoprotein, LDL 
= low density lipoprotein, 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.  In cases of a safety concern, blood samples will be 
split (or 2 samples drawn) to allow a local laboratory analysis in addition to the central 
laboratory.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse [beats 
per minute], respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) 
will be obtained as designated in the Schedule of Procedures/Assessments (Table 2) by a 
validated method.  Blood pressure and pulse will be measured after the subject has been 
sitting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person. 
When vital signs are to be obtained concurrently with PK or other blood samples, the vital 
sign measurements will be performed prior to drawing blood samples in order to maximize 
the accuracy of blood sampling times while minimizing the potential effects of blood 
drawing on recordings obtained during safety assessments.
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9.5.1.5.5
HEIGHT MEASUREMENTS
Height (cm) measurements will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 2).
9.5.1.5.6
PHYSICAL EXAMINATIONS
Physical
examinations will be performed as 
designated in
the Schedule of 
Procedures/Assessments (Table 2).  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.  Results of the C-SSRS will be reviewed. 
9.5.1.5.7
ELECTROCARDIOGRAMS
Twelve-lead 
ECGs 
will 
be 
obtained 
as 
designated 
in
the 
Schedule 
of 
Procedures/Assessments (Table 2). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.8
OTHER SAFETY ASSESSMENTS
An assessment of suicidality using the C-SSRS will be performed at Baseline and at study 
visits as designated in the Schedule of Procedures/Assessments (Table 2). 
9.5.1.6
Other Assessments
9.5.1.6.1
PREGNANCY TEST
A urine pregnancy test will be performed at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 2).
9.5.1.6.2
URINE DRUG AND COTININE TEST
A 30-mL urine sample will be collected at designated time points as specified in the 
Schedule of Procedures/Assessments (Table 2).  This sample will be tested for common 
drugs 
of 
use/abuse: 
eg, 
ethyl 
alcohol, 
cocaine, 
cannabinoids, 
phencyclidine, 
nicotine/cotinine, opioids (as a group), benzodiazepines, barbiturates, and amphetamines.
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9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 2 presents the Schedule of Procedures/Assessments for the study.
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-
up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
Informed Consent
X
Demography
X
Medical History 
X
X
Prior/concomitant 
medication assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion criteria
X
X
Physical Examination
X
X
X
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist/Hip circumference
X
X
X
X
X
X
X
X
X
X
Routine clinical laboratory 
tests 
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
HbA1c sampling
X
X
X
X
X
Drugs of abuse screen
X
Pregnancy test (Urine)
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
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Table 2
Schedule of Procedures/Assessments in Study APD356-A001-403
Phase:
Prerandomizationa
Randomization
Other
Period:
Screening
Treatment
Follow-
up
Visit Number:
1
2a
3
4
5
6
7
8
9
10
11 
(EOT)
EOS
Un-
scheduled
Early 
discon-
tinuation
Day:
-30 to -1
1
Weeksb,c:
0
1
5
8
12
20
28
36
44
52
56
Procedure
IxRS
X
X
X
X
X
X
X
X
X
X
Study drug dispensing
X
X
X
X
X
X
X
X
X
Collect study medication  
X
X
X
X
X
X
X
X
X
X
X
Drug accounting and 
compliance
X
X
X
X
X
X
X
X
X
X
X
Adverse event monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
US CDC growth chart
X
X
X
X
X
X
X
X
X
Tanner Staging
X
X
X
X
X
X
X
C-SSRS 
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample
X
X
X
X
X
Pharmacogenomic sample
X
Prolactin
X
X
X
X
X
ECG
X
X
X
X
Lifestyle modification 
counselingd
X
X
X
X
X
X
X
X
X
X
CDC = Center for Disease Control, C-SSRS = Columbia-Suicide Severity Rating Scale, ECG = electrocardiogram, EOS = end of study, EOT = end of treatment, HBA1c = 
hemoglobin A1c, IxRS = interactive voice and/or web response system, PK = pharmacokinetics, US = United States, 
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a:
Baseline measurements will be collected on Day 1, prior to drug administration unless specified otherwise.
b:
Window ±7 days for all visits after Visit 2 except for Weeks 12 and 28 (the window for these visits will be broader at ±14 days). Week is shown unless otherwise 
indicated.
c:
On Weeks 12, 28, and 52, subjects will take the morning dose at the clinic, and 2 blood samples for determination of plasma concentrations of lorcaserin will be taken: 
predose (within 30 minutes prior to dosing) and within 1 to 3 hours postdose (time in which the dose was taken on the night previous to the visit must be recorded). On 
Week 36 the subjects will take the morning dose at home (time of morning dosing at home must be recorded), and 1 blood sample for determination of plasma 
concentrations of lorcaserin will be collected at the investigational within 4 to 6 hours postdose.
d:
Lifestyle modification counseling will also be performed at Weeks  3, 24, 32, 40, and 48in addition to counseling at the visits in the schedule of assessments table above. 
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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Assessments (Table 2) for details, giving particular attention 
to all footnotes.  
9.5.2.3
Total Volume of Blood Sampling
Table 3 presents the number of blood samples and the total volume of blood that will be 
collected throughout the study. Additional samples may be taken at the discretion of the 
investigator if the results of any tests fall outside reference ranges or clinical symptoms 
necessitate testing to ensure subject safety.
Table 3
Summary of Blood Sample Volumes
Sample Volume per 
Collection (mL)
Number of Collection Time 
Points
Total Volume
Collected (mL)
Clinical laboratory tests
12
Screening: 1
Visits 2, 3, 4, 6, 8; 11/EOT, EOS
128=96
PK blood sampling
4
Visits 6, 8, 9, and 11/EOT (2 
samples each)
84=32
Total
128
EOS = end of study, EOT = end of treatment, PK = pharmacokinetics.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of obesity. 
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 1 business day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the 
through the last visit and for 30 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.
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The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
The investigator must notify his/her IRB/IEC of the occurrence of the SAE, in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 30 days of last study treatment must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
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9.5.4.3
Reporting of Events Association with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows: 
Overdose
Accidental or intentional use of the study drug in an amount higher
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol or authorized dose, route of administration, or 
indication(s) or use of prescription-only study drug without a 
prescription
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 the 
healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or
systems,
including prescribing,
order 
communication,
product labeling/packaging/nomenclature,
compounding,
dispensing,
distribution,
administration, education,
monitoring, or use.
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 Section 9.5.4.1
even if the AEs do not meet serious criteria.  Abuse is always to be captured as an AE.  If the 
AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should 
be noted as nonserious on the SAE form and the Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events (serotonin syndrome, psychosis, suicidal behavior, priapism, new onset 
valvular heart disease, new onset PH, malignant neoplasms [with the exception of basal cell 
and squamous cell carcinomas of the skin], and fibroadenomas of the breast or ductal 
carcinoma in situ) should always be considered as serious important medical events and be 
entered on the Adverse Event CRF and reported using the procedures detailed in Reporting 
of Serious Adverse Events (Section 9.5.4.1), even if the study-specific event does not meet 
other serious criteria.  
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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
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects will continue in the study until the 52 week evaluation is completed.  
Subjects who discontinue treatment prematurely will be followed up until study completion.  
All subjects who discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments (Table 2).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, withdrawal of consent, pregnancy, study 
terminated by sponsor, or other.  In addition to the primary reason, the subject may indicate
1 or more of secondary reasons for discontinuation.  Study disposition information will be 
collected on the Subject Disposition CRF.
A subject removed from the study for any reason may not be replaced.
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9.5.6
Abuse or Diversion of Study Drug
During the study, the investigator will report any concern about abuse or diversion of study 
drugs by completing the CRF.  The DEA Registrant has the responsibility to comply with 
local, state and Federal laws to notify the Field Division Office of the Drug Enforcement 
Administration of any theft or significant loss of any controlled substances upon discovery of 
such theft or loss.  
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
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9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released for unblinding.  Statistical analyses will be 
performed using WinNonlin and SAS software or other validated statistical software as 
required.  Details of the statistical analyses will be included in a separate statistical analysis 
plan (SAP).  
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT

Proportion (%) of patients achieving ≥5% BMI reduction at Week 52 
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints are:

Proportion (%) of patients achieving ≥10% BMI reduction at Week 52 

Proportion (%) of patients achieving ≥5% BMI reduction at Week 12

Change and percent in BMI from Baseline to Week 52

Change in waist circumference from Baseline to Week 52

Change in HbA1c from Baseline to Week 52

Change in fasting glucose, fasting insulin, and HOMA-IR (HOMA-IR=glucose 
[mg/dL] x insulin [mU/L] /405) from Baseline to Week 52

Change in blood pressure (systolic and diastolic) from Baseline to Week 52

Change in lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, 
triglycerides) from Baseline to Week 52

Proportion of subjects with Metabolic Syndrome at Week 52

Proportion (%) of subjects with pre-hypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52
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9.7.1.2
Definitions of Analysis Sets

The 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.

The Full Analysis Set (FAS) is the group of all randomized subjects who received at 
least 1 dose of study drug and had at least 1 postdose measurement.

The Intent-to-Treat set (ITT) is the group of all randomized subjects regardless of 
whether they took study drug or not.

Per-Protocol Analysis Set (PP) is the group of all randomized subjects who are 
80% or greater compliant with study medication, completed the study, have no major 
protocol deviations,  violations of inclusion/exclusion criteria, and have BMI data at 
Baseline, Week 12, and Week 52.  The determination of subjects to be excluded from 
this population based on the above criteria and list of major protocol violations will 
be included in the SAP and finalized prior to data base lock.

The PD Analysis Set is the group of subjects who had sufficient PD data to derive at 
least 1 PD parameter.

The PK Analysis Set is the group of all randomized subjects from whom at least 
1 valid BELVIQ plasma concentration was obtained with associated documented 
dosing history.

The population PK/PD set is the group of randomized subjects with PK information 
and who have at least 1 adequately documented measurement of body weight.
9.7.1.3
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed 
screening and the reasons for screen failure will be summarized, based on data reported on 
the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Analysis Sets will be summarized for 
each treatment group using descriptive statistics.  Continuous demographic and baseline 
variables include age, height, BMI, waist circumference, and weight; categorical variables 
include sex and race.
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9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary (WHO DD) 
(01 Mar 2015).  The number (percentage) of subjects who took prior and concomitant 
medications will be summarized on the Safety Analysis Set by treatment group, Anatomical 
Therapeutic Chemical class, and WHO DD preferred term (PT).  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that started on or after the date of the dosing of 
study drug and continued up to 30 days afterward.  All medications will be presented in 
subject data listings.
9.7.1.6
Efficacy Analyses
For the primary and secondary endpoints, a 2-sided α=0.05 significance level will be used.
The primary analysis is:

The proportion of subjects achieving ≥5% BMI reduction will be analyzed using 
logistic regression model with treatment and site as factors and baseline BMI as a 
covariate.  Comparison between BELVIQ and placebo will be made at Week 52.  The 
FAS analysis set will be used for this analysis.  Sensitivity analysis will be conducted 
treating subjects with missing BMI data at Week 52, as nonresponders (did not 
achieve ≥5% BMI reduction).
The secondary analyses are:

The proportion of subjects achieving ≥5% BMI reduction will be analyzed using 
logistic regression model with treatment and site as a factors, and baseline BMI as a 
covariate.  Comparison between BELVIQ and placebo will be made at Week 12.  The 
FAS analysis set will be used for this analysis.  Sensitivity 
analysis 
will 
be 
conducted treating subjects with missing BMI data at Week 12, as nonresponders (did 
not achieve ≥5% BMI reduction).

Change and percent change from baseline in BMI will be analyzed using an analysis 
of covariance model with treatment and site as factors and baseline BMI as a 
covariate.  Comparison between BELVIQ and placebo will be made at Week 52 using 
the last observation carried forward (LOCF) approach.  The FAS analysis set will be 
used for this analysis.  Additional sensitivity analyses will be performed using 
model-based imputation methods that will be described separately in the SAP.

Rates of growth in height will be summarized by the height distribution of percent 
change from Baseline to Week 52 by treatment group.  The Safety Analysis Set will 
be used for this analysis.

Tanner Staging (II, III, IV, and V) will be summarized using shift tables from 
Baseline to Week 52 by treatment group.  The Safety Analysis Set will be used for 
this analysis.
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
C-SSRS: The incidence of suicidal ideation or suicidal behavior will be summarized 
by treatment groups.  The Safety Analysis Set will be used for this analysis.

The change from baseline for the endpoints HbA1c, fasting plasma glucose, fasting 
insulin, HOMA-IR, waist circumference, blood pressure (systolic and diastolic), and
lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) will 
be analyzed using a mixed-effects model with repeated measures with treatment and 
site as factors and baseline as a covariate.  Comparison between BELVIQ and 
placebo will be made at Week 52.  The FAS analysis set will be used for this analysis.

The proportion of subjects achieving ≥10% BMI reduction will be analyzed using 
logistic regression model with treatment and site as factors, and baseline BMI as a 
covariate.  Comparison between BELVIQ and placebo will be made at Week 52.  The 
FAS analysis set will be used for this analysis.  Sensitivity analysis will be conducted 
treating subjects with missing BMI data at Week 52 as nonresponders (did not 
achieve ≥10% BMI reduction).

A logistic regression model with treatment and site as factors will be used to analyze
the following endpoints.  Comparison between BELVIQ and placebo will be made at 
Week 52.  The FAS analysis set will be used for these analyses.  Sensitivity analysis
will be conducted using LOCF for subjects with missing data at Week 52.
o
Proportion (%) of subjects with confirmed pre-hypertension or primary 
hypertension
o
Proportion (%) of subjects with dyslipidemia
o
Proportion (%) with metabolic syndrome that met at least 2 IDF criteria
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Lorcaserin plasma concentration-time data will be subjected to population PK analysis using 
nonlinear mixed effects modeling.  The effect of covariates, such as baseline 
characteristics/demographics, on PK will be explored.  Derived exposure parameters such as 
the maximum observed concentration (Cmax) and the area under the concentration-time curve 
from time zero to 24 hours at steady-state (AUC0-24,ss) will be calculated from the final PK 
model using individual posterior estimates of the PK parameters and from dosing history.  
The PK analysis set will be used for this analysis.
9.7.1.7.2
PHARMACODYNAMIC ANALYSES
Proportion (%) of patients achieving ≥5% and ≥10% BMI reduction, and BMI change from 
baseline will be assessed as the PD analysis.  The PD analysis set will be used for this 
analysis.
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Other assessments (ie, BMI change, percentage of BMI change, proportion [%] of patients 
achieving ≥10% BMI reduction, and waist circumference from baseline) will also assessed as 
PD analysis.  The PK/PD analysis set will be used for this analysis.
9.7.1.7.3
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Population PK/PD modeling will be used to explore the relationship between exposure to 
BELVIQ and response, including but not limited to change in BMI from baseline and the 
probability of achieving ≥5% and ≥10% change in BMI from baseline to Week 52.  
Additionally, exposure-safety relationships for select safety parameters may be explored 
graphically.  Any emergent relationship may be modeled as appropriate.  Any parameters 
based on the study data may be considered for exploratory assessment for its relationship to 
PK.
9.7.1.7.4
PHARMACOGENOMIC AND PHARMACOGENETIC ANALYSES
At the time of randomization, when applicable, a blood sample will be taken for potential 
investigation of genetic variability associated with genotypes relating to response to 
BELVIQ, weight loss, susceptibility to diabetes, and their associated risk factors
(Appendix 3).
Data obtained from the PD and PG samples will be used for research. The PD and 
PGsamples will not be used to determine or predict risks for diseases that an individual 
subject does not currently have.  Any sample or derivatives (DNA, RNA, and protein) may 
be stored for up to 15 years to assist in any research scientific questions related to BELVIQ 
and for potential diagnostic development. If the subject reaches 18 years of age prior to the 
date of final sample analyses they will be reconsented. No further analyses will be performed 
on these collected samples from subjects who either do not reconsent after their 18th birthday 
or cannot be reached for re-consenting and the sample will be destroyed
9.7.1.8
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set.  The incidence of AEs 
(including changes from baseline in physical examination), suicidal ideation/behavior 
(C-SSRS), neuropsychiatric events, out-of-normal-range laboratory safety test variables, 
along with change from baseline in laboratory safety test variables, and vital sign 
measurements at end of treatment will be summarized by treatment group using descriptive 
statistics.  Study Day 1 for all safety analyses will be defined as the date of the first dose of 
study drug.
9.7.1.8.1
EXTENT OF EXPOSURE
Subjects will receive BELVIQ 20 mg or placebo QD for up to 52 weeks. 
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 
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(MedDRA).  Adverse events will be coded to the MedDRA (Version 18.0 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 treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that were 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 a SOC and PT, even if the subject experienced more than
1 TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs 
will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by maximum severity (mild, moderate, or severe).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
Adverse events will be summarized using the Safety Analysis Set.  The number of AEs and 
number and incidence (%) of subjects with AEs will be summarized by treatment group and 
overall.  To obtain the incidence (%), the number of subjects with at least 1 event and the 
percentage of subjects with AEs by SOC and by PT will be calculated.  Incidence (%) by 
causal relationship with study drug and by severity will also be calculated.  For clinically 
significant events, time of onset, and recovery will be reported.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT for each treatment group.  A subject data listing of all AEs leading to 
death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events 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.
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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment group using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.5.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  Within-treatment comparisons for each laboratory parameter will be based 
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH 
classification at each postbaseline visit and at the end of treatment.  Similar shift tables will 
also compare the baseline LNH classification to the LNH classification for the highest and 
lowest value during the treatment period.
Appendix 1
presents the criteria that will be used to identify subjects with 
treatment-emergent markedly abnormal laboratory values (TEMAV).  Except for phosphate, 
a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or 
higher.  For phosphate, a TEMAV was defined as a postbaseline value with an increase from 
baseline to a grade of 3 or higher.  When displaying the incidence of TEMAVs, each subject 
may be counted once in the laboratory parameter high and in the laboratory parameter low 
categories, as applicable.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, weight) and changes from baseline will be presented by day 
and time after dosing.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
treatment group. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Bazett and QTc Fridericia during the treatment period will be summarized.  
Clinically abnormal ECG results in QTc Bazett and QTc Fridericia will be categorized as 
follows:
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Absolute QTc interval prolongation:
QTc interval >450 ms
QTc interval >480 ms
QTc interval >500 ms
Change from baseline in QTc interval:
QTc interval increases from baseline >30 ms
QTc interval increases from baseline >60 ms
9.7.1.8.6
OTHER SAFETY ANALYSES
Not applicable
9.7.2
Determination of Sample Size
A sample size of 360 subjects in a 1:1 ratio (n=180 in the BELVIQ 20 mg QD treatment 
group: n=180 in the placebo group) will have 90% power to detect a 20% difference in 
proportions of subjects with at least 5% reduction in BMI, assuming the placebo response is 
20%, using a 2-sided test and α=0.05, assuming a 35% dropout rate.  The assumption is 
based on lorcaserin adult Phase 3 and adolescent studies with orlistat and sibutramine 
(Chanoine JP, 2005; Berkowitz. R, 2006).
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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10 REFERENCE LIST
Barlow SE and the Expert Committee. Expert committee recommendations regarding the 
prevention, assessment, and treatment of child and adolescent overweight and obesity: 
summary report. Pediatrics 2007;120 Supplement December 2007:S164—S192.
Berkowitz RI, Fujioka K, Daniels SR, Hoppin AG, Owen S, Perry AC, et al.  Effects of 
sibutramine treatment in obese adolescents:  a randomized trial.  Ann Intern Med 
2006;145:81-90.
CDC/NCHS, Health, United States, 2000, 2000 CDC Growth Charts for the United States: 
Methods and Development.
CDC/NCHS, Health, United States, 2013, Table 64. Data from the National Health and 
Nutrition Examination Survey (NHANES).
Chanoine JP, Hampl S, Jensen C, Boldrin M, Hauptman J,  Effect of orlistat on weight and 
body composition in obese adolescents: A randomized controlled trial. JAMA 
2005;293:2873-83. 
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510). 2003; 
Clinical review for NDA 20-766/S018. 
FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510). 2007; 
Clinical review for NDA 21-687/S023. 
Flegal, K. M. Graubard, B. I. Williamson, D. F. Gail, M. H. Excess Deaths Associated with 
Underweight, Overweight, and Obesity. JAMA 2005, 293(15): 1861-67.
IDF.  Criteria of metabolic syndrome in children and adolescents.  2014. Available from: 
http://www.idf.org/metabolic-syndrome/children/criteria.
McGovern L1, Johnson JN, Paulo R, Hettinger A, Singhal V, Kamath C, et al.  Clinical 
review: treatment of pediatric obesity: a systematic review and meta-analysis of randomized 
trials. J Clin Endocrinol Metab. 2008;93(12):4600-5. doi: 10.1210/jc.2006-2409. Epub 2008 
Sep 9.
Rofey, D. L. Kolko, R. P. Ana-Maria, I; Silk, J. S. Bost, J. E. Fang, W. et al. A longitudinal 
Study of Childhood Depression and Anxiety in Relation to Weight Gain. Child Psychiatry 
Hum Dev  2009; 40(4): 517-26.
Rosner B, Prineas R, Loggie J, Daniels SR. Percentiles for body mass index in U.S. children 
5 to 17 years of age. J Pediatr. 1998;132:211-22.
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Spear BA, Barlow SE, Ervin C, Ludwig DS, Saelens BE, Schetzina KE, et al., 
Recommendations for Treatment of Child and Adolescent Overweight and Obesity.
Pediatrics 2007;120 (Supplement 4).
Trasande, L. Chatterjee, S. The Impact of Obesity on Health Service Utilization and Costs in 
Childhood. Obesity (Silver Spring) 2009 17(9): 1749-54.
Xenical Package Insert, 2006
Wang, Y, Lobstein, T. Worldwide trends in childhood overweight and obesity Int J Pediatric 
Obes 2006;1:11-25).
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC should be kept informed of such changes as required by local 
regulations.  In these cases, the sponsor may be required to send a letter to the IRB/IEC and 
the Competent Authorities detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to ICH 
E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The 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 IRB/IEC review.
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In accordance with ICH E6, Section 1.52, source documents include, but are not limited to 
the following:
•
Clinic, office, or hospital charts
•
Copies or transcribed health care provider notes which have been certified for accuracy 
after production
•
Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports, (eg, sonograms, computerized tomography scans, magnetic resonance images, 
radioactive images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function 
tests) regardless of how these images are stored, including microfiche and photographic 
negatives
•
Pain, quality of life, or medical history questionnaires completed by subjects
•
Records of telephone contacts
•
Diaries or evaluation checklists
•
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel
•
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)
•
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs
•
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each 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 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.  
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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/IEC correspondence).  In addition, the 
sponsor will send a list of treatment codes by study subject to the investigator after the 
clinical database for this study has been locked.  The site should plan to retain study 
documents, as directed by the sponsor, for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
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 the routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  Investigational product 
will be stored in accordance with the DEA Regulations for Scheduled III - V Drugs and 
labeled storage conditions.  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. 
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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/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or 
Clinical 
Trial 
Agreement 
executed 
between 
the 
sponsor/CRO 
and 
the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
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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 APPENDIX
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Appendix 1
Sponsor’s Grading for Laboratory Values
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3 
Lymphocytes 
<LLN – 800/mm3 
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3 
<0.5109/L
<500/mm3 
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening 
consequences; 
seizures
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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).
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Appendix 2
Family-Based Lifestyle Program
Program Overview
All subjects and their caregivers (participating parent/guardian) in Study 403 will participate 
in a standardized weight management program for adolescents consisting of multicomponent 
behavior therapy.  The therapy will focus on healthy eating, physical activity, and lifestyle
changes that will facilitate weight loss and weight-loss maintenance. The role of the 
caregivers is to support their adolescents’ lifestyle changes and their taking of study 
medication.
The objectives of this program are as follows:

Develop a weight management program for all BELVIQ study participants and their 
caregivers (caregivers are instructed in methods to support their adolescents’ progress 
but caregivers are themselves not instructed to lose weight or take medication)

Standardize the weight management program across all study sites

Maximize participant retention

Promote participant’s adherence to both taking study medication and following the 
lifestyle program
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Appendix 3
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic (PD), pharmacogenomic (PG), and other biomarker analysis.  These 
samples may be used for discovery or validation to identify biomarkers that may be used for 
exploratory evaluation of response and/or safety-related outcomes as well as for use in 
diagnostic development.
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or non-coding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the study 
drug pharmacokinetics or therapeutic response.
Collection of the PD, PG, and other biomarker samples will be bound by the sample 
principles and processes outlined in the main study protocol.  Sample collection for PD, PG, 
and other biomarker analysis is required as per the study protocol unless the collection and 
use of the samples is prohibited by specific country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy. 
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All PD and other biomarker samples will be 
single coded.  Genomic DNA samples used to explore the effects on PK, treatment response, 
and safety will be single coded.  Genomic DNA samples that will be stored for long-term use 
(defined as 15 years after the completion of the study) will be double coded.  Double coding 
involves removing the initial code (subject ID) and replacing with another code such that the 
subject can be re-identified by use of 2 code keys.  The code keys are usually held by 
different parties.  The key linking the sample ID to the subject number will be maintained 
separately from the sample.  At this point, the samples will be double-coded, the first code 
being the subject number.  Laboratory personnel performing genetic analysis will not have 
access to the “key.”  Clinical data collected as part of the clinical trial will be cleaned of 
subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:
•
Clinical research organizations retained by the sponsor 
•
Independent ethics committees or institutional review boards that have responsibility for 
this research study 
•
National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
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Given the research nature of the PD, PG, and other biomarker analysis, it will not be possible 
to return individual data to subjects.  The results that may be generated are not currently 
anticipated to have clinical relevance to the patients or their family members.  Therefore, 
these results will not be disclosed to the patients or their physicians.
If at any time, PD, PG, and/or other biomarker results are obtained that may have clinical 
relevance, IRB review and approval will be sought to determine the most appropriate manner 
of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments (CLIA)-certified setting will be required.  Sharing of research 
data with individual patients should only occur when data have been validated by multiple 
studies and testing has been done in CLIA-approved laboratories.
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Efficacy and Safety of BELVIQ® in 
Conjunction with Lifestyle Modification for Weight Loss in 
Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/BELVIQ® (lorcaserin hydrochloride)
IND Number:
069888
SIGNATURES
Authors:
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
Eisai Inc.
Date
Neuroscience and General Medicine Product Creation Unit
Eisai Inc.
Date
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PPD
PPD
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Clinical Study Protocol
APD356-A001-403
Eisai
FINAL:  16 Apr 2015
Confidential
Page 75 of 75
INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
APD356-A001-403
Study Protocol Title:
A 52-Week, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study to Evaluate the Efficacy and Safety of 
BELVIQ® in Conjunction with Lifestyle Modification for 
Weight Loss in Obese Adolescents, Age 12 to 17 Years
Investigational Product 
Name:
APD356/BELVIQ® (lorcaserin hydrochloride)
IND Number:
069888
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
Page 897 of 897

SAP_001.pdf: 
Statistical Analysis Plan
APD356-A001-403
Eisai
18FEB2020
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Page 1 of 23
STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
APD356-A001-403
Study Protocol 
Title:
A 52-Week Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of 
Belviq XR® in Conjunction With Lifestyle Modification for Weight 
Loss in Obese Adolescents, Age 12 to 17 Years
Date:
18FEB2020
Version:
Final 1.0


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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...............................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................4
3
INTRODUCTION.........................................................................................................6
3.1
Study Objectives..................................................................................................6
3.1.1
Primary Objective ......................................................................................6
3.1.2
Secondary Objectives .................................................................................6
3.1.3
Other Secondary Objectives .......................................................................6
3.2
Overall Study Design and Plan.............................................................................7
4
DETERMINATION OF SAMPLE SIZE.......................................................................8
5
STATISTICAL METHODS..........................................................................................9
5.1
Study Endpoints...................................................................................................9
5.1.1
Primary Endpoint .......................................................................................9
5.1.2
Secondary Endpoints..................................................................................9
5.2
Study Subjects ...................................................................................................10
5.2.1
Definitions of Analysis Sets......................................................................10
5.2.2
Subject Disposition...................................................................................10
5.2.3
Protocol Deviations ..................................................................................10
5.2.4
Demographic and Other Baseline Characteristics......................................11
5.2.5
Prior and Concomitant Therapy................................................................11
5.2.6
Treatment Compliance .............................................................................11
5.3
Data Analysis General Considerations................................................................12
5.3.1
Pooling of Centers....................................................................................12
5.3.2
Adjustments for Covariates ......................................................................12
5.3.3
Multiple Comparisons/Multiplicity...........................................................12
5.3.4
Examination of Subgroups........................................................................12
5.3.5
Handling of Missing Data, Dropouts, and Outliers....................................12
5.3.6
Other Considerations................................................................................12
5.4
Efficacy Analyses ..............................................................................................14
5.4.1
Primary Efficacy Analyses .......................................................................14
5.4.1.2
Sensitivity Analysis ........................................................................14
5.4.1.3
Subgroup Analysis..........................................................................14
5.4.2
Key Secondary Efficacy Analyses ............................................................14
5.4.3
Other Secondary Efficacy Analyses..........................................................14
5.4.3.1
Proportion of subjects achieving at least a 5% BMI reduction at 
Week 12 .........................................................................................15
5.4.3.2
Proportion of subjects achieving at least a 10% BMI reduction at 
Week 52 .........................................................................................15


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5.4.3.3
Percent change in BMI from baseline at Week 52 ...........................15
5.4.3.4
Change and percentage change in BMI from Baseline to Week 52 
by the outcome of achieving at least a 5% BMI reduction at 
Week 12 .........................................................................................15
5.4.3.5
Proportion of subjects achieving at least a 5% BMI reduction at 
Week 52 by the outcome of achieving at least a 5% BMI 
reduction at Week 12 ......................................................................15
5.4.3.6
Proportion of subjects achieving at least a 10% BMI reduction at 
Week 52 by the outcome of achieving at least a 5% BMI 
reduction at Week 12 ......................................................................15
5.5
Pharmacokinetic, Pharmacodynamics, Pharmacogenomics, and Other 
Biomarker Analyses...........................................................................................15
5.5.1
Pharmacokinetic Analyses........................................................................15
5.5.2
Pharmacodynamics, and Other Biomarker Analyses.................................15
5.6
Safety Analyses..................................................................................................15
5.6.1
Extent of Exposure...................................................................................16
5.6.2
Adverse Events.........................................................................................16
5.6.3
Laboratory Values ....................................................................................16
5.6.4
Vital Signs................................................................................................17
5.6.5
Electrocardiograms...................................................................................18
5.6.6
Other Safety Analyses ..............................................................................18
6
INTERIM ANALYSES...............................................................................................18
7
CHANGES IN THE PLANNED ANALYSES ............................................................18
8
HANDLING OF MISSING DATA, DROP-OUTS, AND OUTLIERS........................19
8.1.1
Visit Windowing ......................................................................................19
9
PROGRAMMING SPECIFICATIONS .......................................................................20
10
STATISTICAL SOFTWARE......................................................................................20
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................20
12
REFERENCES............................................................................................................20
13
APPENDICES.............................................................................................................21
13.1
Sponsor’s grading for Determining Markedly Abnormal Laboratory Results......21


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of covariance
ANOVA
analysis of variance
BOCF
baseline observation carried forward
BMI
body mass index
CDC
Centers for Disease Control and Prevention
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
EOS
end of study
EOT
end of treatment
FAS
full analysis set
HDL
high density lipoprotein
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
LDL
low density lipoprotein
LS
least squares
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed effect model repeated measurement analysis
PD
pharmacodynamics
PHQ-9
Patient Health Questionnaire
PK
pharmacokinetic
PP
per-protocol analysis set
PT
preferred term
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation


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Abbreviation
Term
SOC
System Organ Class
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
WHO DD
World Health Organization Drug Dictionary


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Eisai
18FEB2020
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3
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol APD356-
A001-403.
Since this study has been terminated early and when only about 20% of subjects have 
completed week 52 visit, many of the planned efficacy outputs will not show enough data as 
initially planned for this study. Most planned efficacy tables will not be produced. For details 
on changes in planned analysis, please see section 7 “Changes in Planned Analysis”.
This document is prepared based on the final study protocol (protocol V10.0 12Feb2018).  
Reader is referred to the final study protocol, the case report form (CRF), general CRF 
completion guidelines for details of study design, conduct and data collection.
3.1
Study Objectives
3.1.1
Primary Objective

To demonstrate weight loss efficacy by change in body mass index (BMI) during 52 weeks 
of treatment with Belviq XR 20 mg administered QD as compared to placebo
3.1.2
Secondary Objectives
Key Secondary Objective
To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with a 
at least a 5% reduction in BMI during 52 weeks of treatment with Belviq XR 20 mg 
administered QD as compared to placebo
3.1.3
Other Secondary Objectives 

To demonstrate weight loss efficacy by achieving a greater proportion (%) of subjects with 
at least a 5% reduction in BMI after an initial 12 weeks of treatment with Belviq XR
20 mg administered QD compared to placebo

To demonstrate that achieving at least a 5% reduction in BMI after an initial 12 weeks of
treatment with Belviq XR 20 mg administered QD is predictive of sustained change in BMI 
during 52 weeks of treatment with Belviq XR 20 mg administered QD

To demonstrate weight loss efficacy by percentage change from baseline in BMI during 52 
weeks of treatment with Belviq XR 20 mg administered QD compared to placebo

To demonstrate the efficacy of treatment with Belviq XR 20 mg QD by assessing:


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Eisai
18FEB2020
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- Other weight loss effects (e.g., proportion [%] of subjects achieving at least a 10%
BMI reduction, change in waist circumference) at the end of 52 weeks of treatment
- Effects on fasting glucose, hemoglobin A1c (HbA1c), insulin levels, and Homeostatic
Model Assessment of Insulin Resistance (HOMA-IR; glucose [mg/dL] × insulin
[mU/L]/405) in subjects with Type 2 diabetes at baseline during 52 weeks of treatment 
- Effects on fasting glucose, HbA1c, insulin levels, and HOMA-IR; glucose [mg/dL] ×insulin 
[mU/L]/405 in subjects without Type 2 Diabetes at Baseline during 52 weeks of treatment 
- Effects on body fat and lean mass composition by Dual-energy X-ray
Absorptiometry (DEXA) in a subset of randomized subjects (selected prior to randomization) 
at selected sites during 52 weeks of 
- Changes in cardiovascular risk factors associated with obesity (e.g., hypertension,
dyslipidemia) including fasting lipid changes (total cholesterol, triglycerides, high density 
lipoprotein [HDL], low density lipoprotein [LDL]), systolic and diastolic blood pressure, and 
heart rate) during 52 weeks of 

To assess the safety of Belviq XR, including the effects on cognition by Leiter-3
International Performance Scale (Leiter-3), depression with the Patient Health
Questionnaire (PHQ-9), signal of suicidal ideation or behavior with the
Columbia-Suicide Severity Rating Scale (C-SSRS), growth measured by CDC growth chart, 
sexual maturation (pubescence) measured by Tanner Staging scores, and other growth and 
development parameters by measuring sex hormones, thyroid function, adrenal function, 
bone age, and biochemical markers of bone health, bone mineral density and content, total 
body fat mass and total body lean mass by DEXA in a subset of randomized subjects 
(selected prior to randomization) at selected sites, valvular function, pulmonary arterial 
pressure. 

To assess the pharmacokinetic (PK) of lorcaserin using population PK modeling

To assess relationships between plasma exposure to lorcaserin and pharmacodynamics
(PD) parameters including but not limited to reduction from baseline in BMI and probability 
of achieving at least a 5% and at least a 10% reduction in BMI from baseline at Week 52 
using population PK/ PD modeling
3.2
Overall Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study
in obese adolescents ages 12 to 17 years. Approximately 260 subjects will be randomized
in a 1:1 ratio to Belviq XR 20 mg QD (130 subjects) and placebo (130 subjects). Subjects
will be stratified by sex. Subjects will receive Belviq XR 20 mg or matched placebo
QD in a 1:1 ratio for up to 52 weeks. A recruitment plan will be developed to ensure
at least 20% of younger subjects (12 to 13 years of age) are enrolled in the study.


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Throughout the duration of the study, subjects will be encouraged to adhere to a lifestyle
modification program that includes a standardized, age-appropriate diet and exercise
counseling (see Appendix 2).
The study will consist of 2 phases: Prerandomization and Randomization. The
Prerandomization Phase will last up to 30 days and consists of 1 visit during which
subjects will be screened for eligibility. The Randomization Phase consists of a Treatment 
Period and a Follow-Up Period. The Treatment Period will last for a maximum of 52 
weeks, with visits at Weeks 1, 5, 8, 12, 20, 28, 36, 44, and 52; the Follow-Up Period
will extend from the End of Treatment (EOT) visit to the End of Study (EOS) visit.
Subjects who screen fail can be rescreened only once. All subjects will continue in the
study until the 52-week evaluation is completed. Subjects who discontinue treatment
prematurely will be followed up until study completion. All attempts will be made to
capture height and weight in all subjects whether or not they are still on study drug
at the end of the study.
Details of the study procedures and schedule of assessments can be found in Table 2 of the 
protocol.
4
DETERMINATION OF SAMPLE SIZE
The proposed sample size is based on the comparison of the primary efficacy endpoint, change 
from baseline in BMI at Week 52 between the Belviq XR 20-mg treatment group and placebo 
group.
Assuming a SD of 2.2 kg/m2 and a 40% dropout rate, a sample size of 260 subjects in a 1:1
ratio (n=130 in the Belviq XR 20-mg treatment group; n=130 in the placebo group) will have 
at least 80% power to detect a treatment difference of 1 kg/m2 in BMI, using a 2-sided t-test 
with α=0.05. 
Assuming the proportion of subjects achieving at least a 5% BMI reduction at Week 52 is 20%
for the placebo group and a 40% dropout rate, this sample of 260 subjects (130 subjects for 
Belviq XR 20 mg and 130 subjects for placebo) will also have greater than 78% power to detect 
an absolute difference of 20% between the Belviq XR 20-mg group and placebo group, using
a 2-sided Chi-Square test with α=0.05.
The assumption used in the sample size calculation is based on the 2 pivotal lorcaserin studies,
APD356-009 and APD356-011 in obese and overweight non-diabetic adult subjects. (Revised 
per Amendment 02)


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5
STATISTICAL METHODS
Descriptive statistics will be reported for continuous variables using mean, standard deviation 
(SD), median, minimum and maximum.  Categorical variables will be summarized using 
frequency count as number (percentage) of subjects.  
5.1
Study Endpoints
5.1.1
Primary Endpoint
•
Change in BMI from Baseline to Week 52 
5.1.2
Secondary Endpoints
KEY SECONDARY ENDPOINT

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 52
OTHER SECONDARY ENDPOINTS

Proportion (%) of subjects achieving at least a 5% BMI reduction at Week 12 

Proportion (%) of subjects achieving at least a 10% BMI reduction at Week 52

Percentage change in BMI from Baseline to Week 52

Association between change and percentage change in BMI from Baseline to 
Week 52 with the outcome of achieving at least a 5% BMI reduction at Week 12 
(revised per Amendment 02)

Association between the proportion (%) of subjects achieving at least a 5% or 10% 
BMI reduction at Week 52 with the outcome of achieving at least a 5% BMI reduction 
at Week 12 (revised per Amendment 02)

Change in waist circumference from Baseline to Week 52

Change in total body composition (total fat and lean mass) in a subset of randomized
subjects at end of 52 weeks of treatment (revised per Amendment 03)

Change in HbA1c from Baseline to Week 52 for subjects with Type 2 diabetes at 
baseline (revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 
for subjects with Type 2 diabetes at baseline (revised per Amendment 03)

Change in fasting glucose, fasting insulin, and HOMA-IR from Baseline to Week 52 
for the subjects without Type 2 diabetes at baseline (revised per Amendment 03)


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
Change in BP (systolic and diastolic) and heart rate from Baseline to Week 52

Change in fasting lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol,
triglycerides) from Baseline to Week 52

Proportion (%) of subjects with prehypertension or primary hypertension at Week 52

Proportion (%) of subjects with dyslipidemia at Week 52

Subject compliance rate at each visit by pill count during 52 weeks of treatment (per
Amendment 03)
5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug 
and had at least 1 post dose safety assessment.
The Full Analysis Set (FAS) is the group of all randomized subjects who received at least 1 
dose of study drug.
PK Analysis Set: the PK analysis set is the group of subjects who have at least 1 quantifiable 
plasma concentration of lorcaserin with adequately documented dosing history.
The number (percentage) of subjects in each analysis set will be summarized by treatment 
groups using descriptive statistics.  
5.2.2
Subject Disposition
The number of subjects screened and the number (percentage) of subjects who failed screening 
and the reasons for screen failure will be summarized, based on data reported on the CRF.  
For study completion, the number (percentage) of treated subjects who completed study 
treatment and who discontinued from study treatment will be summarized according to the 
primary reason for discontinuation and also according to secondary reason(s) for 
discontinuation, based on data reported on the CRF.  The number (percentage) will be 
presented by treatment.  The reasons for discontinuation from study treatment will be 
documented in the CRF and source documentation.  
5.2.3
Protocol Deviations
Major protocol deviations will be identified, reviewed and documented by the clinical team 
prior to database lock/treatment unbinding.  All protocol deviations will be categorized 
according to standard classifications including the following:
•
Violations of inclusion/exclusion criteria


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•
Noncompliance with protocol procedures/assessments
•
Noncompliance of drug dosage
•
Use of prohibited treatments
All significant protocol deviations will only be presented in the listings.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS and Safety Analysis set will be 
summarized for each treatment group and overall using descriptive statistics or frequency 
count.  Continuous variables include age, weight, height, body mass index (BMI) and waist 
circumference; categorical variables include age group, sex, ethnicity, and race.  
MEDICAL HISTORY
All medical histories as documented by the Investigator will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA).  
The number (percentage) of subjects reporting a history of any medical condition, as recorded 
on CRF, will be summarized by System Organ Class (SOC), preferred term for each treatment 
group and overall based on FAS.
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit 
character code using the World Health Organization Drug Dictionary (WHO DD).  
Prior medications are defined as medications that stop prior to the first dose of study drug.  
Concomitant medications are defined as medications that (1) start before the first dose of study 
drug and are continuing at the time of the first dose of study drug, or (2) start on or after the 
date of the first dose of study drug, up to 30 days after the last dose of study drug.
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized for the Safety Analysis Set by treatment group, Anatomical Therapeutic Chemical 
class, and WHO DD preferred term (PT).  If a subject takes the same medications for the same 
class level or drug name, the subject will be counted only once for that class level or drug name.
5.2.6
Treatment Compliance
Treatment compliance is defined as follows: Total number of tablets dispensed – total number 
of tablets lost or returned divided by total number of tablets subject should have taken. 
Treatment compliance will be summarized using descriptive statistics by treatment group 
based on FAS and Safety Analysis Set.  Treatment compliance will also be summarized by 
treatment group using the categories <80%, ≥80% to ≤100%, >100% to ≤120%, and >120%.


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5.3
Data Analysis General Considerations
The FAS will be used for all efficacy analyses, and since study has been terminated early, 
there will be no additional supportive or sensitivity analysis. 
5.3.1
Pooling of Centers 
No pooling of centers will be done since there will be no ANCOVA analysis. 
5.3.2
Adjustments for Covariates
There will be no analysis of covariance and only basic summary of descriptive statistics will 
be performed for the BMI.
5.3.3
Multiple Comparisons/Multiplicity
No adjustment for multiplicity is planned for other secondary endpoints, subgroup, and 
sensitivity analyses.
5.3.4
Examination of Subgroups
Subgroup analyses will be performed on the primary efficacy endpoint using age group (<12,  
12 - <13, 13 - <14, 14 - <15, 15 - <16, 16 - <17, 17 - <18 and > 18 yrs.), sex (male and female), 
race (white, black, Asian, and other).  Additional subgroup analysis may also be explored, if 
deemed appropriate.
5.3.5
Handling of Missing Data, Dropouts, and Outliers
Due to the early termination of the study, no imputation analysis will be performed.
5.3.6
Other Considerations
Due to the early termination of the study, only simple summary of descriptive statistics will be 
provided for efficacy endpoint.
Individual subject data in the database will be presented in data listings.
The following rules/definitions will be applied in the final outputs:

Homeostatic Model Assessment of Insulin Resistance ( (HOMA-IR Fasting insulin
(mIU/L) x Fasting glucose (mmol/L) / 22.5)

Dyslipidemia: Please use the following link:  
(https://www.nhlbi.nih.gov/files/docs/peds_guidelines_sum.pdf) and consider subject 
“with Dyslipidemia” if TC ≥170 or LDL-C ≥ 110 or Non- HDL-C ≥ 120 or TG ≥ 90 
or HDL-C ≤ 40. Values given are in mg/dL. To convert to SI units, divide the results 
for total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density 


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lipoprotein cholesterol (HDL-C), and non-HDL-C by 38.6; for triglycerides (TG), 
divide by 88.6.

Prehypertension or Hypertension:
  BP is classified as SBP and DBP percentiles for age/sex/height.
Prehypertension: If SBP or DBP ≥ 90th percentile or < 95th percentile or BP >120/80 
mmHG to < 95th percentile 
Hypertension: If SBP or DBP ≥ 95th percentile or BP ≥ 95th percentile

Subjects who are type 2 diabetes (T2DM) at Baseline are defined as follows: 
Positive diagnosis of diabetes (Preferred Term: Type 2 diabetes mellitus) based on
Medical History Form or AE with the start date prior to the first dose of the study 
drug.
The formula for BMI is weight in kilograms divided by height in meters squared.
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, standard deviation (SD), minimum value (min), and 
maximum value (max). Minimum and maximum values will be reported with the same 
precision as the units of measure. The mean and median will be reported to 1 greater decimal 
place, and the SD will be reported to 2 additional decimal places.
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline Value: The baseline value will be defined as the most recent non-missing 
measurement (scheduled or unscheduled) collected prior to the initial administration of study 
drug. Unscheduled visit measurements will be included for derivation of baseline. 
Change (Absolute Change) from baseline: will be calculated as Post baseline value -
Baseline value.
Percent change from baseline: will be calculated and expressed in percentages as 100×(Post 
baseline value - Baseline value)/Baseline value.
Unscheduled Visits: Unscheduled visit measurements will be included in listings, for 
derivation of visit windows and computation of baseline/last on-treatment visit.
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers.


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5.4
Efficacy Analyses
The FAS will be used as the primary population for the efficacy analyses. Due to the early 
termination of the study, only summary of descriptive statistics will be presented for efficacy 
variables.
5.4.1
Primary Efficacy Analyses
Due to the early termination of the study, only summary of descriptive statistics will be 
presented.
Multiple Imputation
No multiple imputation will be performed.
5.4.1.2
Sensitivity Analysis
There will be no sensitivity analyses due to the early termination of the study.
5.4.1.3
Subgroup Analysis
Due to the early termination of the study, the analysis of following planned subgroups will not 
be performed:

age group 

sex (male and female)

race (white, black, Asian and other)

BMI group
5.4.2
Key Secondary Efficacy Analyses
Due to the early termination of the study, only summary of descriptive statistics will be 
presented.
5.4.3
Other Secondary Efficacy Analyses
The following efficacy analyses are for exploratory purpose only.  For each efficacy endpoint 
specified below, only basic summary of descriptive statistics will be presented.


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5.4.3.1
Proportion of subjects achieving at least a 5% BMI reduction at Week 12
5.4.3.2
Proportion of subjects achieving at least a 10% BMI reduction at Week 52
5.4.3.3
Percent change in BMI from baseline at Week 52
5.4.3.4
Change and percentage change in BMI from Baseline to Week 52 by the 
outcome of achieving at least a 5% BMI reduction at Week 12
5.4.3.5
Proportion of subjects achieving at least a 5% BMI reduction at Week 52 by the 
outcome of achieving at least a 5% BMI reduction at Week 12
5.4.3.6
Proportion of subjects achieving at least a 10% BMI reduction at Week 52 by the 
outcome of achieving at least a 5% BMI reduction at Week 12
5.5
Pharmacokinetic, Pharmacodynamics, Pharmacogenomics, and 
Other Biomarker Analyses
The methodology for these analyses will not be included in this SAP but will be described in 
a separate analysis plan if deemed necessary.
5.5.1
Pharmacokinetic Analyses
Lorcaserin plasma concentration-time data will be summarized.
5.5.2
Pharmacodynamics, and Other Biomarker Analyses
No PK analysis will be performed. Only lorcaserin plasma concentration-time data will be 
summarized.
5.6
Safety Analyses
Evaluations of safety will be performed on the Safety Analysis Set. Safety assessments 
including the incidence of AEs (including changes from baseline in physical examination, 
neuromuscular sign assessment, and signs and symptoms of priapism and 
hyperprolactinemia), out-of-normal-range laboratory safety test values, and change from 
baseline in laboratory safety test values, ECGs, and vital sign measurements will be 
summarized by treatment group using descriptive statistics or frequency count as appropriate. 
No hypothesis testing will be performed for the safety assessment.
Study Day 1 for all safety analyses will be defined as the date of the 1st dose of study drug.
All safety analyses should be based on “as treated” groups.  


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5.6.1
Extent of Exposure
Subjects will receive Belviq XR 20 mg or placebo QD for up to 52 weeks. The extent of
exposure will be characterized by duration of exposure (in weeks) for each treatment group.
Duration of exposure will be defined as the number of weeks between the date the subject
received the 1st dose of study drug and the date the subject received the last dose of study
drug. Duration of exposure will be summarized using descriptive statistics by treatment
group. In addition, the duration of exposure will be categorized and will be summarized
using frequency count by treatment group.
5.6.2
Adverse Events
A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment (up to
28 days after the last dose of study drug), having been absent at pretreatment (Baseline) or
•
Reemerges during treatment (up to 28 days after the last dose of study drug), 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 were 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 following summaries will be 
reported for TEAES:

Incidence of TEAEs in descending order of frequency

Incidence of TEAEs by SOC and PT

Incidence of treatment-related TEAEs by SOC and PT

Incidence of TEAEs by SOC, PT and maximum severity (mild, moderate, or severe)

Incidence of treatment-related TEAEs by SOC, PT, and maximum severity (mild, 
moderate, or severe)
Incidence of TEAEs by SOC, PT, and relationship to study drug (Yes [related] or No 
[not related])
A subject will be counted only once within a SOC or PT, if the subject experienced more
than 1 TEAE within a specified SOC and PT.
The following summaries will also be presented for the treatment-emergent SAEs.

Incidence of TEAEs leading to death

Incidence of treatment-emergent SAE by SOC and PT

Incidence of treatment-related treatment-emergent SAE by SOC and PT
5.6.3
Laboratory Values
Laboratory results will be summarized using standard international units, as appropriate. For
all quantitative parameters, the actual value and the change from baseline to each post 
baseline visit and to the end of treatment (defined as the last on-treatment value) will be 


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summarized by visit and treatment group using descriptive statistics. Percentages will be 
based on the number of subjects with both no missing baseline and relevant post baseline
results.
Laboratory test results will be assigned a low/normal/high (LNH) classification according to
whether the value was below (L), within (N), or above (H) the laboratory parameter’s
reference range. Within-treatment comparisons for each laboratory parameter will be based
on 3-by-3 tables (shift tables) that compare the baseline LNH classification to the LNH
classification at the End of Treatment and the Follow-Up visits. Similar shift tables will also
compare the baseline LNH classification to the LNH classification for the highest and lowest
value during the treatment period.
5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (e.g., systolic and diastolic BP, pulse,
respiratory rate, temperature, weight) and changes from baseline will be presented by visit
and treatment group.
Descriptive statistics for vital signs parameters (e.g., systolic and diastolic BP, pulse,
respiratory rate, temperature, weight) and changes from baseline will be presented by visit
and treatment group.
In addition, clinically notable vital sign values will be identified using the criteria in Table 2.  
The clinically notable vital sign values will be summarized using frequency count at each 
visit by treatment group.  
Table 2
Vital Sign Criteria
Variable
Criterion valuea
Change relative to baselinea
Clinically notable range
Pulse rate
>120 bpm
Increase of  15 bpm
H
<50 bpm
Decrease of  ≥15 bpm
L
Systolic BP
>180 mmHg
Increase of  ≥20 mmHg
H
<90 mmHg
Decrease of ≥20 mmHg
L
Diastolic BP
>105 mmHg
Increase of ≥15 mmHg
H
<50 mmHg
Decrease of ≥15 mmHg
L
Weight
--
Increase of ≥7% 
H
--
Decrease of ≥7%
L
Respiratory Rate
>20 bpm
--
H
< 10 bpm
--
L
BP = blood pressure, H = high, L = low.
a.
Clinically notable means that a value must meet the criterion value and must attain the specified 
magnitude of change relative to baseline.


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5.6.5
Electrocardiograms
For each ECG parameter (including PR interval, RR interval, QRS interval, QT interval, QTc
interval (Bazett formula), QTc interval (Fridericia formula), the actual value and change from 
baseline will be summarized by visit and treatment group using descriptive statistics.
Shift tables will present changes from baseline in ECG interpretation (categorized as normal;
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment.
Maximum post baseline QTc (Bazett) and QTc (Fridericia) will also be tabulated by 
treatment group as follows:

Number (percentage) of subjects with

greater than 450 msec, 

greater than 480 msec, and

greater than 500 msec during the treatment, and

Number (percentage) of subjects with an increment of greater than 30 msec and 
greater than 60 msec from the baseline visit.
5.6.6
Other Safety Analyses
Other safety analyses will include the following:

Change in puberty status

Waist circumference 

DEXA Z-score

Cognition

Depression

Valvular function

Pulmonary pressures
6
INTERIM ANALYSES
"No interim analyses are planned for this study."
7
CHANGES IN THE PLANNED ANALYSES
Due to the early termination of the study, the following changes are made from the initial 
planning for the study:


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1. There will be no ANCOVA or MMRM analysis for any of the efficacy endpoints. Only 
basic summary of descriptive statistics will be presented.
2. All secondary endpoint analysis of type 2 diabetes will not be provided since there is 
only 1 subject of type 2 diabetes.
3. All planned supportive and sensitivity analysis (MMRM, MNAR imputation, per 
protocol) will not be performed.
4. Summary of major protocol deviation will not be performed and only data listing will 
be presented.
5. No subgroup analysis will be performed for the primary endpoint analysis.
8
HANDLING OF MISSING DATA, DROP-OUTS, AND OUTLIERS
For determining treatment emergent markedly abnormal lab values, a missing baseline lab 
value will be assumed to be of grade 0.
No special handling of missing data is planned for the analysis of any of the efficacy or safety
variables.
8.1.1
Visit Windowing
Table 1 will be applied to all measurements including those from unscheduled visits and early 
termination visits to attain the measurement for analysis for the given scheduled visit.  
Table 1
Windowing Rules for Safety Endpoints
Visit 
Target Visit Day
(in study days)
Visit Window (in study days)
Week 0
Day 1
Day 1
Week 1
7
2-21
Week 5
35
22-45
Week 8
56
46-70
Week 12 
84
71-112
Week 20
140
113-168
Week 28
196
169-224
Week 36
252
225-280
Week 44
308
281-336
Week 52
364
337-379
Week56/FU
              >379 or analysis 
visit date > last dose date +14
EOT
For last non missing analysis visit date 
≤<= 379 or ≤=< last dose date +14 
days.


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In case of multiple assessments within the same visit window, the assessment closest to the 
target visit day will be used in data analyses; in the event of two assessments being equally 
close to the scheduled visit day, the latest assessment in the sequence will be used. 
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
10 STATISTICAL SOFTWARE
Statistical analyses will be performed using SAS version 9.4 (or later versions).  
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study tables, listings and graphs shells will be provided in a separate document, which 
will show the content and format of all tables, listings, and graphs in detail.
12 REFERENCES
1. American Diabetes Association. Standards of Medical Care - 2013. Diabetes Care 
2013; 36 Suppl 1:S11-S66.
2. Children and Adolescents: Summary Report Pediatrics. 2011; 128:S213-S256.
3. FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510). 2003;
4. FDA CDER Division of Metabolic and Endocrine Drug Products (HFD - 510). 2007;


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13 APPENDICES
13.1
Sponsor’s grading for Determining Markedly Abnormal Laboratory 
Results
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
life-threatening 
consequences; 
seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high (hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: 28 May 2009 (v4.03: 14 Jun, 2010).
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, , LLN = lower limit of normal, N/A = not applicable, ULN = upper limit of normal, 
WBC = white blood cell.


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SIGNATURE PAGE
Author(s):  
Date
Approval:
 
Date
Date
PPD
PPD
PPD